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Surgery_Schwartz_2302
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Surgery_Schwartz
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cancer.Nonresectable subependymal giant cell astrocytoma associated with tuberous sclerosisGefitinibIressaEGFRNSCLC with known/previous benefit from gefitinib (limited approval)IbrutinibImbruvicaBruton’s Tyrosine KinaseChronic lymphocytic leukemiaImatinibGleevecKIT, ABL, PDGFRCML,GIST (KIT+),Dermatofibrosarcoma protuberansLapatinibTykerbEGFR and HER2Breast cancer (HER2+)NilotinibTasignaABLCML (Philadelphia chromosome+)PanitumumabVectibixEGFRColorectal cancer (KRAS wild type)PazopanibVotrientVEGFR, PDGFR, KITRCCPertuzumabPerjetaHER2Breast cancer (HER+)PonatinibIclusigABL, FGFR1-3, FLT3, VEGFR2CML, ALL (Philadelphia chromosome+)RegorafenibStivargaKIT, PDGFRβ, RAF, RET, VEGFR1/2/3Colorectal cancer, GISTSorafenibNexavarVEGFR, PDGFR, KIT, RAFHCCRCCSunitinibSutentVEGFR PDGFR KIT, Flt-3, RETGIST,RCC,PNETTemsirolimusToriselmTORRCCTrastuzumabHerceptinHER2Breast cancer (HER2+)Gastric cancer (HER2+)VandetanibCaprelsaEGFR, RET, VEGFR2Medullary thyroid cancerVemurafenibZelborafBRAFMelanoma (BRAF
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Surgery_Schwartz. cancer.Nonresectable subependymal giant cell astrocytoma associated with tuberous sclerosisGefitinibIressaEGFRNSCLC with known/previous benefit from gefitinib (limited approval)IbrutinibImbruvicaBruton’s Tyrosine KinaseChronic lymphocytic leukemiaImatinibGleevecKIT, ABL, PDGFRCML,GIST (KIT+),Dermatofibrosarcoma protuberansLapatinibTykerbEGFR and HER2Breast cancer (HER2+)NilotinibTasignaABLCML (Philadelphia chromosome+)PanitumumabVectibixEGFRColorectal cancer (KRAS wild type)PazopanibVotrientVEGFR, PDGFR, KITRCCPertuzumabPerjetaHER2Breast cancer (HER+)PonatinibIclusigABL, FGFR1-3, FLT3, VEGFR2CML, ALL (Philadelphia chromosome+)RegorafenibStivargaKIT, PDGFRβ, RAF, RET, VEGFR1/2/3Colorectal cancer, GISTSorafenibNexavarVEGFR, PDGFR, KIT, RAFHCCRCCSunitinibSutentVEGFR PDGFR KIT, Flt-3, RETGIST,RCC,PNETTemsirolimusToriselmTORRCCTrastuzumabHerceptinHER2Breast cancer (HER2+)Gastric cancer (HER2+)VandetanibCaprelsaEGFR, RET, VEGFR2Medullary thyroid cancerVemurafenibZelborafBRAFMelanoma (BRAF
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Surgery_Schwartz_2303
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Surgery_Schwartz
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cancer (HER2+)Gastric cancer (HER2+)VandetanibCaprelsaEGFR, RET, VEGFR2Medullary thyroid cancerVemurafenibZelborafBRAFMelanoma (BRAF V600E mutant)VorinostatZolinzaHistone deacetylasesCutaneous T-cell lymphomaCML = chronic myelogenous leukemia; EGFR = epidermal growth factor receptor; EPHA2 = ephrin A2; FDA = Food and Drug Administration; Flt-3 = fms-related tyrosine kinase 3; GIST = GI stromal tumor; HCC = hepatocellular cancer, HER2 = human epidermal growth factor receptor 2; mTOR = mammalian target of rapamycin; NSCLC = non-small cell lung cancer, PDGF = platelet-derived growth factor; PDGFR = platelet-derived growth factor receptor; PNET = pancreatic neuroendocrine tumor; RCC = renal cell carcinoma; RET = rearranged during transfection; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor.Brunicardi_Ch10_p0305-p0354.indd 34322/02/19 2:14 PM 344BASIC
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Surgery_Schwartz. cancer (HER2+)Gastric cancer (HER2+)VandetanibCaprelsaEGFR, RET, VEGFR2Medullary thyroid cancerVemurafenibZelborafBRAFMelanoma (BRAF V600E mutant)VorinostatZolinzaHistone deacetylasesCutaneous T-cell lymphomaCML = chronic myelogenous leukemia; EGFR = epidermal growth factor receptor; EPHA2 = ephrin A2; FDA = Food and Drug Administration; Flt-3 = fms-related tyrosine kinase 3; GIST = GI stromal tumor; HCC = hepatocellular cancer, HER2 = human epidermal growth factor receptor 2; mTOR = mammalian target of rapamycin; NSCLC = non-small cell lung cancer, PDGF = platelet-derived growth factor; PDGFR = platelet-derived growth factor receptor; PNET = pancreatic neuroendocrine tumor; RCC = renal cell carcinoma; RET = rearranged during transfection; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor.Brunicardi_Ch10_p0305-p0354.indd 34322/02/19 2:14 PM 344BASIC
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Surgery_Schwartz_2304
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Surgery_Schwartz
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RET = rearranged during transfection; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor.Brunicardi_Ch10_p0305-p0354.indd 34322/02/19 2:14 PM 344BASIC CONSIDERATIONSPART IGlucoseAminoAcidsIRS1PI3KPDK1PIP2PIP3ATPAMPKActivatorsMAP4K3AMPKRapalogsFKBP12AktTSC2TSC1PI3KInhibitorsAktInhibitorsPTENmTORC2ProctorRICTORmTORmLST8SIN1GSK3FOXOBADASK1GDPGTPRhebRhebmTORC1PRAS40mTORRAPTORmLST84EBP1S6KeIF4EPDCD4eEF3KS6eIF4BmTORKinase InhibitorsDual Pl3K/mTORKinase InhibitorsPPFigure 10-15. Targeting PI3K/Akt/mTOR signaling. This central pathway is altered in many tumor types and is being pursued as a therapeu-tic target through development of numerous pathway inhibitors targeting PI3K, Akt, mTOR, and dual inhibitors as well as several upstream and downstream regulators. (Reproduced with permission from McAuliffe PF, Meric-Bernstam F, Mills GB, et al: Deciphering the role of PI3K/Akt/mTOR pathway in breast cancer biology and pathogenesis, Clin Breast
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Surgery_Schwartz. RET = rearranged during transfection; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor.Brunicardi_Ch10_p0305-p0354.indd 34322/02/19 2:14 PM 344BASIC CONSIDERATIONSPART IGlucoseAminoAcidsIRS1PI3KPDK1PIP2PIP3ATPAMPKActivatorsMAP4K3AMPKRapalogsFKBP12AktTSC2TSC1PI3KInhibitorsAktInhibitorsPTENmTORC2ProctorRICTORmTORmLST8SIN1GSK3FOXOBADASK1GDPGTPRhebRhebmTORC1PRAS40mTORRAPTORmLST84EBP1S6KeIF4EPDCD4eEF3KS6eIF4BmTORKinase InhibitorsDual Pl3K/mTORKinase InhibitorsPPFigure 10-15. Targeting PI3K/Akt/mTOR signaling. This central pathway is altered in many tumor types and is being pursued as a therapeu-tic target through development of numerous pathway inhibitors targeting PI3K, Akt, mTOR, and dual inhibitors as well as several upstream and downstream regulators. (Reproduced with permission from McAuliffe PF, Meric-Bernstam F, Mills GB, et al: Deciphering the role of PI3K/Akt/mTOR pathway in breast cancer biology and pathogenesis, Clin Breast
