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pmc-6180886-2	A 51-year-old female was referred for a CT scan of the abdomen with a clinical suspicion of vesicovaginal fistula (VVF). The patient was diagnosed with cancer of the cervix a year ago and underwent total hysterectomy in the following month. Thereafter, she underwent radiotherapy and chemotherapy. A follow-up CT scan after 11 months showed extensive post-radiation thickening of the pelvic fat planes, bladder walls, vagina and rectosigmoid colon. No enhancing mass lesion, adenopathy, metastatic nodule or other definite evidence of residual tumour was demonstrated. 1 year later, she developed stress incontinence and dripping of urine.
pmc-6180887-1	A 43-year-old female presented with a history of right-sided chest pain. She has been diabetic for the past 4 years and hypertensive, and has been on treatment. She had a history of primary amenorrhoea, which was never investigated previously. On examination, the patient was 155 cm tall, weighed 58 kg, blood pressure and secondary sexual characteristics were normal, and systemic examination showed absent breath sounds on the right side with mediastinal shift to the right.
pmc-6180888-1	A 30-year-old male presented with history of lower abdominal pain and periumbilical erythema, which had been persisting for 15 days, with nausea, vomiting, fever and umbilical discharge for the past 8 days. Physical examination revealed a temperature of 38.7°C. His abdomen was soft and there was umbilical discharge with erythema and a tender umbilical mass. Laboratory tests revealed leucocytosis of 22,000 mm–3. A urinalysis was within normal ranges. Ultrasonography revealed the presence of a heterogeneous mass of size 7.2 × 3.2 cm in the midline extending from the anterior and superior wall of the urinary bladder to the umbilicus with presence of gas (). Colour power Doppler showed increased vascularity (). CT scan of the abdomen confirmed the presence of a tubular mass extending from the umbilicus to the dome of the urinary bladder (). Contrast CT scan showed rim enhancment, with low density of the fluid collection and fat stranding (). The cystoscopy showed an inflamed area of the bladder dome with poor purulent drainage. The patient received antibiotic therapy for a week and the mass was removed by surgical excision. Histopathological evaluation revealed an umbilical–urachal sinus with xanthogranulomatous inflammation. The patient presented satisfactory resolution of his symptoms.
pmc-6180891-1	This 82-year-old white female had a past medical history of a pruritic and erythematous plaque extending over her right interlabial fold. She was diagnosed with non-invasive vulvar Paget’s disease 33 years ago that was surgically treated with local excision, removing full thickness of skin involving the epidermis and dermis with a 1-cm lateral margin. Apparently, she remained asymptomatic during the next 15 years, and in 1995, a second conservative resection was preformed. In 2013, she sought medical care, with a history of a 2-year vaginal discharge described as non-purulent, odourless and painless. Physical examination revealed left inguinal andenopathies of approximately 5 mm diameter, left hemivulvectomy and erythematous urethral meatus. Vulvar and urethral biopsies were positive for EMPD; immunohistochemistry was positive for cytokeratin (CK) 7, Ep-CAM/epithelial specific antigen (MOC-31) and carcinoembryonic antigen (CEA) and negative for CK20 and breast cancer antigen 2 (BRST-2). Non-invasive EMPD was found on the right labia majora, and right and left introitus. Infiltrative disease was found in the right and left lateral urinary meatus (), CEA+ and CK20– (). The vaginal wall was free of disease. Inguinal Tru-cut biopsies of adenopathies were positive for metastatic adenocarcinoma, CK7+, MOC31+, CEA+, CK20– and BRST2– (compatible with primary lesion in the vulva). Extension studies were all negative for malignancy (sigmoidoscopy, CT scan and mammography). Urethral cystoscopy showed evidence of a proliferative lesion that was not biopsied. Blood work levels were normal. Owing to the extension of the disease, the patient’s comorbidities and, most importantly, preferences, intensity-modulated radiation therapy of the pelvis was elected with a goal of completing a total of 6660 cGy.
pmc-6180898-1	An 82-year-old female patient presented with a history of goitre for 10 years with recent rapid increase in its size, dysphagia and hoarseness of voice for 1 month. She also had low backache and swelling over the right parietal region for 5 months. She had tenderness over the lower lumbar spine on examination. Palpation revealed a large 10 × 8 cm firm mass in the anterior neck, predominantly on the right side, and an immobile hard swelling over the scalp in the right parietal region. Contrast-enhanced CT imaging () performed previously showed a large enhancing mass involving the right lobe and isthmus of the thyroid gland with multiple subcentimetre nodules in bilateral lungs. Fine needle aspiration cytology of the thyroid mass revealed it to be a follicular neoplasm (Bethesda category IV). Based on this clinical information, a tentative diagnosis of metastatic follicular thyroid carcinoma was made. The patient was planned for thyroidectomy followed by radioactive iodine therapy depending on the histopathology. She underwent right hemithyroidectomy in December 2014 under cervical block. Intraoperatively, the surgeon visualized a very small atrophic left lobe of the thyroid but in view of the patient's overall condition, complete thyroidectomy was considered a difficult procedure to perform. The final histopathology report revealed follicular carcinoma with capsular and vascular invasion. The patient was referred to the department of nuclear medicine for further management. As per institutional protocol, after hemithyroidectomy, she underwent radioactive iodine uptake (RAIU) and thyroid scan, which showed 1.4% 24 h RAIU and no pertechnetate uptake in the region of the thyroid gland. A pertechnetate whole-body sweep was performed in the same sitting and revealed no uptake in the already known metastatic site. Thyroid function test showed a low normal thyroid-stimulating hormone (TSH) value (0.5 µIU ml–1) with normal T3 and T4 levels. Neck ultrasonography showed residual tissue in the neck, predominantly on the left side. In view of the history of a contrast-enhanced CT scan 4 weeks ago, the possibility of iodide interference was considered. The patient was given tablets of furosemide 40 mg day–1 for 2 weeks and a repeat RAIU and pertechnetate study was planned after 2 weeks. The repeat pertechnetate scan did not show abnormal tracer accumulation anywhere in the body and no uptake in the thyroid bed, and there was persistently low RAIU at both 2 (1.5%) and 24 h (1.4%). Repeat thyroid testing showed that the TSH level was 0.5 µIU ml–1, while T3 and T4 levels were now lower than normal. Thyroglobulin level post hemithyroidectomy was reported as > 300 ng ml–1 (normal range 0–52 ng ml–1) by chemiluminescence. The progressively decreasing total T3 and T4 levels ruled out the possibility of extensive functioning metastasis. The possibility of metastases from a second primary was also considered in view of the absence of iodine uptake in the lung and bone lesions. Whole-body 18F-fludeoxyglucose positron emission tomography–CT (18F-FDG PET-CT) scan () demonstrated significant residual thyroid tissue in the thyroid bed, multiple skeletal metastases with mild FDG uptake and bilateral pulmonary nodules. In addition to this, there was a small iso- to hyperdense lesion in the sellar region with mildly increased FDG uptake. Furthermore, MRI of the brain () showed a hypointense lesion on T 1 weighted images and isointense lesion on T 2 weighted images based over the sphenoid bone in the suprasellar cistern with no bleeding or necrosis. The pituitary gland was seen separately. The right parietal lesion seen in both 18F-FDG PET-CT scan and MRI showed only dural involvement with no infiltration of adjacent brain parenchyma. The MRI and 18F-FDG PET-CT findings pointed toward the possibility of pituitary insufficiency owing to sellar metastasis resulting in low TSH. To evaluate the pituitary insufficiency further, serum cortisol and adrenocorticotrophic hormone (ACTH) assay was performed. Early morning (4 am) ACTH was < 5 pg ml–1 (10–60 pg ml–1) and cortisol was 1.16 µg ml–1 (4.3–22.4 µg ml–1). This reconfirmed the diagnosis of pituitary insufficiency due to sellar metastasis with low iodine and pertechnetate uptake owing to the low TSH level. The treatment option in this clinical context was discussed thoroughly with a neurosurgeon and the radiotherapist. The patient had neither diabetes insipidus nor symptoms of cranial nerve involvement. In view of the extensive metastases and no significant neurological manifestation, surgery, external beam radiotherapy (EBRT) and stereotactic radiosurgery were not considered feasible. Finally, it was decided to use high-dose empirical radioiodine therapy. The persistently low TSH level was deemed to be the cause of low radioiodine uptake; therefore, recombinant human thyroid-stimulating hormone (rhTSH) stimulation was planned. After two rhTSH injections (0.9 mg on two consecutive days), the patient’s TSH levels went up to 664 µIU ml–1. She was subsequently treated with high-dose radioiodine of 3.7 GBq (100 mci). We used a lower dose keeping in mind the proximity of the sellar lesion to the optic chiasma and the fact that the patient was currently experiencing good vision in both eyes. A tapering dose of corticosteroid was administered to avoid any potential mass effect. A post-therapy scan () revealed an intensely iodine-avid remnant in the thyroid bed, multiple skeletal metastasis and faint uptake in the sellar region. Iodine uptake in the sellar region again confirmed the diagnosis of metastasis. The patient was stable during admission and at the time of discharge. An endocrinologist’s opinion was sought for further management of the hypopituitarism. 6 months post radioiodine treatment, the patient was clinically stable and an early second radioiodine therapy was planned under rhTSH stimulation.
pmc-6180899-1	A 41-year-old female presented to our department with long-standing pain, with development of palpable soft tissue nodules over the volar and dorsal aspect of her right wrist and progressively worsening flexion contractures affecting the middle and ring finger metacarpophalangeal joints (MCPJs) of the right hand. Physical examination confirmed the presence of soft tissue nodules and flexion contractures, with markedly reduced movement of the middle and ring finger MCPJs.
pmc-6180927-1	A 51-year-old male was admitted to our hospital with a three-day history of shortness of breath. He mentioned of dry cough associated with chest discomfort. The pain was localized to the mid-sternum, nonradiating, exacerbated in supine position, and improved with sitting. He was taking aspirin at home for his symptoms. He denied history of sick contact, fever, chills, weight loss, night sweat, diaphoresis, palpitation, or dizziness. He had an extensive past history including FVL homozygous mutation, recurrent lower extremity deep venous thrombosis (DVT) with inferior vena cava (IVC) filter placed, congestive heart failure requiring automatic implantable cardioverter-defibrillator (AICD) placement, and hypertension. The patient was initially diagnosed with FVL mutation when he had his first episode of lower extremity DVT in 2002. At that time, he was placed on warfarin therapy with a goal international normalized ratio (INR) of 2-3. In 2007, he had a recurrent episode of lower extremity DVT and bilateral pulmonary embolism (PE) despite being compliant with warfarin and close INR monitoring. His INR on admission was 2.1. During admission, he had an IVC filter placed and his goal INR was increased to 2.5–3.5. In 2015, he had another recurrent lower extremity DVT despite having a higher target INR of 3.2. Warfarin was switched to rivaroxaban 15 mg twice a day for 21 days followed by 20 mg once daily. He denied a family history of malignancy or thrombophilia. He did undergo computed tomography (CT) of the abdomen and pelvis in 2015 which did not show gross evidence of intra-abdominal or pelvic mass. CT of the chest did not show evidence of pulmonary nodule. The patient was taking aspirin 81 mg daily, atorvastatin 40 mg daily at bedtime, carvedilol 3.125 mg twice daily, lisinopril 5 mg daily, furosemide 40 mg daily, and rivaroxaban 20 mg once daily. The vital signs on admission were 99.5°F, heart rate 130 beats per minute, blood pressure 120/75 mmHg, respiratory rate 18 breaths per minute, and oxygen saturation 94% on 32% fraction of inspired oxygen. Physical examination was remarkable for distend jugular vein and crackles at bilateral lung bases. The results of blood work including complete blood count and comprehensive metabolic panel were within normal limits. Blood urea nitrogen was 19 mg/dL and serum creatinine was 0.9 mg/dL. Work up for autoimmune diseases came back negative. His prothrombin time was 26.1 seconds, activated partial thromboplastin time was 31.9 seconds, and the international normalized ratio was 2.35. Anterior-posterior chest X-ray illustrated a normal pattern. Venous Doppler of lower extremities revealed acute nonocclusive extensive thrombosis involving the bilateral common femoral, femoral, and popliteal veins. CT of the chest with contrast showed absence of pulmonary embolism, questionable right ventricular mass, moderate-sized pericardial effusion, and reflux of iodine contrast into the IVC and hepatic veins, suggesting right heart strain (). Transthoracic echocardiogram showed ejection fraction between 25 and 30%, moderate diffuse hypokinesis of the left ventricle, and dilated left atrium. There was a definite, large, echogenic, highly mobile mass measuring 5.29 cm × 8.61 cm, up to 9.1 cm in length. The mass extended from the right atrium to the right ventricle, moving back-and-forth across the tricuspid valve (). Ultrasound of IVC showed patent IVC filter without clots. He was taken for emergent right atrial and ventricular embolectomy. The thrombus was found to be originating from the coronary sinus (). There were a small amount of clots around the AICD wires which were removed. Repeat transthoracic echocardiogram showed no mass, but mildly dilated right atrium and ventricle with trace pericardial effusion. The patient was then started on unfractionated heparin drip. On postoperative day 11, the patient underwent sternal wound re-exploration due to gradual downward trend of his hemoglobin. He had a sternal dehiscence during which an extensive clot was found despite being on anticoagulation with unfractionated heparin drip. Heparin-induced antibody was negative. He had the clot removed surgically. The patient continued to improve and transitioned from unfractionated heparin drip with target PTT 50–60 seconds to dabigatran 150 mg oral twice a day. He was subsequently discharged to cardiac rehab facility and has been doing well.
pmc-6180928-1	A 25-year-old Hispanic male with HIV infection (CD4 count <40 cells/μL, viral load 307 copies/mL on antiretroviral therapy) and pulmonary KS on chemotherapy presented with progressive dyspnea and cough productive of rubbery red and white material (). Physical examination revealed hypoxia, coarse crackles to the bilateral lower lung fields, and multiple violaceous cutaneous plaques. Chest computed tomography showed diffuse peribronchovascular consolidative opacities with surrounding ground glass opacities, interlobular septal thickening, and infiltrative soft tissue densities throughout the mediastinum (). Blood and sputum cultures, autoimmune serologic tests, and serologic tests for Coccidioides and Cryptococcus were negative. Bronchoscopy revealed “tissue-like” material within the tracheobronchial tree, forming casts (Figures and ). On histopathological analysis, the casts were composed of fibrin with sparse leukocytic infiltrate, consistent with a diagnosis of PB (). Attempts made to clear the fibrinous material from the lung with nebulized dornase alfa, high-frequency oscillation treatments (MetaNeb System (Hill-Rom, Chicago, IL)), and a percussion vest were unsuccessful. Nebulized ipratropium and albuterol and supplemental oxygen by nasal cannula afforded occasional symptomatic relief. Multiple bronchoscopic procedures were performed to remove the fibrinous material from the lung, but it quickly reaccumulated. The expectorated material did not dissolve with tissue plasminogen activator (TPA) ex vivo, and thus a trial of nebulized TPA was not conducted. A prednisone taper provided only transient improvement. In some cases, PB has been due to lymphatic leakage into the bronchi either from surgical trauma or pulmonary lymphatic abnormalities, with resolution of the condition after ligation of the thoracic duct []. In this patient, KS of the intrapulmonary lymphatics was likely causing a chyle leakage. Thus, a lymphangiogram was attempted to determine sites of lymphatic leakage that might be amenable to surgical intervention; however, tracer injected into the lymph vessels in the groin area failed to migrate, likely due to lymphatic involvement with KS. Lymphoscintigraphy was also performed, using the hands as injection sites, but no abnormal uptake of tracer within the lungs was demonstrated. Although thoracic duct embolization was offered to the patient, he declined the procedure. Over approximately three months, the patient was repeatedly readmitted for respiratory distress and ultimately required endotracheal intubation and mechanical ventilation. Repeated bronchoscopy was performed in an effort to clear the casts, but it was unsuccessful. While on the ventilator, he empirically received multiple therapies for the reduction of lymphatic flow (including total parenteral nutrition (TPN), midodrine, and octreotide) and the treatment of KS (with sirolimus) to curb cast production. Unfortunately, the patient developed refractory respiratory failure and was transitioned to comfort measures. An autopsy revealed extensive pulmonary KS with hepatization of the lung and near obliteration of the normal alveolar architecture with copious mucin and cellular debris within the airways (Figures , , and ).
pmc-6180937-1	A 52-year-old man, without a history of neurological or muscle disorders, presented with slowly progressing upper and lower limb girdle weakness lasting for about 7-8 years. In particular, he complained of difficulties in going up- and downstairs and in carrying weights. He also complained of dyspnea, even with mild efforts. No dysphagia or dysphonia was reported. A recent check-up blood test showed mild hyperCKemia (CK= 468 UI/L; n. v. 10-167 UI/L). At neurological examination he presented lumbar hyperlordosis, abdominal breath, and waddling gait. Manual muscle test (MRC) revealed bilateral and symmetric weakness of deltoid (4, R+L), pectoralis (3, R+L), biceps b. (4, R+L), triceps b. (4, R+L), ileo-psoas (4, R+L), and quadriceps (4, R+L). All remaining muscles had normal strength. Hypotrophy was evident in the axial musculature, with the presence of winged scapulae. On blood tests, CK was slightly elevated and serum protein electrophoresis was normal. Functional respiratory test showed a moderate restrictive ventilatory deficit. Nerve conduction studies were unremarkable. By concentric needle EMG, abundant fibrillation potentials and positive sharp waves, associated with sporadic fasciculation potentials and complex repetitive discharges with MUPs of increased amplitude, duration, and polyphasic aspect, were detected in tibialis anterior muscles. Other muscles (L deltoid and R vastus) showed milder signs of neurogenic MUPs remodeling. Only in R infraspinatus, MUPs of reduced amplitude and duration were found, indicating a myopathic pattern. MRI of the thighs showed a bilateral fibro-adipose degeneration of the adductor and biceps femoris muscles, together with hypertrophy of the gracilis muscles (). The patient underwent a muscle biopsy of the left vastus lateralis that showed few necrotic and numerous atrophic fibers, the majority of which containing small, medium, and large vacuoles. At the PAS reaction, performed on cryostat and, for a better resolution, resin sections [], these vacuoles appeared filled with polysaccharide material that showed glycogen structure at electron microscopy (EM) observation. By the acid phosphatase reaction, all optically visible vacuoles, plus a large number of small, intracytoplasmic foci, stained positively, indicating a lysosomal nature of the vacuoles. ATPase histochemistry revealed that vacuoles were present almost exclusively in type 1 fibers, which were also diffusely atrophic, as opposed to the normal appearance of type 2 fibers. Furthermore, many of these atrophic fibers (7% of all fibers contained in transverse sections) displayed numerous, discrete, deposits of basophilic material, located centrally within the fiber cytoplasm or, in some instances, in a subsarcolemmal position (). By EM, this material was distributed in multiple, cigar-shaped, stereotyped formations oriented consistently with the longitudinal axis of the fibers and representing nemaline bodies (NBs). These were composed of myofibrillar material in apparent continuity with Z-bands (). No cores, or other typical alterations seen in congenital myopathies, were observed. In order to substantiate a diagnosis of Pompe disease, we performed alpha-glucosidase (GAA) assay by mass spectrometry on dry blood spots which showed GAA 0.27 μmol/L/h (n.v. 1.86–21.9 μmol/L/h); alpha-galactosidase, as control enzyme, was within normal limits (8.13 μmol/L/h; n.v. 5.71–49.02 μmol/L/h). Consistently, GAA value in blood lymphocytes was also very low (1 nM/mg/h; n.v. 13-32 nM/mg/h). Enzymatic assay on muscle biopsy was not performed due to shortage of tissue. Diagnosis was finally confirmed by molecular analysis, which showed a compound heterozygosis for the known c.-32-13 T>G splice mutation and the known c.2544delC deletion (p.Lys849fs) in the GAA gene.
pmc-6180957-1	A 66-year-old Caucasian woman with past medical history of dermatomyositis, dysphagia, gastro-esophageal reflux, and hypertension presented to the emergency department (ED) with several days of mid-epigastric, constant, moderate intensity, nonradiating abdominal pain. Additionally, she reported 4-5 days of erythematous rash that began on her face and chest that then spread to her arms and abdomen (Figures -). She also reported white “spots” in her mouth. At that time, CBC, CRP, ESR, CK, and UA were within normal limits. Lipase was 675 U/L and CMP was remarkable for sodium 129 mEq/L, amino alanine transferase (ALT) 158 U/L, and aspartate aminotransferase (AST) 111 U/L; the rest of the CMP including alkaline phosphatase (ALP) was normal. CXR was normal and abdominal radiograph showed evidence of constipation. An abdominal ultrasound was ordered due to elevated lipase and LFTs and showed no evidence of gallbladder dysfunction or liver lesions. She was diagnosed with pancreatitis, thrush, and folliculitis and was discharged home with clear liquid diet orders and prescriptions for nystatin oral solution and oral doxycycline for possible secondary skin infection. Two days later, she returned to the ED with persistent symptoms and decreased urine output. She reported nausea, constipation, and worsened dysphagia, but denied vomiting, weight change, night sweats, fever, chills, chest pain, cough, and shortness of breath. She also denied pertinent past surgeries, family history, recent travel, sexual activity, drug use, and alcohol and tobacco use. She reported allergy to penicillin. Her medication list included prednisone, mycophenolate mofetil (which she held since previous ED visit per doctor recommendations), trimethoprim/sulfamethoxazole (T/S), nystatin oral suspension, carvedilol, ranitidine, estradiol, calcium, and vitamin D. She was told by her dermatologist not to fill the doxycycline prescription from the ED and increase the dose of T/S. On physical examination, the patient was alert and oriented with normal vital signs. The exam was significant for oral thrush, but normal heart, lung, and abdominal exams. Skin exam showed a diffuse maculopapular eruption with a few vesicles on face, trunk, and extremities. Significant laboratory data was as follows: AST 1389 U/L, ALT 1570 U/L, ALP 68 U/L, international normalized ratio (INR) 1.6, and prothrombin time (PT) 18 seconds. Complete abdominal ultrasound demonstrated normal gallbladder without stones, no biliary ductal dilation, no focal liver lesions, and no ascites or abnormal fluid collections. The patient's dermatologist had performed skin biopsies 2 days prior to admission that showed multinucleated giant cells with viral inclusions suggestive of some type of herpes virus infection (Figures –). The patient was initiated on intravenous (IV) acyclovir, micafungin, vancomycin, aztreonam, and stress dose steroids for presumed disseminated herpes simplex with possible secondary bacterial infection and sepsis. Over the subsequent 48-72 hours, AST and ALT increased to the 4000s, INR increased to 1.8 and PT to 20.6. Due to worsening acute liver failure, she was transferred to our facility for liver transplant evaluation. On arrival to our hospital, her skin lesions were thought to be most consistent with VZV and skin biopsy cultures from the outpatient dermatologist later confirmed VZV. IV acyclovir and antibiotics for secondary bacterial sepsis were continued. As part of her liver transplant evaluation, extensive serologic investigation ensued. Acute hepatitis A-E serologies, ANA, IgG4, smooth muscle antibody (Ab), LKM-1 Ab, ceruloplasmin, a-1 antitrypsin, mitochondrial M2 Ab, AFP, HIV, HSV and EBV PCRs, blood cultures, galactomannan, and cryptococcal antigen were submitted and later found to be negative. She was also found to be pANCA MPO positive and PR3 negative. Liver biopsy was performed which revealed multiple areas of necrotic hepatocytes (up to 35% of liver parenchyma) (Figures -) in zones 2 and 3 of the liver. This was associated with some bile extravasation and acute inflammation. No signs of bridging or confluent necrosis were seen. A trichrome stain outlined regions of immature deposition of collagen near necrotic areas. This stain also showed increased perivenular fibrosis around the central veins but no evidence of periportal fibrosis. The portal triads showed nominal chronic inflammation with small lymphocytes, rare large lymphocytes, and a few scattered neutrophils. There was no bile duct injury, paucity, or vasculitis. The hepatocytes did not demonstrate significant steatosis, but there was bile stasis in a few canalicular spaces and hepatocytes. Viral inclusions were not seen. An iron stain showed no accumulation of hemosiderin within the hepatocytes. PCR was negative for HSV, EBV, and CMV and positive for VZV. The necrosis also abutted portal triads seen in the specimens (). A Periodic acid-Schiff stain with diastase did not show cytoplasmic globules. Blood PCRs were positive with high levels of VZV and low levels of CMV. The CMV viremia was attributed to secondary reactivation due to her severely immunosuppressed state. VZV immune globulin was considered as therapy, but IVIG was administered instead due to her severe coagulopathy and thrombocytopenia. Outpatient skin biopsy cultures later confirmed VZV; PCR was positive for VZV and negative for HSV. Her hospital stay was complicated by multidrug-resistant Enterobacter cloacae hospital acquired pneumonia and bacteremia, respiratory failure requiring prolonged intubation, and multiple organ failure. VZV PCR copies decreased with treatment, but her severity of illness and active infection prevented liver transplantation. The patient's code status was eventually changed to “do not resuscitate” and she expired.
pmc-6180980-1	A 50-year-old female returning traveler presented to an emergency room in South Carolina for evaluation of syncope. Thirteen days prior she had returned from a 10-day trip to Lagos, Nigeria, where she visited family. While in Lagos, she felt well. Six days after returning to the U.S., she developed nausea and diarrhea. Three days later, she developed fevers and sweats that occurred multiple times daily. Twelve days after returning to the U.S., she experienced two episodes of syncope and then sought medical care. She had no headache, neck stiffness, sore throat, or respiratory symptoms. She reported that while in Lagos, she stayed in a home in an urban environment. She used mosquito repellent with N, N-diethyl-meta-toluamide (DEET), and slept indoors with closed windows but no mosquito net. She did not recall any mosquito bites. While in Lagos, she ate food prepared in the home after purchase from a local grocery store, and she drank only bottled water. She did not recall having been in contact with anyone who was sick while she was in Lagos. She reported having taken a prescription medication for malaria prevention, but we were unable to verify this. She had received oral typhoid, yellow fever, hepatitis A, TDaP, influenza, and meningococcal vaccines within the preceding year. The recent trip was her third to Nigeria; she had been well during and after her previous two trips. She was born and raised in South Carolina and had no other international travel. She had no significant past medical history and was not taking any medications at the time of presentation. She worked as a manager at a retail clothing store. On examination at presentation, the temperature was 100.8°, pulse 117/minute and regular, blood pressure 127/78, respirations 18/minute and unlabored, and O2 saturation was 99% breathing ambient air. She appeared comfortable, well-nourished, and not chronically ill. There was no jaundice or lymphadenopathy. Lungs were clear. Heart sounds were normal aside from tachycardia, and there was no murmur. The abdomen was not tender, and there was no hepatosplenomegaly. She was alert, and neurologic exam was unremarkable. Laboratory test results are shown in . There was no hemoglobin detected in the urine. Blood cultures were drawn. Thick and thin blood smears were prepared and Giemsa-stained. Microscopic examination showed a microcytic normochromic anemia, numerous erythrocytes with trophozoite rings, and rare banana gametocytes characteristic of P. falciparum malaria. Parasitemia was 3.5%. Rapid malaria diagnostic testing using the BinaxNOW® Malaria test (Alere Inc., Waltham Massachusetts) was positive for P. falciparum. An ARCHITECT HIV Ag/Ab Combo (Abbott, Wiesbaden, Germany) test was negative. Nucleic acid amplification-based testing of a stool specimen was negative for adenovirus, Campylobacter, Cyclospora cayetanensis, Clostridium difficile, enteroaggregative Escherichia coli, enteropathogenic E. coli, enterotoxigenic E. coli, Shiga-like toxin producing E. coli, Shigella, enteroinvasive E. coli, Entamoeba histolytica, Giardia lamblia, human astrovirus, norovirus GI/GII, Plesiomonas shigelloides, rotavirus A, Salmonella, sapovirus, Vibrio, Vibrio cholera, and Yersinia enterocolitica (FilmArray™ Gastrointestinal Panel, BioFire Diagnostics LLC, Salt Lake City, UT). At 48 hours of incubation, blood cultures obtained at presentation grew gram-negative rods identified as a Salmonella species by MALDI-TOF mass spectrometry. A triple sugar iron agar slant showed a nontyphoidal Salmonella phenotype. The isolate was identified as Salmonella enterica subspecies enterica serovar stanleyville (1,4,12,27:z4,z23:[1,2]) by the South Carolina Department of Health and Environmental Control Public Health Laboratory using serotyping with specific O and H antisera according to the Kaufman–White scheme. She was treated for uncomplicated P. falciparum malaria with oral doxycycline and quinidine for 7 days. Fevers resolved by day 3 at the hospital and repeat blood smear remained negative for malaria 16 days later. For nontyphoidal Salmonella bacteremia, she was treated with ceftriaxone for 2 weeks; diarrhea and all other signs/symptoms resolved within 10 days.
pmc-6180998-1	This patient was a 71-year-old male who presented with abdominal discomfort and was found to have significant splenomegaly upon physical exam, confirmed by imaging. He was diagnosed clinically with SMZL and underwent splenectomy to control his disease. We have not been able to determine whether he had peripheral blood lymphocytosis at that time of initial presentation. Ten years after the initial diagnosis of lymphoma, he presented to our institution with weight loss and extensive anterior mediastinal, hilar, and retroperitoneal lymphadenopathy with an anterior mediastinal mass measuring 9.8 × 5.6 cm. Serum lactate dehydrogenase was elevated (281 U/L, reference range: 135–225 U/L). He was started on weekly rituximab with no response. In view of progressive symptoms, he was switched to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy at an outside institution. He presented to our institution after his first cycle of R-CHOP for additional recommendations. He felt dramatically better at that time. The clinical impression was that he had a large-cell transformation of his previously diagnosed low-grade SMZL. Laboratory analysis showed a white blood cell count of 9.4 × 103 cells/μL, hemoglobin level of 12.2 g/dL, platelet count of 242 × 103/μL, and absolute lymphocyte count of 1.33 × 103/μL. Peripheral smear was morphologically unremarkable. Peripheral blood flow cytometry showed a minor monotypic B-cell population, CD5, CD10, and CD23 negative, comprising 0.7% of analyzed events, consistent with minimal peripheral blood involvement by his previously diagnosed lymphoma. He was referred for lymph node biopsy to clarify the diagnosis. Excisional biopsy of the axillary lymph node showed extensive involvement by lymphoma composed of both small, cytologically atypical lymphoid cells with abundant cytoplasm admixed with more predominant intermediate to large-sized lymphoma cells with variably abundant cytoplasm, large nuclei, and prominent, centrally located nucleoli, consistent with prolymphocytes (Figures and ). The aggregates of prolymphocytes did not resemble proliferation centers seen in CLL/SLL as they were more discrete, monotonous, and expansile in nature. Transformed cells, defined as having intermediate to large-sized nuclei and central nucleoli, comprised more than 50% of all lymphoma cells. Sheets of large cells were not present; thus, designation as a large-cell transformation was not warranted [, ]. By immunohistochemistry, lymphoma cells were positive for CD20, CD5 (dim, subset), BCL2, and cyclin D1 (diffuse, positive in small lymphoma cells and those with prolymphocytic features), and negative for CD3, CD10, LEF1, and SOX11 (Figures –). EBER staining by in situ hybridization was negative. The KI67 proliferation index was estimated at 40%, and it highlighted the large transformed cells in particular. Based on these findings, the possibility of mantle cell lymphoma (MCL) was considered. The previous material (splenectomy and bone marrow biopsy from 10 years before) was then reviewed at our institution, and the original interpretation of SMZL was indeed confirmed. In the splenic resection, the lymphoma cells were present in a micronodular pattern within white pulp, invaded red pulp, and were composed of small-sized lymphoma cells with monocytoid morphologic features, negative for CD5 and cyclin D1 (). Staging bone marrow biopsy performed at the time of initial splenectomy showed extensive involvement by low-grade lymphoma with an interstitial nodular and focally intrasinuoidal pattern (). Lymphoid cells in the aspirate smear were small and did not have features of large-cell or prolymphocytic transformation. Karyotype and FISH studies performed in the bone marrow were negative for t(11; 14)(CCND1-IgH). Given the confirmation of the initially diagnosed SMZL, we performed FISH for t(11; 14)(CCND1-IgH) using IgH and CCND1 dual-labeled probes in the lymph node sample both at our institution as well as at an external reference lab, and both were negative for CCND1-IgH rearrangement (). An additional FISH test using a CCND1 break apart probe was also performed and failed to detect rearrangements involving CCND1. Additional copies of CCND1 were not present. To assess the clonal relationship between the splenic and nodal neoplasms, PCR analysis for IgH rearrangement was performed in both samples. The same monoclonal IgH peaks (framework region (FR) 1: splenectomy: 342.24, lymph node: 342.38; FR2: splenectomy: 277.71, 285.58; lymph node: 277.69 and 285.36; FR3: splenectomy: 146.14, lymph node: 146.3, Figures and ) were identified in the original and current samples, supporting that the two lymphomas were clonally related. Next-generation sequencing (NGS) using the FoundationOne Heme comprehensive genomic profiling assay (Foundation Medicine, ) identified genomic alterations of NOTCH2, BRCA2, and SRSF2 but was negative for rearrangements involving CCND1 in both samples from the two different time points, further supporting that the lymphomas were clonally related and that despite the acquired strong expression of cyclin D1, the neoplasm lacked CCND1 gene rearrangement or mutation. Taken together, these findings indicate that the lymphoma with prolymphocytic transformation involving the lymph node represented disease progression of the patient's original SMZL. The prolymphocytic histologic transformation was defined in this case by the presence of sheets of intermediate to large-sized lymphoma cells with prolymphocytic morphologic features and was associated with acquired partial CD5 and diffuse cyclin D1 expression in the absence of acquired t(11; 14) (CCND1-IgH).