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Surgery_Schwartz_2305
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Surgery_Schwartz
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regulators. (Reproduced with permission from McAuliffe PF, Meric-Bernstam F, Mills GB, et al: Deciphering the role of PI3K/Akt/mTOR pathway in breast cancer biology and pathogenesis, Clin Breast Cancer. 2010 Nov;10 Suppl 3:S59-S65.)Calmette-Guérin. This approach is thought to activate the effec-tors of antitumor response such as natural killer cells and macro-phages, as well as polyclonal lymphocytes.149 Another approach to nonspecific immunotherapy is systemic administration of cytokines such as interleukin-2, interferon-α, and interferon-γ. Interleukin-2 stimulates proliferation of cytotoxic T lympho-cytes and maturation of effectors such as natural killer cells into lymphokine-activated killer cells. Interferons, on the other hand, exert antitumor effects directly by inhibiting tumor cell prolif-eration and indirectly by activating host immune cells, includ-ing macrophages, dendritic cells, and natural killer cells, and by enhancing human leukocyte antigen (HLA) class I expression
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Surgery_Schwartz. regulators. (Reproduced with permission from McAuliffe PF, Meric-Bernstam F, Mills GB, et al: Deciphering the role of PI3K/Akt/mTOR pathway in breast cancer biology and pathogenesis, Clin Breast Cancer. 2010 Nov;10 Suppl 3:S59-S65.)Calmette-Guérin. This approach is thought to activate the effec-tors of antitumor response such as natural killer cells and macro-phages, as well as polyclonal lymphocytes.149 Another approach to nonspecific immunotherapy is systemic administration of cytokines such as interleukin-2, interferon-α, and interferon-γ. Interleukin-2 stimulates proliferation of cytotoxic T lympho-cytes and maturation of effectors such as natural killer cells into lymphokine-activated killer cells. Interferons, on the other hand, exert antitumor effects directly by inhibiting tumor cell prolif-eration and indirectly by activating host immune cells, includ-ing macrophages, dendritic cells, and natural killer cells, and by enhancing human leukocyte antigen (HLA) class I expression
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Surgery_Schwartz_2306
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prolif-eration and indirectly by activating host immune cells, includ-ing macrophages, dendritic cells, and natural killer cells, and by enhancing human leukocyte antigen (HLA) class I expression on tumor cells.149Antigen-specific immunotherapy can be active, as is achieved through antitumor vaccines, or passive. In pas-sive immunotherapy, antibodies to specific tumor-associated antigens can be produced by hybridoma technique and then administered to patients whose cancers express these antigens, inducing antibody-dependent cellular cytotoxicity.The early attempts at vaccination against cancers used allo-geneic cultured cancer cells, including irradiated cells, cell lysates, and shed antigens isolated from tissue culture supernatants. An alternate strategy is the use of autologous tumor vaccines. These have the potential advantage of being more likely to contain anti-gens relevant for the individual patient but have the disadvantage of requiring a large amount of tumor tissue for
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Surgery_Schwartz. prolif-eration and indirectly by activating host immune cells, includ-ing macrophages, dendritic cells, and natural killer cells, and by enhancing human leukocyte antigen (HLA) class I expression on tumor cells.149Antigen-specific immunotherapy can be active, as is achieved through antitumor vaccines, or passive. In pas-sive immunotherapy, antibodies to specific tumor-associated antigens can be produced by hybridoma technique and then administered to patients whose cancers express these antigens, inducing antibody-dependent cellular cytotoxicity.The early attempts at vaccination against cancers used allo-geneic cultured cancer cells, including irradiated cells, cell lysates, and shed antigens isolated from tissue culture supernatants. An alternate strategy is the use of autologous tumor vaccines. These have the potential advantage of being more likely to contain anti-gens relevant for the individual patient but have the disadvantage of requiring a large amount of tumor tissue for
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Surgery_Schwartz_2307
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Surgery_Schwartz
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vaccines. These have the potential advantage of being more likely to contain anti-gens relevant for the individual patient but have the disadvantage of requiring a large amount of tumor tissue for preparation, which restricts eligibility of patients for this modality. Strategies to enhance immunogenicity of tumor cells include the introduction of genes encoding cytokines or chemokines, and fusion of the tumor cells to allogeneic MHC class II-bearing cells.150 Alternatively, heat shock proteins derived from a patient’s tumor can be used because heat shock protein peptide complexes are readily taken up by dendritic cells for presentation to T cells.150Identification of tumor antigens has made it possible to perform antigen-specific vaccination. For example, in the case of melanoma, several antigens have been identified that can be recognized by both CD8+ cytotoxic T cells and CD4+ helper T cells, including MART-1, gp 100, MAGE1, tyrosinase, TRP-1, TRP-2, and NY-ESO-1.151 Antigens tested