pmc-6180998-2	This patient was a 53-year-old male without relevant past medical history who presented with one week of intermittent fevers, night sweats, weight loss, early satiety, cough, and exertional shortness of breath. Physical examination revealed diffuse small lymphadenopathy and massive splenomegaly. Imaging studies confirmed massive splenomegaly with the spleen measuring 31 cm in craniocaudal dimension with diffuse hypermetabolic activity, SUV 5.6, in keeping with lymphomatous involvement. There were also numerous subcapsular wedge-shaped areas of photopenia and hypodensities measuring up to 3.5 cm, which were suspected to be splenic infarcts (). Laboratory analysis showed an elevated LDH of 421 U/L (normal range: 132–225 U/L), leukocytosis (white blood count: 210 × 109 cells/L), anemia, and thrombocytopenia. Peripheral blood smear confirmed lymphocytosis with many circulating lymphoma cells being small to intermediate in size with mature nuclear chromatin (). Approximately 50% of circulating lymphoma cells were large with abundant cytoplasm, more open and vesicular nuclear chromatin and prominent nucleoli, consistent with prolymphocytes (). Cells with villous or circumferential cytoplasmic projections were not seen. Flow cytometry immunophenotyping in peripheral blood showed that lymphoma cells were positive for CD20, CD19, CD79a, CD22, and CD23 with lambda surface light chain restriction and negative for TdT, CD34, CD10, and CD5. Initial diagnostic considerations included prolymphocytic transformation of atypical CD5 negative CLL, B-prolymphocytic leukemia (B-PLL), and leukemic MCL, noting that the immunophenotypic expression patterns of B-PLL and SMZL can be indistinguishable. Bone marrow core biopsy showed diffuse infiltration by intermediate-sized cytologically atypical lymphoma cells, and aspirate smear showed that most lymphoma cells had prolymphocytic morphologic features in the bone marrow (Figures –). An intrasinusoidal pattern of involvement was difficult to appreciate due to the extensive degree of marrow involvement. Immunohistochemistry in the bone marrow core biopsy showed lymphoma cells were diffusely and strongly positive for cyclin D1 () and negative for CD5, LEF1, and SOX11. Chromosome analysis in bone marrow aspirate showed a normal karyotype 46, XY in 20 metaphases. FISH studies for t(11; 14) (CCND1-IgH) in the peripheral blood and bone marrow aspirate were negative but were positive for deletion 7q (33% of cells), deletion 17p (97% of cells), and deletion 13q (18% of cells). Next-generation sequencing using the FoundationOne Heme comprehensive genomic profiling assay identified a genomic alteration of TP53 and was negative for rearrangements or mutations involving CCND1 and other tested genomic alterations. Extra copies of CCND1 were not detected. Based on the absence of t(11; 14)(CCND1-IgH) as detected by FISH, karyotype, and NGS, a diagnosis of MCL was excluded despite diffuse cyclin D1 expression. The presence of massive splenomegaly, the lymphoma cell morphology and immunophenotype, and presence of deletion 7q, support that this lymphoma is best classified as SMZL with prolymphocytic transformation and diffuse cyclin D1 expression. However, extreme leukocytosis, presenting with B symptoms and diffuse lymphadenopathy, as seen in this case, is unusual for SMZL; thus, we cannot exclude that this lymphoma is a B-PLL with diffuse cyclin D1 expression. The presence of deletions 13q and 17p, although not specific, are recurrent abnormalities seen in approximately 27% and 50% of B-PLL, respectively, and may support this classification []. Because this patient did not have splenectomy, we also cannot completely exclude the possibility of splenic diffuse red pulp small B-cell lymphoma, although CCND3 mutations, which are recurrent in that lymphoma, were not identified, and the presentation was more aggressive than typically reported in diffuse red pulp small B-cell lymphoma.
pmc-6180999-1	A baby girl aged seven months presented to our clinic, Etomie Oral and Maxillofacial Clinic, Kaduna, Kaduna State, Nigeria, with a thick tubular structure in the medial canthus of the left eye and cleft of the left upper lip, left alveolus, and primary and secondary palates from birth. The antenatal history revealed nine months of uneventful gestation with uncomplicated spontaneous vaginal delivery. There was no prenatal history of exposure to alcohol, ionizing radiation, or drugs and consanguinity. The mother denied any family history of congenital anomalies of any type. Clinical examination revealed an otherwise normal baby weighing 3 kg with a tubular fleshy structure measuring about 3 cm in the medial canthus of the left eye and cleft of the left upper lip, alveolus, and primary and secondary palates (). The globes and the nose were all normal. Other systemic examinations were also normal. Laboratory investigations were all within normal limits. Based on this clinical presentation, a diagnosis of lateral proboscis with cleft of the left upper lip, alveolus, and palate was made, and the patient was subsequently prepared for surgery. After routine cleaning and draping, the upper lip cleft was repaired using the straight-line technique, while the proboscis was excised using an elliptical incision. The resultant wound was closed in layers using 4/0 Vicryl sutures (). Gross examination of the specimen showed an oblong skin-covered tubular mass measuring about 3 cm, while histological examination showed the stratified squamous epithelium, overlying collagenized dermis containing adnexal structures, and admixture of fat lobules and collagen bundles (). The patient was managed with I.M. lincomycin 150 mg 8 hourly for 5 days, with I.M. pentazocine 7.5 mg statum, and thereafter with paracetamol 5 ml for 3 days. Sutures were removed 7 days postoperatively, and the patient was subsequently discharged the same day.
pmc-6181002-1	A 56-year-old woman presented to our emergency department with complaints of sore throat and cervical swelling. Her medical history included hypertension, habitual smoking, and occasional alcohol consumption. She developed a sore throat and visited a local clinic 3 days before presenting to our emergency department. She was diagnosed with tonsillitis. Group A antigen test was negative, and she was administered amoxicillin 750 mg/day. However, 2 days later, she developed dyspnea, dysphagia, and neck stiffness. On arrival at our hospital, she had a severe sore throat and muffled voice and was drooling. Laryngeal fiberscopy revealed swelling of the caudal oropharyngeal mucosa on the right side and a severely swollen epiglottis and arytenoid region that caused upper airway occlusion. Her SpO2 was 97% on 2 L oxygen, and her body temperature was 37.4°C. Blood test results suggested strong inflammation (white blood cell count, 15.3 × 109/L; C-reactive protein, 27.6 mg/L). We established a diagnosis of parapharyngeal abscess. Because of a high risk of suffocation, we first performed tracheostomy with the patient under local anesthesia. Enhanced computed tomography after tracheostomy revealed hypodense lesions at the left lateral and posterior pharyngeal walls (). Incision and drainage of the abscess was performed with the patient under general anesthesia using a rigid curved laryngoscope. Peritonsillitis containing mucus and pus from the posterior pillar was observed (). We incised and opened a part of the swollen posterior pillar and lateral and posterior pharyngeal walls, draining pus from these regions (). The operation was completed without any adverse events. The patient was administered 3 g/d meropenem as empiric therapy. On postoperative day 4, culture for aerobes and anaerobes revealed GGS and Parvimonas micra, respectively. Therefore, the antibiotics were changed to 4 g/d piperacillin and 1.2 g/d clindamycin. The recovery course was uneventful.
pmc-6181066-1	A 34-year-old male driver who was suffering from myasthenia gravis presented to the medical emergency department of Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India, with increasing fatigability, ptosis, and diplopia for seven days. The patient was a native from the same city. Informed consent was obtained from the patient for using his clinical information and images for the academic and research purposes. The patient had undergone thymectomy four years ago for myasthenia gravis and was on tablet prednisolone 40 mg once daily, tablet pyridostigmine 90 mg six-hourly for five years, and tablet cyclosporine 200 mg twice daily for the last one year. The patient had also developed steroid-induced diabetes mellitus one year ago and had received insulin therapy. His vitals were stable. There were multiple painless swellings in the right leg region for the preceding one month; the biggest swelling measured 10 × 7 cm near the knee region () and multiple small swellings were noticed between the knee and ankle. There was no history of previous similar swellings. His random blood sugar at the time of admission was 345 mg/dl and HbA1c 10.7%. Insulin dose was adjusted and it reduced to 135 mg/ml on the fifth day of admission. Ultrasound of the swelling near the right knee showed multiloculated collections with moving echoes in the knee joint. The pus was yellowish, not foul smelling and not blood stained. The 10% potassium hydroxide (KOH) mount showed thin, septate, hyaline, and branched hyphae (). The pus was inoculated on Sabouraud Dextrose Agar (SDA) and incubated at 25°C in multiple tubes. All the culture tubes grew flat, densely floccose, and velvety lilac colour colonies and the reverse was off-white within seven days of incubation (). Lactophenol cotton blue stain (LPCB) preparation of the growth revealed thin hyaline septate hyphae with irregularly branching conidiophores. Phialides were more elongated and densely clustered and had a tapering end. The conidia were elliptical, in long unbranched chains, and phenotypically identified as Purpureocillium lilacinum (). Purpureocillium lilacinum was again isolated from two more pus aspirates, which were sent at varied intervals over the next one week. Antifungal susceptibility testing could not be performed because of logistic reasons. The fungal culture was confirmed by National Culture Collection of Pathogenic FungiCentre of Advance Research in Medical Mycology, WHO Collaborating Centre, Chandigarh, India (ID no. IL2892) by sequencing of internal transcribed spacer (ITS) region. The sequence was submitted to the gene bank database with the accession number MH714911. The patient was started on antifungal tablet itraconazole 300 mg once daily. The swellings were surgically excised and histopathological examination of the excised tissue revealed thin septate hyaline hyphae. After three months of itraconazole therapy, the patient had no new swellings but complained of a serous discharge at one of the excision sites. The discharge was collected and 10% KOH mount of the discharge was negative for fungal elements, but the culture grew Purpureocillium lilacinum again. Itraconazole therapy was extended for another month at the same dose, but the patient had recurrence of small swellings. Treatment was changed to tablet ketoconazole 200 mg once a day for three months. The swellings responded well to ketoconazole. He remained asymptomatic and swelling regressed after one month of ketoconazole therapy.
pmc-6181245-1	A 65-year-old male with a past medical history significant for hypertension initially presented with episodes of double vision, fatigue, dysphagia, and generalized weakness. Neurological examination was remarkable for ptosis of the right eye which improved with the ice pack test. Serology was positive for anti-acetylcholine receptor antibodies. Further workup revealed a decremental response to slow (2Hz) repetitive nerve stimulation of the right spinal accessory nerve. The patient was then diagnosed with myasthenia gravis. A computed tomography (CT) scan of the chest revealed thymoma for which the patient underwent resection and was subsequently placed on a high dose (50 mg daily) oral prednisone, in addition to mycophenolate and pyridostigmine. Four months after starting the above treatment, the patient presented to the hospital with shortness of breath. A chest X-ray revealed reticulonodular infiltrates. Further workup led to the diagnosis of histoplasmosis. Mycophenolate was then stopped. However, the patient was on a tapering dose of prednisone. The patient then developed refractory diarrhea and was diagnosed with Cytomegalovirus (CMV) colitis. Subsequently, the patient was completely weaned off steroids. However, he continued to develop recurrent pneumococcal infections. Eight months post discontinuation of steroids, the patient developed disseminated candidal infection. Immunological studies were remarkable for hypogammaglobulinemia (immunoglobulin G (IgG): 100 mg/dl; normal IgG: 700-1600 mg/dl). There was cutaneous anergy to intra-dermal antigen challenge. Subsequently, flow cytometry revealed reduced mature circulating B cells, reduced CD4 count, and reversal of the CD4:CD8 ratio (patient value: 0.5; normal CD4/CD8 ratio: 2.0). The patient then underwent a bone marrow biopsy which revealed reduced pre-B cell lineage. This led to the diagnosis of Good’s syndrome. The patient was successfully treated with IVIG (1g/kg) and since then has remained stable on a monthly IVIG regimen which is used to treat both MG and Good's syndrome.
pmc-6181246-1	A 41-year-old previously healthy Korean man presented with fever and headache for four days, and altered mental status for one day. The family had difficulty waking him up and he was "picking things out of the air". He had no past medical history or any family history of autoimmune diseases. Upon arrival, he was lethargic but without a focal neurologic deficit and had a fever of 100.6°F. Remarkable labs included white blood cell (WBC) count of 3.55 x 109/L with a bandemia of 20%. Routine cerebral spinal fluid (CSF) study results showed elevated WBC count of 72/ml, red blood cell count (RBC) of 24/ml, and protein of 118 mg/dl. CSF glucose was within normal limit at 70 mg/dl. He was empirically treated with vancomycin, ceftriaxone, acyclovir, and dexamethasone. However, his mental status worsened quickly and required intubation. He was placed on continuous video electroencephalogram (EEG) and found to be in non-convulsive status epilepticus (NCSE) (Figure ). Extensive infectious workup and cancer screening, including a whole body computed tomography (CT), testicular ultrasound, and flow cytometry of peripheral blood were negative. However, autoimmune workup was remarkable for elevated anti-GAD of >250 u/ml and antinuclear antibody (ANA) titer 1:320. Magnetic resonance imaging (MRI) brain demonstrated increased signal in the bilateral mesial temporal lobes (Figure ). NCSE continued despite pentobarbital-induced burst suppression necessitating the addition of midazolam and ketamine drips with multiple failed attempts to wean off these sedative-hypnotic medications. All other available intravenous seizure medications (Phenytoin, valproic acid, levetiracetam, phenobarbital and lacosamide) were utilized in various combinations while trying to wean sedative-hypnotic drips. Besides, the patient received a ketogenic diet. Diagnosis of anti-GAD-associated autoimmune encephalitis was made based on the clinical course and workup. Immune targeted therapies began with high dose intravenous steroids, then intravenous immunoglobulin (IVIG). Next, he was treated with plasmapheresis which allowed for improvement of seizures activity, tapering of sedative-hypnotic medications and regaining consciousness. However, frequent intermittent seizures continued despite the use of multiple seizure medications. Thus, additional immunotherapies were given. Anakinra (an interleukin 1 receptor antagonist) and Mycophenolic acid were also added. Three months later, he was decannulated. He improved to be alert and oriented to person and place, with intelligible speech, memory impairment, and mild generalized weakness. Short-term seizure control was achieved using with five seizure medications including oxcarbazepine, phenobarbital, lorazepam, clonazepam, and perampanel. Anti-GAD level was decreased to 17.6 u/ml at the time of discharge.
pmc-6181250-1	A 16-year-old female presented in a private dental clinic with a chief complaint of pain and swelling on the right maxillary side. Upon intra-oral examination, a bony swelling was noticed in the right buccal vestibule. The patient was then referred to a private dental imaging center for imaging of the jaws to determine the presence and extent of the lesion. A cone beam computed tomography (CBCT) scan was taken for the area of interest. A board-certified oral and maxillofacial radiologist performed the radiographic interpretation of the CBCT scan. The scan revealed a mixed radiopacity in the right side of the maxilla. Sagittal cuts show that the lesion extended from the alveolar crest of the right posterior teeth (from the first premolar to the third molar and pterygoid plates) to the right orbital floor in the superior-inferior direction (Figure ). Axial cuts revealed that the lesion obliterated the right maxillary sinus completely and caused expansion of the anterior, posterior, and lateral walls of the right maxillary sinus while maintaining the maxillary sinus outline (Figure ). Coronal cuts showed that the lesion extended from the lateral wall of the right nasal cavity to the lateral wall of the right maxillary sinus and zygomatic arch with expansion in both lateral and superior walls of the maxillary sinus (Figure ). The lesion blended with the surrounding normal bone, and the internal structure showed mixed radiopaque-radiolucent areas characterized by a homogenous “ground glass” appearance (Figure ). Additional observations included a loss of bone trabeculation, thinning of the cortical boundaries, and a loss of the lamina dura around the right posterior permanent teeth (Figure ). Differential diagnosis included ossifying fibroma, fibrous dysplasia, and osteomyelitis. Based on the radiographic features such as anatomical expansion, lack of root resorption, lack of onion skin appearance, an impression of fibrous dysplasia was made. In our case no aggressive surgical treatment was planned because of recurrence during the active growth phase.
pmc-6181251-1	A 28-year-old female presented with complaints of vomiting for three days. For the last one day, the patient was bedridden secondary to extreme fatigue and weakness. She denied fever, vaginal discharge, or diarrhea. Her blood pressure was 100/60 mmHg, respiratory rate 22/min, heart rate 56/min, and she was conscious and alert. An examination of her nervous system revealed that there was proximal muscle weakness and that her reflexes were flaccid. There was no evident muscle tenderness or sensory deficit. Her blood work was normal except for low serum bicarbonate (7.0 mmol/L) and serum potassium (1.5 mmol/L). A spot urine sample showed a pH of 6.5 and a positive anion gap (urinary sodium 5.1 mmol/L, potassium 34 mmol/L, and chloride < 5 mmol/L). On arterial blood gas analysis, the pH was 7.04 (7.35-7.45), pCO2 6.1 kPa (4.5-6.1), PO2 12.8 kPa (12.0-15.0), bicarbonate 12.0 mmol/L (22.0-26.0), and oxygen saturation 92.6%. All of these findings were compatible with the diagnosis of dRTA. While receiving therapy with potassium replacement, the patient developed increasing shortness of breath from respiratory muscle weakness. Repeat biochemical analyses showed serum potassium of 1.8 mmol/L. She was transferred to the intensive care unit and intubated for ventilation. Further tests were arranged to establish the cause of dRTA. On serum protein electrophoresis, we did not find paraproteins. Ultrasound of the abdomen was normal, excluding medullary sponge kidney, nephrocalcinosis, and obstructive uropathy as potential causes of dRTA. Her autoantibody profile showed negative anti-mitochondrial, anti-smooth muscle, and anti-double-stranded DNA antibodies. However, anti-nuclear antibody, anti-Ro/SSA, and anti La/SSB were positive. This autoantibody pattern was consistent with Sjogren's syndrome. There was no history of dry eyes and dry mouth. We did not perform a Schirmer test or salivary gland biopsy. Therapy with intravenous corticosteroids was started while the potassium replacement continued. Her condition improved and her hypokalemia resolved. The patient was extubated and discharged after one week with the advice of follow-up.
pmc-6181467-1	A 33-year-old pregnant woman (3 gestations, 1 delivery, and 1 abortion) had antenatal diagnosis of gestational diabetes mellitus, which was treated by dietary control. A preplanned ultrasound assessment detected the presence of congenital left diaphragmatic hernia of poor prognosis (initial lung area to head circumference ratio = 0.85) and normal fetal karyotype. A fetoscopic endotracheal occlusion was successfully performed at 28 weeks 1/7 days gestation with subsequent improvement of lung area to head circumference ratio to 1.07. During a follow-up ultrasound examination performed at 32 gestational weeks, the mother complained of lower belly pain and contractions. On physical examination, she presented 4 uterine contractions in 30 minutes and had cervicodilatation of 2 cm. She was then hospitalized to remove the fetal endotracheal balloon by ultrasound-guided puncture to prevent fetal asphyxia after delivery and placental detachment. Before the procedure, the fetus was routinely anesthetized with an intramuscular injection on the left thigh (targeting the quadriceps muscle) containing pancuronium (0.50 mg/0.25 mL) and fentanyl (40.0 μg/0.8 mL), using a 20 G × 6 in. needle. After written informed consent was provided by the mother, and for the purposes of assessing putative pain-related behaviours noninvasively during the procedure, we have added a second ultrasound machine in the operating room (Voluson E8; GE Health-care, Zipf, Austria) operated by a second foetal medicine specialist exclusively to monitor the facial expressions of the foetus during the anaesthetic puncture. We have recorded the preanaesthetic and postanaesthetic 4D ultrasound films and presented it to 3 coders to assess facial expressions using the NFCS, which is validated to detect pain behaviours and suffering healthy and preterm newborns, but never before used during the intrauterine life during acute pain conditions (Fig. and Supplemental Digital Content, ). The 10 facial actions of the NFCS were coded: brow lowering, eyes squeezed shut, deepening of the nasolabial furrow, open lips, vertical mouth stretch, horizontal mouth stretch, taut tongue (cupping of the tongue), chin quiver (high frequency vibration of the chin), lip purse (tightening the muscles around the lips to form “oo”), and tongue protrusion. Each face action was classified as visible or not, and, if visible, they were coded as 1/0 (occurred/did not occur). Four dimensional ultrasound images were recorded before and after the anaesthetic procedure and were anonymized for off-line assessment including: (1) a baseline period defined as the least 30 seconds before the anaesthesia puncture and (2) the 45 seconds immediately after the puncture (Supplemental Digital Content, ). Thus, video extracts were presented to 3 coders with no previous background in behavioural coding: a neurologist, a psychologist, and a fetal medicine obstetrician specialized in 4D ultrasound of foetuses. All coders were blinded to the timing of the videos (before vs after puncture), which were randomly presented to each coder (scores were illustrated in Tables ).
pmc-6181502-1	Patient 1, female, aged 30 years, received sharp needle injection in the labial tubercle area. After injection of about 0.2 ml of hyaluronic acid, the patient experienced sudden pain, and injection was stopped immediately. Even after 20 minutes, the pain did not subside; dark purple discoloration of the upper lip and spotted contusions on the left side of the face were observed (Fig. A). Two local injections of 1 ml of hyaluronidase at a concentration of 750 U/ml were administered 30 minutes apart, followed by continuous massage for 30 minutes. Five hours after injection, local cooling was applied using gauze pads soaked with saline containing gentamicin (80,000 units of gentamicin + 50 ml saline). Partial relief of pain was achieved after the local cooling. At the same time, hyperbaric oxygen therapy was administered once daily, and cefazolin sodium 2.0 g and 10 mg of dexamethasone were administered per day by intravenous infusion for 3 days. After treatment for up to 5 days postoperatively, 3 scattered purulent spots appeared at the base of the nasal columella; therefore, 0.5 ml of hyaluronidase at a concentration of 750 U/ml was injected again. One week after the injection, further disease progression was not observed; therefore, all treatment was discontinued. Two weeks after the injection, with exception of a residual 2 mm diameter scar at the junction of the left philtrum and the columella, as well as local pale purple ecchymosis, complete recovery was achieved at all other sites (Fig. B).
pmc-6181502-2	Patient 2, female, aged 24 years, received blunt needle injection in the nasolabial folds. When the injection on the right side was almost completed, the patient experienced pain; however, this was not noticed by the injecting doctor. Six hours after the injection was completed, the injection site and adjacent area appeared bruised, and pain worsened. The patient developed localized oozing of blood. Two days after the injection, localized pain did not subside, and skin ulcers developed at the right alar base. Patient was admitted 3 days after injection, with skin ulcers at the right alar base and visible purulent spots. Immediately, injections of hyaluronidase at a concentration of 150–300 U/ml were administered at sites filled with hyaluronic acid and in areas showing abnormal skin color. After injection, the affected sites were massaged for 30 minutes, followed by local cooling using an antibiotic saline-soaked gauze pad applied to each site. Pain significantly reduced 2 hours after treatment. There was no increase in the area of skin ulceration and number of purulent spots after treatment. After continuous treatment for 5 days, pain disappeared, and scabs developed over the skin ulcers. After 10 days of treatment, the scabs fell off, and the exposed skin was red in color without any obvious scarring (Fig. ).
pmc-6181506-1	A 46-year-old man presented to our clinics with a mass located to his left buttock. He observed the gradual enlargement of this lesion for 2 years with no eliciting event. The lesion did not cause any neurological, urological, or colorectal symptoms. His main complaints were discomfort while sitting and embarrassment for cosmetic reason. The patient was a nonsmoker, nonalcohol drinker, and otherwise healthy with no family history of any cancer. Positive surgical history included a bilateral hip replacement 10 years ago post motor-vehicle accident complicated by multiple episodes of seroma. Physical examination showed a large left buttock mass with overlying intact skin and several neighboring scars from the previous hip surgery. It was soft, compressible, and nontender in consistency. Magnetic resonance imaging (MRI) from another hospital was reported as a large (20 × 10 × 10 cm) solid, lobulated lesion, spanning from retro-pubic anteriorly to left buttock posteriorly, well confined to subperitoneal space (Figs. , ). As there was no local or regional lymph node enlargement on MRI, there was no suspicion of metastasis. Patient underwent an en-bloc excision of the lesion with excess skin via gluteal incision. The lesion was lobulated and infiltrative. It had a distinctive appearance similar to plexiform neurofibroma (Fig. ). The resection margin was the overlying capsule with all the tumor being completely excised. After ensuring the integrity of bladder and rectum in a multidisciplinary approach, the incision site was closed primarily with a drain. Pathology reported as aggressive angiomyxoma. Macroscopically the specimen measured 23 × 17 × 10 cm. Microscopically, the tumor was composed of hypocellular, monotonous, and small spindled fibroblasts with no atypical mitotic figures (Fig. ). Stroma was myxoid with collagen fibers and surrounded by dilated, thick walled vessels. Immunohistochemical stains revealed S100, desmin, and progesterone receptor negative with CD34 and focal estrogen receptor positive.
pmc-6181516-1	A 34-year-old woman was admitted to department of urology in April 2017 with chief complaint of progressive left abdominal pain for 1 month and can be alleviated by oral pain killer, not accompanied by urinary frequency, urgency, nausea, and vomiting. Physical examination revealed rebound, tender, and large abdominal mass was palpable at left upper quadrant. Laboratory tests showed normal renal function and elevated carbohydrate antigen 72–4 (CA72–4) level. Dynamic renal imaging revealed that glomerular filtration rate (GFR) of left and right kidney was 3.8 and 62.93 mL/min, respectively. Computed tomography urography (CTU) (Philips Brilliance 64 CT scanner, Philips Medical Systems Co., Ltd, USA) was performed and confirmed the presence of a 6 × 9 × 8 cm enhancing capsulated solid mass with cystic and necrotic areas in the retroperitoneum (Fig. B,C), compressing left ureter and causing severe hydronephrosis (Fig. A). Retrograde pyelography was done, and the left pelvis and upper ureter were not shown, further indicating the ureter blockage due to mass compression. Transabdominal ultrasound-guided biopsy of the mass was performed preoperatively, and the pathology diagnosis was inconclusive, showing aggregation of fibrillary, elongated cells, and no cellular atypia was visible. Then the patient was scheduled for laparoscopy exploration and open surgical exploration as alternative. Considering the huge volume and abundant blood supply of the mass, adequate volume of blood products was prepared. In case intestine resection might be performed during the operation, bowel preparation and cleansing enema was performed preoperatively. After preparation, the patient underwent laparoscopy exploration. Intraoperatively, the retroperitoneal mass was found closely adhered to adjacent tissue, the limited space made it hard to operate and converted to open surgical exploration. The encapsulated mass, measuring 6 × 9 × 8 cm, was densely adherent to mesentery and left kidney. The left ureter was located left rear to the mass and the small intestine was squeezed to the periphery of the mass. Following the separation of the mass from adjacent tissues, the mass was completely excised from retroperitoneum. Then the artery, vein of left kidney and the left ureter were separated and ligated separately. The blood loss during the excision was estimated to be around 400 mL. Macroscopically, the well-circumscribed mass was round and yellowish with areas of necrosis and hemorrhage in the center, outer surface was smooth and no sign of invasion was observed. The left kidney showed thinning of the renal parenchyma and dilation of the renal pelvis and calyces (Fig. ). The specimens were then fixed in 10% buffered-formalin, embedded in paraffin, and cut into 5 mm. Histopathological examination of specimens revealed areas of spindle-shaped cells in a typical palisading pattern and areas of myxoid and degenerative tissue with fewer cells (Fig. A). No atypical large nuclei or mitosis was observed. Immunohistochemical staining showed cellular positivity for S-100, vimentin and Ki67 (sporadic +) (Fig. B–D). The final diagnosis was benign retroperitoneal schwannoma. Postoperative course of the patient was uneventful and the left abdominal pain was greatly improved. At the 12-month follow-up, no evidence of recurrence or operation-correlated complication was observed.
pmc-6181536-1	A 29-year-old man (height = 180 cm, weight = 60 kg) was admitted to our hospital due to sudden onset of palpitation, chest tightness, mild fever, and night sweats, accompanied with bilateral double lower extremities adynamia and paralysis for 5 days, but no obvious syncope and edema. Examination on admission revealed a normal heart rate of 96 beats/minute (bpm) and blood pressure of 120/80 mmHg. On cardiac auscultation, 3/6 grade systolic murmur (Levine Scale) was heard between the third and fourth ribs at the left margin of sternum. The sensory below the sternum was dysfunctional. Muscle strength on both legs was at 1/6 levels (Lovett Scale), and tendon reflex diminished. Electrocardiography showed a sinus rhythm with pulmonary P-wave. An X-ray image of the chest showed discrete and scattered miliary nodules over both lungs, and cardiac silhouette was enlarged. Magnetic resonance imaging (MRI) (Fig. ) showed an erosive space-occupying lesion located between the first and third thoracic vertebrae, which resulted in stenosis of the spinal canal and thinning of the spinal cord. Transthoracic echocardiography (TTE) (Fig. ) showed a huge mobile mass (72 × 58 mm) in the RA and myxoma was considered. The left ventricular ejection fraction was 60%. The remaining physical examination findings were unremarkable, and laboratory tests were normal, except for the accelerating erythrocyte sedimentation rate. There was no family history of heart disease, including tumors and other cardiovascular problems. The preliminary diagnosis was thoracic vertebra tumor and cardiac myxoma. To treat the incomplete paraplegia caused by thoracic vertebra tumor erosion, the operation including resection of thoracic vertebral lesions, decompression, and internal fixation with nail-rod must be carried out immediately. A multiple disciplinary team consisting of cardiologist, orthopedist, sonologist, and anesthesiologists, was created. Fatal complications of cardiac myxoma, such as intracardiac obstruction and pulmonary embolism, were assessed. Informed consent of critical illness was signed by the patient's legal representative. The patient did not receive premedication before anesthesia. On arrival in the operating room, peripheral venous access was established on the dorsum of the hand, and continuous electrocardiogram and pulse oximetry monitoring were instituted. Invasive arterial blood pressure (IBP) was measured in the left radial artery, and the central venous pressure (CVP) was measured in the right femoral vein. Anesthesia induction was carried out with intravenous injection of midazolam 4 mg, penehyclidine hydrochloride 1 mg, etomidate 16 mg, and sufentanil 50 μg. Cisatracurium 12 mg was used to facilitate tracheal intubation. Maintenance of compound anesthesia consisted of 2% sevoflurane in an air–oxygen mixture, and remifentanil was continuously injected intravenously at 0.2 μg/kg/min. Intermittent bolus dose of 5 mg cisatracurium was administered for muscle relaxation. After anesthesia induction, hemodynamic parameters were stable at the supine position: heart rate of 80 bpm, IBP of 110/65 mmHg, and CVP of 8 mmHg. However, after the patient was turned to the prone position on the level of the standard operating table (lying on a pair of bolsters, unpressurized abdomen), the patient's heart rate increased gradually to 130 bpm, IBP dropped to 70/45 mmHg, and CVP increased to 22 mmHg. Moreover, the jugular vein was filled observably. Emergency treatment was carried out immediately against the symptoms of right heart failure. Fluid infusion was restricted and vasoactive drugs were used to maintain appropriate arterial blood pressure. Dopamine at 5 to 10 μg/kg/min and norepinephrine at 0.03 to 0.05 μg/kg/min were continuously injected intravenously, keeping the mean arterial pressure above 70 mmHg during the operation. During the 3 hours of surgery, blood volume supplementation totally consisted of sodium chloride 500 mL, hydroxyethyl starch 500 mL, fresh-frozen plasma 600 mL, and suspended red blood cells 2 U. Total blood volume loss was 600 mL, and urine output was 500 mL. After the operation, anesthetic drugs were stopped, and the patient was returned to the supine position. At this moment, his hemodynamic status was stabilized gradually with a heart rate of 84 bpm, IBP of 130/88 mmHg, and CVP of 10 mmHg. Dopamine and norepinephrine intravenous titration was suspended. When the patient recovered spontaneous respiration and responded to verbal commands, tracheal extubation was performed. After ventilated with 100% oxygen via a facemask in 5 min, the patient was transferred to the post-anesthesia care unit. Evaluation of spinal function was performed on the second postoperative. The muscle strength of the left leg was 4/6 levels, and the right leg was 3/6 levels; meanwhile, the superficial sensibility was considered dysesthesia. Furthermore, hemodynamic parameters were stable at the ward.
pmc-6181542-1	A 50-year-old Chinese female with a history of right breast neoplasm was treated with repeat lumpectomy for 4 times during 8 years. Physical examination revealed a 2.0-cm palpable mass in the right breast at the original surgical site. The lesion was not associated with any edema or blister, and no skin discoloration or ulcer was found. Subsequent mammogram and ultrasound examination demonstrated a possible malignancy (BI-RADS-4B and BI-RADS-4C, respectively). Digital mammography and ultrasonography indicated that there were no other specific characteristics compared with breast cancer. A CT scan for brain, lung, liver, and bone were conducted to exclude metastasis. The patient had a history of repeat lumpectomy, and the pathological analysis showed adenosis, phyllodes tumor, and fibrous tissue, accompanied by glass changes and highly differentiated AS. Therefore, mastectomy was suggested by our multidisciplinary team, and the patient underwent a right mastectomy with sentinel lymph node biopsy in January, 2018. The lesion was diagnosed as AS (Fig. A–D), which was immunohistochemically positive for endothelial markers CD31 (Fig. A), CD34 (Fig. B), ETS related gene (Fig. C), and FVIII-R-Ag (Fig. D). No other therapy was given postsurgery, and the patient had no recurrence after 3 months. This study was proved by the Ethical Committee of our hospital, and a written consent was obtained from the patient.
pmc-6181546-1	A 73-year-old female patient visited the hospital due to left-sided hemiparesis. She did not have a family history of stroke and had been taking antihypertensive medication for the past 10 years and angina medication for the past 6 years. She had a chronic headache for past few years. She had frequent headache with nausea or vomiting on 15 days per month. A neurological examination was conducted, and left hemiparesis, paresthesia, and dysarthria were found (Fig. ). The muscle power of the left upper and lower limbs was Medical Research Council (MRC) grade III and the brain diffusion-weighted MRI (diffusion weighted image [DWI]) showed a right lenticulostriate artery territorial infarction. Obstruction and stenosis of the main vessel were not observed. Multiple CMBs were found in the bilateral deep gray matter and pons on GRE MRI (Fig. A). Transthoracic echocardiography was normal. Cilostazol 50 mg twice daily was administered for secondary prevention of stroke in consideration of the multiple CMBs. The muscle power of the patient's left upper and lower limbs improved to MRC grade IV on the 7th day of hospitalization so she was discharged. Outpatient follow-up examination found that the muscle power of patient's left upper and lower limbs improved to MRC grade V 1 month after discharge. However, her hypertension was not controlled. Therefore, the dose of existing hypertension medication was increased and the follow-up examination found that her blood pressure was well controlled afterward. The patient presented with numbness in the left upper limb 6 months after discharge, and DWI and GRE brain MRI were performed. The newly taken DWI and GRE brain MRI were not different from previous images (Fig. B). Eight months after discharge, the patient experienced acute left hemiparesis and paresthesia with headache and she visited the emergency room within 1 hour of its onset. Neurological examination revealed that the muscle strength of the left upper and lower limbs was decreased to MRC grade IV. The blood pressure of the patient was 200/110 mm Hg when she visited the emergency room and electrocardiography did not show any abnormal findings except sinus bradycardia. The blood test was normal. The recurrence of cerebral infarction was suspected so brain MRI and DWI were performed but an acute infarction was not found. However, a new microbleed was observed in addition to previous CMBs in the right thalamus on the GRE sequence (Fig. C). The muscle power of the patient's left upper and lower limbs improved to MRC grade V from the 2nd day after admission and the patient was discharged 3 days later. After admission, the patient's blood pressure was not well controlled and she complained of headache. Therefore, the dose of previous hypertension medication was adjusted again, and the blood pressure was well controlled afterward. Outpatient follow-up found that the left paresthesia improved to normal, as well improvements with headache. Two months after the occurrence of the new CMBs, the patient experience left-sided paresthesia and visited the emergency room within 2 hours of its occurrence. Neurological examination was performed on presentation and found that the muscle power of the left upper and lower limbs was normal (MRC grade V) but paresthesia, which was previously improved, and headache occurred again. Her blood pressure was 210/110 mm Hg on admission and electrocardiography and blood test results were normal. Laboratory studies and abdominal ultrasonography for evaluation of secondary hypertension were normal. Brain MRI was obtained again to confirm the recurrence of cerebral infarction. No new lesions were seen on DWI. However, it was confirmed that another new microbleed had occurred, in addition to the 2 existing CMBs in the right thalamus on GRE MRI (Fig. D). After admission, her blood pressure was too high and the dose of hypertension medication had to be adjusted again. The blood pressure was well maintained afterward. The patient's paresthesia and headache improved from the next day, and the patient was discharged 5 days later. The left-sided paresthesia began to improve from the 2nd week after discharge and she has been treated as an outpatient without recurrence of neurological symptoms. Patient was followed up for 12 months at the outpatient clinic. Blood pressure was well controlled and there was no abnormal neurological symptoms.
pmc-6181600-1	A healthy 33-year-old male office worker with no history of TB, surgery, or medication was hospitalized in the Second Hospital of Jilin University on October 27, 2016, for intermittent bloody sputum for 3.0 months that was left untreated. The condition became aggravated 1.0 week before admission. The hemoptysis showed bright-red or dark-red blood of 3.0 to 5.0 mL/day. The patient did not have a significant fever, night sweats, or weakness. Wet rales were heard during auscultation of the lower left lung; however, the results of other physical examinations were normal. A chest computed tomography (CT) scan showed mild inflammation in the lower left lobe. The thick dorsal wall of the lower left lobe formed a cavity with an irregular inner wall, a thick dorsal wall, and burr changes around the lesion, and the upper lobe showed evidence of pulmonary emphysema. Laboratory tests were negative for bacterial growth in the sputum culture, sputum acid-fast bacilli, T-SPOT, (1→3)-β-D-glucan test, and galacto-mannan test; they also showed a normal erythrocyte sedimentation rate. Initially, treatment with empirical antibiotics combined with experimental anti-TB drugs showed no significant improvement in symptoms. After a bronchoscopic lung biopsy and exfoliative cytology, the patient's exfoliative cells showed pathological changes in the epithelial cells, phagocytes, and nonmalignant cells. After 1.0 week of antibiotic treatment, the hemoptysis symptoms remained. An enhanced thoracic CT was then performed on the patient and cavitary nodules containing a fungus ball, which was not enhanced (Fig. A–D). A video-assisted thoracoscopic surgery (VATS) left lower-lobe resection was performed under general anesthesia. The postoperative pathological reports indicated a large number of chronic inflammatory cells and tissue infiltration, lymphoid follicle formation, a large amount of local necrosis, multinucleated cells, and fungi. The fungal morphology was mainly that of Aspergillus (Fig. E, I, J, K), surrounded by fibers, with granulomatous inflammation and spore-like structural necrosis. The size of the spores was consistent with that of Cryptococcus (Fig. E–H). The fungal infections coexisted but the fungal foci of each was separate (Fig. E). The result of the latex agglutination test for cryptococcal capsular polysaccharide antigen was positive. An acid-fast stain was also applied; however, TB was not found. The patient was eventually conclusively diagnosed as having invasive pulmonary aspergillosis with PC. He was treated with amphotericin B and fluconazole until being discharged 7.0 days after surgery, and was prescribed oral amphotericin B and fluconazole daily for 4.0 months after discharge. The patient continues his outpatient visits. Chest CT scan demonstrated no obvious abnormality except the postsurgical chordae shadow in the left lower lobe 1.0 month after discharge. The follow-up was conducted for 1.0 year.
pmc-6181800-1	FM was a right-handed 70-year-old male who initially presented with behavioural disorders and attentional deficits. His family reported apathy, irritability and appetite augmentation. No memory, language, visuoperceptual or orientation deficits were initially reported. Neuropsychological assessment showed difficulties in executive functions, theory of mind and multitasking, while memory, language and praxis were preserved. Brain MRI indicated moderate bilateral frontal involution. FM received a diagnosis of the behavioural variant of FTD and was invited to take part in the study. When presented with the phonological verbal fluency task, he produced 6 words in the allowed 1 min. Afterwards, when presented with the categorical verbal fluency task, after correctly mentioning 4 animals, he produced an animal whose initial letter was the letter “p”. Immediately after, he switched to the former task and started to produce words with the letter “p” that were not animals till the task was finished. Of note, the first animal produced also started with the letter “p”.
pmc-6181800-2	DF was a right-handed 64-year-old male IT technician. When he was 61 years old he presented progressive behavioural changes and emotional liability. Within 2 years his deficits progressed to other cognitive functions including memory and language, with word finding difficulties. Behavioural deficits became more prominent including hyperorality and marked inappropriate behaviours. MRI indicated clear bilateral frontotemporal involution with left frontal predominance. DF received a diagnosis of behavioural variant of FTD and was invited to take part in the study. When presented with the phonological verbal fluency task, he produced 7 words in the allowed 1 min. When subsequently he was asked to generate animals, he produced 3 in the first 15 sec, with the first one starting with the letter “p”. Around second 15 he produced a new animal beginning with the letter “p” and then switched back to the former task, producing a word with the letter “p” that was not an animal.
pmc-6181800-3	DG was a right-handed 79 year old woman who complained of widespread musculoskeletal pain and fatigue, within many other physical symptoms. Given other transient symptoms such as dizziness, tension headache, tinnitus, cold feet, dry mouth and difficulty to swallow, she was seen by doctors from different specialities. She did not present pathological findings during her neurological examination nor any other explanation for her symptoms. An informant reported other changes of behaviour including cognitive rigidity and perseverative behaviours and thoughts. Her brain SPECT showed hypoperfusion in bilateral anterior and medial frontal lobes. When she was presented with the phonological fluency task, she produced 16 words in the given minute. Subsequently, in the categorical fluency task around second 15, she produced an animal which started with the letter “p”. Immediately afterwards she produced a word starting with the letter “p” that was not an animal.
pmc-6181800-4	MH was a right-handed 70-year-old female lawyer who volunteered to participate in the study as a control subject. She reported no cognitive or behavioural problems. When she was presented with the phonological verbal fluency task, she produced 15 words in the allowed 1 min. Subsequently, when she was asked to generate animals, she produced 8 in the first 30 sec. Around second 30 she generated an animal beginning with the letter “p” and then reverted to producing “p” words that were not animals.
pmc-6182403-1	A 62-year-old woman diagnosed with pancreatic cancer T3N0M0 Stage IIA [] underwent pylorus-preserving pancreatoduodenectomy (PPPD) + D2. The pathological findings revealed invasive ductal carcinoma of the head of the pancreas, nodular and well-moderately differentiated type with a 3.8 cm diameter, with direct cancer cell invasion of the duodenal mucosa and extra-pancreatic nerve plexuses, as well as lymph node metastasis (#13b involving five nodes). The dissected peripancreatic tissue margin was positive for pathological stage III pT3N2M0 cancer [] (Fig. a–c). The patient provided written, informed consent to undergo adjuvant treatment using gemcitabine, tegafur, and uracil (a 5-fluorouracil prodrug). However, this therapy was stopped after only 14 days as the patient developed Grade 4 neutropenia. Three months after surgery, the patient was enrolled in a clinical study of SVN-2B peptide vaccination. The vaccine at 1 mg/mL was mixed with the incomplete Freund’s adjuvant, Montanide ISA 51 (Seppic, Paris, France), emulsified, and then immediately injected subcutaneously once every 2 weeks. Human IFN-α at a dose of 3,000,000 IU (Dainippon-Sumitomo Pharmaceutical, Osaka, Japan) was also injected subcutaneously near the SVN-2B peptide injection site on days 1, 4, 8, and 11 (Fig. ) [, ]. Serum CA19-9 levels did not increase over a period of 12 years postoperatively (Fig. a). A follow-up CT at 82 months after the surgery detected three small lesions (Fig. a–c) that were removed by thoracoscopic excisional biopsy. All of them were pathologically well-differentiated adenocarcinoma and immunohistochemically positive for CK7 and negative for TTF-1 and CK20, indicating that they were pancreatic tumor metastases (Fig. d–g). Twelve years after the primary operation, periodic computed tomography (CT) and positron emission tomography did not uncover any new local recurrences or metastases. The clinical course did not include severe adverse events, although low-grade adverse events included transient headache, nausea, fatigue, and a persistent red flare with induration at the injection site (Grade 1).
pmc-6182574-1	A 26-year-old female was referred to the Sarcoma group at Oslo University Hospital with a large soft tissue lesion in her left thigh, described histologically as inactive fibromatosis. MRI-findings were consistent with this diagnosis. Subcutaneous soft tissue tumours were detected in her right buttock and along the spine. Histologically a surgical biopsy from one of these lesions was described as fibrous tissue but not fibromatosis. It was suggested that it could be a Gardner fibroma. The patient reported some pain in her hip and back. She had been diagnosed with desmoid type fibromatosis as a child following removal of several subcutaneous soft tissue tumours and epidermoid cysts. The initial tumour was detected when she was 2 months old. Three tumours were removed during her first year and nine tumours were subsequently removed before she turned three. Neurofibromatosis was considered as a differential diagnosis but as she did not have any café-au-lait spots, this diagnosis was excluded. Over the years she had several small lesions removed. Biopsies revealed epidermoid cysts and fibromatous tissue. Based on her medical history, FAP was suggested and upper and lower endoscopic examinations were performed. Some fifty adenomas were detected throughout her colon but predominantly in the distal part. Biopsies showed low-grade dysplasia. In her stomach, 50–70 fundic gland polyps and some adenomas were detected and one adenoma with low-grade dysplasia was detected in the duodenum. Phenotypically she had a mild colon polyposis. There was no history of fibromatosis, polyps or CRC in her close family. She was referred to genetic counselling and testing. Germline testing of the APC gene was initially performed utilizing Sanger sequencing and Multiplex Ligation-dependent Probe Amplification Analysis. Sanger sequencing of leukocyte DNA from peripheral blood indicated presence of a pathogenic mutation, c.4348C > T (p.Arg1450*), in the APC gene. The signal representing the mutation was very weak, indicating somatic mosaicism. DNA was extracted from normal colonic mucosa and from adenoma tissue. Sanger sequencing revealed significantly higher levels of the mutation in these tissues compared to the blood sample (Fig. ). After the initial investigation we were able to perform next generation sequencing (NGS) of a cancer gene panel library (Illumina TruSight cancer Sequencing panel). This showed that the frequency of the mutation varied among different tissue types, and hence confirmed somatic mosaicism of the APC mutation in the patient. Her parents and siblings were tested but did not have the mutation, consistent with a de novo origin of the mutation. The mutation in this patient affected codon 1450, a site of the APC gene associated with classical polyposis and desmoid development. Based on her high risk of CRC, prophylactic proctocolectomy was recommended, and she underwent laparoscopic proctocolectomy with an ileal pouch and ileoanal anastomosis without diverting ileostomy. She has been followed with regular endoscopic examinations of the ileal pouch and oesophagogastroduodenoscopy is performed every 6 months due to duodenal adenomas. Abdominal MRI 9 months post surgery was unremarkable. A year later, less than 2 years after surgery, she presented with three desmoids. Two were located in the abdominal wall (laparoscopy port site and Pfannenstiel incision) and the third intra-abdominally in the mesentery. MRI 6 and 9 months later showed desmoid progression. However, due to the risk of triggering a more aggressive course of the disease and the unlikeliness of a radical excision, a “wait and see” approach was adopted. MRI, taken almost 3 years after surgery, showed that the desmoids had remained stable. However, since then, the latest MRI has shown that the lesions have grown.
pmc-6182784-1	An 83-year-old Greek woman, without any prior significant medical history, referred to the outpatient department of the 2nd Department of Ophthalmology of the Medical School of Athens, complaining for visual deterioration at her left eye (OS). At presentation she underwent a complete ophthalmological examination. Best corrected visual acuity (BCVA) was 10/10 in her right eye (OD) and 2/10 in OS. Slit lamp examination did not identify any abnormalities in the anterior segments in both eyes. Her intraocular pressure was normal bilaterally. Funduscopy and fundus photography revealed an unremarkable retina in OD. However, in OS a dark brown lesion, with “fuzzy” borders was identified, which covered partially the optic nerve head and extended temporal into the adjacent choroid and retina (Fig. ). Furthermore, hard exudates were observed temporal to the aforementioned pigmented lesion. Fluorescein angiography (FA) (Fig. ) and ICGA (Fig. ) showed diffuse blocked hypofluerescence in all phases in the area covered by the pigmented lesion, with diffuse hyperfluorescence at the temporal rim of the lesion. As well, ICGA detected 3 hyperfluorescent polypoidal lesions arising from the choroidal circulation (Fig. ). The pigmented lesion was shown in optical coherence tomography (OCT) (SPECTRALIS, Heidelberg Engineering, Heidelberg, Germany) as a gradually sloped nodular elevation, with hyperreflective anterior surface and dense posterior shadowing. OCT also revealed subretinal fluid, RPE detachment, and a round protrusion attached beneath the posterior surface of the detached RPE, at the site corresponding to polypoidal lesions in ICGA (Figs. and ). A diagnosis of PCV associated with ODMC was made. The treatment strategy included a session of verteporfin photodynamic therapy (PDT) in combination with 3 monthly intravitreal aflibercept injections. PDT was performed according to the standard TAP guidelines []. Fifteen minutes after the infusion of verteporfin (dose of 6 mg/m2 body surface area), its irradiation was performed using an ocular photoactivation diode and a laser-linked slit lamp. The treatment spot diameter, based on the ICGA findings, was approximately 1500 μm (Fig. ) and it was targeted against the polyps and not the surrounding branching vascular network. The intravitreal injections of 2.0 mg aflibercept (Eylea, Bayer Healthcare, Germany), were performed under standard sterile conditions, while topical antibiotics were applied 4 times per day for 2 days after the injection. PDT session was performed 7 days after the first intravitreal aflibercept injection. One and two months later, the several injections were applied. Three months after the treatment initiation, significant improvement was observed. Patient’s new BCVA was 5/10, while ICGA demonstrated total polyp regression (Fig. ). In OCT RPE detachment was present, whereas subretinal fluid was not evident (Fig. ). Thirteen months since the beginning of the treatment, the patient was re-examined. ODMC remained stable, her BCVA rose to 7/10, no polyps were detected, while total resolution of RPE detachment was achieved (Fig. ).
pmc-6182787-1	A 15-year-old Japanese boy with no medical history presented to our hospital with a chief complaint of decreased vision in his right eye for the past 6 months. At the initial examination, the best corrected visual acuity (BCVA) was 20/100 for the right eye and 20/16 for the left eye. No abnormalities were observed in intraocular pressure or in the anterior ocular segment findings. A fundus examination of the right eye revealed exudative retinal detachment with subretinal haemorrhage and orange-red lesion (arrow, Fig. ) from the upper intermediate periphery to the posterior pole (Fig. ). Fluorescein angiography (Heidelberg Retina Angiography; Heidelberg Engineering, Heidelberg, Germany) revealed fluorescence leakage from the orange-red lesion (arrows, Fig. ). Abnormal telangiectatic vessels and microaneurysms were found at the nasal peripheral retina (arrowheads, Fig. ). Using B-mode ultrasonography, we observed elevation of the retina due to the haemorrhagic exudative retinal detachment, but no features of solid tumour, such as acoustic shadow, were present (arrow, Fig. ). The fundus of the left eye had no abnormal findings. No special findings were observed in the whole-body examination. Based on these findings, we diagnosed the case as Stage 3A Coats disease. With the approval of the ethics committee of Okayama University Hospital, we treated the right eye with PDT. Before performing PDT, we explained the risks and benefits of the treatment to the patient and his parents and obtained written informed consent. PDT was performed according to the standard protocol treatment regimen [–]. Briefly, 6 mg/m2 of verteporfin (Visdyne, Novartis Ophthalmics AG, Basel, Switzerland) was administered intravenously, and 15 min later a 689 nm laser (Visulas 690S; Carl Zeiss Meditec Inc) was used to irradiate the haemorrhage for 83 s. The irradiation area had a diameter of 7200 μm, which was large enough to cover the entire subretinal haemorrhage. Exudative retinal detachment was noted before PDT (Fig. and ). At 1 month after treatment, the exudative changes had partially regressed (Fig. and ). Although the subfoveal fluid had disappeared at 1 month after treatment, the ellipsoid zone (Ez) was discontinuous and BCVA was 20/200 (Fig. ). At 10 months after PDT, both the subretinal haemorrhage and the exudative retinal detachment had disappeared completely (Fig. ). Furthermore, the Ez was partially recovered (arrows, Fig. ) and BCVA had improved to 20/20.
pmc-6182792-1	A 78-year-old (height 163.3 cm, weight 61.3 kg) Japanese man was admitted to our intensive care unit (ICU) after esophagectomy with gastric reconstruction for esophageal cancer. His body temperature was 36.9 °C and heart rate was 96 beats/minute. His blood pressure was 148/68 mmHg on ICU admission. Physical and neurological examinations were not significant. His past medical history included appendectomy (8 years of age) and lumber canal stenosis (70 years of age). He did not smoke cigarettes but drank Japanese alcohol (360 ml/day). Regarding family history, his elder brother died of esophageal cancer. On ICU day 5, he developed new onset fever up to 38.0 °C, increase in sputum, and hypoxemia with 90% arterial oxygen saturation by pulse oximetry (SpO2) with mask oxygen at 10 L/minute with bilateral pulmonary coarse crackles. Therefore, he was intubated. A chest X-ray revealed diffuse bilateral pulmonary infiltrates predominantly in his right lung with pleural effusion (Fig. ). Laboratory findings revealed white blood cell count 5.7 × 109/L, red blood cell count 2.25 × 1012/L, hemoglobin 7.3 g/dL, hematocrit 21.4%, platelet 145 × 109/L, aspartate aminotransferase 54 U/L, alanine aminotransferase 55 U/L, total bilirubin 4.11 mg/dL, albumin 2.2 g/dL, urea nitrogen 38 mg/dL, creatinine 0.83 mg/dL, C-reactive protein 18.7 mg/dL, and urinary creatinine 95 mg/dL after intubation. Because sputum culture revealed Streptococcus pneumoniae on ICU day 7, the antibiotic was changed from cefmetazole to meropenem. He underwent a long period of mechanical ventilation, ultimately undergoing tracheostomy on ICU day 38. Although his oxygenation was good with partial pressure of arterial oxygen/fraction of inspired oxygen (PaO2/FIO2) > 300 mmHg, restrictive pulmonary dysfunction developed: tidal volume 230–240 mL, static compliance 14–15 mL/cmH2O with 10 cmH2O pressure support ventilation, respiratory rate 34 beats/minute, and partial pressure of arterial carbon dioxide (PaCO2) 46 mmHg. We tried to wean him from mechanical ventilation with support by HFT setting the flow at 40 L/minute with FIO2 of 0.25 because the maximum inspiratory flow of the ventilator was 40 L/minute during 10 cmH2O pressure support ventilation. By setting the flow at the same rate as the ventilator, we hoped to reduce his inspiratory effort. HFT was used in the daytime, and a ventilator with 5 cmH2O pressure support with 5 cmH2O positive end-expiratory pressure (PEEP) was used at night for the first 8 days. In the next 8 days, HFT was used around the clock. Table presents the respiratory parameters during HFT. Under respiratory support with HFT, his condition was stable, and his physiotherapy rehabilitation continued uneventfully. The HFT optimally delivered humidified gas, which improved the thinning of his bronchial secretions. He was discharged from the ICU to the general ward on ICU day 127. His physiotherapy rehabilitation continued for 2 months, and he was transferred to a rehabilitation hospital on day 201 of hospitalization.
pmc-6182792-2	A 69-year-old (height 160.0 cm, weight 37.1 kg) Japanese man was admitted to our ICU from the emergency room due to severe dyspnea. His past medical history included extracorporeal shock wave lithotripsy due to urinary calculus (56 years of age), endoscopic colon polypectomy because of colon polyps (66 years of age), and esophagectomy with gastric reconstruction for esophageal cancer after a stint of preoperative chemoradiation therapy (66 years of age). He smoked 30 cigarettes/day for 40 years and drank whisky (1 bottle/4 days). He was not on any medication. Regarding family history, his grandmother died of liver cancer. On physical examination, he was confused and restless, and his breathing was shallow with reduced air entry to both lungs. A neurological examination was not significant. His vital signs were as follows: heart rate 122 beats/minute, blood pressure 80/58 mmHg, respiratory rate 26 breaths/minute, and temperature 38.7 °C. Arterial blood gases exhibited respiratory acidosis: pH 7.21, PaCO2 117 mmHg, PaO2 76 mmHg, and bicarbonate ion (HCO3−) 45.9 mmol/L with mask oxygen at 6 L/minute. Even bag-valve-mask ventilation could not provide proper ventilation. He was immediately intubated, and numerous food particles, such as beans and rice, were aspirated from his trachea. Therefore, we removed these food particles by bronchoscope as soon as possible. A chest X-ray revealed diffuse bilateral pulmonary infiltrates (Fig. ). He was diagnosed as having aspiration pneumonia and placed on mechanical ventilation. Laboratory findings revealed white blood cell count 0.9 × 109/L, red blood cell count 4.66 × 1012/L, hemoglobin 12.1 g/dL, hematocrit 41.0%, platelet 297 × 109/L, aspartate aminotransferase 17 U/L, alanine aminotransferase 7 U/L, total bilirubin 0.59 mg/dL, albumin 2.2 g/dL, urea nitrogen 26 mg/dL, creatinine 0.75 mg/dL, and C-reactive protein 1.7 mg/dL on ICU admission. He underwent tracheostomy on ICU day 32 due to prolonged mechanical ventilation. Although his oxygenation was good (PaO2/FIO2 > 300 mmHg), he had restrictive pulmonary dysfunction: tidal volume 210–220 mL, static compliance 16–17 mL/cmH2O with 10 cmH2O pressure support ventilation, respiratory rate 30 beats/minute and PaCO2 46 mmHg. We tried to wean him from mechanical ventilation with support by HFT (flow at 40 L/minute with FIO2 of 0.25). Table presents the respiratory parameters over the 4-day period HFT was administered. On HFT day 4, his arterial blood gases were pH 7.41, PaCO2 58 mmHg, PaO2 68 mmHg, and HCO3− 35.7 mmol/L. Judging his condition as satisfactory, we switched from HFT to a 3 L/minute oxygen T-piece. One hour after the T-piece was commenced, he complained of dyspnea and his arterial blood gases moderately worsened (pH 7.34, PaCO2 72 mmHg, PaO2 106 mmHg, and HCO3− 37.3 mmol/L). At that time, his tidal volume was 200 mL. We decided to switch back to HFT (flow at 40 L/minute with FIO2 of 0.25), and his arterial blood gases improved 1 hour later: pH 7.40, PaCO2 60 mmHg, PaO2 71 mmHg, and HCO3− 35.9 mmol/L. On HFT day 5, his PaCO2 increased to 70 mmHg. This condition suggested respiratory muscle fatigue; however, no complaints of dyspnea were noted. We decided to apply the HFT at daytime and switch to a ventilator (10 cmH2O pressure support with 5 cmH2O PEEP) at night, and the treatment regimen was continued accordingly for the next 8 days. We evaluated tracheal pressure during HFT using a flow analyzer (CITREX®, TOKIBO, Co. Ltd, Tokyo, Japan) to measure airway pressure and at the entrance of the tracheostomy tube. The measured values were as follows: 0.21– 0.3 cmH2O, 0.21–0.56 cmH2O, 0.54–0.91 cmH2O, 0.76–2.01 cmH2O, 1.17–2.01 cmH2O, and 1.76–2.01 cmH2O at 10 L/minute, 20 L/minute, 30 L/minute, 40 L/minute, 50 L/minute, and 60 L/minute, respectively. The airway pressure was continuously positive and did not become negative even during inspiration. These results suggest that HFT reduces inspiratory effort. Under respiratory support with HFT and physiotherapy rehabilitation, our patient was successfully weaned from the ventilator. He was discharged from the ICU to the general ward on ICU day 51. His physiotherapy rehabilitation continued for 1 month. He was discharged to home on day 86 of hospitalization and returned for a follow-up visit.