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Surgery_Schwartz. vaccines. These have the potential advantage of being more likely to contain anti-gens relevant for the individual patient but have the disadvantage of requiring a large amount of tumor tissue for preparation, which restricts eligibility of patients for this modality. Strategies to enhance immunogenicity of tumor cells include the introduction of genes encoding cytokines or chemokines, and fusion of the tumor cells to allogeneic MHC class II-bearing cells.150 Alternatively, heat shock proteins derived from a patient’s tumor can be used because heat shock protein peptide complexes are readily taken up by dendritic cells for presentation to T cells.150Identification of tumor antigens has made it possible to perform antigen-specific vaccination. For example, in the case of melanoma, several antigens have been identified that can be recognized by both CD8+ cytotoxic T cells and CD4+ helper T cells, including MART-1, gp 100, MAGE1, tyrosinase, TRP-1, TRP-2, and NY-ESO-1.151 Antigens tested
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Surgery_Schwartz_2308
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Surgery_Schwartz
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have been identified that can be recognized by both CD8+ cytotoxic T cells and CD4+ helper T cells, including MART-1, gp 100, MAGE1, tyrosinase, TRP-1, TRP-2, and NY-ESO-1.151 Antigens tested usually are over-expressed or mutated in cancer cells. Tissue specificity and immunogenicity are important determinants in choosing an appropriate target. Vaccines directed at defined tumor antigens aim to combine selected tumor antigens and appropriate routes for delivering these antigens to the immune system to optimize antitumor immunity.152 Several different vaccination approaches have been studied, including tumor cell-based vaccines, pep-tide-based vaccines, recombinant virus-based vaccines, DNA-based vaccines, and dendritic cell vaccines.In adoptive transfer, antigen-specific effector cells (i.e., cytotoxic T lymphocytes) or antigen-nonspecific effector cells Brunicardi_Ch10_p0305-p0354.indd 34422/02/19 2:14 PM 345ONCOLOGYCHAPTER 10(i.e., natural killer cells) can be transferred to a
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Surgery_Schwartz. have been identified that can be recognized by both CD8+ cytotoxic T cells and CD4+ helper T cells, including MART-1, gp 100, MAGE1, tyrosinase, TRP-1, TRP-2, and NY-ESO-1.151 Antigens tested usually are over-expressed or mutated in cancer cells. Tissue specificity and immunogenicity are important determinants in choosing an appropriate target. Vaccines directed at defined tumor antigens aim to combine selected tumor antigens and appropriate routes for delivering these antigens to the immune system to optimize antitumor immunity.152 Several different vaccination approaches have been studied, including tumor cell-based vaccines, pep-tide-based vaccines, recombinant virus-based vaccines, DNA-based vaccines, and dendritic cell vaccines.In adoptive transfer, antigen-specific effector cells (i.e., cytotoxic T lymphocytes) or antigen-nonspecific effector cells Brunicardi_Ch10_p0305-p0354.indd 34422/02/19 2:14 PM 345ONCOLOGYCHAPTER 10(i.e., natural killer cells) can be transferred to a
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Surgery_Schwartz_2309
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Surgery_Schwartz
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cytotoxic T lymphocytes) or antigen-nonspecific effector cells Brunicardi_Ch10_p0305-p0354.indd 34422/02/19 2:14 PM 345ONCOLOGYCHAPTER 10(i.e., natural killer cells) can be transferred to a patient. These effector cells can be obtained from the tumor (tumor-infiltrating lymphocytes) or the peripheral blood.Clinical experience in patients with metastatic disease has shown objective tumor responses to a variety of immunothera-peutic modalities. It is thought, however, that the immune sys-tem is overwhelmed with the tumor burden in this setting, and thus adjuvant therapy may be preferable, with immunotherapy reserved for decreasing tumor recurrences. Trials to date sug-gest that immunotherapy is a potentially useful approach in the adjuvant setting. How to best select patients for this approach and how to integrate immunotherapy with other therapies are not well understood for most cancer types.Tolerance to self-antigens expressed in tumors is a limi-tation in generating antitumor
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Surgery_Schwartz. cytotoxic T lymphocytes) or antigen-nonspecific effector cells Brunicardi_Ch10_p0305-p0354.indd 34422/02/19 2:14 PM 345ONCOLOGYCHAPTER 10(i.e., natural killer cells) can be transferred to a patient. These effector cells can be obtained from the tumor (tumor-infiltrating lymphocytes) or the peripheral blood.Clinical experience in patients with metastatic disease has shown objective tumor responses to a variety of immunothera-peutic modalities. It is thought, however, that the immune sys-tem is overwhelmed with the tumor burden in this setting, and thus adjuvant therapy may be preferable, with immunotherapy reserved for decreasing tumor recurrences. Trials to date sug-gest that immunotherapy is a potentially useful approach in the adjuvant setting. How to best select patients for this approach and how to integrate immunotherapy with other therapies are not well understood for most cancer types.Tolerance to self-antigens expressed in tumors is a limi-tation in generating antitumor
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Surgery_Schwartz_2310
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Surgery_Schwartz