pmc-6182834-1	A 56-year-old male with early satiety for 2 mouths was admitted to our hospital. There was no history of weight loss, without relevant past and family history. An 1825 cm oval tumor with medium texture was palpable below the left costal margin during the physical examination. The routine biochemical and hematogical parameters were within normal limits, and tumour markers including CA-125, carcinoembryonic antigen (CEA) and CA19–9 levels were nothing special. Upper gastrointestinal endoscopy (GI) revealed a tumor arising from the greater curvature of gastric body and extending into the lumen (Fig. ). Contrast enhanced CT scans of the abdomen showed a marked enhancement of polypoid mass protruding into the gastric lumen, a large poorly enhancing oval mass in the left abdomen and a heterogeneous round-like tumor adjacent to the left psoas (Fig. ). Axial plain CT revealed the intro-abdominal tumor with CT values ranging from − 78 HU (consistent with fatty tissue) to 27 HU (related to the pancreas), with a mean CT value as 2 HU. However, the retroperitoneal tumor had CT values ranging from − 57 HU (consistent with fatty tissue) to 18 HU (related to the blood), with a mean CT value as 10 HU. The patient was diagnosed with coexistence of a gastric GIST, intro-abdominal and retroperitoneal tumors preoperatively. A surgical operation was performed. Intraoperatively, a huge oval lobulated oozing soft mass (about 18.025.015.0 cm) originating from the descending colon mesentery was identified. A tumor (about 2.52.02.0 cm) at the greater curvature of gastric body and a tumor (about 5.04.0*2.5 cm) close to the left psoas were detected. Adjacent to the anterior wall of the abdominal aorta, the intro-abdominal tumor was surrounded by the small bowel and left hemicolon. The round-like lobulated retroperitoneal tumor was found among the left psoas, left iliac vessels, sigmoid colon and intro-abdominal tumor. The tumors were well-circumscribed from the surrounding organs and without signs of infiltrating tumor growth. Furthermore, the tumors were not related to the adjacent major vessels, without the detection of distant metastasis or nodal involvement. Wedge resection for gastric tumor, complete resection for intro-abdominal and retroperitoneal tumors were performed. In histopathological examination, the intro-abdominal tumor was a myxoid liposarcoma and the retroperitoneal mass shared the same pathological type with the tumor (Fig. ). Further histopathological examination of the gastric carcinoma indicated a GIST of the low-risk category (mitotic index < 5 mitoses/50 high-power fields) (Fig. ). Immunohistochemistry displayed strong staining for c-Kit/CD117, Dog-1 and CD34, while expression of SMA and Desmin was negative (Fig. ). Furthermore, mutations in KIT exons and PDGFRA exons were evaluated in the sample, but, nothing special was found. Nested reverse transcription-polymeras-ase chain reaction (RT-PCR) technique was employed to detect the FUS-CHOP mRNA expression in the formalin-fixed paraffin-embedded lipsarcoma samples. Type II FUS-CHOP mRNA was successfully detected in the retroperitoneal liposarcoma (Fig. ). The postoperative course was uneventful. Adjuvant radiotherapy was targeted to the former liposarcoma bed: Dosage in total, 50 Gy; single dose, 1.6 Gy. The patient received CT scans twice a year, displaying no evidence of tumor recurrence in a follow up period of 15 months.
pmc-6182885-1	A 33-year-old woman sought dental assistance and presented multiple unilateral lesions distributed throughout the oral mucosa, retro commissural region, inserted gingiva lateral borders of the tongue on the right side (Figs. -) and desquamative gingivitis located in the inserted gingiva. The asymptomatic lesions showed an atrophic leuco-erythroblastic reticular aspect, with an ulcerated surface. Teeth 17, 15, 14 and 48 had extensive amalgam restorations two years prior, in close contact with the injured areas. During the anamnesis, she reported having been submitted to periodontal therapy. The main complaint motivating her search for professional assistance was halitosis associated with spontaneous gingival bleeding. Periodontal examination was carried out with a periodontal probe (PCPUNC15, Hu-Friedy, Chicago, IL, USA) and the measure of probing depth was registered, as well as the presence of bleeding during the probing step (MÜHLEMANN; SON, 1971) and the plaque index (O’LARY; DRAKE; NAYLOR, 1972). The gingival depth ranged from 1 to 7 mm; however, in the region affected by the gingival desquamation, the depths ranged from 2 to 6 mm. The bleeding index during probing was 91.3%, and the plaque index was 74%. With such results, the patient was diagnosed with generalized periodontitis. The patient’s medical history did not reveal any systemic alterations, such as hypertension, diabetes or any autoimmune diseases, nor did she mention the use of any medication. Blood analysis did not reveal any alterations. A perilesional biopsy was then carried out using hematoxylin-eosin staining. The oral mucosa fragment was covered by focal acantholytic, atrophic and parakeratinized squamous epithelium. The connective tissue showed chronic subepithelial and deep inflammatory infiltrate, predominantly composed of lymphocytes and plasmocytes, with the formation of lymphoid follicles and subepithelial cleft, compatible with oral lichenoid reaction (Figs. -). The histological section of the gingiva also revealed chronically inflamed connective tissue and subepithelial cleft (Figs. -) A provisional diagnosis of OLL-DA was initially taken. The patch test reading confirmed allergy to thimerosal, a compound of mercury metal. Therefore, all the metallic restorations were removed in one single appointment. Afterwards, basic periodontal therapy was accomplished in four consecutive weekly appointments, with scaling and root debridement, structured plaque control, dental brushing and interdental cleaning instructions. The follow-up period ranged from three (Figs. & ) to six (Figs. & ) months, during which time the desquamative gingivitis was reduced. However, the leucoplast lesions located on the retro commissural area and tongue were unchanged. A new perilesional biopsy for the direct immunofluorescence test was conducted in order to exclude other diagnostic hypotheses. The results in question showed non-specific focal granular deposits of IgM 2+ (on a scale of 1+ to 3+) in the basement membrane zone of the epidermis (Figs. & ). The findings were compatible with Lichenoid Stomatitis. After clinical-pathological correlation, the diagnosis of idiopathic oral lichenoid lesion was finally established. Nine months after the removal of all the amalgam restorations, remission of the desquamative gingivitis (Fig. ) and disappearance of reddish-white plaques, as well as the ulcerated surface of the oral mucosa were observed. Nevertheless, the reticular leucoplast and retro commissural region lesions persisted (Fig. ).
pmc-6182913-1	A 57-year-old female complaining of masticatory and functional problems was referred by her orthodontist to the Department of Oral and Maxillofacial Surgery, Aalborg University Hospital, Denmark, for surgical correction of a skeletal Angle Class I relation with a dental Class II malocclusion due to the lack of orthodontic treatment effect. The patient had begun an orthodontic treatment a year ago. The patient´s medical history was unremarkable. Clinical examination demonstrated a lower anterior facial height with the lower lip placed behind the Rickett's E-line and a deep labiomental fold (Fig. ). Intra-oral examination revealed an exaggerated curve of Spee with an overjet and overbite of 8 mm and 7 mm, respectively. Minor buccal gingival recessions without probing pocket depths were observed around the mandibular incisors (Fig. ). Radiographically, orthopantomogram and lateral cephalogram revealed mandibular dental retrusion in combination with a deep bite and a prominent chin (Fig. ). The treatment approach plan including AMSDO to create space for tooth alignment and later placement of dental implants was presented to the patient and accepted. Preoperative orthodontic treatment involved fixed orthodontic appliances to increase the inter-root space between the canines and first molars for the planned vertical osteotomies. A rigid custom-made distraction device was fabricated (Fig. ). The distraction device consisted of an anterior segment and the posterior distraction segment. The distraction device was fixed in tubes on to the buccal surfaces of the molar bands and the expansion screws were positioned parallel to the occlusal plane of the lower arch. The surgical procedure was performed in general anaesthesia with nasotracheal intubation, supplemented by local anaesthesia. An intraoral vestibular incision was made from the right mandibular first premolar to the mandibular left first premolar. The mucoperiosteum was reflected, exposing the mandibular symphyses and mental foramens. Two horizontal osteotomies were made with piezoelectric surgery from the right canine to the left canine, at least 5 mm below the dental apices. Vertical osteotomies were made with piezoelectric surgery between the two horizontal osteotomies and a bone block of approximately 4.0 x 1.0 cm was removed with care to maintain the lingual periosteum and mucosa intact. Then, incomplete vertical osteotomies were performed with piezoelectric through the outer cortex between the canines and first premolars without detaching the dental papillae from the alveolar bone. The osteotomies were completed with a fine chisel until the anterior dentated segment could be mobilized without any bony resistance. The dentated anterior segment was repositioned in a more caudal position to level the dental arch. Two T-plate 9 mm bone anchors (Orthodontic Skeletal Anchorage System, Stryker Craniomaxillofacial, USA) were contoured to the outer cortex of the tooth-bearing segment and fixed with 5 mm monocortical screws (Fig. ). The bone anchors were ligated to the distraction device with wires and tested to ensure that the tooth-bearing segment was moving in a parallel direction without resistance (Fig. ). The distraction device was activated until a 1 mm diastema was achieved between the canines and the first premolars. The wound was irrigated with saline and the mucosa was re-adapted and sutured with resorbable sutures (Vicryl 3-0, Ethicon, Norderstedt, Germany). The patient was discharged later the same day. Postoperative x-rays disclosed satisfying osteotomies and placement of bone anchors (Fig. ). The postoperative period and healing was uneventful. After a latent period of 5 to 7 days, the patient was instructed to activate the distraction device by 0.33 mm three times a day until the planned expansion was achieved. After the distraction phase was completed, a temporary composite tooth was bonded to the canines and first premolars, and the segment was retained by the distraction device for 6 months to allow callus ossification and stabilization of the tooth-bearing segment. Orthodontic treatment was continued to finalize the occlusion and preparing the interdental distance between the mandibular canines and the premolars for a later implant placement. The bone anchors were surgically removed after six months. Two dental implants (NobelActive NP 3.5 X 11.5 mm, Nobel Biocare, Goteborg, Sweden) were inserted without additional bone grafting. A fixed retainer was bonded between the first mandibular premolar and canine. A removable retention was applied to the maxilla. The total treatment period was 20 months (Fig. ).
pmc-6183218-1	A 38-year-old female who had undergone right mastectomy for breast carcinoma was referred to our department for evaluation of the multiple liver masses detected on routine follow-up examinations. Sonographic examination of the patient revealed hepatosplenomegaly and multiple heterogeneous hypoechoic masses of varying sizes that were located centrally in the right lobe of the liver and tended to form clusters. Some of the larger lesions had central necrosis and cavitation areas (). We observed hypoechoic curvilinear tracts extending from the liver capsule to the parenchyma, which did not demonstrate abnormal vascularity on colour Doppler ultrasound examination (). The gallbladder had normal wall thickness and endoluminal echogenicity. Contrast-enhanced CT obtained in the portal venous phase revealed multiple, clustered, hypodense nodular liver masses with irregular margins (). In addition, the presence of at least three hypodense curvilinear tracts, extending from the liver capsule to the parenchyma, were confirmed (). The lesions did not demonstrate any contrast enhancement. There were a number of enlarged lymph nodes in the porta hepatis. Ultrasound-guided fine needle aspirations of the selected lesions were performed. Pathological examination of the specimens showed no evidence of malignancy but eosinophil-rich inflammatory necrotic tissue was reported. Blood tests also revealed elevated levels of eosinophils and serological tests confirmed the presence of F. hepatica infestation. The patient was discharged after a course of triclabendazole treatment. A follow-up CT scan, obtained 2 years after her first admission, showed slight regression in the size of all the liver lesions ( and and there were no new lesions.
pmc-6183323-1	A 20-year-old man complained of exertional dyspnea for two months, cough and asthenia. He had no fever, chest pain or lower limb edema. Past medical history, physical examination and lab results were unremarkable. Cardiac ultrasound showed an abundant compressive pericardial effusion and a “mediastinal mass” that was present on the topographic scan of the chest computed tomography (CT) as a mediastinal widening (Figure ). The contrast-enhanced chest CT itself comprehensively displayed the pericardial effusion and the diffusely hypodense infiltration of the mediastinum extending to hila (Figure ). There was diffuse thickening of the lung interstitium and patchy ground glass opacities (Figure ). A thoracoscopy with pleuro-pericardial window and biopsy was performed and led to the diagnosis of pulmonary lymphangiomatosis. The patient’s symptoms subsided after this surgery followed by multiple pleural punctures. An immunosuppressive treatment with Sirolimus (Rapamicyn) was initiated, and the patient has now had good clinical and radiological evolution for four years.
pmc-6183326-1	A 54-year-old woman was admitted to our hospital for stress incontinence, overactive bladder and the feeling of prolapse. There was no relevant medical history. Physical examination revealed no clinical signs of prolapse. Urologic ultrasound was performed and showed a fluid-filled tubular enlargement beneath the bladder. MRI colpocystodefecography showed an intrapelvic fusiform enlargement (ureterocele), hyper-intense on T2-weighted MR images (Figure and ). Computed tomography of the abdomen with intravenous contrast demonstrated a duplicated collecting system on the left side with proximal implantation on the renal upper pole, ureterocele and distal ectopic ureteral insertion on the proximal third of the vagina (Figure ). Due to the hydronephrosis there was secondary parenchymal loss on the upper pole of the left kidney (Figure ). The contralateral kidney and ureter were normal.
pmc-6185874-1	A 75-year-old woman was admitted to our hospital for the treatment of recurrent HCC located in segment 2 of the liver (S2). The patient had been diagnosed with hepatitis B virus-related liver cirrhosis 17 years earlier and with HCC (S2 and S7) 8 years earlier. Since then, RFA (percutaneous [four times] and laparoscopic [two times]) and transcatheter arterial chemoembolization (TACE; seven times) had been performed repeatedly for HCC. During laparoscopic RFA for recurrent S2 HCC, the left lateral lobe of the liver was mobilized. For recurrent HCC located in S2 of the liver, TACE was repeatedly performed; however, the therapeutic response was insufficient, and the patient was referred for further treatment. Abdominal enhanced computed tomography (CT) showed a 1.5-cm mass in the left lateral lobe of the liver (S2) with arterial phase enhancement followed by washout in the portal phase (Fig. , ). A laboratory analysis provided the following results: serum levels of α-fetoprotein (AFP), 124.9 ng/mL; des-γ-carboxy prothrombin (DCP), 29 mAU/mL; platelet count, 106 × 103/μL; serum aspartate aminotransferase, 39 U/L; alanine aminotransferase, 15 U/L; total bilirubin, 1.2 mg/dL; albumin, 3.6 g/dL; and prothrombin time, 13.6 s. The indocyanine green retention rate at 15 min (ICG-R15) was 30.7%, and the ratio of the 99mTc-galactosyl human serum albumin (GSA) scintigraphy taken up by the liver to that taken up by the liver plus heart at 15 min (LHL 15) was 0.86. The Child-Pugh score was Grade A, and liver damage, as defined by the Liver Cancer Study Group of Japan [], was Grade B. Given that the liver function was severely impaired and the patient had already undergone RFA and TACE several times, we decided to perform RFA, not liver resection, for the treatment of this TACE-refractory small HCC. Because the tumor was adjacent to the heart (Fig. c), percutaneous RFA was considered to carry a high risk, laparoscopic RFA was selected. The left lateral lobe of the liver had adhered severely to the diaphragm, stomach, and lesser omentum due to mobilization of this portion during a previous session of laparoscopic RFA (Fig. a). We peeled away those adhesions and observed the S2 HCC tumor just below the heart (Fig. b). To avoid thermal injury of the stomach and heart, we first mobilized the left lateral lobe and made space between the tumor and the heart. We then placed gauze and some water between the stomach and left lateral lobe of the liver to prevent thermal injury of the neighboring organs. After observation of the tumor and liver parenchyma using a laparoscopic ultrasonography (US), we inserted a 2-cm cooled-tip needle (Radionics, Burlington, MA, USA) vertically into the liver to prevent heart injury under visual guidance, as the tumor was detected on the surface of the liver (Fig. , ). After the insertion of the electrode into the lesion, we confirmed the position of the needle by US and started ablation, increasing the power to 60 W and then 100 W. The duration of the ablation (at 100 W) was 8–10 min, and the temperature was closely monitored. During the procedure, there were no major complications. At 1 week after the treatment, the patient complained of dysphagia and thoracic pain. Upper gastrointestinal endoscopy revealed a perforated esophageal ulcer at the esophago-gastric junction, and the liver could be directly seen through the perforated ulcer (Fig. ). Contrast-enhanced CT revealed localized free air between the left lateral lobe of the liver and the esophagus (Fig. ). Laboratory data revealed no exacerbation of the inflammatory response, such as via an elevated white blood cell or neutrophilic leukocyte count or C-reactive protein levels. Because inflammation was localized due to the severe intra-abdominal adhesion, we decided to treat the patient conservatively with fasting, administration of proton pump inhibitors and antibiotics, and enteral nutrition via a nasogastric tube. The perforated region of the esophagus gradually scarred over, and exacerbation was not observed after the initiation of oral intake. After discharge from our hospital, the patient complained of difficulty swallowing, and upper gastrointestinal endoscopy revealed esophageal stenosis. Although the patient later required balloon dilatation to treat the esophageal stenosis, the perforation was cured conservatively (Fig. ), and there has been no evidence of HCC recurrence.
pmc-6185941-1	Patient 5 (P5, Fig. ), a five-year-old boy of Central European ancestry, presented with congenital microcephaly that progressed into severe postnatal microcephaly. He showed multiple minor facial anomalies (Fig. ; straight eyebrows, telecanthus, bilateral epicantic folds, broad nasal tip and thin upper lip vermilion) and had significant delays in speech development, which progressed with combined speech and physical therapy. This patient also displayed hematological anomalies including leukocytosis with increased eosinophil count, monocytosis, and thrombocytopenia. However, he did not have a history of recurrent infections or spontaneous bleedings. P5 had platelet anisotropy with enlarged platelets (Fig. ), an elevated fraction of immature platelets in the peripheral blood (Supplementary Data ) and bone marrow examination showed increased MK count (Supplementary Fig. ). Whole exome sequencing revealed a de novo in frame deletion in the last exon of ACTB, c. 1012_1023del (Supplementary Data ), which results in the deletion of resides 338–341 within SD1 of β-CYA (Fig. right, Supplementary Fig. ).
pmc-6185941-2	Patient 6 (P6, Fig. ), a five-year-old girl of Western European origin, presented with early developmental delay, microcephaly and a history of recurrent thrombocytopenia during the first year of life, which normalized spontaneously. She made good developmental progress following intensive combined therapies, achieving a low normal IQ at 5 years of age. Brain MRI demonstrated two unilateral periventricular nodular heterotopias with otherwise normal brain morphology. No seizures were documented at the last follow up. Whole exome sequencing revealed a de novo insertion in the last exon of ACTB, c.1101dup (Supplementary Data ), resulting in the substitution of 8 amino acids and addition of 4 residues at the far C-terminus of β-CYA (Fig. right, Supplementary Fig. ). Common features amongst this cohort of patients with 3′ ACTB variants include developmental delay, mild intellectual disability, microcephaly, and thrombocytopenia with platelet anisotropy and enlarged platelets (Fig. ). Given the distinct genotype–phenotype correlation, we name this actinopathy ACTB-associated syndromic thrombocytopenia (ACTB-AST).
pmc-6186031-1	A 51-year-old male presented with a 3 year history of a mass in his right foot with recent enlargement associated with pain. Imaging revealed a soft tissue mass in the plantar arch of the right foot anterior to the calcaneus deep to the fascia. Staging imaging showed no evidence of metastatic disease. The mass was excised. Histologic sections revealed a cellular tumor with scattered ectatic and hyalinized vessels composed of spindle-shaped cells (Fig. ) focally arranged in intersecting fascicles admixed with islands of epithelioid cells (Fig. ). The spindle cells have vesicular nuclei of variable shape and contour and indistinct cytoplasmic borders with occasional mitoses (Fig. ). The epithelioid cells have round to ovoid nuclei with occasional bi-nucleation, and ample eosinophilic cytoplasm, some with focal vacuolation, with distinct cytoplasmic borders (Fig. ). No significant necrosis was observed. Immunohistochemical analysis was performed and showed tumor cells positive for S100 (Fig. ), specifically the spindle cells were strongly positive while the epithelioid cells were weakly positive. Tumor cells were also positive for TFE3 and vimentin. Immunostains were negative for desmin, MSA, AE1/3, A103, SOX10, MelanA, HMB45, MITF, Tyrosinase and BRAF. S100 positive, SOX10 negative spindle cell malignancy is a broad pathologic differential. This pattern is observed commonly in a number sarcoma subtypes including synovial sarcoma, Ewing sarcoma, rhabdomyosarcoma, and extraskeletal myxoid chondrosarcoma []. S100 positivity is also common in ossifying fibromyxoid tumors, though is typically negative in the malignant cases []. SOX10 negative melanoma, clear cell sarcoma, and malignant peripheral nerve sheath tumor (MPNST) are also diagnostic possibilities. We therefore performed additional molecular profiling studies. There was retained nuclear staining of INI-1 and H3K27m3 by immunohistochemistry. Molecular testing performed and interpreted at University of Nebraska, Omaha NE reported the tumor as negative for fusion of the EWSR1 (22q12) and ATF1 (12q13) loci, negative for rearrangement of the TFE3 (Xp11) locus, and negative for fusion of the EWSR1 (22q12) and CREB1 (2q33.3) loci. Additionally, no SS18/SSX1 or SS18/SSX2 fusion transcript was detected by RT-DNA amplification. Given the lack of a more specific molecular finding, the malignant S100-positive tumor was therefore favored to be a soft tissue sarcoma that could not be further subtyped, though could not rule out either a spindle cell melanoma or a fusion-negative clear cell sarcoma. Given the uncertainty in diagnosis, reference laboratory molecular tumor profiling was performed to identify additional molecular alterations and to potentially aid in patient management. Hybrid capture-based comprehensive next-generation sequencing (Foundation Medicine Inc., Cambridge, MA) revealed a fusion between MTAP exons 1–7 and RAF1 exons 8–17 (Fig. ). Presence of the fusion was supported by both DNA evidence (150 supporting read pairs) and RNA evidence (437 supporting read pairs). The fusion product disrupts MTAP (S-methyl-5′-thioadenosine phosphorylase) activity but conserves the RAF1 tyrosine kinase domain with loss of the autoinhibitory N-terminal domain []. Loss of MTAP, which functions as a tumor suppressor and is vital for methionine salvage, has been observed in a spectrum of cancers including melanoma and sarcoma [, ]. Next-generation sequencing (NGS) also reported a low tumor mutation burden of two mutations per megabase and lack of an ultraviolet (UV)-signature as measured by C → T mutations at dipyrimidine sites. Taken in whole, the clinicopathologic and genomic feature of the case including location and size of the mass (deep soft tissue without cutaneous involvement), immunohistochemistry findings, low mutation burden, and lack of a UV-signature ruled against the possibility of this being a melanoma variant. Therefore a fusion-positive soft tissue sarcoma, not otherwise specified, was the final diagnosis.
pmc-6186080-1	A 33-year-old man visited an outpatient clinic with haematuria and proteinuria. One year later, the patient was diagnosed with IgA nephropathy by a renal biopsy and was treated with diet and medication. At 36 years of age, his began to experience fatigue and weight loss. He was had generalized lymphadenopathy, hepatosplenomegaly, and elevated CRP levels, and his IL-6 level had gradually increased. Chest CT revealed slight enlargement of the mediastinal lymph nodes, centrilobular nodules, thickening of the bronchovascular bundles, and ground-glass opacities. These clinical findings were consistent with MCD. Hepatitis B, hepatitis C, syphilis, and HIV screening were negative. His renal function gradually declined over the following decade, resulting in ESRD. At 44 years of age, peritoneal dialysis was started for the treatment of ESRD, and an inguinal lymph node biopsy was performed to confirm the diagnosis, revealing the typical features of plasma cell-type MCD. Oral prednisolone (PSL) (10 mg/day) was initially administered; however, none of his clinical or laboratory parameters were fully resolved. At 45 years of age, he was referred to our hospital for further evaluation and treatment including living-donor KTx. To histopathologically determine the primary cause of ESRD (i.e., IgA nephropathy, AA amyloidosis, or other causes) and to make a pathological diagnosis of his interstitial lung disease, renal and lung biopsies, respectively, were performed. Similar to the immunostaining findings of the inguinal lymph nodes, which showed significant deposits of IgA and IL-6 (Fig. ), lung biopsy specimens showed plasma cell proliferation with positive staining for IgA and IL-6 (Fig. ), and renal biopsy specimens showed predominant IgA deposition in the glomerular mesangium (Fig. ). These findings led us to the possible diagnosis of MCD with lung involvement complicated by ESRD associated with IgA nephropathy. Since treatment with oral PSL failed to suppress the disease activity of MCD, the therapeutic regimen was changed to intravenous TCZ (8 mg/kg, every 2 weeks), which successfully controlled his MCD symptoms without the further exacerbation of his lung disease. At 50 years of age, he had recurrent peritonitis and therefore decided to undergo KTx. Preoperatively, tacrolimus (TAC) and mycophenolate mofetil (MMF) were administered starting 5 days before transplantation. TAC was administered at 0.1 mg/kg/day, and the trough level was maintained at 8–12 ng/mL for the first few weeks after transplantation. MMF was administered at a dosage of 1000 mg twice daily. In addition, induction with intravenous methylprednisolone (mPSL; 1 dose of 500 mg) and basiliximab (1 dose of 20 mg) therapy was administered on the day of transplantation. Basiliximab was also administered 4 days after transplantation. mPSL was gradually tapered to 40 mg by the end of the first post-transplantation week and switched to an oral formulation. To prevent over-immunosuppression, TCZ was discontinued after transplantation. However, the extension of the interval between TCZ administrations was associated with a slight increase in the patient’s CRP levels, but his constitutional symptoms did not reappear, and after the repeated administration of TCZ (8 mg/kg, every 2 weeks), improvements in his CRP levels were immediately noted (Fig. ). The patient’s IL-6 levels decreased dramatically after transplantation and are now maintained at 300–500 pg/ml under immunosuppression with a triple-drug regimen (TAC, MMF and mPSL) with TCZ (Fig. ). In addition, the patient experienced increases in albumin, haemoglobin and haematocrit (data not shown), along with normalized CRP and IgG (Fig. ). On post-operative days 20 and 238, a transplant renal biopsy was performed and showed no rejection or virus infection. To evaluate for the presence of anti-HLA antibodies, a single-antigen bead assay (LABScreen Single Antigen) was performed. DSA was negative both before transplantation and on post-operative day 239. At present, 17 months after KTx, the patient remains asymptomatic, and the allograft function has been preserved without evidence of rejection. In addition, haematologic follow-up has not demonstrated any significant adverse effects of TCZ (such as dyslipidaemia or myelosuppression) or cytomegalovirus (CMV) infection events.
pmc-6186087-1	After the incidental sonographic finding of a huge inhomogeneous expansion near the ovarian fossa, a 43-year-old, previously healthy, Austrian woman was referred to our university hospital. She reported a slight performance weakness, but denied any abdominal pain. Her medical history was unremarkable. She was a mother of two children, both by spontaneous vaginal delivery. Her abdominal surgical history included only an open appendectomy in childhood. She had no significant family or psychosocial history. She did not take any medication and denied tobacco smoking and alcohol intake. She was married and worked as a child carer. A clinical examination at the initial presentation showed a well-oriented, apyretic patient. Her vital signs were stable with a blood pressure of 135/70, a pulse rate of 73 beats/minute, and a body temperature of 36.4 °C. In abdominal examination, a poorly displaceable mass in her lower abdomen was palpable. Further physical examination showed no other abnormalities. A neurological examination was unremarkable. Laboratory findings (including complete blood count, liver function, renal function, coagulation status, and C-reactive protein) were within normal ranges, except for a slightly raised level of creatinine (1.02 mg/dL). A performed magnetic resonance imaging (MRI) showed a partially solid tumor within the lesser pelvic region with a size of 11.4 × 8.6 × 11.7 cm that infiltrated her left ureter, which resulted in consecutive urine retention and eventually in third grade hydronephrosis of her left kidney (Fig. ). Then, an explorative laparotomy was applied, in which a conglomerate tumor of unknown primary origin with deteriorating affection of uterus and left adnexa was confirmed, which was adherent to the pelvic wall and musculature of her retroperitoneum (Fig. ). The radiologically detected infiltration of her left ureter and her urinary bladder was also verified intraoperatively. A rapid histopathological incision examination of intraoperatively sampled tumor tissue was prepared, which yielded an uncertain status with assumed leiomyosarcoma. For treatment of the left-sided urinary stasis, a ureteral stent was placed, which postoperatively had to be relocated by nephrostomy. According to interdisciplinary consultation following the stated initial surgery, the tumor had to be classified as inoperable. Extended immunohistological analysis revealed DLBCL of the activated B cell-like (ABC) subtype with an International Prognostic Index (IPI) 1 and tumor cells positive for CD20 and CD79a (Fig. ). A biopsy was conducted followed by histological and cytological investigation; they did not detect any involving affection or infiltration of the bone marrow. Fluorodeoxyglucose-positron emission tomography (FDG-PET) showed bone marrow activation among the central region without significant focal accentuation. In an interdisciplinary tumor board, a therapeutic regime for our patient with a potential curative therapy objective utilizing R-CHOP was determined. After beginning the treatment, an intestinal perforation occurred that induced another surgical intervention. On intraoperative examination, peritonitis as well as massive intraabdominal adhesions in terms of a frozen abdomen could be verified. The small intestine itself was found to be partly necrotic and obviously infiltrated by the lymphoma. The necrotic intestinal parts were resected, but due to massive peritonitis neither creation of ostomy nor enteroanastomosis was feasible. Therefore, a closure of the small intestine was performed and a jejunal probe as well as a percutaneous endoscopic gastrostomy (PEG) tube were installed. Among further exploration, a colon fistula was identified and sewed over. Blood cultures were taken at varying times and were prepared according to the standard procedure. All of these cultures yielded negative results. Chemotherapy was then proceeded with the objective to reduce tumor mass and enable a following reconstruction of the intestinal passage. However, after four cycles of R-CHOP, only a slight tendency toward remission could be achieved, which provided a quite limited treatment effect. Thus, a histological examination of the residual tumor by surgical intervention was recommended by hematologist-oncologists. As her poor general condition did not allow higher doses of chemotherapy, a continuation of the current therapy with R-CHOP was determined, despite only partial remission. After a total of eight cycles of R-CHOP, re-surgery addressing enteroanastomosis to enable self-administered food intake and to improve quality of life as far as possible was performed. Furthermore, according to consensus of the institutional tumor board, another biopsy of the residual tumor and further histopathological analyses were conducted. At the time of the stated intervention, she had been parenterally fed for 8 months already. After this long period, the creation of a re-anastomosis seemed doubtful. Intraoperative findings confirmed a conglomerate tumor imposing deteriorating effects on her jejunum, her sigmoid, her left adnexa, and part of her uterus. Extended inspection of the morphological aspects of the tumor mass on sight and pondering surgical/technical possibilities resulted in the rather unforeseen decision to attempt a resection of the tumor mass as a whole, accompanied by the reconstructive procedures outlined above. Thus, a complete resection of the tumor according to this intraoperative decision by entrainment of the left adnexa and part of her uterus could finally be implemented. A rapid histopathological incision examination confirmed R0 resection (Fig. ). Against the odds, the residual smaller bowel appeared recovered and therefore both a successful end-to-end jejunostomy as well as a descendosigmoidostomy were implied (Fig. ). The recovery period passed uneventfully and shortly after, she could be released from hospital in good condition to out-patient follow-up treatment. A full remission could be determined and close-meshed follow-up inspections were carried out. In these follow-up inspections, no evidence of relapse was found so that at least 7 months of PFS and 7 months overall survival (OS) after R0 resection could be registered. An abdominal sonography without pathological findings was conducted 6 months after the last surgery.
pmc-6186097-1	A 59-year-old black male with type 2 diabetes mellitus progressed to end stage renal failure; he received a kidney from his wife 11 years prior to presentation. He came to the outpatient clinic for routine screening and was asymptomatic. Maintenance immunosuppression therapy included tacrolimus, prednisone, and azathioprine. He was also taking medications for hypertension (atenolol and enalapril), dyslipidemia (atorvastatin), hypothyroidism (levothyroxine), and diabetes (insulin NPH). Surprisingly, he was found to have a blood creatinine level of 7.2 mg/dL and blood urea of 81 mg/dL. His previously blood creatinine levels were 2.0 mg/dL 2 months prior and in the range of 2.0 to 2.5 mg/dL 4 months prior, estimated glomerular filtration rate (GFR) by MDRD (Modification of Diet in Renal Disease Study equation): 39.6 mL/min/1.73 m2). Other laboratory results were as follows: hemoglobin (Hb), 12.0 g/L; sodium (Na), 145 mEq/L; potassium (K), 4.3 mEq/L; uric acid, 10.5 mg/dL; aspartate aminotransferase (AST), 14 U/L; alanine transaminase (ALT), 13 U/L; total calcium, 8.3 mg/dL; bicarbonate, 16.6 mE/L; albumin, 3.4 g/dL. The patient did not smoke or drink alcohol and denied any type of surgery. He also denied recent episodes of diarrhea or antibiotic use. On physical examination, he had a blood pressure of 130/80 mmHg, pulse rate of 68 beats/min, respiratory rate of 16/min, and weight of 54 kg. He had no signs of edema or dehydration. The patient was admitted to the hospital and underwent hemodialysis. A kidney biopsy was performed. Histologic analysis showed cortical and medullary areas with nine glomeruli, one of which was sclerotic, and two arteries. The pathology report of the kidney biopsy was compatible with oxalate nephropathy and severe acute tubular necrosis associated with intense calcium oxalate deposition (Fig. ). There were no signs of rejection and C4d immunohistochemistry was negative. Fibrosis of the interstitium was moderate. Two days after the biopsy, urine sample was collected and centrifuged; calcium oxalate crystals could be seen under polarized light. The patient denied ingestion of products containing ethylene glycol, any other medication such as orlistat, and any other drugs different from what was prescribed to him. However, he reported that in the last month he had been eating 5 cashew pseudofruit (“cashew apple”) every day and drinking a large amount of cashew pseudofruit juice (about 1000 mL) every day instead drinking water. The fruits were picked up from a tree in the patient’s backyard. He did not eat cashew nuts. We could deduce that the patient was ingesting every day, for at least 1 month, approximately 2 to 3 g of ascorbic acid in his diet. This calculation was based on an ascorbic acid concentration of 219.3 mg/100 mL in the pseudofruit. The patient underwent five hemodialysis sessions and was discharged with a creatinine of 3.9 mg/dL and no further requirement for dialysis. Three months after hospital discharge, his creatinine was 3.4 mg/dL (MDRD GFR: 24 mL/min/1.732).
pmc-6186105-1	A 37-year-old woman presented with a painless nodule in her umbilicus which histopathology examination suggested to be a malignant umbilical tumor. Fourteen months before admission, the patient had a history of umbilical tumor surgery, with histopathology examination suggesting moderately-differentiated adenocarcinoma. The patient also had additional oral chemotherapy six times, using Capecitabine 2 × 1500 mg. The patient complained about a recurrent mass in her umbilicus at the surgical scar site. On examination, cytology examination using Fine Needle Aspiration Biopsy (FNAB) results identified some malignant cells (+). As seen in Figs. and , the adenocarcinoma of the sudoriferous gland is arranged into tubular and papillary patterns consisting of polymorphic cells, scanty cytoplasm, irregular nuclei, and coarse chromatin. Colonoscopy examination was performed to ascertain whether the tumor was primary or secondary colonic metastasis. Results were in the normal range, without intraluminal mass or stricture, and subsequent colon mucosa biopsy showed chronic colitis. CT (Computed tomography) scan was also performed, and the results showed no metastasis. A recurrent tumor mass of adenocarcinoma with the diameter of 7 cm had been excised with the tumor margin of 5 cm. Wide excision surgery was performed leaving a 17 cm surgical defect on the anterior abdominal wall (Fig. ). The reconstruction was performed using anti-adhesive Parietex polyester mesh. Reasonable collagen barrier on one side to limit visceral attachment was sized 30 × 30 cm. Histopathology examination of the excised tissue suggested sudoriferous gland adenocarcinoma with adjacent tissue free of tumor cells. Treatment was continued with additional chemotherapy using Capecitabine 500 mg dose 3–0-2 mg and Bevacizumab (Avastin) 400 mg 12 times. Follow up PET (Positron Emission Tomography) scan six months post-surgery was performed and showed no residual tumor in the umbilical region, and no apparent paraaortic nor mesenteric lymphadenopathy. Postoperative follow-up after 2 years is shown in Fig. .
pmc-6186106-1	A 36-year-old, white-haired Korean man (Fig. . II-2: Proband) visited the ophthalmology department complaining of loss of vision in the inferior visual field of his right eye. His face was characterized by lateral displacement of the inner canthus of both eyes with a medial eyebrow and a high broad nasal bridge (Fig. ). His medical history was significant for paralysis of one arm after a cerebral infarction 13 years earlier and right-sided sensorineural hearing loss. His father (Fig. . I-1), who had had hearing impairment, died of a myocardial infarction in his 50s, and his brother (Fig. . II-1) had bilateral hearing loss and heterochromia iridis. His best corrected vision was 20/25 with myopic correction (− 2.50 diopters) on the right and 20/20 with myopic correction (− 3.50 diopters) on the left. His intraocular pressure was 15 mmHg in the right eye and 13 mmHg in the left eye. A hypochromic left iris (Fig. ) was observed on slit-lamp examination. Funduscopy showed an ischemic change at the posterior pole with sparing of the foveal center along with retinal hemorrhages and white patches along the superotemporal arcade (Fig. ). Optical coherence tomography revealed thickening and opacification of the retinal layers corresponding to the ischemic area (Fig. ). Both BRVO and BRAO were detected on fluorescein angiography (Fig. ). An intravitreal anti-vascular endothelial growth factor (Avastin®, bevacizumab) injection (1.25 mg in 0.05 mL) was administered in the right eye for macular edema. After 2 months, the patient’s macular edema was significantly improved and his visual acuity was maintained at 20/25. Single nucleotide polymorphism analysis was performed by comparing a peripheral blood sample with the NM_181457 reference, and a PAX3 mutation was confirmed in exon 2 on chromosome 2q35 (Fig. ). An ACTCC deletion was noted at c.91–95, causing a frameshift of protein Thr31. A diagnosis of WS type 1 was made on the basis of this genetic mutation and the patient’s clinical features. Further biochemical workup revealed a raised serum homocysteine level (28.3 μmol/L). Antiphospholipid antibodies, including anticardiolipin and lupus anticoagulant, were also detected. Other blood coagulation factors were in the normal range or negative. The electrocardiogram showed no significant abnormality.
pmc-6186112-1	A 47-year-old female with history of high myopia − 10 diopters presented with acute visual field defect for 2 days. Best-corrected visual acuity of right eye was counting finger in front of 10 cm distance. Both eyes were phakic. Indirect ophthalmoscopy of right eye showed a superotemporal RRD with a tear at 11 o’clock (Fig. ). OCT showed compatible result of a bullous macular off RD (Fig. ). The 23 gauge pars plana VT, endolaser and gas temponade with 25% SF6 were performed. The patient was instructed to maintain prone position for 7 postoperative days. Two weeks after surgery, OCT revealed focal ellipsoid zone disruption at macular area (Fig. ). Two months afterward, OCT showed intraretinal cyst formation (Fig. ). Visual acuity remained 4/60 over the right eye for four months postoperatively. Progression of juxtafoveal intraretinal cyst was noted after 4 months and increased cystoid change was found at the 5th month (Fig. and ). Topical ketorolac, a kind of Non-Steroidal Anti-Inflammatory Drug was given to the patient three times a day since then. Lamellar hole developed about half year later (Fig. ). Finally, OCT and fundus exam demonstrated through MH formation with halo and adjacent lamellar hole at the 10th month (Figs. and ). Her visual acuity of right eye remained 5/60 since the fifth month and dropped to 3/60 at the tenth. Thus, patient received 23 gauge pars plana VT, internal limiting membrane peeling, and gas tamponade with 20% SF6 10 months after previous surgery. Successful hole closure was revealed by OCT and fundus exam on the 10th day after second operation (Figs. and ). Two years after macular hole surgery, her recent visual acuity recovered to 6/30.
pmc-6186261-1	A 28-year-old woman presented with unilateral blurred visual acuity associated with photopsias. Approximately 2 days before the visual symptoms presentation, the patient reported flu-like symptoms, such as fever and headache. The patient had an unremarkable previous medical and ocular history, and there was no recent contact with animals, including cats. Laboratory and systemic imaging tests revealed a normal complete blood count (CBC) and chest and sinus X-rays. Serologies for syphilis, cytomegalovirus, herpes simplex virus, human immunodeficiency virus, Bartonella, Histoplasma capsulatum, Toxoplasma gondii, Toxocara canis, and Borrelia burgdorferi were negative. On ocular examination, the best-corrected visual acuity (BCVA) was 20/20 in the right eye and 20/25 in the left eye. Biomicroscopy of anterior segment, pupillary reactions, and intraocular pressure were normal in both eyes. Color fundus photograph of left eye revealed subtle deep retinal white spots in the posterior pole and around the optic disk. FA demonstrated wreath-like punctate areas of early hyperfluorescence that corresponded to the deep white retinal lesions. Optic disc staining was observed in the late phase of FA. FAF showed several hyperautofluorescent lesions corresponding topographically to the white lesions observed on color fundus photograph. Cross-sectional OCT (DRI Swept Source OCT Triton, Topcon, Japan) demonstrated disruption of the EZ at the same topography of the spots seen on both the FAF and FA. Punctate hypereflective lesions and hypereflective dots were observed in the outer nuclear layer (ONL) and choroid, respectively. En-face OCT at the level of outer retina (DRI Swept Source OCT Triton, Topcon, Japan) showed multiple hyporeflective spots corresponding to the disruption of the EZ seen on the cross-sectional OCT. There was absence of flow impairment in both the retinal and choroidal vasculature on OCTA (Fig. ). At 6 month follow-up, the MEWDS lesions spontaneously disappeared, and the visual acuity returned to 20/20. A 33-year-old woman presented with unilateral decreased visual acuity associated with photopsias. Approximately 10 days before the visual symptoms presentation, the patient reported flu-like symptoms, such as fever and headache. The patient had an unremarkable previous medical and ocular history, and there was no recent contact with animals, including cats. Laboratory and systemic imaging tests revealed a normal CBC and chest and sinus X-rays. Serologies for syphilis, cytomegalovirus, herpes simplex virus, human immunodeficiency virus, Bartonella, Histoplasma capsulatum, Toxoplasma gondii, Toxocara canis, and Borrelia burgdorferi were negative. On ocular examination, the BCVA was 20/200 in the right eye and 20/25 in the left eye. Biomicroscopy of anterior segment, pupillary reactions, and intraocular pressure were normal in both eyes. Color fundus photograph of left eye revealed subtle deep retinal white spots in the posterior pole and midperipheral retina. Similar confluent lesions were also observed around the optic disk. FA demonstrated wreath-like punctate areas of early hyperfluorescence that corresponded to the deep white retinal lesions. FAF showed several hyperautofluorescent lesions corresponding topographically to the white lesions observed on color fundus photograph. Cross-sectional OCT (DRI Swept Source OCT Triton, Topcon, Japan) demonstrated punctate hypereflective lesions in the ONL and hypereflective choroidal dots, and disruption of the EZ at the same topography of the spots seen on both the FAF and FA. En-face OCT at the level of outer retina (DRI Swept Source OCT Triton, Topcon, Japan) shows an intrinsic lower reflectivity correspondent to the diffuse attenuation due to the EZ disruption on cross-sectional OCT. There was absence of flow impairment in both the retinal and choroidal vasculature on OCTA (Fig. ). At 6 month follow-up, the MEWDS lesions spontaneously disappeared, and the visual acuity returned to 20/20.
pmc-6186294-1	We report the case of a 69-year-old Sri Lankan Tamil man from Kandy who presented to the toxicology unit following a wasp sting. He was stung by three wasps in the evening and was brought to the toxicology unit of Teaching Hospital, Peradeniya with acute onset slurring of speech, deviation of mouth to the left side, with right-side weakness of his body. He had mild local reaction at the sites of wasp sting, but no anaphylaxis. He was apparently well before this event without any chronic medical illnesses. On admission to the toxicology unit he was conscious and rational. He was neither pale nor plethoric. He had a regular pulse of 80 beats per minute and blood pressure of 140/90 mmHg. On clinical examination he had no cardiac murmurs or carotid bruits. He had expressive aphasia, right-side upper motor neuron-type facial nerve palsy, with grade four weakness of the right side of his body. Random blood sugar on admission was 121 mg/dL. Magnetic resonance imaging (MRI) of his brain revealed an acute infarction in the left posterior frontal white matter, which was compatible with the clinical presentation (Fig. ). His complete blood count showed hemoglobin of 13.6 g/dL and platelet count of 350 × 109/L. Clotting profile was within normal limits. An electrocardiogram (ECG) was in sinus rhythm and two-dimensional echocardiogram was normal with good left ventricular systolic function. Carotid duplex showed anatomically normal carotid arteries. Fasting blood sugar was 4 mmol/L. Total cholesterol was 148 mg/dL (< 180) and low-density lipoprotein (LDL) cholesterol was 90 mg/dL (< 130). His erythrocyte sedimentation rate was 11 mm in first hour. His renal functions were normal. He was started on aspirin and atorvastatin. Rehabilitation was arranged with physiotherapy and speech therapy. His place of residence was visited by the authors and the members of the wasp species were found and identified as Vespa tropica of family Vespidae (Fig. ). On discharge, he had a mild right facial droop but normal strength in his right arm and leg.
pmc-6186323-1	Case 1, female, 46 years old, presented with a history of recurrent lower respiratory tract infections at the age of 38. She developed suppurative meningitis at the age of 43, with a sequela of blindness. Other clinical conditions included chronic sinusitis, pancytopenia, splenomegaly, and sensorineural hearing loss. Immunological findings showed decreased levels of IgG, IgA, and IgM in serum and a low proportion of B cells (). GLILD was suspected according to the chest CT without a pathologic confirmation (). Pulmonary function tests (PFTs) demonstrated a mild restrictive ventilatory defect and a diffusion impairment. Abdominal contrast-enhanced CT revealed multiple hypodense lesions in the spleen, which mimicked splenic infarction ().
pmc-6186323-2	Case 2, female, 54 years old, presented with a history of recurrent lower respiratory tract infections at the age of 39. She suffered from tuberculous pleuritis at the age of 46. Other clinical conditions included chronic sinusitis, intermittent gastrointestinal infections, neutropenia, sensorineural hearing loss, and splenomegaly. The patient had extremely low levels of IgG, IgA, and IgM, a low proportion of B cells, and an inverted CD4+/CD8+ ratio (). Chest CT showed bilateral bronchiectasis with multiple infiltrates (). PFTs demonstrated a severe obstructive ventilatory defect and a diffusion impairment.
pmc-6186323-3	Case 3, female, 34 years old, presented as recurrent lower respiratory tract infections with an onset age of seven. Other clinical conditions included autoimmune hemolytic anemia, splenomegaly, hypothyroidism, and nephrotic syndrome. Decreased levels of IgG, IgA, and IgM and an inverted CD4+/CD8+ ratio were also detected (). Chest CT demonstrated diffused nodules, bronchiectasis, and mediastinal lymphadenopathy (), with a severe restrictive ventilatory defect and a diffusion impairment confirmed by PFTs. Wedge resection of the right middle lobe and right lower lobe was performed; the diagnosis of GLILD was confirmed by pathology subsequently (Figures and ). The three cases met the criteria for CVID established by European Society for Immunodeficiencies/Pan-American Group for Immunodeficiency []. All the cases received antibiotics and immunoglobulin replacement therapy and survived to date. Case 3 received extra corticosteroids treatment for GLILD with clinical improvement. Normal IgG, IgA, and IgM levels were detected in the offspring of the probands, including the daughter and the son of case 1, the son of case 2, and the son of case 3.
pmc-6186326-1	A 76-year-old Japanese woman with type 2 diabetes was referred to our hospital for further investigation of anemia. An upper endoscopy to exclude gastrointestinal bleeding demonstrated an IIc+IIa lesion in the antrum. Tubular adenocarcinoma was diagnosed via biopsy and ESD was planned. Initial blood tests showed pancytopenia with white blood cells (WBC) 1,500/μL, hemoglobin (Hb) 4.6 g/dL, and platelets 5.1×104/μL. Serum biochemistry was normal except for HbA1c 7.0%. On admission, the patient was diagnosed with MDS by the hematology team. She was given transfusions and follow-up was arranged. After a preoperative transfusion, repeat blood tests showed Hb 8.3 g/dL and platelets 23.4×104/μL. ESD was performed due to this improvement and the patient's desired treatment. The patient was subsequently diagnosed with pseudothrombocytopenia based on repeat platelet count levels. ESD (Figures and ): There was an IIc+IIa lesion in the antrum. There was only a small amount of intraoperative bleeding and the resection took 80 minutes. The size of the mucosa resected en bloc was 38×34 mm2 in diameter including 11×10 mm2 of cancer lesion. No perforation and minimal bleeding were observed after finishing ESD. Post-ESD course (): No bleeding was observed on repeat endoscopy performed the day after ESD; therefore, the patient was allowed to eat. Her temperature spiked to around 38°C that day, and post-ESD abdominal computed tomography (CT) was performed on day 3 (), which showed full-circumference thickening of the gastric wall. However, the patient did not exhibit abdominal pain, so a definitive diagnosis of phlegmonous gastritis could not be concluded. Antibiotic treatment with cefmetazole sodium (CMZ, 3 g/d) was started to cover for E. coli urinary tract infection with a positive urine culture. However, after Klebsiella pneumoniae was detected in a blood culture, the possibility of a bloodstream infection related to ESD injection was considered. C-reactive protein (CRP) levels increased to 51.5 mg/dL; therefore, antibiotic treatment was switched to meropenem hydrate (MEPM, 1.5 g/d) on day 4 post-ESD, after which the inflammatory reaction gradually improved. Abdominal CT performed on day 20 post-ESD () showed full-circumference thickening of the gastric wall and increased levels of perigastric fat stranding. At this time, the patient had no high fever and abdominal pain; therefore, antibiotic treatment was terminated. On day 29 post-ESD, upper endoscopy was performed () because the patient began experiencing epigastric pain after eating on day 27 post-ESD. In addition to a post-ESD ulcer in the antrum, we observed expansion of the ulcer floor, a false lumen between the ulcer floor and surrounding folds on the lesser curvature side, and yellow mucus thought to be purulent matter adhered to the superior portion of the gastric body. Based on these findings, a diagnosis of phlegmonous gastritis was made. Contrast examination with gastrografin did not show any exudate outside the gastric wall from the false lumen. Therefore, antibiotic treatment was continued. Klebsiella pneumoniae, Pseudomonas aeruginosa, and Candida albicans were detected from a pus culture. The patient was made nil by mouth, given intravenous hyperalimentation, and was treated with antibiotics (CMZ 3 g/d) and proton-pump inhibitors (PPI). Endoscopy performed on day 37 post-ESD (Figures and ) showed granulation on the ulcer floor. Endoscopy performed on day 51 post-ESD () showed that the ulcer shrunk and the false lumen disappeared and, on the basis of these findings, antibiotic treatment was terminated. The phlegmonous gastritis was considered to have been cured with medical therapy. The patient resumed eating on day 55 post-ESD, and acute cholecystitis occurred the next day. She underwent cholecystectomy which was complicated by a postoperative wound infection and intra-abdominal abscess, which improved with antibiotic therapy. She was discharged from the hospital on week 16. Endoscopy at 4 months post-ESD () showed complete resolution.
pmc-6186336-1	A 71-year-old female with a history significant for hypertension, hepatitis B, and hypothyroidism, underwent bone marrow biopsy which showed a hypercellular bone marrow with >90% cellularity and 81% myeloblasts expressing CD 34 and CD 117 markers, confirming a diagnosis of acute myeloid leukemia (AML). Molecular testing showed no evidence for FMS-like tyrosine kinase 3 internal tandem duplication, absence of nucleophosmin1 and KIT exon 8, and 17 mutations, suggesting a lower risk of relapse after chemotherapy. Based on cytogenetic studies, secondary AML was diagnosed. Given her advanced age, decitabine therapy was commenced. A baseline 2-D transthoracic echocardiogram (TTE) showed normal function with an ejection fraction (EF) of 55–60%. After completing 10 cycles of decitabine, she was noted to have a tachycardia and dyspnea by self-report. She was therefore referred to cardiology with these symptoms in preparation for allogeneic stem cell transplant. The heart rate was 110/min, and a 2/6 ejection systolic murmur and a loud P2 with an S3 and S4 gallop were heard. Lungs were clear. No jugular venous distension or pedal edema was noted. Laboratory data is significant for a serum creatinine level of 0.8 mg/dl, estimated glomerular filtration rate of 80 ml/min per 1.73 m2, and N-terminal pro-b-type natriuretic peptide level of 517 pg/ml. Her complete blood count showed a white blood cell count of 12.6 × 109/l with greater than 50% blasts, low hemoglobin at 7.8 g/dl, hematocrit value of 25%, large platelet count of 212 × 109/l, and lactate dehydrogenase level of 588 U/l. Serum troponin or creatinine phosphokinase levels were not performed due to a lack of discernibility in patients undergoing chemotherapy for cancer. Echocardiogram showed severe left ventricular systolic dysfunction (EF 28%), mildly abnormal end systolic dimension (), and a mild reduction in right ventricular systolic function. Global averaged left ventricular longitudinal peak systolic strain was abnormal at −12% (normal more negative than −18%) (). Nuclear stress test showed no evidence of coronary disease. Patient was euthyroid at the time of diagnosis. The patient was diagnosed with New York Heart Association class II and American Heart Association stage B heart failure with reduced ejection fraction. In the absence of any viral illness, toxins, or coronary disease, or concomitant cardiotoxic medication use and known recent normal ejection fraction, the etiology was attributed to decitabine use. The patient was subsequently started on metoprolol succinate 50 mg twice a day and furosemide 20 mg daily. Follow-up echocardiogram 4 weeks later showed no change in the ejection fraction of 28%, but there was mild improvement in the global left ventricular longitudinal peak systolic strain at −15% (improved from −12%).
pmc-6186340-1	A 50-year-old Caucasian male presented with 5 days of significant central vision changes in both eyes. About 4 days prior to visual symptoms, he started a viral like illness with severe headaches, fevers, chills, and joint pain. He was given Tamiflu by an urgent care clinic after being diagnosed with the flu. His vision was found to have a best corrected visual acuity of (BCVA) 20/25 OD and count fingers OS. Intraocular pressures: 14mmHg OD 15mmHg OS. Brisk pupil reactions were found with no afferent pupillary defect in both eyes. Extraocular movements were full. Anterior chamber examination showed normal cornea, iris, and lens with deep chambers and no cell/flare in both eyes. Posterior segment examination showed a clear media with no vitritis as well as normal disc and vessels. There were, in the posterior pole of both eyes, multiple yellow-white chorioretinal placoid lesions more significant on the left eye (). Spectral domain optical coherence tomography showed the placoid lesions with disruption of the RPE, external limiting membrane, and ellipsoid zone as well as small focal points of hyperreflective material at the level of the ellipsoid zone (). Fundus autofluorescence (FAF) showed the placoid lesions to have hyperautofluorescence center with hypoautofluorescence edges (). Fluorescein angiogram showed the placoid lesions had the characteristic early blocking with late hyperfluorescent staining of edges (). Based on imaging and clinical exam, the patient was diagnosed APMPEE. Due to the concern for cerebral vasculitis, the patient was admitted for imaging and treatment. A lab work-up showed an elevated ESR and CRP, positive IgG toxocara, and toxoplasma. IgM toxocara and toxoplasma were negative and the rest of the lab workup was negative. MRI brain, CTA head/neck, and lumbar puncture performed were found to be normal. After ruling out infectious causes, the patient was started on intravenous high dose steroids with transition to PO steroids of 1mg/kg and a planned slow taper. After a couple of weeks of starting steroids, the patient had an incidence of bright red blood per rectum and underwent a rapid steroid taper as well as a colonoscopy. A biopsy was performed during the colonoscopy which showed a gastrointestinal stromal tumor. The lesion later excised showed on pathologic analysis a high grade gastrointestinal stromal tumor. The patient was advised that he may need adjuvant chemotherapy. Also during work-up of the GIST, a thyroid nodule was found. Subsequent fine needle biopsy of the lesion showed atypical Hurthle cells. Genetic testing of the atypical cells showed benign characteristics with low malignant potential. The patient currently is pending excision of the thyroid lesion. On the 3-month follow-up visit on no systemic steroids, the BCVA stabilized at 20/25 with the patient's paracentral scotomas persisting. Imaging showed maturing of the lesion with stable size on FAF, more apparent late staining on FA, and mild improvement of the ellipsoid zone on the edges of the lesions on OCT (Figures , , and ). On the 5-month follow-up, the BCVA was 20/20 OU.
pmc-6186356-1	The patient is a 33-year-old man with a history of progressive idiopathic recurrent intrahepatic cholestasis diagnosed initially at the age of 15. He was managed with ursodeoxycholic acid, cholestyramine, rifampin and naloxone but eventually failed medical therapy as evidence by the development of cirrhosis complicated by ascites, esophageal variceal hemorrhage, pruritus, and progressively rising Model for End-Stage Liver Disease score. At the age of 22, the patient underwent deceased-donor LT. At the time of LT, the patient's native bile duct was noted to be 10 mm in diameter, while the donor bile duct was 2.5mm in diameter. In order to make the two orifices more congruent, a ductoplasty was performed with part of the recipient bile duct being oversewn and an end-to-end choledochocholedochostomy being created with running circumferential 5-0 absorbable sutures. The total cold ischemia time was 8 hours, 32 minutes, and the total warm ischemia time was 41 minutes. There were no intraoperative complications, and the patient recovered well following surgery. He was managed on tacrolimus and did well for a decade. Approximately half-way through this period, for geographical and insurance reasons, the patient transferred LT care to our institution. At his 10 year post-LT appointment, the patient endorsed new-onset generalized pruritus and was noted to have developed multiple albeit relatively minor abnormalities in his serum liver test profile, with an alkaline phosphatase of 121 (normal: 35-115 U/L), aspartate aminotransferase of 53 U/L, alanine aminotransferase of 68 U/L, and total bilirubin of 1.2 mg/dL. Abdominal ultrasound showed no evidence of intrahepatic or extrahepatic biliary ductal dilatation but did note a linear filling defect within the common bile duct (CBD) as seen in . MRI/MRCP was thus performed, which was significant for an abrupt change in caliber at the biliary anastomosis consistent with stricture (ABS), dilatation of the common hepatic duct (CHD) to 7 mm, and a curvilinear filling defect at the level of the anastomosis (). Given these findings, the patient's original LT operative report was retrieved from the performing institution; this revealed that in addition to the ductoplasty, a 3.5cm segment of 5 Fr pediatric feeding tube had been placed through the biliary anastomosis to serve as a temporary internal stent. Given the patient's new-onset pruritus, worsening serum liver tests, and abnormal imaging findings, endoscopic retrograde cholangiography (ERC) was performed. This revealed a small, tortuous native (i.e., recipient) CBD and a short ABS with proximal CHD dilatation. The ABS was first balloon dilated to 6 mm followed by sweeping of the extrahepatic duct was performed with a 9 mm extraction balloon; this first yielded biliary sludge, but with additional sweeps, a 3.5 cm long, black tubular structure with overlying sludge/biofilm was extracted (Figures and ). This was grasped and brought out per os using forceps and appeared to be consistent with an oxidized pediatric feeding tube (). An 8 mm × 4 cm CRE balloon was then used to further dilate the ABS, and two 10 Fr x 7 cm Cotton-Leung plastic biliary stents were deployed across it. In doing so, the patient's serum laboratory tests returned to baseline, and his pruritus resolved over the ensuing weeks. The patient now nears completion of serial ERCs at three month intervals as part of a 1-year long maximal stenting protocol in order to achieve durable ABS resolution [].
pmc-6186360-1	A 32-year-old Japanese woman (gravida 4, para 3) with no medical history was admitted to our hospital for a term delivery. She had a normal vaginal delivery of a healthy child at 39 weeks of gestation and underwent a suture of first-degree perineal laceration on the left side of the external urethral orifice. She used a perineal pad and no intravaginal packings after delivery. Furthermore, she did not have fever and wound pain during hospitalization. She was doing well and was discharged on the fifth day. Twelve days after delivery, she presented with a 2-day history of fever of 40oC and focal perineal pain. On physical examination, the patient was conscious but had hypotension (88/56 mmHg), tachycardia (144 beats/minute), and tachypnea (23 breaths/minute). Her body temperature was 40.2°C. Abdominal examination findings were normal, and pelvic examination disclosed that the uterus and the vagina were not tender. Although the external genitalia around the laceration were accompanied by pain and fever, reddening and swelling were absent. Laboratory data revealed abnormal results; she had neutrophilic leukocytosis (white blood cells were 19,600/mm3 with 96.1% neutrophils, 1.2% lymphocytes and 2.4% monocytes), hypoproteinemia (6.6 g/dl), and hypoalbuminemia (3.6 g/dl). Furthermore, the serum electrolyte concentrations were abnormal: sodium, 136 mEq/L; potassium, 3.2 mEq/L; chloride, 97 mEq/L; calcium, 8.2 mg/dl; phosphate, 3.7 mg/dl; magnesium, 1.5 mg/dl. She was treated with aggressive intravenous fluid resuscitation and antimicrobial agent therapy with intravenous ceftriaxone (2 g every 12 hours). On admission, vaginal, urine, stool, and blood cultures were performed prior to initiating the administration of antibiotics. She developed emesis and watery diarrhea on the night of admission. On the second hospitalization day, a diffuse cutaneous macular rash appeared over her trunk. Laboratory values indicated mild renal disturbance (BUN 19.5 mg/dL, creatinine 0.93 mg/dL, and eGFR 57.40), and she also had leukocytosis (WBC 13,400/µL), thrombocytopenia (platelets 124,000/µL), hyperbilirubinemia (total bilirubin 3.01 mg/dL), and elevated creatine kinase (319 IU/L). Since these symptoms and results were compatible with a typical course of TSS, clindamycin was also added to the antibiotic therapy. On hospitalization day 4, desquamation on her palms and fingers strongly suggested the diagnosis of TSS. Furthermore, the bacteriological results indicated that the TSS was due to methicillin-resistant Staphylococcus aureus. Although the urine, stool, and blood cultures were negative, cultures from the vagina yielded a significant growth of MRSA with dramatic reduction in genital flora that was resistant to ceftriaxone but susceptible to clindamycin. We routinely test the nares and vaginal cultures during pregnancy, but no bacterium including MRSA were not detected. The treatment outcome was favorable. On hospitalization day 5, her vital signs became normal, the erythematous skin rash disappeared, and biological abnormalities were also resolved. She was discharged at the end of an 11-day course of antibiotic therapy (ceftriaxone for 7 days, clindamycin for 11 days). After discharge, the TSS toxin assay results were obtained. MRSA was isolated from the vaginal secretion and was found to produce TSS toxin-1 (TSST-1). One month after discharge, she has not had any recurrences, and the baby is doing well without infectious diseases.