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approach and how to integrate immunotherapy with other therapies are not well understood for most cancer types.Tolerance to self-antigens expressed in tumors is a limi-tation in generating antitumor responses.153 Recently, several pathways that modulate tolerance and approaches to manipulat-ing these pathways have been identified: pathways that activate professional antigen-presenting cells such as Toll-like receptors, growth factors, and the CD40 pathway; cytokines to enhance immunoactivation; and pathways that inhibit T-cell inhibitory signals or block the activity of immune-suppressive regulatory T cells (Tregs).153A new and highly effective strategy to activate the T-cell arm of anticancer immunity is the use of monoclonal antibodies to block inhibitory signaling pathways employed by the immune system to prevent T cell over activation and the development of auto-immunity. CTLA-4 and PD-1 are two important inhibitory T-cell checkpoints that can be blocked with neutralizing
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Surgery_Schwartz. approach and how to integrate immunotherapy with other therapies are not well understood for most cancer types.Tolerance to self-antigens expressed in tumors is a limi-tation in generating antitumor responses.153 Recently, several pathways that modulate tolerance and approaches to manipulat-ing these pathways have been identified: pathways that activate professional antigen-presenting cells such as Toll-like receptors, growth factors, and the CD40 pathway; cytokines to enhance immunoactivation; and pathways that inhibit T-cell inhibitory signals or block the activity of immune-suppressive regulatory T cells (Tregs).153A new and highly effective strategy to activate the T-cell arm of anticancer immunity is the use of monoclonal antibodies to block inhibitory signaling pathways employed by the immune system to prevent T cell over activation and the development of auto-immunity. CTLA-4 and PD-1 are two important inhibitory T-cell checkpoints that can be blocked with neutralizing
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Surgery_Schwartz_2311
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Surgery_Schwartz
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by the immune system to prevent T cell over activation and the development of auto-immunity. CTLA-4 and PD-1 are two important inhibitory T-cell checkpoints that can be blocked with neutralizing antibod-ies and result in an effective antigen-specific anti-tumor response.CTLA-4 is an inhibitory receptor expressed by activated T cells that belongs to the immunoglobulin superfamily. CTLA4 is related to the T-cell costimulatory receptor, CD28, and both are bound by CD80 and CD86 (also known as B7-1 and B7-2) which are expressed on antigen-presenting cells. CTLA-4 con-veys an inhibitory signal to the T cell, whereas engagement of CD28 with ligand sends a stimulatory signal. CTLA-4 is able to outcompete CD28 for CD80 and CD86 ligands and therefore is able to dominate immune signaling in the setting of antigen recognition. CTLA-4 is also expressed by regulatory T cells, which contributes to their ability to inhibit T-cell function.154 Programmed death ligand 1 (PD-L1) is a 40 kDa type 1
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Surgery_Schwartz. by the immune system to prevent T cell over activation and the development of auto-immunity. CTLA-4 and PD-1 are two important inhibitory T-cell checkpoints that can be blocked with neutralizing antibod-ies and result in an effective antigen-specific anti-tumor response.CTLA-4 is an inhibitory receptor expressed by activated T cells that belongs to the immunoglobulin superfamily. CTLA4 is related to the T-cell costimulatory receptor, CD28, and both are bound by CD80 and CD86 (also known as B7-1 and B7-2) which are expressed on antigen-presenting cells. CTLA-4 con-veys an inhibitory signal to the T cell, whereas engagement of CD28 with ligand sends a stimulatory signal. CTLA-4 is able to outcompete CD28 for CD80 and CD86 ligands and therefore is able to dominate immune signaling in the setting of antigen recognition. CTLA-4 is also expressed by regulatory T cells, which contributes to their ability to inhibit T-cell function.154 Programmed death ligand 1 (PD-L1) is a 40 kDa type 1
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Surgery_Schwartz_2312
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Surgery_Schwartz
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setting of antigen recognition. CTLA-4 is also expressed by regulatory T cells, which contributes to their ability to inhibit T-cell function.154 Programmed death ligand 1 (PD-L1) is a 40 kDa type 1 trans-membrane protein that is thought to play an important role in suppressing the immune system. PD-L1 binds to its receptor, PD-1, which is found on activated T cells. The PD1/PDL1 path-way is increasingly recognized as a key contributor to tumor-mediated immune suppression. The interaction between PD-1 leads to reduced proliferation, altered production of stimulatory cytokines, and reduced T-cell lytic activity. Thus, both anti-PD1 and anti-PD-L1 strategies are actively being pursued for cancer therapy.155The FDA-approved CTLA-4 blocking antibody ipi-limumab has shown efficacy in patients with metastatic mela-noma.156,157 Nivolumab and pembrolizumab are antibodies that target PD-1, whereas blockade of PD-L1 is accomplished with agents such as atezolizumab.158 Cancers for which
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Surgery_Schwartz. setting of antigen recognition. CTLA-4 is also expressed by regulatory T cells, which contributes to their ability to inhibit T-cell function.154 Programmed death ligand 1 (PD-L1) is a 40 kDa type 1 trans-membrane protein that is thought to play an important role in suppressing the immune system. PD-L1 binds to its receptor, PD-1, which is found on activated T cells. The PD1/PDL1 path-way is increasingly recognized as a key contributor to tumor-mediated immune suppression. The interaction between PD-1 leads to reduced proliferation, altered production of stimulatory cytokines, and reduced T-cell lytic activity. Thus, both anti-PD1 and anti-PD-L1 strategies are actively being pursued for cancer therapy.155The FDA-approved CTLA-4 blocking antibody ipi-limumab has shown efficacy in patients with metastatic mela-noma.156,157 Nivolumab and pembrolizumab are antibodies that target PD-1, whereas blockade of PD-L1 is accomplished with agents such as atezolizumab.158 Cancers for which