pmc-6186361-1	A 65-year-old African-American male with no significant past medical history presented to facility with complaints of worsening abdominal distention for approximately one year, associated with dyspnea, early satiety, and weight loss of about 23 pounds. He denied chest pain, melena, or hematochezia. He had never had an endoscopy or colonoscopy performed. The patient did have a remote history of smoking of about a half pack of cigarettes per day for 10 years; however, he had quit 15 years prior. Family history was significant for a brother with lung cancer, otherwise noncontributory. On physical examination, he was noted to have bitemporal wasting and marked abdominal distension secondary to a large firm mass with ill-defined margins. A contrast-enhanced CT scan of the abdomen and pelvis showed a large, heterogeneous, partially necrotic mass measuring 38 cm × 25 cm, arising from the left upper quadrant with no evidence of metastases seen. There was displacement of the stomach and duodenum to the right and the left kidney was displaced inferiorly. The mass was suggestive of a sarcoma or possibly a GIST tumor with malignant degeneration (). Chest radiograph was done which confirmed no pulmonary pathology or metastatic disease. Preoperative laboratory analysis showed a white blood cell count of 5.9 K/mm3 with 80% neutrophils. Hemoglobin of 10 G/dl and hematocrit 31.2% with a platelet count of 328 K/mm3. Basic metabolic panel and liver function tests and PT/INR were unremarkable. The patient was taken for an exploratory laparotomy, which revealed a large mass arising from the posterior gastric wall with a giant omental vessel as well as dilated gastroepiploic vessels. The mass was invading the spleen, distal pancreas, and the mesentery of the transverse colon. Over the next 7 hours, the mass was completely resected with a total gastrectomy, esophagojejunostomy and feeding jejunostomy, distal pancreatectomy, and splenectomy. Resection required division of the mesentery of the transverse colon, which resulted in ischemia of the transverse colon warranting resection with end colostomy creation. The tumor, spleen, distal pancreas, and transverse colon were all sent for frozen section. As expected of GISTs, pathology reports showed that the 6 harvested lymph nodes as well as the surgical margins were all negative for malignancy. During the 7-hour procedure, the patient lost nearly 3 l of blood and received 6 l of IV fluids, 12 units of packed red blood cells, 4 units of fresh-frozen plasma, 1 unit of single donor platelets, and 4 units of albumin with intermittent pushes of vasopressive medications. The patient was taken to the surgical intensive care unit postoperatively, was weaned off vasopressive medications, extubated, and started on tube feeds, and eventually fed orally. The remainder of his hospital course was uneventful, and the patient was discharged to home on postoperative day 14. The patient was started on imatinib at this time and has been maintained on that with no recurrence approximately 1.5 years postoperatively. The patient returned 8 months later for a planned colostomy take-down, which was successful and uneventful. Macroscopically, the mass was irregularly shaped, attached to the posterior-inferior aspect of the stomach, weighed 18,500 grams, and measured 42.0 × 31.0 × 23.0 cm in maximum dimensions (). Histopathology showed gastric stromal tumor cells staged as high grade with >5 mitoses per high power field (hpf). Immunohistochemistry confirmed GIST with strong positive staining for CD117, DOG1, and CD34 (). Postoperative recovery was uneventful.
pmc-6186364-1	The patient is a 29-year-old G3P2002 woman at 39-week and 1-day gestation, who was referred from a health center for management of fetal demise. She had attended 03 antenatal visits at the same health center wherein the fundal height was documented at each visit and routine care given. Except for occasional painful fetal kicks, she was otherwise well throughout the antenatal period. Three days prior to admission into our service, she experienced reduced fetal movements for which she consulted at the said health center and a diagnosis of fetal demise was made. On admission to our unit, she had stable vital parameters. There was no abdominal tenderness and an apparent fundal height of 32cm was measured, fetal parts were not easily palpable, and fetal heart tones were not perceived. There were no signs of per vaginal bleeding. Her cervix was long, posterior, firm, and closed. An emergency ultrasound scan was requested which confirmed fetal demise (gross cranial deformation was noted) but failed to diagnose an intra-abdominal location. Cervical ripening was started with 50µg of misoprostol vaginally every 6 hours and after 4 applications; the cervix remained unchanged. A decision for operative delivery was made, indicating failed induction and in a bit to reduce the risk of disseminated intravascular coagulation. The intraoperative findings were a third-degree macerated female fetus floating freely in the peritoneal cavity, weighing 2650g with a tight cord round neck and with no amniotic sac (). The uterus was about 14 weeks () and the fallopian tubes and ovaries were normal. The placenta was implanted on the ascending colon and mesocolon. The placenta was left in place. No intraoperative complications were encountered. Postoperatively, she was placed on ampicillin, gentamycin, and metronidazole parenterally for five days. She also received 50mg of methotrexate every other day (04 doses) with 5mg of folinic acid each day proceeding the methotrexate. She was discharged on day 8 postoperation to continue follow-up as an outpatient with regular βHCG and ultrasound checks. Her recovery was uneventful with resorption of placenta 6 months later.
pmc-6186366-1	A 44-year-old Caucasian male presented with an 8-month history of reflux and heart burn, which was relieved by Esomeprazole. Endoscopic evaluation showed a polypoid shaped mass measuring 1 cm in size at the gastroesophageal junction. Ultrasonic evaluation revealed a hypoechoic lesion that was confined to the deep mucosa and submucosa with no deeper layer involvement. The nodule was resected via the endoscopic mucosal resection technique (EMR). Grossly, the specimen was a 1 cm GEJ nodule. It was a single irregular fragment of tan-pink soft tissue that was bisected and entirely processed for microscopy. Microscopic evaluation showed squamous mucosa with oxyntic-type mucosa with moderate chronic inflammation, ectatic vessels, congestion in the mucosa, and a few lymphoid aggregates. In addition, there were prominent mucus glands with chronic inflammation consistent with heterotopic salivary glands, surrounded by prominent adipose tissue and congested vessels in the submucosa (Figures and ).
pmc-6186366-2	A 62-year-old Caucasian male with a history of hypothyroidism, Sjogren's syndrome, Raynaud syndrome, chronic GERD, and grade 3 esophagitis presented for an upper endoscopy for the evaluation of suspected Barrett's esophagus. Endoscopic evaluation and barium swallow showed a dilated esophagus. The z-line appeared slightly irregular and there were 2 small islands of salmon colored mucosal lesions immediately proximal to the GE junction. Grossly, the specimen consisted of one piece of tan-white soft tissue, measuring < 1cm. Microscopic evaluation showed fragments of squamous mucosa with focal mild acute erosive esophagitis and basal hyperplasia that was consistent with reflux. In addition, detached fragments of salivary gland type glandular tissue with chronic inflammation, consistent with heterotopic salivary gland tissue, were seen (Figures and ).
pmc-6186366-3	A 72-year-old Caucasian male with past medical history of Barrett's esophagus and high-grade dysplasia presented for EGD and biopsy in order to rule out invasive carcinoma. Endoscopic evaluation revealed a large hiatal hernia and an approximate 3 cm segment of Barrett's esophagus. There was a concerning focal area of ulceration which was removed via EMR. Grossly, the specimen was one piece of tan-white soft tissue, measuring 0.7 x 0.4 x 0.2 cm. Microscopic evaluation revealed focal high-grade dysplasia adjacent to squamous epithelium in the middle portion of the specimen. In the deeper aspect of the tissue, there were cavernous and ectatic venous channels as well as a few prominent lobules of minor salivary glands with cystification in the ducts (Figures and ). The patient was treated with radiofrequency ablation.
pmc-6186367-1	A 45-year-old male presented to our hospital with diaphoresis, chills, and worsening right flank pain. He had a past medical history of cirrhosis due to alcoholism and portal hypertension with esophageal varices managed with prior transjugular intrahepatic portosystemic shunt (TIPS) procedure. He had a history of hepatic encephalopathy, hypertension, and type II diabetes. He had a recent admission to another institution for septic shock secondary to recurrent cholecystitis and had recently had an LC fifty-eight days prior. The patient was admitted to the outside hospital fifty-nine days prior to admission to our institution for subacute cholecystitis, which had initially required a cholecystostomy drain on prior admissions, and then ultimately an LC at that hospital. The gallbladder was not noted to be perforated, but the procedure was complicated by dropped gallstones, some of which were retrieved as stated in the operative report. On the current admission, the patient was hypotensive requiring vasopressors and was anemic and thrombocytopenic, requiring blood and platelet transfusions. A CT scan of the abdomen and pelvis with IV contrast was performed on admission demonstrating residual gallstones in the gallbladder fossa and/or cystic duct remnant and multiple small fluid collections and/or forming granulomatous masses surrounding additional retained/dropped gallstones in the surgical tracts and vicinity. A fistula with gallstones was also seen extending through the posterior and inferior wall of the second portion of the duodenum, to the anterior and superior aspect of a right renal cyst, which measured 3.4 cm x 3.0 cm and which contained gas in its superior aspect (Figures and ). A previous CT of the abdomen and pelvis performed with IV contrast sixty-five days prior to admission and seven days prior to the LC demonstrated a simple right renal cyst in the location of the now complex and infected cyst, measuring 2.8 cm x 2.5 cm (). Drainage of the infected renal cyst seen on the initial CT was considered; however, the cyst was relatively small and inaccessible. A repeat CT of the abdomen and pelvis with oral and IV contrast was performed four days after admission due to concern for abscess formation as the patient continued to have right flank pain. The CT demonstrated an unchanged superinfected cyst in the right kidney, with the fistula tract still visible, and heterogeneous retention of IV contrast in the right kidney, which was consistent with associated pyelonephritis (Figures and ). On initial presentation, the patient was noted to have a history of Klebsiella pneumoniae and vancomycin-resistant enterococcus (VRE) in the cholecystectomy drain and was treated for the gallstone abscess and fistula accordingly with meropenem as there was no other source of infection. Blood cultures were later positive for K. pneumoniae and VRE. The patient was ultimately treated with linezolid and meropenem was deescalated to ceftriaxone. Discussion between the patient's outside hepatologist, the abdominal radiologist, the interventional radiologist, and the gastroenterologists determined that the most likely etiology of the initial sepsis was an infected renal cyst secondary to an infected dropped gallstone. The patient was ultimately transferred to the outside hospital where he previously had his cholecystectomy for surgical follow-up.
pmc-6186371-1	A 77-year-old female patient was admitted in our institution following a ground-level fall due to relatively sudden grade 3-4 right hemiparesis with lower limb predominance. This patient was not known for any systemic disease, no rheumatoid arthritis, or other joint-related generalized disease. An initial enhanced CT was performed for the suspicion of an ischemic stroke. The exam revealed a smooth and well-corticated bone ossicle measuring 14 mm and located superiorly to the odontoid process corresponding to an os odontoideum (Figures –). The ossicle was associated with an atlantoaxial subluxation and with the posterior wall of 14 mm on spinal canal (Figures and , white lines) that has increased since a previous CT 8 years ago. The late enhanced phase showed an intracanal hyperattenuated but no enhancing pseudomass situated just posterior to the ossicle (). A complementary cervical enhanced MRI with administration of Gadolinium confirmed a well-corticated ossicle and demonstrated a tissular retroodontoid process (Figures and ). The tissue component showed a low signal on T1- and T2-weighted images and no enhancement (), compatible with a ROP. The main diagnosis was a noninflammatory ROP developed on atlantoaxial instability, secondary to an os odontoideum. The main differential diagnosis was pseudoarthrosis of an old fracture of the dens of axis. Inflammatory arthritis such as gout, rheumatoid, or psoriatic arthritis was suggested as differential diagnosis, but less likely because of the negative history of those diseases. There was no enlargement of space between this os odontoideum and the anterior arch of C1 (). A subcentimetric geode, in low signal on T1-weighted images and enhancement after contrast administration, was seen in the posterior dens basis of C2 (Figures and ). The pseudotumor indenting into cervicomedullary cord and resulting in cord compression is shown (), with cervical myelopathy seen in high signal on T2-weighted images in sagittal plane (). Given the severity of the radiological findings and the clinical impact due to spinal cord compression and the life-threatening risk, patient was treated with cervical posterior screw fixation and a decompressive laminectomy at C1-C2 level (Figures –). Unenhanced CT after posterior C1–C2 shows posterior cervical fixation and spinal canal decompression by laminectomy. The intracanal ROP is not removed but regressed in size in each postoperative CT compared to preoperative CT (Figures –). The patient showed a progressive improvement of her neurological recovery, with complete neurological recovery 6 months after surgery. In the postoperative follow-up, entire cervical spine showed marked degenerative changes, best viewed on postoperative cervical spine X-rays (Figures and ) as disco-uncarthrosis (white arrowheads), interarticular posterior arthrosis (black arrowheads), and anterior marginal osteophytosis (black-framed white arrowheads).
pmc-6186373-1	A 68-year-old male with past medical history of coronary artery disease status post coronary artery bypass graft (CABG), aortic valve replacement along with replacement of the root of the ascending aorta 10 months prior to presentation and recent hemorrhagic cerebrovascular accident (CVA), came to the hospital with complains of acute onset of severe abdominal pain and melena for 1 day. He also attested to chronic abdominal pain and a 30-pound weight loss over the last 8 months prior to these acute symptoms. His physical exam on presentation was positive for severe bilateral lower abdominal tenderness. Apart from a hemoglobin of 10 mg/dl and a positive stool occult blood test, the rest of his basic lab work up was unremarkable (white blood cell/platelet count, comprehensive metabolic panel, and PT/INR included). Hepatitis B, hepatitis C, and human immunodeficiency virus (HIV) testing were negative. The electrocardiogram (EKG) showed sinus rhythm and left ventricular hypertrophy (). An emergent computerized tomography (CT) scan of the abdomen revealed features suggestive of an embolic infarct in the left kidney (Figures and ) and within the mid-one-third of the superior mesenteric artery causing luminal narrowing and also suspected to be extending to the takeoff of small bowel branches. Segmental mural thickening of at least one small bowel loop was noted which strongly favored acute bowel ischemia as a cause of his abdominal pain (). Incidental findings on CT of the abdomen were also strongly suspicious for large eccentric thrombus in the ascending aortic graft and the aortic root which were further investigated and confirmed with a CT scan of the chest (). Cardiology and cardiothoracic surgery were consulted. A CT scan of the head was performed to assess the recent CVA and showed a subacute hemorrhage along the left-sided temporal parenchyma (). CT head imaging was obtained from the facility where the patient presented 3 months prior for cerebral hemorrhage and in comparison, to the most recent CT scan of the head, the hemorrhage appeared stable. The hemorrhage was suspected to be secondary to thromboembolism. After a review of the risks and benefits of anticoagulation to prevent extension of this suspected thrombus, heparin was initiated. An echocardiogram revealed dilatation of the ascending aorta and mild paravalvular leak around the bioprosthetic aortic valve. Gastroenterology was consulted and an emergent esophagogastroduodenoscopy was performed which was negative for any causes of upper gastrointestinal bleed. A hypercoagulable workup was performed which did not reveal any apparent cause of a prothrombotic state. Anticoagulation was held and subsequently, the patient underwent a redo sternotomy under cardiopulmonary bypass with extensive lysis of adhesions, removal of the thrombosed aortic valve and graft, ascending and proximal aortic arch replacement utilizing a 30 mm Dacron graft, and aortic valve replacement with a 25 mm Edwards Magna Ease bovine pericardial valve. The patient also underwent an explorative laparotomy as a part of a staged procedure to address the ischemic bowel caused by the presumed septic emboli. Intraoperatively, the patient was found to have a portion of small bowel that had become necrotic. The necrotic bowel was excised and an end to end anastomosis was performed. The aortic graft and thrombus were sent for culture and pathology. Histopathological examination of the aortic graft and cusps of the aortic valve revealed chronic inflammation and was also notable for abundant acute angle branching septate fungal hyphae (). The patient was immediately started on amphotericin B and voriconazole pending finalization of cultures and sensitivities. On postoperative day four, three culture reports from the graft came back positive for dematiaceous mold, suggestive of Bipolaris species. The minimum inhibitory concentration (MIC) was 0.25 ug/dl for voriconazole and 0.03 ug/ml for amphotericin B. A decision was made to continue the same antifungal regimen on the basis of sensitivities and further speciation was not performed. Patient had a good postoperative course and was later discharged on amphotericin B and voriconazole for at least 1 month with continued follow-up with an infectious disease specialist.
pmc-6186374-1	A 37-year-old man reported exercise/activity-related muscle pain and fatigue from early childhood. His symptoms were labelled as “growing pains” by different medical professionals, and he was often called “a lazy child”. He had difficulties to keep up with his friends and family when walking. He reported physical education classes and school games as bad experiences. Throughout his life he continued to avoid activities that provoked muscle symptoms. Despite not being aware of the second wind phenomenon, he used strategies such as slowing down or stopping and restarting when symptoms eased off. He reported pain in his muscles within a few minutes or sometimes seconds of initiating physical activity, particularly noticeable when walking upstairs, walking up hills, and carrying shopping bags. He had a previous medical history of four episodes of myoglobinuria triggered by playing football or lifting heavy items. He was diagnosed with McArdle disease at the age of 20 years based on an abnormal muscle biopsy. He was later confirmed to have a homozygous mutation (p.Gln567Pro) in PYGM. Physical examination at the age of 29 revealed rounded shoulders with hypertrophy of deltoid, biceps, and calf muscles. He had significantly wasted pectoralis muscles and bilateral scapular winging, but muscle strength was normal. When diagnosed he had been advised to complete at least three sessions of walking 30 minutes per week. However, he did not change his physical activity levels and did not report changes in his quality of life. After graduation he started his first office job. He became more sedentary, his weight increased, and symptoms worsened. He reported difficulties in walking short distances. Everyday tasks such as vacuuming and cutting grass became more difficult. He joined a local gym, where he has been a member for approximately 9 years. Initially exercises included walking on a treadmill and cycling on a stationary bike. He tried resistance machines but was not confident in using them. Four years ago, he approached a personal trainer, who took the time to learn about his metabolic condition []. He suggested that weight lifting could be safe and effective if using principles of strength training after considering the pathophysiology of McArdle disease. Initial phase of training consisted of gentle 15-20 minutes aerobic exercise to warm up and get into second wind (walking on a treadmill, cycling on a stationary bike) followed by learning strengthening exercise techniques using body weight and very light weights. Training intensity gradually progressed towards mobility movements (e.g., Turkish get ups, walking lunges), increasing resistance as well as adding high intensity interval training (HIIT) protocol on the rowing ergometer at the end of the session. Strength exercises were mainly performed using compound movements with free weights rather than resistance machines. Currently, he performs a 15-20 minute aerobic warm up. He performs 1-5 repetitions with 2-5 minutes rest in between sets depending on the % of one repetition max (1RM). He also tried a different protocol involving four repetitions with 30 seconds rest followed by another four repetitions of the same weight. He has been doing two sessions with the personal trainer and two sessions on his own each week. When without the trainer, he only performs exercises he is familiar with. Over the past four years of strength training his weight increased from 65kg to 70kg; body composition dramatically changed by significantly increasing muscle bulk, in particular of his quadriceps, gluteus, pectoralis, deltoids, and trapezius muscles. His waist remained the same; collar size increased from size 14.5 to 15.5/16.0. He had to purchase new clothing due to dramatic change in body composition. Importantly, his muscle strength increased significantly as described in . He also performed other exercises, including lateral pull downs, TRX rows, TRX pull-ups, body weight pull-ups from jumps, Olympic lifting movements, box jumps, medium height approx. 45cm, and pistol squats. He has never experienced any McArdle symptoms during or after strength training and has not had myoglobinuria following his gym sessions. His serum CK level varied as expected in McArdle disease, with a decreasing trend (average CK in 2011-2014: 3,006 IU/L, average in 2015-2017: 1,029 IU/L; last measured in July 2017: 941 IU/L; reference range: up to 240 IU/L). Improvement in McArdle symptoms was described as a delayed onset of skeletal muscle symptoms, which now occurs at much higher physical activity intensity. Reaching the second wind is more efficient. In general, his quality of life improved significantly. He has been eating high protein diet with a bigger portion of carbohydrates on training days. He autonomously chose not to take any supplements containing glucose pre- or intra-training sessions.
pmc-6186374-2	A 46-year-old man also reported exercise/activity-related pain and fatigue from early childhood. As patient 1, he was always considered to be “a lazy child”. He was not able to run and physical activities such as walking or swimming were challenging. As a child he reported trying to build a good relationship with his physical education teachers, so they would feel pity for him and he could avoid any strenuous physical activities (PA). He experienced three severe episodes of rhabdomyolyses in his life. The first one happened during childhood, which followed vigorous physical activities. The second rhabdomyolysis episode was at the age of 18 following multiple squats, which he performed during a physical test for military service. Not qualifying for the military service, instead he had to complete a civilian service at the university hospital at the age of 22. As he was clearly weaker than his colleagues, a diagnostic investigation took place, which included a skeletal muscle biopsy. At that time, doctors advised him to avoid excessive physical effort. He was told about the second wind phenomenon; however, it was not explained how to reach it. Additionally, he was recommended to eat a maximum of 20% of his daily food intake in carbohydrates. However, the rest of the macronutrients recommendations were not specified. In the following years, his physical activity level decreased, leading to physical deconditioning, loss of muscle mass, and increase in fatty adipose tissue and body weight. The third rhabdomyolysis episode was experienced one year ago and was nearly fatal. He was undergoing physical assessment for the insurance company and pushed himself too hard, resulting in a severe contracture of his lower back muscles. He was admitted to hospital. During the hospital stay he was also diagnosed with myocarditis. Following this episode, he decided to learn more about the condition to manage it better. He began doing gentle aerobic exercises, which improved his ability to attain a second wind. He attended a conference where he met a Spanish team from whom he learnt about the strength training trial performed in Madrid and decided to try it himself in a local gym []. Initially he approached a personal trainer. However, he did not feel the trainer understood his condition and was pushing him too hard. He decided to write his own programme based on strength training principles and exercises he learnt at the conferences and meetings. When in the gym he reports always doing an aerobic “warm up” by cycling on a stationary bike for 20 minutes, he then exercises on resistance machines (chest press, seated row, butterfly, chest horizontal adduction, reversed butterfly, rare deltoids and trapezius, lat pulldown, leg press, leg adductors, and leg abductors). He finishes his sessions with more aerobic exercise by walking on a treadmill and/or cycling on a stationary bike. and illustrate his progress during the first three months of training (based on personal records). He completes between 5 and 15 repetitions of each exercise with one-minute rest in between sets. He stops a set of exercise earlier if he feels any discomfort in the muscle. He did not report Delayed Onset Muscle Soreness (DOMS) or McArdle symptoms following initial sessions. After three months of resistance training, he found his sleep pattern, overall stamina and McArdle symptoms improved. He is now able to walk two kilometres stopping only once, as opposed to previously when he would have to stop multiple times. He has also found it easier to perform everyday tasks such as changing a car tyre. He has been eating a balanced diet. He autonomously chose not to take any supplements containing glucose pre- or intratraining session.
pmc-6186383-1	A 62-year-old male patient was followed by the Department of Medicine, Division of Nephrology of Mantua Hospital for treatment of recurrent pyelonephritis. The patient was on oral anticoagulant treatment (Warfarin) for pulmonary embolism, stage I obesity was diagnosed with the BMI amounting to 32.4, and he also had right-sided inguinoscrotal hernia permagna since 4 years, never treated for patient decision. The patient complained of symptoms during the last three weeks, such as dysuria, incomplete urinary bladder emptying, reduction of the size of the hernia after voiding, and increased urination after compression of the scrotal area. The blood test shown haemoglobin 11.3 g/dl, hematocrit 34.9%, platelet count 354 × 109/l, leukocytosis (13.5 × 109/l), and increased creatinine level (1.52 mg/dl), with urea level 57 mg/dl, international normalized ratio (INR) of 2.39. Urinalysis demonstrated hematuria, 61 white cell count/hpf, and the presence of Escherichia coli in urine culture. Nephrologist required surgical evaluation of that huge hernia. During the physical examination, the patient complained of pain and right-sided inguinal and scrotal discomfort with associated swelling in the ipsilateral testicle and scrotum. His abdomen was soft, nontender, and nondistended. Under clinical suspicion of bladder inguinoscrotal hernia, a scrotal ultrasound and an abdominal and pelvic CT scan with endovenous contrast were performed, revealing a right inguinoscrotal hernia, containing the whole urinary bladder and the right pelvic ureter, associated with right hydronephrosis with ipsilateral renal atrophy (Figures –). Therefore, the patient was admitted to the Department of Surgery of Mantua Hospital for treatment of right-sided inguinoscrotal hernia. Before surgical intervention, Warfarin therapy was replaced with therapeutic low molecular weight heparin (LMWH), and antibiotic prophylaxis was performed. A urethral catheter (18 Fr) was placed to decompress the bladder and to look for hematuria in the postoperative period. After spinal anaesthesia, a right inguinal incision was performed. After opening the right inguinal canal, we detected a direct inguinal hernia with complete breakthrough of the inguinal canal posterior wall. We opened the hernial sac containing the bladder and right ureter. After a long and careful isolation of the elements of the spermatic cord, physiological solution (500 ml) was injected by the urethral catheter to fill the bladder and, consequently, the pelvic ureter, in order to better define hernia content. The right ureter was very dilated, with a maximum diameter of more than 3 cm, as shown in , because of grade 4 vesicoureteral reflux. The bladder and the right ureter were gently separated from the spermatic cord. Without violating the urinary bladder wall integrity, the content of the hernial sac was reduced into the abdominal cavity. Hernioplasty was performed applying a polypropylene mesh, 10 × 15 cm in size, by means of Lichtenstein's method. The postoperative period was uneventful. Five days after surgery, the patient was discharged from the hospital in good general condition. Patient follow-up, with clinical examination and ultrasound, at one month and one year did not reveal hernia recurrence neither urinary disorders.
pmc-6186531-1	A 29-year-old woman visited the Oral and Maxillofacial Surgery Department of Seoul National University Hospital in December 2014 to resolve a malocclusion after fracture surgery. In March 2014, she sustained a maxillary comminuted fracture from a traffic accident, and ORIF was performed in another hospital. Thereafter, she received splint treatment for severe malocclusion and TMJ pain. The patient was admitted to our clinic because of persistent severe malocclusion. We observed a 3-mm deviation to the left, a downward displacement of the maxillary on the right side, and severe open bite in which all teeth were not touching except for the upper and lower right second molars. In addition, the patient complained of severe pain in the right TMJ and face. Treatment with orthognathic surgery using maxillary Le Fort 1 osteotomy was finalized as a treatment plan for the unresolved malocclusion by orthodontic treatment alone (Figs. and ). After 1 month of orthognathic surgery, the patient was maintained in intermaxillary fixation. After that, the malocclusion was resolved, and the temporomandibular joint and facial tenderness disappeared and the treatment was terminated (Figs. , , and ).
pmc-6186531-2	A 54-year-old man underwent placement of several localized flaps for complicated bone exposures after ORIF surgery in another department because of an extensive fracture of the mandible in November 2016. Several teeth were removed without a plan during surgery. To solve the resulting dental problems, he was referred for oral and maxillofacial surgery. On examination, the maxillary left central incisor and mandibular left central incisors to the first premolar had disappeared. The incomplete fixation of the fractured segment of the anterior teeth area resulted in bone resorption. After the operation, the height of the vestibule was significantly decreased, resulting in an abnormal shape and movement of the lower lip and incomplete pronunciation. Computed tomography (CT) was performed to determine the exact state of the bone fragments and confirmed that the bone fragments at the fracture site were extensively resorbed owing to bony necrosis. Mandibular reconstruction for the removal of the misplaced metal plate and extensive mandibular bone loss, additional vestibuloplasty and scar revision, and subsequent implant placement were planned. Therefore, conservative treatment was performed for the teeth with pulp necrosis due to trauma until the operation. Finally, mandibular reconstruction using an iliac bone graft was planned. In May 2017, conventional metal plate removal and mandibular reconstruction using an iliac bone graft were performed under general anesthesia. Bone grafting was performed using the extracted ilium, alveolar bone fragments, and synthetic bone. Six months after the operation, adequate union of the bone fragment was observed on CT, and the implant was placed in the edentulous area. The primary stability of the implants was excellent, and the implants were implanted using a one-step procedure. An artificial dermis graft was performed on the soft tissue defects. Three months after the implantation, the prosthetic treatment was performed. Currently, the prosthesis is attached, and vestibuloplasty is planned (Figs. and ).
pmc-6186811-1	In June 2016, a 34-year-old woman from Hunan Province in South China came to our hospital presenting with apparent weakness of the whole body, muscular atrophy, facial diplegia, hypophonia, dysphagia, and intermittent fasciculations of facial muscles starting in 2007 when she delivered her first child. The patient’s symptoms gradually deteriorated and worsened after her second child was born in 2011. She was diagnosed in local hospitals with gastritis at that stage. In 2012, she developed dysphagia and dysarthria. She had electromyography (EMG) in 2013, and the result showed extensive neurogenic damage, supported by reduced amplitude on musculus facialis, all limb muscles, and the sternocleidomastoid muscle. Two other hospitals diagnosed her with motor neuron disease (MND). She refused to use Riluzole, the first-line drug for amyotrophic lateral sclerosis (ALS), so no specific treatment was taken. She came to our hospital with respiratory distress, accompanied with symptoms of pneumonia such as cough and expectoration. She did not complain of visual or hearing impairment. She was a pharmacist and denied any poisonous substance exposure. Her father and mother had a first-degree consanguineous marriage. No other member in her family presented with any similar disorder. On physical examination, her higher mental function was found to be unaffected. Her height was 157 cm, and weight was 27 kg, with a body mass index of 10.95 kg/m2. She had facial diplegia (Figure ) with incomplete eyelid closure, and Bell sign was positive on the right side. Her muscles of mastication had decreased power and salivation was obvious. Sluggish palatal and gag reflexes, and fasciculation and atrophy of the tongue (Figure ) were observed. Fasciculation of the facial muscles was detected. She had generalized and symmetrical muscular atrophy, involving the face, trunk, and limbs (Figures ). She had an exhausted look with bulbar palsy and severe dyspnea. Muscle strength in the upper and lower limbs was assessed at United Kingdom Medical Research Council (MRC) grade IV. Bilateral Rossolimo sign was positive, and Babinsiki sign was positive on the right side. Tendon reflexes in the arms and legs were feeble. No sensory abnormality was detected. Coordinative movements including finger–nose incoordination, alternating movement, heel knee incoordination, and Romberg sign were normal. Meningeal irritation sign was absent. After admission, the following tests were normal or negative: serum creatinine kinase, copper, mercury, anti-neutrophil cytoplasmic antibody, anti-nuclear antibodies, thyroid hormones and antibodies, HIV antibody, tumor markers, and electrocardiogram. Paraneoplastic antibodies including Hu, Yo, Ri, CV2, Ma2, Amphiphysin, TR, ANNA-3, PCA-2, and GAD were negative. Genetic studies for whole exome sequencing were negative, including SOD1, ALS2, SETX, C9orf72, and FUS. Results of the following serum tests were abnormal (normal reference range in brackets): creatine 27 μmol/L (31.8–91.0 μmol/L), prealbumin 83 mg/L (200–400 mg/L), uric acid 74 μmol/L (90–420 μmol/L), low density lipoprotein 1.93 mmol/L (2.07–3.10 μmol/L), apolipoprotein B 0.52 g/L (0.6–1.1 g/L), cysteine protease inhibitor 0.39 mg/L (0.55–1.55 mg/L), β2 microglobulin 0.72 mg/L (1.00–3.00 mg/L), serum iron 2.1 μmol/L (11.0–27.0 μmol/L), and zinc 9.64 μmol/L (11.1–19.4 μmol/L). Superoxide dismutase (SOD) 121 U/ml (129–216 U/ml), vitamin B12 184 pg/ml (200–900 pg/ml), and vitamin B2 189.7 μg/L (>200 μg/L). Her blood white cell count was 10.8 × 10E9/L, neutrophil rate 87.4% (40–75%). Arterial blood gas analysis showed her oxygen was 72 mmHg and carbon dioxide 57 mmHg, and lactic acid 0.8 mmol/L, while the pH was normal. Sputum smear found gram positive cocci and Candida albicans, but sputum cultures for bacteria and fungus were negative. Abdomen ultrasound revealed hepatic microhemangioma. Chest CT showed bilateral pneumonia. Mild reduction in low frequencies (125, 250, and 500 Hz) in the left ear was detected by pure tone audiometry. EMG showed denervation in the muscles of the right paravertebral T10 and lower limbs, and chronic reinnervation in the upper and lower limbs. The patient refused EMG of the sternocleidomastoid muscle. Brain MRI demonstrated atrophy of cerebellum, with anterior lobe involved more severely (Figure ). Our patient was characterized with progressive general muscle weakness and atrophy, involving the limbs, trunk, and muscles of cranial nerves (cranial nerve VII, X, and XI). Clinical signs and symptoms and EMG suggested damage to the pyramidal tract, anterior horn cells, and bulbar nuclei. Her history and laboratory findings excluded intoxication, metabolism disorders, vascular diseases, trauma, tumors, and autoimmune diseases. The consanguineous parents suggested that it might be an inherited disorder, though exome investigations were normal. Her condition was special in the involvement of the facial nerve, which is rare in MND. After analysis, her clinical manifestations indicated MMND. So, the final diagnosis of MMND, with complications of pneumonia, respiratory failure (type 2), and malnutrition, was made. We treated her with intravenous immunoglobulin (IVIG) (0.4 g/kg once daily for 5 days) and other symptomatic treatment (e.g., oxygen inhalation, intravenous levofloxacin, and nutritional support). Her symptoms of cough and expectoration relieved a little, but her other symptoms did not improve. She refused ventilatory support by continuous positive airway pressure. She was discharged after the pneumonia was controlled, but intermittently needed treatment for pneumonia and respiratory failure. Her condition deteriorated and she died of respiratory tract obstruction caused by sputum in March 2017. We got her husband’s inform consent for reporting this case.