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Surgery_Schwartz_2313
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Surgery_Schwartz
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with metastatic mela-noma.156,157 Nivolumab and pembrolizumab are antibodies that target PD-1, whereas blockade of PD-L1 is accomplished with agents such as atezolizumab.158 Cancers for which checkpoint inhibitors have found utility include melanoma, renal cell car-cinoma, bladder carcinoma, squamous cell carcinoma of the head and neck, and carcinoma of the lung. These agents pro-duce durable shrinkage of advanced disease in 20% to 40% of patients, and combination strategies that employ checkpoint inhibitors with cytokines, vaccines, cellular therapies, and other targeted agents are under active investigation.GENE THERAPYGene therapy is being pursued as a possible approach to modify-ing the genetic program of cancer cells as well as treating meta-bolic diseases. The field of cancer gene therapy uses a variety of strategies, ranging from replacement of mutated or deleted tumor-suppressor genes to enhancement of immune responses to cancer cells.159 Indeed, in preclinical models,
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Surgery_Schwartz. with metastatic mela-noma.156,157 Nivolumab and pembrolizumab are antibodies that target PD-1, whereas blockade of PD-L1 is accomplished with agents such as atezolizumab.158 Cancers for which checkpoint inhibitors have found utility include melanoma, renal cell car-cinoma, bladder carcinoma, squamous cell carcinoma of the head and neck, and carcinoma of the lung. These agents pro-duce durable shrinkage of advanced disease in 20% to 40% of patients, and combination strategies that employ checkpoint inhibitors with cytokines, vaccines, cellular therapies, and other targeted agents are under active investigation.GENE THERAPYGene therapy is being pursued as a possible approach to modify-ing the genetic program of cancer cells as well as treating meta-bolic diseases. The field of cancer gene therapy uses a variety of strategies, ranging from replacement of mutated or deleted tumor-suppressor genes to enhancement of immune responses to cancer cells.159 Indeed, in preclinical models,
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Surgery_Schwartz_2314
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Surgery_Schwartz
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gene therapy uses a variety of strategies, ranging from replacement of mutated or deleted tumor-suppressor genes to enhancement of immune responses to cancer cells.159 Indeed, in preclinical models, approaches such as replacement of tumor-suppressor genes leads to growth arrest or apoptosis. However, the translation of these findings into clinically useful tools presents special challenges.One of the main difficulties in getting gene therapy tech-nology from the laboratory to the clinic is the lack of a perfect delivery system. An ideal vector would be administered through a noninvasive route and would transduce all of the cancer cells and none of the normal cells. Furthermore, the ideal vector would have a high degree of activity, that is, it would produce an adequate amount of the desired gene product to achieve target cell kill. Unlike genetic diseases in which delivery of the gene of interest into only a portion of the cells may be sufficient to achieve clinical effect, cancer
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Surgery_Schwartz. gene therapy uses a variety of strategies, ranging from replacement of mutated or deleted tumor-suppressor genes to enhancement of immune responses to cancer cells.159 Indeed, in preclinical models, approaches such as replacement of tumor-suppressor genes leads to growth arrest or apoptosis. However, the translation of these findings into clinically useful tools presents special challenges.One of the main difficulties in getting gene therapy tech-nology from the laboratory to the clinic is the lack of a perfect delivery system. An ideal vector would be administered through a noninvasive route and would transduce all of the cancer cells and none of the normal cells. Furthermore, the ideal vector would have a high degree of activity, that is, it would produce an adequate amount of the desired gene product to achieve target cell kill. Unlike genetic diseases in which delivery of the gene of interest into only a portion of the cells may be sufficient to achieve clinical effect, cancer
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Surgery_Schwartz_2315
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gene product to achieve target cell kill. Unlike genetic diseases in which delivery of the gene of interest into only a portion of the cells may be sufficient to achieve clinical effect, cancer requires either that the therapeutic gene be delivered to all of the cancer cells or that a therapeutic effect be achieved on nontransfected cells as well as transfected cells through a bystander effect. However, treatment of a meta-bolic disease requires prolonged gene expression, whereas tran-sient expression may be sufficient for cancer therapy.Several vector systems are under study for gene ther-apy; however, none is considered ideal. One of the promising approaches to increase the number of tumor cells transduced is the use of a replication-competent virus like a parvovirus, human reovirus, or vesicular stomatitis virus that selectively replicates within malignant cells and lyses them more efficiently than it does normal cells. Another strategy for killing tumor cells with suicide genes
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Surgery_Schwartz. gene product to achieve target cell kill. Unlike genetic diseases in which delivery of the gene of interest into only a portion of the cells may be sufficient to achieve clinical effect, cancer requires either that the therapeutic gene be delivered to all of the cancer cells or that a therapeutic effect be achieved on nontransfected cells as well as transfected cells through a bystander effect. However, treatment of a meta-bolic disease requires prolonged gene expression, whereas tran-sient expression may be sufficient for cancer therapy.Several vector systems are under study for gene ther-apy; however, none is considered ideal. One of the promising approaches to increase the number of tumor cells transduced is the use of a replication-competent virus like a parvovirus, human reovirus, or vesicular stomatitis virus that selectively replicates within malignant cells and lyses them more efficiently than it does normal cells. Another strategy for killing tumor cells with suicide genes
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Surgery_Schwartz_2316
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Surgery_Schwartz
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or vesicular stomatitis virus that selectively replicates within malignant cells and lyses them more efficiently than it does normal cells. Another strategy for killing tumor cells with suicide genes exploits tumor-specific expression elements, such as the MUC-1, PSA, CEA, or VEGF promoters, that can be used to achieve tissue-specific or tumor-specific expression of the desired gene.Because the goal in cancer therapy is to eradicate systemic disease, optimization of delivery systems is the key to success for gene therapy strategies. Gene therapy is likely to be most successful when combined with standard therapies, but it will provide the advantage of customization of therapy based on the molecular status of an individual’s tumor.MECHANISMS OF INTRINSIC AND ACQUIRED DRUG RESISTANCESeveral tumor factors influence tumor cell kill. Tumors are het-erogeneous, and, according to the Goldie-Coldman hypothesis, tumor cells are genetically unstable and tend to mutate to form different cell
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Surgery_Schwartz. or vesicular stomatitis virus that selectively replicates within malignant cells and lyses them more efficiently than it does normal cells. Another strategy for killing tumor cells with suicide genes exploits tumor-specific expression elements, such as the MUC-1, PSA, CEA, or VEGF promoters, that can be used to achieve tissue-specific or tumor-specific expression of the desired gene.Because the goal in cancer therapy is to eradicate systemic disease, optimization of delivery systems is the key to success for gene therapy strategies. Gene therapy is likely to be most successful when combined with standard therapies, but it will provide the advantage of customization of therapy based on the molecular status of an individual’s tumor.MECHANISMS OF INTRINSIC AND ACQUIRED DRUG RESISTANCESeveral tumor factors influence tumor cell kill. Tumors are het-erogeneous, and, according to the Goldie-Coldman hypothesis, tumor cells are genetically unstable and tend to mutate to form different cell
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Surgery_Schwartz_2317
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Surgery_Schwartz
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tumor factors influence tumor cell kill. Tumors are het-erogeneous, and, according to the Goldie-Coldman hypothesis, tumor cells are genetically unstable and tend to mutate to form different cell clones. This has been used as an argument for giv-ing chemotherapy as soon as possible in treatment to reduce the likelihood that resistant clones will emerge. Tumor size is another important variable. Larger tumors may have greater het-erogeneity, although heterogeneity may also differ based on bio-logic subtype. Tumor growth may be described by a Gompertz curve, named after Benjamin Gompertz, which has the form of a sigmoid function. Gompertzian models have thus been used to describe changes in tumor cell numbers over time where growth is slowest at the start and end of a time period, but are quite rapid in the middle. Theoretically, for any tumor, there is a period of time where cancer cells grow rapidly (exponential growth Brunicardi_Ch10_p0305-p0354.indd 34522/02/19 2:14 PM 346BASIC
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Surgery_Schwartz. tumor factors influence tumor cell kill. Tumors are het-erogeneous, and, according to the Goldie-Coldman hypothesis, tumor cells are genetically unstable and tend to mutate to form different cell clones. This has been used as an argument for giv-ing chemotherapy as soon as possible in treatment to reduce the likelihood that resistant clones will emerge. Tumor size is another important variable. Larger tumors may have greater het-erogeneity, although heterogeneity may also differ based on bio-logic subtype. Tumor growth may be described by a Gompertz curve, named after Benjamin Gompertz, which has the form of a sigmoid function. Gompertzian models have thus been used to describe changes in tumor cell numbers over time where growth is slowest at the start and end of a time period, but are quite rapid in the middle. Theoretically, for any tumor, there is a period of time where cancer cells grow rapidly (exponential growth Brunicardi_Ch10_p0305-p0354.indd 34522/02/19 2:14 PM 346BASIC
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Surgery_Schwartz_2318