pmc-6186866-1	A 43-year-old female presented with a 3-month history of right-sided facial swelling associated with dry eyes, dysphagia with dry foods, fevers, and weight loss. On examination, there was right-sided facial swelling, nontender. Serology for tuberculosis, human immunodeficiency virus, antinuclear, anti-Ro, and anti-La antibodies was all negative. A chest radiograph showed bilateral hilar adenopathy. MRI (Figure ) revealed asymmetric right parotid enlargement involving both superficial and deep lobes. The parotid tail was excised, demonstrating non-necrotizing granulomas (Figure ). Closer examination (Figure ) showed a foreign body giant cell with Schaumann body present. These findings were consistent with sarcoidosis, presenting as Heerfordt syndrome. Sarcoidosis is a granulomatous disorder of unknown etiology and one of the “great masqueraders” of medicine. Although most patients have thoracic involvement, more than half do not have respiratory symptoms at presentation. Up to 30 percent of patients present with extrathoracic manifestations. Heerfordt syndrome was first described by the Danish ophthalmologist Christian Heerfordt in 1909, and the association with sarcoidosis was made by the Swedish internist Jan Waldenstro¨m in 1937. Due to its rarity, the exact prevalence is unknown and physicians should include the disease in the differential of parotid swelling. As in this case, chest radiography is helpful and definitive diagnosis can be made by histopathology.
pmc-6186870-1	In 2007, a 34-year-old woman was referred to the Hematology Department of Tor Vergata University Hospital in Rome with a IgA kappa multiple myeloma (MM) (DS stage IIA; ISS-1; symptomatic for Anemia). Her past medical history was unremarkable. She was diagnosed after presentation to a dermatologist for a febrile rash with erythematoviolaceous nodules on hands, forearms, and trunk (See also Figure ). Bone marrow (BM) aspirate revealed 50% infiltration by mature plasma cells. A skin-lesion biopsy confirmed the diagnosis of malignancy-associated Sweet's syndrome, according to the criteria proposed by Walker and Cohen's. The patient was started on PAD (bortezomib, doxorubicin, and dexamethasone) chemotherapy. Considering immunosuppression, due to MM and the concomitant treatment with dexamethasone, she was given colchicine (1.5 g/die) for the treatment of the Sweet's syndrome. The lesions disappeared after 10 days, and she continued the MM therapy. She later underwent peripheral blood stem cells (PBSC) mobilization with cyclophosphamide, and received high-dose melphalan (MEL200) with PBSC transplantation in February 2008, achieving a very good partial response (VGPR). After Bortezomib/Interferon-alpha-based post-transplant maintenance, the cutaneous rash relapsed in April 2011, concomitant with MM recurrence. She restarted colchicine and Lenalidomide-Dexamethasone. The three subsequent MM relapses were accompanied by occurrence of Sweet's Syndrome, which was indeed the first sign of relapse in all cases and reverted under colchicine and salvage treatment for MM (Table ).
pmc-6186872-1	A 22-year-old female, sexually active, patient referred to our department with fever and abdominal pain. The patient referred an obscure history of recurrent urinary tract infections. Palpation during clinical examination revealed acute pain of the left flank reflecting to the unilateral abdominal region. The patient presented high fever up to 39°C. Patient's history included left renal pelvic ectopia, and autoimmune hepatitis, which both diagnosed 8 years ago. During all this period, prezolon 10 mg x2 and azathioprine 50 x3 were administrated systematically. Leucocytosis with left turn of the type with predominance of neutrophils was the main finding in blood examinations. The urine analysis revealed increased white blood cells in the sample (100-120 ps). Further examination with abdominal ultrasound and CT scan revealed an hypoplastic left pelvic kidney without hydronephrosis but with multiple abscesses in its upper pole (Figures and ). The patient treated conservatively with antibiotics. Ciprofloxacin (400 mg twice a day) and metronidazole (500 mg every 8 hours) were administrated intravenously. Although an initial temporary improvement, the disease progressed leading to an inevitable surgically performed left transabdominal nephrectomy. Macroscopical histological examination of the removed specimen revealed multiple abscesses in the upper pole of the kidney (Figure ). Microscopical examination of the specimen confirmed the presence of multiple necrotic abscesses and the destruction of the normal renal parenchyma (Figure ).
pmc-6186873-1	In January 2014, a 53-year-old man experienced dyspnea induced by medium intensive efforts. His comorbidities included essential hypertension and gastroesophageal reflux disease (GERD). In February 2014, the patient reported left chest pain, which was initially attributed to GERD. Past medical history revealed no history of smoking. As a factory worker, however, he had been exposed to environmental asbestos. In March 2014, results of the chest radiograph showed massive left pleural effusion. One week later, a computed tomography scan of the chest revealed a large mediastinal, parietal, and diaphragmatic left pleural thickness, along with paratracheal and contralateral enlarged right hilar lymph nodes (Figure A). In April 2014, the patient underwent left video-assisted thoracoscopic surgery with talc pleurodesis for pleural effusions. Histologic analysis of the three pleural biopsies revealed morphology that was consistent with epithelioid subtype MPM. At baseline, the total tumor measurement of target lesions (according to modified Response Evaluation Criteria in Solid Tumors [RECIST]) was 116 mm, and the forced vital capacity (FVC) was 2.57 L. The overall course of treatment is described in Figures , , . Following the initial diagnosis, the patient was enrolled in the LUME-Meso Phase II randomized, double-blind study. Although it was not known at the time, the patient was randomized to receive nintedanib in addition to pemetrexed plus cisplatin in April 2014. Pemetrexed plus cisplatin was administered for six 21-day cycles at standard doses: 500 mg/m2 of pemetrexed administered intravenously (IV) over 10 minutes on Day 1, and 75 mg/m2 of cisplatin administered IV over 2 hours on Day 1. Nintedanib was given orally at 200 mg twice daily (bid) on Days 2–21 of each 21-day cycle. The patient also received maintenance treatment from August 2014 to December 2014. In June 2014, during the third treatment cycle, Grade 3 venous thromboembolism was reported. The event was considered unrelated to study treatment and did not require any change to treatment. Follow-up imaging was carried out every 6 weeks from randomization. From June 2014 to October 2014, the patient showed a very good partial response (Figure ), as evidenced by a decrease in the total tumor measurement of target lesions from baseline (116 mm) to 64 mm, 50 mm, 40 mm, and 41 mm at Week 6, Week 12, Week 18, and Week 24, respectively. There was an increase in FVC from baseline, as measured in May (24.1%), June (22.6%), July (16.0% and 21.0%), August (19.1%), September (15.6%), October (21.4% and 25.7%), and November 2014 (25.3%). In December 2014, there was tumor progression, as indicated by an increase of 77.5% in the total tumor measurement of target lesions from the nadir at Week 24. In the same month, the change in FVC from baseline was 14.4%. Treatment was subsequently stopped due to disease progression that was seen in the final tumor assessment. Following discontinuation, the patient reported an increase in symptoms such as thoracic pain and dyspnea during tasks requiring mild effort. In January 2015, the patient was enrolled in the Phase II ATREUS study, at which time the total tumor measurement of target lesions was 92 mm. The patient received 1.1 mg/m2 IV trabectedin infusion in 5% glucose via central venous catheter over 3 hours every 21 days. The trabectedin infusion was preceded by 20 mg of IV dexamethasone. The best response to trabectedin was progressive disease (total tumor measurement of target lesions: 107 mm). In February 2015, third-line treatment with gemcitabine plus carboplatin was administered for three cycles but, again, showed progressive disease (Figure A). In May 2015, the patient was rechallenged with six cycles of fourth-line pemetrexed, with the addition of nintedanib 200 mg bid from the second cycle onwards. Treatment was received through individual compassionate use. This regimen stabilized disease progression again for >5 months (Figure ), with the sustained response indicated by a decrease of 12.6% in the baseline tumor measurement between July 2015 and September 2015 (Figures and B). This disease stabilization was associated with a clear clinical benefit in terms of symptom relief and improved dyspnea. During the rechallenge, the patient reported a Grade 2 perimalleolar edema, for which furosemide was administered at 10 mg per day. Although the patient showed stable disease according to RECIST, a slight increase in target lesions was observed in September 2015 (Figure C), and therefore, carboplatin was added to the treatment regimen; however, disease progression continued. In December 2015, the patient's total tumor measurement of target lesions had increased to 219 mm, with new nontarget lesions observed. At the end of December 2015, the patient was administered three cycles of fifth-line vinorelbine; however, the disease continued to progress and the patient died at the end of March 2016, 23 months after the diagnosis of MPM.
pmc-6186874-1	A 71-year-old African American female with a history of hypertension was diagnosed with stage IIa classical HL in 2003. She underwent four cycles of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) achieving a complete remission (CR). In 2016, she developed progressive bilateral patchy visual loss over 4 months prior to seeking medical attention. She was seen by an ophthalmologist (AKR) who diagnosed bilateral FBA (Figure ). Based on the ophthalmologic findings, patient was evaluated for HL relapse. She was otherwise asymptomatic and has gained 1.4 kg over the past year. Full blood count and chemistry profile were unchanged. Testing for other causes of FBA was negative, including fluorescent treponemal antigen absorption (FTA-ABS), T-spot, angiotensis-1-coverting enzyme, muramidase-lysozyme, Antineutrophil cytoplasmic antibodies (ANCA), and toxoplasma IgG and IgM antibodies. Testing from an ocular fluid sample for viral causes was deferred by the patient. Computed tomography (CT) scan of the chest, abdomen, and pelvis showed a mildly prominent left supraclavicular lymph node as well as enlarged nodes at the right iliac chain and right iliac fossa. Positron emission tomography (PET) scan showed diffuse involvement of the left supraclavicular, bilateral iliac chain, and retroperitoneal lymph nodes with maximum standardized uptake values (SUV-max) of 10.7. There were right paracolic soft tissue tumor implants with SUV-max of 5.8, and metabolically active sclerotic lesions in the left iliac bone with SUV-max of 3.4. A right external iliac node biopsy confirmed classical HL with the same histological and immunohistochemical findings as the biopsy at presentation. Reed-Sternberg cells were positive by immunohistochemistry for CD15 and CD30, and negative for CD45, CD20, CD3, EBER, and AE1/AE3. Flow cytometry showed no immunophenotypic evidence of monoclonal B lymphocytes or immune-phenotypically abnormal T lymphocytes. Patient started intravenous therapy for HL with brentuximab vedotin and intraocular injections of bevacizumab 1.25 mg/0.05 mL monthly for 4 months. After two cycles of brentuximab, the patient achieved a CR by PET/CT scan. Because of the long first remission, patient's age, and preference, it was decided to continue brentuximab and not proceed with autologous stem cell transplant. Her vision improved from 20/30 to 20/25 OD (right eye) and worsened from 20/50 to 20/65 OS (left eye) over the course of 6 months after the beginning of HL treatment. The lack of improvement in the left eye was secondary to a choroidal neovascular membrane which developed subfoveally. On follow-up imaging with fluorescein angiography her periphlebitis minimally improved in both eyes and she had resolution of her angiographic edema in the right eye, but no improvement in the left eye. (Figure ).
pmc-6186875-1	A 68-year-old female patient visited Hiroshima University Hospital with a chief complaint of gingival discomfort around the left mandibular first molar (tooth 36). She had no history of trauma, orthodontic treatment, or bleaching, however, the affected tooth and the second premolar were abutments of a three-unit metal cantilever bridge. The pontic, which was connected to the two crowns, extended into the missing second molar space. This bridge had been fixed approximately 15 years before the first visit. She had a malocclusion, open bite, and crossbite (Figure A). There was no relevant medical history. There was bleeding on probing on 36 with a pocket depth of 3 mm in all areas except the buccal furcation (6 mm). The tooth responded positively to thermal and electric pulp vitality tests by PULPER® (GC Dental Industrial Corp.) and Digitest® (Parkell) after removal of the metal crown. Attached gingiva was observed around tooth 36 (Figure A). There was no spontaneous and percussion pain. A dental radiograph showed a radiolucent lesion extending from the distocervical level to the coronal third of the root and no pathological change around the root apex (Figure B). A radiographic examination revealed an “irregular mottled” or “moth-eaten” pattern in the main lesion area of the cervical area and the lesion showed a radiopaque mineralized outline of the canal through radiolucency of the external resorptive defect (Figure B)., , To determine the extent and depth of the lesion area in three spatial levels, cone-beam computed tomography (CBCT) was performed. In sagittal and axial slices, we observed the entry points of the granulomatous tissue, which were located in the distal and furcation areas of the buccal cervical root (Figure C,D). Communication with the root canal was observed in sagittal and axial slices (Figure C,D). Buccal alveolar bone resorption, which continued with ICR, was observed in coronal slices (Figure E). A series of CBCT images showed the resorptive lesion with an “outside-in” appearance. According to dental radiography and CBCT findings, tooth 36 was diagnosed as Heithersay Class 3 ICR. In addition, the new three-dimensional classification of ICR using CBCT showed that the ICR in this case was classified as 3Bp (ICR lesion height 3: extends into the mid-third of the root, circumferential spread B: <180°, proximity to the root canal p: probable pulpal involvement). Debridement, perforation repair of the resorptive area with mineral trioxide aggregate (MTA) (ProRoot MTA®, Dentsply Maillefer) and root canal treatment were performed with the patient's informed consent. The full thickness flap was raised to allow visualization of the entry point of the granulomatous (Figure A), which was subsequently removed from the surgical site with a spoon excavator (Figure B). A sonic instrument (Varios 750®; Nakanishi Inc.) was then used to remove the residual granulomatous tissue (Figure C). As a result, a larger defect size was observed and the pulp was exposed. Because the exposed size measured approximately 3 mm in diameter (Figure D), endodontic treatment was performed. The working length was determined by using an electric apex locator (Root ZX®; J Morita). The root canals were cleaned and shaped by a rotary NiTi file (size 45/.04, K3®, SybronEndo) using the crown-down technique. MTA was subsequently used for perforation and defect repair (Figure E). The cavity was temporarily double-sealed with temporary stopping (Temporary stopping®, GC Dental Industrial Corp.) and glass ionomer cement (Base cement®, Shofu Inc.). The flap was then repositioned without tension and sutured interproximally (Figure F). The patient was recalled 1 week after the operation. The tooth had been asymptomatic. The tooth was isolated with a rubber dam. After removal of the temporary seal (Figure G), the root canals were copiously irrigated with sodium hypochlorite (Neo Cleaner®, Neo Dental) and ethylenediaminetetraacetic acid (Smear Clean®, Nippon Shika Yakuhin KK). Calcium hydroxide (Calcipex Plane II®, Nippon Shika Yakuhin KK) was used as an intracanal medication. Since the patient exhibited no clinical symptoms after 3 months, bacterial examination using an anaerobic culture system was performed to evaluate the presence or absence of bacteria in the root canals. The root canals were filled with gutta-percha (Dentsply Maillefer) and sealers (Canals-N®, Showa Yakuhin Kako Co., Ltd.) using the single-cone technique since the bacterial examination was negative (Figure H). One month after root canal filling, thin attached gingiva and plaque accumulation on the cervical contour were observed in tooth 36 with the temporary crown (Figure A). The width of attached gingiva after the first stage of treatment (Figure A) was narrower than that at the first visit (Figure A). To increase the width of attached gingiva surrounding the tooth, free gingival graft (FGG) was performed. The graft recipient site was prepared by partial-thickness dissection (Figure B). Hardened MTA (Figure B), which had been used to fill the resorptive site in the first stage of treatment, was covered with glass ionomer cement (Fuji IX®, GC Dental Industrial Corp.) using the sandwich technique or multidisciplinary approach (Figure C). Donor tissue was procured from the palate. The graft was then sutured at the coronal margin to ensure immobilization (Figure D). The 3-year follow-up demonstrated that the tooth with the full metal crown exhibited no clinical symptoms (eg, no pain, swelling, or mobility with a periodontal pocket depth <3 mm) and adequate width of attached gingival was maintained (Figure A) compared with before FGG (Figure A). In radiographs, the affected tooth and its surrounding tissues demonstrated no pathological changes (Figure B-D).
pmc-6186876-1	A 68-year-old woman presented to the Department of Oral and Maxillofacial Surgery at Nagoya Ekisai Hospital (Nagoya, Japan) with a chief complaint of malaise and a 7-month history of swelling of the left buccal mucosa. The patient had no congenital swelling of the left buccal mucosa at birth and no history of systemic disease or relevant family history. The patient had undergone maxillary molar restoration treatment 2 years earlier, after which she reported biting regularly on her buccal mucosa. On most occasions, the wound had healed within a week, so she had not sought medical treatment. An extraoral examination revealed no facial swelling or asymmetry. However, an intraoral examination revealed an area of diffuse swelling on the left buccal mucosa measuring about 15 mm × 30 mm and containing a papillary lesion with multiple red, blue, and clear pebble-like vesicles (Figure ). On palpation, the lesion was nontender and soft. The swelling had not expanded to the veins and was pulsatile. An orthopantomogram confirmed that the adjacent bone was intact. Magnetic resonance imaging revealed a soft tissue mass with a clearly distinguishable outline of the buccinator muscle (Figure ). The lesion was surgically excised under local anesthesia with a margin of 3 mm and a depth of 2 mm via the inside surface of the fascia of the buccinator muscle. The outcome was favorable. Pathologic examination of the specimen revealed expanded lymphatic vessels lined by thin endothelial cells and containing lymphatic fluid. A diagnosis of lymphatic malformation was confirmed on histopathology and immunohistochemical studies. Immunohistochemistry was negative for vascular markers such as CD31 and CD34, and the lymphatics stained specifically for D2-40 (podoplanin) (Figures , , ). On follow-up, the wound was found to have healed with no evidence of trismus or recurrence. The patient continued to be recurrence-free at her 2-year follow-up. Informed consent was obtained from the patient, and the procedures were in accordance with the Helsinki Declaration.
pmc-6186881-1	A 76-year-old man presented to our department with intractable pneumothorax with IP. Pleurodesis and endobronchial Watanabe spigot embolization were attempted by the previous treating physician after drainage but were ineffective. The chest x-ray and computed tomography scan demonstrated severe fibrotic changes in both lung fields, left pneumothorax, and a chest tube that was not appropriately positioned (Figure A,B). We prioritized conservative treatment because the patient had been prescribed 15 mg of prednisolone for IP since the age of 74 years. First, the drainage tube was repositioned, and pleurodesis was performed twice. Next, the thoracographic fibrin glue sealing method was performed. However, these treatments failed. We opened the chest through the fifth intercostal space. The apex of the lung was adhered to the chest wall, but there were no other abnormalities identified other than an air leakage point on the dorsal side of the S1+2 segment. The position of the air leak was consistent with the identified region during thoracography. Two bullae were identified with no air leakage. The air leakage defect was cauterized with a soft coagulation system, and then the defect was closed with U stitches using 4-0 Prolene (Ethicon, New Brunswick, NJ, USA), with TachoSil (Zurich, Zurich, Switzerland) sutured to the lung surface (Figure A,B). The other two bullae were covered with TachoSil in the same manner. A chest tube was inserted into the thoracic cavity, and the chest was closed in the typical manner. His postoperative course was favorable.
pmc-6186885-1	A 27-year-old postpartum woman presented to the emergency room with pruritic pink macules and papules distributed on the bilateral legs, forearms, shoulders, and abdomen (Figure ). Two weeks prior to presentation she was diagnosed with a hospital-acquired pulmonary embolus following preterm delivery of her twin pregnancy. She was immediately started on enoxaparin (50 mg) administered daily following identification of the embolus. After approximately 10 days of therapy she first noticed the pruritic lesions beginning. She denied any new food, medication, or other exposures with the exception of enoxaparin (50 mg daily). Review of systems was negative for fevers, chills, sick contacts, sores on the mucus membranes, abdominal pain, or other systemic complaints. No viral sampling was performed given the lack of systemic symptoms. Laboratory work-up for heparin/platelet factor-4 antibodies was negative and complete blood count was unremarkable (WBC = 3.9 × 103/μL; RBC = 3.74 × 106/μL; Hemoglobin = 11.2 g/dL; platelet count = 246 × 103/μL). She was diagnosed with a nonspecific inflammatory papular dermatitis and started on triamcinolone ointment with planned outpatient follow-up. Three days after evaluation in the emergency department she presented to the outpatient dermatology clinic for progression of her rash and significant pruritus. A review of systems was unchanged. Physical examination revealed dozens of 2-8-mm blanching pink papules with surrounding faint halos distributed on the arms, legs, abdomen, and back (Figure A). Due to the change in morphology, biopsies of an active abdominal lesion for H&E stain and immunofluorescence were performed to rule out pregnancy-related dermatoses including late onset pruritic urticarial papules and plaques of pregnancy (PUPPP) and pemphigoid gestationis. In the meantime, she was continued on triamcinolone. She returned to the clinic 1 week following biopsy for follow-up. During this time period her condition had considerably worsened necessitating an urgent care visit where she was started on 20 mg of prednisone per day, with minimal improvement after 4 days of treatment. On physical examination, the development of numerous targetoid pink plaques with dusky centers and erosions, distributed on the arms, legs, back, abdomen, and chest, was seen (Figure ). No mucosal involvement or systemic symptoms were present except extreme pruritus. Histologic findings revealed perivascular lymphocytic inflammation, necrotic keratinocytes, and increased dermal mucin consistent with a drug eruption (Figure B). Interestingly, an eosinophilic infiltrate was not identified as would be expected in a drug-related process. Direct immunofluorescence was negative. Based on the temporal relation of lesions to initiation of enoxaparin, a diagnosis of enoxaparin-induced erythema multiforme was made. She was started on prednisone 60 mg daily and initiated warfarin therapy for anticoagulation. Enoxaparin was continued as bridging therapy until achieving therapeutic anticoagulation with warfarin, and subsequently discontinued. Upon discontinuation of enoxaparin there was rapid improvement within a week with cessation of new lesion development and desquamation of old lesions (Figure ).
pmc-6186888-1	An 85-year-old female with a past medical history of diabetes mellitus, hypertension, and hyperlipidemia underwent surgical consultation in October 2015 for an incidentally found right foot mass subsequent to an elective gynecologic procedure. The patient first noticed a small lesion on the dorsum of her right foot approximately 12 years ago. She never sought medical attention for this slowly growing and asymptomatic lesion. However, this lesion had been growing more rapidly and had become foul smelling over the past 3 weeks. She denied any pain, paresthesias, weight loss, or recent trauma to the foot. She also denied any history of smoking or significant sun exposure. Her only surgical history included a recent total abdominal hysterectomy and left salpingo-ophorectomy. On physical examination, she was a well-nourished Caucasian female who was found to have a large exophytic, fungating 8.0 × 8.0 × 0.6 cm malodorous mass on the dorsum of her right foot (Figure ). This mass was insensate to light touch with no surrounding erythema. She had palpable dorsalis pedis and posterior tibial pulses with full range of motion of that foot. The left lower extremity was benign in examination, with no masses or lesions. A thorough dermatologic examination did not reveal any other concerning lesions. A punch biopsy of this mass was consistent with BCC. Subsequent magnetic resonance imaging (MRI) showed a large soft tissue irregularity surrounding the second to fifth extensor tendons (Figure ). Given these findings, the patient underwent a wide local excision of this BCC with full-thickness skin graft for coverage. The lesion was excised in its entirety with a 5-mm circumferential margin beyond the extent of visible tumor. This incision was carried down directly to the fascia overlying the extensor digitorum longus tendons. Intraoperative pathologic evaluation noted a negative deep margin; therefore, resection of extensor tendons was not required. The specimen was sent to pathology en bloc revealing an 8.2 × 6.4 × 1.4 cm lesion consistent with BCC, nodular subtype with clear margins (Figure ). The dorsalis pedis artery was clearly identified and safely avoided during the procedure. A full-thickness skin graft (FTSG) measuring 7 × 10 cm was obtained from the right lower abdomen. Multiple small incisions were made approximately 1 cm apart on the FTSG to allow for egress of fluid. The FTSG was then tacked onto the wound bed using 5-0 chromic sutures. The wound was bandaged with nonadherent Xeroform dressing, bulky gauze fluffs, a compression wrap, and placed in a posterior splint for immobilization. The patient was maintained on bed rest with extremity elevation until postoperative day 3 at which point she was allowed to ambulate with toe-touch weight bearing precautions on her right lower extremity. Dressings were removed on postoperative day 4, revealing a healthy and viable graft. She had palpable pedal pulses and intact motor and sensory function. She was discharged on postoperative day 4 with instructions to continue toe-touch weight bearing precaution on her right foot with continued outpatient follow-up. At 1-year follow-up, her wound had fully recovered without complication (Figure ), and at 2-year surveillance, she remains without any recurrence of disease.
pmc-6186889-1	A 45-year-old woman with a history of stage IV Hodgkin's Lymphoma, which was diagnosed 6 months prior and treated with six cycles of Adriamycin (Doxorubicin), Bleomycin, Vinblastine, and Dacarbazine (ABVD) chemotherapy. Her other past medical history included depression and gastro-esophageal reflux. The patient initially presented to a rural emergency department 2 weeks after her sixth and final scheduled cycle of ABVD. She complained of increasing dyspnoea and paroxysmal nonproductive cough over the past several days. She denied fever, coryzal symptoms, or chest pain. She was tachypneic with a respiratory rate of 44 breaths per minute. Her oxygen saturation was 94% receiving supplemental oxygen of 10 L/min. Her blood and urine laboratory results were unremarkable with the exception of liver function derangement (alkaline phosphatase of 164 units/L and gamma glutamyl transferase of 282 units/L) which was pre-existing. Her electrocardiogram demonstrated sinus rhythm without any ischemic changes. The chest x-ray revealed widespread bilateral pulmonary infiltrates. The patient was treated for a suspected community acquired pneumonia. She was therefore treated with Ceftriaxone (1 g once daily), intravenous Azithromycin (500 mg once daily), and Oseltamivir (75 mg twice daily). She also received intravenous Hydrocortisone (100 mg four times daily). Due to nausea, Ceftriaxone was replaced by intravenous Moxifloxacin. As she was immunosuppressed, oral Trimethoprim/Sulfamethoxazole was added to empirically treat Pneumocystis jeroveci pneumonia (PJP). Blood and urine cultures revealed no growth of micro-organisms. On day 2 and day 3, her condition deteriorated with fever, increased work of breathing and worsening hypoxia, which resulted in intubation and mechanical ventilation. Her repeat chest x-ray revealed worsening bilateral pulmonary infiltrates. Due to limited resources at the rural hospital, she was subsequently transferred to our ICU. In ICU, the antibiotic therapy was escalated to Cefepime and Vancomycin. Moxifloxacin was ceased, and Oseltamivir was later empirically changed to Aciclovir to cover herpes infection. Cisatracurium infusion was added to sedation in order to improve oxygenation and assist ventilation. Other therapies included Furosemide for suspected fluid overload and nebulised Iloprost for further improvement in her gas exchange. The patient had a mild neutrophilic leucocytosis. Her procalcitonin levels were persistently normal. Repeated sputum and blood cultures, respiratory swabs, PJP serology, mycoplasma serology, respiratory viral polymerase chain reaction (PCR), hepatitis B serology, hepatitis C serology, and aspergillus (Galactomannan) were negative. Urinary Legionella pneumophilia serogroup 1 antigen and urinary pneumococcal antigens from the previous hospital and from our hospital were not detected. A fiberoptic bronchoscopy, performed by the treating intensivist, revealed mild inflammation at the carina and mucoid sputum in left bronchial tree. Washings from the alveolar bronchial lavage were negative for bacterial, acid-fast bacilli, and fungal cultures, Mycoplasma, PJP, herpes simplex and zoster, cytomegalovirus PCRs and for cytology. A computed tomography and pulmonary angiogram (Figure ) revealed diffuse ground-glass appearance and consolidation of both lungs. Small segmental emboli in the right upper lobe and lateral basal right lower lobe branches were also detected. However, the thrombus load was not radiologically or echocardiographically significant enough to cause right heart strain or to warrant thrombolysis. Nonetheless, the pulmonary emboli were treated medically with subcutaneous enoxaparin. With exclusion of infection and in consultation with our hematology team, there was an increasing suspicion of BIP. On day 4 of admission to ICU, pulsed intravenous methylprednisolone was commenced at a dose of 1 g daily for three consecutive days followed by a maintenance dose of 1 mg/kg daily for the remainder of admission. However, on day 6 of ICU admission, the patient's condition further deteriorated with worsening hypoxia (PaO2/FiO2 <100), poor ventilation, and increasing bilateral opacities on chest x-ray. In light of persisting respiratory failure with no appreciable response to treatment and no identifiable infective cause, there was an increasing certainty surrounding the diagnosis of BIP. Given its documented success in attenuating bleomycin-induced pulmonary fibrosis in animal models, a single dose of infliximab was administered intravenously at a dose of 5 mg/kg. The patient was monitored for, and did not develop signs of an acute infusion reaction or hypersensitivity. She also did not appear to develop any observable acute adverse effects subsequent to treatment with Infliximab. Over the following week, the patient demonstrated no clinical improvement despite treatment. The patient was not considered to be suitable for extracorporeal oxygenation or lung transplantation due to the irreversible nature of lung injury. It was agreed that the prospects of recovery were exceedingly poor, and all parties including the family were of the view that ongoing treatment and attempts at therapy would be futile. The decision was made for palliation and comfort care. The patient passed away shortly after the withdrawal of ventilation and active treatment on day thirteen of ICU admission. During patient's admission, our ICU maintained consultation with specialist inpatient hematology, respiratory, infectious diseases, and general medical units regarding alternative diagnoses and approaches to management. Imaging studies were discussed with experienced radiologists at multidisciplinary meetings. In the setting of severe disease unresponsive to antimicrobial and glucocorticoid therapy, all teams were of the impression that the clinical, laboratory, and radiological features were most consistent with a diagnosis of fibrotic BIP. For this reason it was decided not to perform a postmortem lung biopsy. We note a number of cases in the literature where a confident clinical diagnosis of BIP has been made in the absence of tissue biopsy.,
pmc-6186987-1	A 75-year-old female patient with previous hystory of active smoking at 75 year-package associated with other cardiovascular risk factors (hypertension, hypercholesterolemia, non-insulin-dependant diabetes, and obesity) has been sent to our university hospital for a suspicion of strangulated umbilical hernia. An abdomen and pelvis CT scan was then performed and found a diffuse infiltration of mesenteric fat evoking a peritoneal carcinosis without primary tumor clearly identified. An exploring laparoscopy showed a visual aspect of inflammatory peritoneum with a thickened epiploon and non-tumorous ovaries. On the contrary, histopathological examinations (biopsy and cytology) suggested an immunohistochemical profile compatible with high-grade serous papillary carcinoma of ovarian or peritoneal origin. The therapeutic strategy included neo-adjuvant chemotherapy by CARBOPLATIN-PACLITAXEL and interval surgery after 3 cycles. Moreover, an 18F-fluorodeoxyglucose (18F–FDG) Positron-emission tomography (PET/CT) was performed not to ignore a supra-diaphragmatic remote extension of disease that would exclude surgery indication. In addition to multiple hypermetabolic known peritoneal carcinomatosis lesions (Figure ), PET CT found fortuitly a pathological 18F-FDG uptake upon a high paramediastinal tissue 3 cm mass located at the left pulmonary apex (SUV max: 12.8) (Figures –). Due to this suspicion of remote extension of disease or secondary primary tumor, a biopsy under CT scan was performed. The histolopatological analysis concluded with an appearance of Schwannoma, without any sign suggestive of malignancy. While awaiting the histological characterization of this mass, the patient finally benefited from 6 cycles of chemotherapy before surgery by laparotomy. Unfortunately due to carcinomatosis extended to the entire abdominal cavity with a peritoneal index at 19 () a complete resection surgery was not possible and new courses of CARBOPLATIN TAXOL were scheduled.
pmc-6187017-1	We present the case of a sixty-year-old male patient, who is a smoker with negative past medical and surgical history. He presented to our surgical clinic, with a right axillary mass which was noted first, three years before presentation. The mass has been slowly increasing in size and becoming painful. There was no history of trauma to the affected area, fever, night sweats, chills or any other systemic symptoms. He only complained of a painful, visible swelling but had no weakness, numbness or loss of function of the right upper limb. He reported no history of any drug intake. Furthermore, family history was unremarkable, he didn’t report any relevant psychosocial history. On examination, no skin changes were observed. He had a right axillary mass that is measuring about 4 × 3 cm, which was firm, mobile and tender on palpation. It was nonadherent to the underlying tissue. No palpable left axillary or cervical lymph nodes. Muscle power in all muscles was 5/5; the sensation was intact. Tinel sign was positive with tingling sensation along the shoulder tip. The left axilla was normal. Chest examination was unremarkable as well. Based on the history provided by the patient and the examination findings, our differential diagnosis included axillary lymphadenopathy, lipoma, fibroma, vascular tumors, and paraganglioma. Laboratory investigations were normal. Furthermore, Ultrasound-Soft tissue of the right axilla, revealed a subcutaneous, well defined, hypodense lesion, measuring 3.7 × 2.4 cm with evidence of cystic degeneration (). Also, an Ultrasound guided tru-cut needle biopsy was performed under complete aseptic technique, with no immediate complications. The histopathology sections show a tumor formed of benign-looking spindle cells with Hypercellular and hypocellular areas and vascular hyalinization. Immuno-histo-chemistry of the tumor cells was positive for S100. The diagnosis was right axillary Schwannoma. MRI of the right brachial plexus revealed an expanding lesion within the right axilla measuring 3.0 × 3.8 × 2.3 cm in maximum dimension, with primary cystic component and an irregular thickened wall that showed significant enhancement after intravenous contrast administration. The lesion is located beneath the axillary vessel. No evidence of osseous infiltration, (). The whole spine MRI was also performed to rule out other synchronous lesions. It showed, straightening of the cervical spine, with a diffuse central disc bulge in C3-4, C5-6, C6-7, there were no masses visualized. He also underwent neurophysiology testing, which was normal with no evidence of neuropathy, radiculopathy, or plexopathy of the right upper extremity. He underwent Exploration of brachial plexus and excision of the tumor. It was performed by the co-authors of this paper. The surgery was performed starting with a transverse incision along the skin line. Dissection carried out through planes, between the borders of Pectoralis Major anteriorly and Latismus Dorsi muscles posteriorly. The tumor was identified, measuring 4 × 4 cm. It was adherent to the musculocutaneous nerve. Using a nerve stimulator, we safely dissected the tumor preserving the nerve nearby. The lesion was completely excised and was sent for histopathology, (). Histopathology confirmed the diagnosis of right axillary schwannoma, with no evidence of malignancy, (). In the post-operative period, the patient had an uneventful recovery. He was followed up in the clinic and displayed no neurological deficits, his wound has healed, the histopathology findings were discussed and he was satisfied with the care provided.
pmc-6187018-1	A 65-year-old woman was admitted to our hospital with generalized bone pain and a progressive painless mass in her jaw since 6 months ago. She had a history of two times parathyroidectomy, first being in 2008 (10 years ago). The patient was evaluated for weakness and elevated serum level of Ca and PTH in laboratory data, the parathyroid scintigraphy with 99mTc-MIBI revealed a left parathyroid adenoma. Then, she underwent surgery and the pathological findings was in favor of left parathyroid adenoma. During the follow up in 2010 (8 years ago) she had been hospitalized due to the elevated serum level of Ca and PTH again. The neck ultrasonography revealed a multi nodular thyroid goiter. The parathyroid scintigraphy was performed which showed bilateral parathyroid hyperplasia. The patient subsequently underwent a second neck operation with removal of right parathyroid glands and exploration of left side of neck. However, the left parathyroid glands were not found. The pathology report was a thyroid nodule, parathyroid tissue with hyperplastic changes. In her recent hospitalization, she presented with complaint of weakness, bone pain and a progressive swelling in her jaw (). On examination a well-circumscribed firm and non-tender swelling in the mandile measuring about 50 mm × 50 mm was revealed. The surface skin over it was shiny but there was no ulcer or discharge. Laboratory analysis showed a hypercalcemia: 13.4 mg/dl (normal range: 8.6–10.4) and plasma PTH was 398 pg/ml (normal range: 8–76 pg/ml), 24-hour urinary calcium was at 328 mg/24 h (N < 300). The vitamin D level was subnormal at 35 nmol/lit (normal range: 45–144 nmol/lit) and dual energy X-ray (DXA) showed osteoporosis with a T-score of -3.8 at the neck of hip and -3.7 at lumbar spine. She had a pathology report of the mandible tumor biopsy that had been done recently in another center via oral cavity which was suggestive of a central giant cell granuloma. The initial management with rehydration, parentral bisphosphonate and diuretics was done and then preoperative localization investigations were performed. The SPECT-CT scintigraphy with 99mTc-MIBI was suggestive of bilateral parathyroid adenomas and/or parathyroid hyperplasia and showed a MIBI- avid lytic lesion in the mandible (). In the spiral mandible CT scan without contrast there was a 53 × 43 × 39 mm expansile lytic mass lesion at mandibular symphysis and left side of mandibular body, which showed well defined nonsclerotic margin without cortical disruption. No periosteal reaction was evident and bony trabecular remnant was sited in central part. Mandibular cortex has been involves by mentioned mass at both sides and extension of mass posteriorly to oral cavity at sublingual space and anteriorly to subcutaneous region was depicted (figure 3). Surgical management consisted of total thyroidectomy and total parathyroidectomy with autotransplantation of about 50 miligrams of excised parathyroid tissue was performed. After removing the adenoma, the PTH marked a decrease from initial (398 pg/ml) value to 57 pg/ml. The histological examination revealed the thyroid tissue with MNG and a left parathyroid adenoma. Follow-up after surgery revealed normal serum calcium and urine calcium levels with no increase. PTH levels also did not increase. The patient was treated with calcium and vitamin D supplements and the jaw mass gradually decreased.
pmc-6187805-1	A 55-year-old male patient presented to the orthopaedic department with the complaint of a left knee blockage. Five years earlier, he underwent a left knee meniscectomy for a posttraumatic medial meniscus tear. Because of persisting pain and swelling of the medial compartment (typical post-meniscectomy syndrome) he underwent synthetic PCU (polycarbonate-urethane) meniscus replacement (type NUsurfaceR), which resulted in regain of full functionality. However, he started experiencing a clicking sensation and sometimes a complete blockage of his left knee a few weeks prior to the consultation. A computed tomography (CT) arthrography was performed. On the coronal view (Figure ) there was a complete opacification of the medial femorotibial joint space devoid of any meniscal structure, together with a degenerative tibial subchondral geode (arrow). The sagittal (Figure ) and axial (Figure ) views showed a hypodense, wedge-shaped structure in the suprapatellar space: the luxated and superiorly migrated synthetic meniscus (arrows).
pmc-6188159-1	A 2.5-year-old male child, apparently healthy but underweight, with a body mass index (BMI) of 17.7 (12.2 pounds, 22.5 inches) presented to the pediatric developmental wellness clinic at The Children’s Hospital, Lahore, Pakistan, with the complaints of complete hearing loss since birth and aphasia. The orientation of the patient could not be assessed due to the aphasia, although he was alert. The patient was afebrile with a heart rate of 85 bpm, blood pressure of 110/85 mmHg, and respiratory rate of 18/min. Upon a physical examination, the patient had blue homochromatic irises with a normal visual response, coarse hair texture, pallor of nails, and a slightly broad high nasal root. Segmental depigmentation was seen affecting the forehead and left forearm (Figures -). The patient's mother reported the presence of a white hair patch (poliosis) in the frontal hair distribution since birth, which diminished upon cutting the hair. A delay in achieving multiple milestones, including neck holding, crawling, sitting, and walking were also reported. The mother had an uneventful natal history with two healthy daughters without the presence of any similar symptoms in them. Past medical history included episodes of bilious vomiting, failure to thrive, and multiple bouts of severe constipation at the age of six months. On imaging, a diagnosis of Hirschsprung's disease was made and confirmed with a rectal biopsy (Figure ). Later, an end-colostomy at the level of the descending colon was made. The patient had a positive family history of the WS present in the father and paternal aunt but without the history of Hirschsprung’s disease and hearing deficits. To evaluate the hearing deficit, an auditory brainstem response was done, which showed a bilateral sensorineural hearing loss. The patient also demonstrated complete mutism and lack of response to commands. A DNA sample from the boy was used as a template for a polymerase chain reaction (PCR) to amplify exon 2 of gene SOX10. The resulting product was subsequently sequenced, employing standard methods on an ABI PRISM 377 DNA sequencer. This patient was found to have a novel truncating mutation of the SOX10 gene, on 22q13. The diagnosis of WS-4C was made.
pmc-6188160-1	The patient is a 21-year-old African American woman, unemployed, living in Brooklyn, New York, with no prior psychiatric history. She was brought in by emergency medical services at the request of her mother due to the patient’s increased aggression and paranoia at home. As per her mother’s account, the patient began acting bizarre two months ago when she left her home to stay with her boyfriend. The mother was contacted by the patient a few days later concerning paranoid ideation that people were trying to kill her. The patient also tried to attack her mother while she was driving a car. Additionally, she also started accusing her family members of being replacements (Capgras syndrome). As per her mother’s account, the patient had been intrusive towards strangers on the street, reading the Bible and getting in people’s faces. When the patient was presented to the hospital, she seemed very confused, internally preoccupied, disorganized, and providing delayed and inappropriate responses to questions when asked. This was her first psychiatric presentation. It was noted that she had an elongated face with small ears rotated backward and exhibited hypernasal speech. She appeared to be labile, crying for no apparent reason then later singing out loud. The patient refused to come out of her room for an initial interview. During her interview, she remained evasive and guarded. Her thought process was illogical, and her thought content was delusional (e.g., she thought her mother was the devil). She denied visual, tactile, olfactory, and gustatory hallucinations but endorsed hearing Jesus’s voice telling her that everything was going to be ok. She denied any suicidal or homicidal ideation. The patient admitted using illicit drugs in the past including marijuana, Ecstasy, Molly, and alcohol but could not quantify them. Urine toxicology testing was performed along with urinary cannabinoid and 3,4-methylenedioxymethamphetamine (Ecstasy) testing; all test results were negative. Assays for thyroid-stimulating hormone, the venereal disease research laboratory test for syphilis, antinuclear antibody, and an enzyme-linked immunosorbent assay for the human immunodeficiency virus were also ordered as a part of her workup; all results were within normal limits. A complete metabolic panel was ordered, and her serum calcium was found to be low (4.14 mg/dL). An electrocardiogram and echocardiogram were performed, but their findings were normal. After an endocrinology consultation, the patient was started on intravenous calcium carbonate. She was medicated with olanzapine and aripiprazole. She was initially started on 2 mg olanzapine then gradually titrated up to 20 mg of olanzapine and 10 mg of aripiprazole, but these displayed marked extrapyramidal side effects, specifically increased rigidity and dystonia of the neck and jaw muscles, so these were abruptly discontinued. Given her poor response to multiple antipsychotics, exaggerated extrapyramidal symptoms (EPS), reaction to olanzapine, and suboptimal absolute neutrophil count, she was started on low-dose quetiapine at 25 mg and gradually titrated up to 400 mg twice a day (BID) in the hospital to target her psychosis, lorazepam to address her agitation, and benztropine for her EPS. We also considered using a newer agent, pimavanserin to target her psychosis given the rapid development of Parkinsonian features after the use of olanzapine, but this could not be initiated due to the patient’s insurance’s reluctance to cover it. The patient showed improvement of her psychosis on quetiapine 400 mg BID, becoming more logical and goal-oriented. A computed tomography (CT) scan without contrast of the head was ordered as a workup of her first-time psychosis. The CT showed extensive bilateral asymmetrical calcifications involving the bilateral basal ganglia including the globus pallidus, putamen, caudate, thalamus, dentate, and subcortical white matter. The patient had a history of motor vehicle injury (MVI) three years ago as a pedestrian. From the MVI, she suffered facial trauma, splenic laceration, and an L3-L4 transverse process fracture. At that time, the patient recovered completely with no sequelae. However, a CT of her head performed at that time showed incidental bilateral basal ganglia calcifications. It was recommended that the patient take oral calcium and continue follow-up evaluations; she never did. Of note, the current CT was unchanged from the previous CT of her head performed three years ago. The case was reviewed with the Neuropsychiatry department. They presumptively diagnosed the patient with Fahr’s syndrome based on the idiopathic basal ganglia calcification and the patient’s hypoparathyroidism, hypocalcemia, and hyperphosphatemia found via the blood work. At that point, there was also a slight concern for DiGeorge syndrome as there is evidence supporting a strong correlation between psychosis and DiGeorge syndrome. This warranted genetic testing for 22q chromosomal abnormalities once the patient was psychiatrically stable. Genetic testing by fluorescence in situ hybridization (FISH) was performed, confirming the diagnosis of a 22q11.2 deletion. From the mother’s report, it was also evident as part of the review of the patient’s developmental history that the patient was born via normal vaginal delivery at term. The only obvious finding at birth was her long fingers. The pediatrician was consulted, but no other abnormality was found until the patient was two years old; at that time, she was diagnosed with a hearing impairment and delayed speech prompting the use of a hearing aid. Afterward, she received an ordinary education and graduated from high school. The patient was discharged on a quetiapine 400 mg BID medication regimen. The patient is still a part of a partial hospitalization program at our hospital and is showing a marked advancement in her quality of life in terms of her behavior.
pmc-6188172-1	A six-month-old male infant, with a significant past medical history of neonatal meningitis on the second day of life, was brought with complaints of disproportionate head enlargement for three months duration. Initial magnetic resonance imaging (MRI) was suggestive of gross asymmetrical hydrocephalus with obstruction at the level of the aqueduct, and no signs of ependymal thickening (Figure ). Ventricular tap was done, and CSF was received for cytology, biochemical analysis, and culture. Cultures were sterile, and there were no features of infection. For intra-cranial pressure reduction, an external ventricular drain (EVD) was placed, and intraventricular vancomycin (10 mg 12 hourly) was started along with parenteral vancomycin (120 mg 8 hourly) and meropenem (240 mg 8 hourly). Serial CSF monitoring was continued. Four weeks later, the child developed a fever. It was noted that the EVD had blocked and a repeat MRI scan revealed gross asymmetric dilatation of left lateral ventricle along with air-fluid level in right periventricular region suggestive of pneumocephalus. The child was managed by right temporoparietal craniotomy and excision of multiloculated abscess done along with the removal of right EVD and placement of left EVD. The CSF samples received showed features of infection and Gram-positive budding yeast was seen on a direct stain (Figure ). Candida parapsilosis was isolated from culture and was susceptible to all antifungals. Fluconazole (50 mg 24 hourly) was started, and serial monitoring of CSF continued. Despite treatment, daily CSF samples continued to grow C. parapsilosis through day 10. The EVD was removed, and an Ommaya reservoir along with a ventricular catheter was placed for better intraventricular antibiotic administration (vancomycin 10 mg 12 hourly). CSF samples taken 13 days and onwards were sterile. Clinically, the infant became afebrile and stable. Antifungal therapy was continued for three weeks. The Ommaya reservoir was removed, and a ventriculoperitoneal shunt was placed five weeks later. Three months later, the infant remains asymptomatic.
pmc-6188173-1	Case A 67-year-old woman with a history of C5-C7 anterior cervical decompression and fusions presented with acute neck and bilateral shoulder pain. The patient did not have a history of trauma, significant family history, or syndromic findings suggestive of Gardner syndrome. Initially, she was managed conservatively using NSAIDs for pain management and physical therapy with minimal symptomatic relief. Her neurological exam, including motor, sensory and reflex testing was nonfocal. Due to the failure of conservative treatments, MRI of the cervical spine was obtained. This showed an approximately 3.5 cm x 1.7 cm x 1.6 cm paraspinal mass in the posterior elements from C2 to C4 (Figures -); the mass was T2 hyperintense and homogenously enhanced (Figures -). She underwent a computed tomography (CT) guided needle biopsy, which showed rare spindle cells, suggestive of a spindle cell neoplasm. Given the size of the mass and the intractable pain associated with it, surgical resection was performed. Surgical observations The mass was identified between spinal levels C2 and C4, below the muscular plane on the left side. The tumor was large, firm, and surrounded by muscle. The lesion was delineated from its attachment to the muscle in different planes. Direct stimulation of the lesion did not elicit an electromyographic response. Postoperative care The patient had an uneventful postoperative course and was discharged home on postoperative day 2. A postoperative MRI confirmed gross total resection of the tumor (Figures -). Given the complete resection and the ultimate pathological diagnosis (see below), oncology consultants advised that adjuvant therapy was unnecessary, but that close monitoring for recurrence was vital. Pathology The tumor was a spindle cell neoplasm of low to moderate cellularity without significant pleiomorphism (Figures -). It infiltrated as single cells between skeletal muscle fibers entrapped in the collagenous matrix of the tumor (Figure ). There was no necrosis or hypervascularity (a typical finding in extra-abdominal desmoids). The cells were not labeled by immunostains for S100 protein, smooth muscle actin, CD34, and e-cadherin, ruling out a neurofibroma, leiomyoma, primary endothelial tumor, and breast cancer metastasis, respectively. There was considerable cytoplasmic and some nuclear immunoreactivity for beta-catenin, a typical characteristic of fibromatoses/DTs (Figure ), leading to a final diagnosis of extra-abdominal desmoid. Furthermore, a Ki67 immunostain demonstrated a low proliferative index of less than 5% (Figure ).
pmc-6188217-1	A 56-year-old woman, a non-smoking teetotaler, was admitted to our hospital in January 2017. Past medical history showed that the patient had rheumatoid arthritis and an allergy to sulfadimezine (at a young age, the syncope reaction occurred several times after taking sulfadimezine). The diagnosis of CML, early chronic phase, intermediate risk group (Sokal score 1.14, Hasford score 1286) was established seven months prior. Imatinib therapy was started three months ago. The patient noted a fever during the first two months after the administration of imatinib therapy, and its cause was not established. She was not taking any drug for rheumatoid arthritis. The patient's baseline values of serum transaminases prior to imatinib treatment were as follows: alanine transaminase (ALT) - 12 U/l, aspartate transaminase (AST) - 18 U/l, and total bilirubin - 0.33 mg/dL. After three months of therapy with imatinib, at a dosage of 400 mg per day, an insufficient reduction in the level of BCR/ABL p210 chimeric gene expression in peripheral blood cells was registered (17.241%). This indicated an absence of partial cytogenetic response according to the criteria of LeukemiaNet (2013). The dosage of imatinib was increased from 400 mg to 600 mg per day. This was accompanied by nausea. In three days after increasing the imatinib dosage, the following changes in biochemical blood analysis were registered: increased levels of ALT - 1155 U/l (normal values less than 31 U/l), AST - 581 U/l (normal values less than 31 U/l), and total bilirubin - 1.99 mg/dL (normal values less than 0.057 to 0.24 mg/dL) (Table ). Before the imatinib dosage increase, the laboratory values were: ALT – 39.78 U/l, AST – 29.20 U/l, and total bilirubin - 0.14 mg/dL). A complete hematologic response was registered in the clinical blood count at that time: red blood cells – 3.46х1012/l (normal values 3.7 to 4.7х1012/l), hemoglobin - 116 g/l (normal values 120 to 140 g/l), white blood cells – 3.8х109/l (normal values 3.98 to 10.4 х109/l), neutrophils – 58.9%, lymphocytes – 27.9%, monocytes - 12,0%, eosinophils - 1.0%, and basophils - 0.2%. Gastroenterology and hematology consults were obtained. Chemotherapy was suspended; hepatoprotector (ademetionine 800 mg QD intravenously) and detoxication therapy (rheosorbilact, Ringer's solution) were prescribed. After two weeks of treatment, cholestasis and jaundice appeared, cytolytic syndrome persisted, and, in addition, international normalized ratio (INR) increased up to 1.9. Despite the discontinuation of imatinib, acute hepatitis transformed from the hepatocellular type to the mixed type (ALT - 692.2 U/l, AST - 978.6 U/l, total bilirubin - 10.72 mg/dL). Screening tests for viral hepatitis markers (HBsAg, anti-HCV antibodies) were negative. A more in-depth examination for markers of viral hepatitis was assigned. The serological markers of hepatitis C virus infection by the enzyme-linked immunosorbent assay (ELISA) - ELISA -anti-HCV-core, ELISA-anti-HCV-NS3, ELISA-anti-HCV-NS4, ELISA-anti-HCV-NS5 also were not detected, as well as serological markers of hepatitis A virus infection – anti-НАV-IgM were not detected. The qualitative HCV RNA and HBV DNA tests were negative. In addition, the markers of cytomegalovirus infection, herpes viruses, and the Epstein-Barr virus were negative. Thus, acute viral hepatitis and the reactivation of chronic hepatitis were excluded. Copper, iron saturation of plasma transferrin, and ceruloplasmin levels were normal. There were negative markers of autoimmune hepatitis - antinuclear antibodies (ANA), antibodies to smooth muscles (ASMA), and antimitochondrial antibodies (AMA). The patient categorically denied acetaminophen usage or other drugs, including cold medications, categorically denied alcohol. The ultrasound examination and computed tomography of the abdominal cavity revealed hepatomegaly (the craniocaudal length of the liver was 170 mm) and hepatic changes similar to hepatitis. Hyperdense liver structures were detected by ultrasonography and periportal edema of the liver parenchyma by computed tomography. The diameter of the common bile duct on ultrasonography was three millimeters. The gallbladder size was 61x27 mm. Intrahepatic bile ducts seen by computed tomography were not dilated. Magnetic resonance cholangiopancreatography was not performed because the common bile duct was not dilated by ultrasonography. The mechanical causes of obstruction were excluded. In addition, splenomegaly was detected (111x49 mm) (Figure ). A hepatic biopsy was not performed because the patient categorically refused to conduct a liver biopsy. However, jaundice increased and nausea and vomiting appeared. The laboratory values at that time were: ALT – 538.7 U/l, AST – 563.1 U/l, and total bilirubin – 23.4 mg/dL. It was the highest total bilirubin level after 27 days of imatanib hepatotoxicity beginning. On that date, serum albumin was 34 g/l. The patient was hospitalized for a clarification of diagnosis and a correction of the therapy. Due to the assessment of the grade of hepatotoxicity according to the recommendations of the US National Cancer Institute - NCCN CTC v 5.0 - there was a registered grade III-IV of hepatotoxicity. Due to this, the West-Haven and Conn classification was established as hepatic encephalopathy grade I. According to King’s College Hospital criteria for predicting mortality in acute liver failure in a non-acetaminophen, acute liver injury was confirmed based on three criteria in a reported patient (duration of jaundice to hepatic encephalopathy more than seven days, age more than 40 years, etiology - non-A/non-B hepatitis, drug-induced). The patient had 26 points according to the model for end-stage liver disease (MELD) score. According to the laboratory and instrumental examinations, the following diagnosis was established: Acute toxic (drug, imatinib-induced) drug-induced liver disease with cholestatic, cytolytic syndromes, chronic myeloid leukemia, Ph-positive, early chronic phase. Steroid therapy was initiated, with prednisolone 40 mg per day intravenously. The solutions of ornithine (20 mg/40 ml in 500 ml sodium chloride 0.9 %) and L-arginine 100 ml for detoxication were assigned due to hepatic encephalopathy development. Ringer's solution and intravenous potassium chloride were assigned to reduce the risk of hypokalemia development due to high prednisolone dosage administration. Pantoprazole 40 mg, intravenously, QD, was assigned for the prevention of steroid gastropathy. In addition, a concomitant therapy with ursodeoxycholic acid 750 mg in the evening QD, pancreatic enzymes - pancrelipase 10,000 units three times a day due to high doses, a long duration of pantoprazole administration that reduced the secretion of pancreatic enzymes in the absence of stimulation with hydrochloric acid, and silymarin 140 mg twice daily were prescribed. For the correction of hypoalbuminemia and the prevention of coagulopathy, fresh frozen plasma (once) and albumin (twice) were administered. Positive clinical and laboratory dynamics was registered during the first week after the beginning of prednisolone therapy: jaundice decreased and bilirubin in the urine disappeared. After the reduction of cytolysis (AST - 137.4 U/l, ALT - 282.7 U/l and total bilirubin - 6.7 mg/dL) during the second week of the therapy, in addition to prednisolone, a hepatoprotective therapy with ademetionine 800 mg per day intravenously was prescribed, which was then changed to tablets. After 30 days of therapy with prednisolone 40 mg per day intravenously, when the levels of serum transaminases were: AST - 32.9 U/l, ALT - 66.2 U/l, total bilirubin - 1.62 mg/dL, the prednisolone dose was reduced according to the scheme with a switching to the tablet drug form. Due to prednisolone administration, such concomitant prescriptions were made: potassium in tablet form for hypokalemia prophylaxis and pantoprazole in tablets for gastroprotection. A loss of the hematologic response and an appearance of blood leukocytosis 13.2х109/l in the clinical blood count were observed. Due to the loss of the hematologic response, hydroxyurea 500 mg two capsules were prescribed twice per day in addition to the above-mentioned therapy. After a normalization of liver enzymes and cholestasis markers, concomitant therapy was stopped (AST - 22.5 U/l, ALT - 40.3 U/l, total bilirubin - 1.12 mg/dL). Prednisolone was tapered within a month with withdrawal (Figure , Table ). After one month follow-up after discharge from the hospital and prednisolone withdrawal, in a total of three and a half months after the onset of acute toxic hepatitis, acute hepatotoxicity recovered and therapy with nilotinib in a reduced dose of 200 mg twice per day was started because of the loss of the hematologic response (white blood cells 13.2х109/l without hydroxyurea). The laboratory values at that time were: ALT – 33.2 U/l, AST – 20.4 U/l, and total bilirubin – 0.77 mg/dL. A further monitoring of liver functions and clinical blood analysis was performed. It was approved by the hospital's ethics committee in February 2017 for a one-year follow-up period.
pmc-6188590-1	A 67-year-old African American female with a past medical history significant for type 2 insulin-dependent diabetes mellitus, hypertension, hypercholesterolemia, severe osteoarthritis of the left shoulder, moderate degenerative disc disease of lumbar spine, gout, chronic kidney disease stage III, and chronic pancreatitis was referred to rheumatology with complains of weakness in her upper extremities proximal muscles for about one month. She was on treatment with atorvastatin for hypercholesterolemia for the last 6 years. Due to concern of statin-induced myopathy, the atorvastatin was discontinued a month before her consultation. Around the time of stopping atorvastatin, the patient described flu-like symptoms (low-grade fevers, myalgia, arthralgia, and runny nose). While she was on therapy with atorvastatin, baseline CPK levels were in the 230 mg/dl, with the highest value being 529 mg/dl at the time of therapy discontinuation (). Her CPK was repeated 20 days later and was increased to 720 mg/dl. The patient was seen in the rheumatology clinic within one week. At the time of her initial evaluation, the patient's main complaint was pain in the right shoulder, irradiating to her neck, right wrist, and fingers. Despite her subjective weakness, strength was 5/5 in her proximal and distal upper extremities muscles. She occasionally reported difficulties swallowing and photosensitivity, but denied any lower extremity weakness or difficulties to rise from a chair, rashes, oral/nasal ulcerations, Raynaud's phenomenon, or shortness of breath. Her physical exam was suggestive of right shoulder impingement syndrome (significantly decreased range of motion, positive Neer's and Hawkins tests, anteroflexion 90°, reduced abduction, adduction, internal rotation, and external rotation), and right wrist examination was significant for mild swelling, limited range of motion, and tenderness to palpation. Left shoulder and wrist examination were unremarkable. Neck flexors and extensors examination was normal. Lower extremities examination revealed 5/5 strength; the patient was able to get out of the chair without pushing herself out. Routine laboratory studies were significant for normocytic anemia; moderate elevated BUN, CRP of 2.5 mg/L, and CPK levels of 720 mg/dl. Plain X-rays were obtained, and they were suggestive of severe degenerative osteoarthritis of the right shoulder, chondrocalcinosis of right wrist and knee, and diffuse osteopenia. Due to her history of gout and CKD, an initial diagnosis of possible crystal induced arthropathy was made. The patient received a steroid injection in the right shoulder and was started on a short taper of prednisone with complete resolution in her symptoms in two weeks. At two-month follow-up, she was free of symptoms and CPK levels were normal (145 mg/dl). Cardiovascular risk being high and having high cholesterol levels, the decision to re-challenge the patient with another statin was made. This time she was resumed on pravastatin, 3 months after her CPK levels were persistently normal, and she was free of symptoms. After three months on therapy with pravastatin, the patient experienced recurrent myalgia in proximal muscles of upper but also lower extremities. CPK levels increased again to 586 mg/dl, and the sedimentation rate (ESR) was 51 mm/hr (). The pravastatin was discontinued. A myositis panel was obtained and was negative for all antibodies (). Anti-HMG-CoA reductase antibody was not tested because the patient could not afford the cost of the test. Therefore, an EMG was performed and revealed peripheral sensory neuropathy but no signs of myopathy. MRI of the right humerus was obtained and showed small bursal effusion, severe osteoarthritis, rotator cuff tear, severe chondral loss, severe tendinosis of subscapularis tendon, and full-thickness tear supraspinatus tendon, but no muscle edema. The patient was referred to neurology to evaluate for muscle weakness. Since her presentation was not consistent with a neurological disease and her CPK increased further to 1400 mg/dl, we made the decision to obtain muscle biopsy. The pathology report was consistent with inflammatory necrotizing myopathy (intrafascicular inflammation with muscle atrophy, the inflammation is predominantly intrafascicular with actively necrotic muscle fibers) (Figures and ).

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