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rapid in the middle. Theoretically, for any tumor, there is a period of time where cancer cells grow rapidly (exponential growth Brunicardi_Ch10_p0305-p0354.indd 34522/02/19 2:14 PM 346BASIC CONSIDERATIONSPART Iphase), and then the growth slows down owing to hypoxia and decreased nutrient supply. Because of the larger proportion of cells dividing, smaller tumors may be more chemosensitive.Multiple mechanisms of systemic therapy resistance have been identified (Table 10-12).160 Cells may exhibit reduced sen-sitivity to drugs by virtue of their cell-cycle distribution. For example, cells in the G0 phase are resistant to drugs active in the S phase. This phenomenon of “kinetic resistance” usually is temporary, and if the drug level can be maintained, all cells will eventually pass through the vulnerable phase of the cell cycle.145 Alternatively, tumor cells may exhibit “pharmacologic resistance,” in which the failure to kill cells is due to insuffi-cient drug concentration. This may
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Surgery_Schwartz. rapid in the middle. Theoretically, for any tumor, there is a period of time where cancer cells grow rapidly (exponential growth Brunicardi_Ch10_p0305-p0354.indd 34522/02/19 2:14 PM 346BASIC CONSIDERATIONSPART Iphase), and then the growth slows down owing to hypoxia and decreased nutrient supply. Because of the larger proportion of cells dividing, smaller tumors may be more chemosensitive.Multiple mechanisms of systemic therapy resistance have been identified (Table 10-12).160 Cells may exhibit reduced sen-sitivity to drugs by virtue of their cell-cycle distribution. For example, cells in the G0 phase are resistant to drugs active in the S phase. This phenomenon of “kinetic resistance” usually is temporary, and if the drug level can be maintained, all cells will eventually pass through the vulnerable phase of the cell cycle.145 Alternatively, tumor cells may exhibit “pharmacologic resistance,” in which the failure to kill cells is due to insuffi-cient drug concentration. This may
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the vulnerable phase of the cell cycle.145 Alternatively, tumor cells may exhibit “pharmacologic resistance,” in which the failure to kill cells is due to insuffi-cient drug concentration. This may occur when tumor cells are located in sites where effective drug concentrations are difficult to achieve (such as the central nervous system) or can be due to enhanced metabolism of the drug after its administration, decreased conversion of the drug to its active form, or decrease in the intracellular drug level caused by increased removal of the drug from the cell associated with enhanced expression of P-glycoprotein (Pgp). Pgp is the protein product of multidrug resis-tance gene 1 and extrudes cytotoxic drugs at the expense of ATP hydrolysis. Other mechanisms of resistance include decreased affinity of the target enzyme for the drug, altered amount of the target enzyme, or enhanced repair of the drug-induced defect. For drug-sensitive cancers, another factor limiting optimal killing is
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Surgery_Schwartz. the vulnerable phase of the cell cycle.145 Alternatively, tumor cells may exhibit “pharmacologic resistance,” in which the failure to kill cells is due to insuffi-cient drug concentration. This may occur when tumor cells are located in sites where effective drug concentrations are difficult to achieve (such as the central nervous system) or can be due to enhanced metabolism of the drug after its administration, decreased conversion of the drug to its active form, or decrease in the intracellular drug level caused by increased removal of the drug from the cell associated with enhanced expression of P-glycoprotein (Pgp). Pgp is the protein product of multidrug resis-tance gene 1 and extrudes cytotoxic drugs at the expense of ATP hydrolysis. Other mechanisms of resistance include decreased affinity of the target enzyme for the drug, altered amount of the target enzyme, or enhanced repair of the drug-induced defect. For drug-sensitive cancers, another factor limiting optimal killing is
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affinity of the target enzyme for the drug, altered amount of the target enzyme, or enhanced repair of the drug-induced defect. For drug-sensitive cancers, another factor limiting optimal killing is inadequate dosing. Relative dose intensity (RDI) is defined as the actual amount of a particular chemotherapy given over a specific time in relation to what was ordered and is usually expressed as a percentage. An RDI below 80% is considered suboptimal and may impact survival in the adjuvant setting.145Cancer cells demonstrate adaptive responses to targeted therapy, like activating alternate pathways of survival; thus, these alterations may blunt therapeutic efficacy. Cancer cells also acquire resistance upon prolonged treatment with targeted therapy through a variety of mechanisms. One mechanism is through the loss of the target. For example, this was observed in a study of patients with HER2-positive breast cancer patients who were treated with neoadjuvant trastuzumab-based
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Surgery_Schwartz. affinity of the target enzyme for the drug, altered amount of the target enzyme, or enhanced repair of the drug-induced defect. For drug-sensitive cancers, another factor limiting optimal killing is inadequate dosing. Relative dose intensity (RDI) is defined as the actual amount of a particular chemotherapy given over a specific time in relation to what was ordered and is usually expressed as a percentage. An RDI below 80% is considered suboptimal and may impact survival in the adjuvant setting.145Cancer cells demonstrate adaptive responses to targeted therapy, like activating alternate pathways of survival; thus, these alterations may blunt therapeutic efficacy. Cancer cells also acquire resistance upon prolonged treatment with targeted therapy through a variety of mechanisms. One mechanism is through the loss of the target. For example, this was observed in a study of patients with HER2-positive breast cancer patients who were treated with neoadjuvant trastuzumab-based
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One mechanism is through the loss of the target. For example, this was observed in a study of patients with HER2-positive breast cancer patients who were treated with neoadjuvant trastuzumab-based chemo-therapy.161 Post neoadjuvant treatment, a third of the samples from patients who did not have a complete pathologic response displayed loss of the HER2 amplification that had been pres-ent in their pretreatment-biopsy specimens.161 Another means by which cancers develop resistance is the acquisition of addi-tional genomic aberrations. In lung cancer, a second mutation in EGFR (T790M) and MET amplification have been described as two main mechanisms of drug resistance to EGFR inhibi-tors erlotinib and gefinitib.162-164 Other mechanisms like novel genetic changes, including HER2 and EGFR amplification, PIK3CA mutations, and markers of epithelial-to-mesenchymal transition have also been reported in EGFR inhibitor resistant lung.165,166 Analysis of metastases from patients with colorectal
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Surgery_Schwartz. One mechanism is through the loss of the target. For example, this was observed in a study of patients with HER2-positive breast cancer patients who were treated with neoadjuvant trastuzumab-based chemo-therapy.161 Post neoadjuvant treatment, a third of the samples from patients who did not have a complete pathologic response displayed loss of the HER2 amplification that had been pres-ent in their pretreatment-biopsy specimens.161 Another means by which cancers develop resistance is the acquisition of addi-tional genomic aberrations. In lung cancer, a second mutation in EGFR (T790M) and MET amplification have been described as two main mechanisms of drug resistance to EGFR inhibi-tors erlotinib and gefinitib.162-164 Other mechanisms like novel genetic changes, including HER2 and EGFR amplification, PIK3CA mutations, and markers of epithelial-to-mesenchymal transition have also been reported in EGFR inhibitor resistant lung.165,166 Analysis of metastases from patients with colorectal
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PIK3CA mutations, and markers of epithelial-to-mesenchymal transition have also been reported in EGFR inhibitor resistant lung.165,166 Analysis of metastases from patients with colorectal cancer who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 60% of the cases.167 These studies emphasize the utility of repeat tumor biopsy specimens at the time of relapse or progression to iden-tify mechanisms of resistance and best combinatorial therapies.RADIATION THERAPYPhysical Basis of Radiation TherapyIonizing radiation is energy strong enough to remove an orbital electron from an atom. This radiation can be electromagnetic, like a high-energy photon, or particulate, such as an electron, proton, neutron, or alpha particle. Radiation therapy is delivered primar-ily as high-energy photons (gamma rays and X-rays) and charged particles (electrons). Gamma rays are photons that are released from
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Surgery_Schwartz. PIK3CA mutations, and markers of epithelial-to-mesenchymal transition have also been reported in EGFR inhibitor resistant lung.165,166 Analysis of metastases from patients with colorectal cancer who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 60% of the cases.167 These studies emphasize the utility of repeat tumor biopsy specimens at the time of relapse or progression to iden-tify mechanisms of resistance and best combinatorial therapies.RADIATION THERAPYPhysical Basis of Radiation TherapyIonizing radiation is energy strong enough to remove an orbital electron from an atom. This radiation can be electromagnetic, like a high-energy photon, or particulate, such as an electron, proton, neutron, or alpha particle. Radiation therapy is delivered primar-ily as high-energy photons (gamma rays and X-rays) and charged particles (electrons). Gamma rays are photons that are released from
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neutron, or alpha particle. Radiation therapy is delivered primar-ily as high-energy photons (gamma rays and X-rays) and charged particles (electrons). Gamma rays are photons that are released from the nucleus of a radioactive atom. X-rays are photons that are created electronically, such as with a clinical linear accelerator. Currently, high-energy radiation is delivered to tumors primarily with linear accelerators. X-rays traverse the tissue, depositing the maximum dose beneath the surface, and thus spare the skin. Elec-trons are used to treat superficial skin lesions, superficial tumors, or surgical beds to a depth of 5 cm. Gamma rays typically are produced by radioactive sources used in brachytherapy.The dose of radiation absorbed correlates with the energy of the beam. The basic unit is the amount of energy absorbed per unit of mass (joules per kilogram) and is known as a gray (Gy). One gray is equivalent to 100 rads, the unit of radiation measurement used in the past.Biologic
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Surgery_Schwartz. neutron, or alpha particle. Radiation therapy is delivered primar-ily as high-energy photons (gamma rays and X-rays) and charged particles (electrons). Gamma rays are photons that are released from the nucleus of a radioactive atom. X-rays are photons that are created electronically, such as with a clinical linear accelerator. Currently, high-energy radiation is delivered to tumors primarily with linear accelerators. X-rays traverse the tissue, depositing the maximum dose beneath the surface, and thus spare the skin. Elec-trons are used to treat superficial skin lesions, superficial tumors, or surgical beds to a depth of 5 cm. Gamma rays typically are produced by radioactive sources used in brachytherapy.The dose of radiation absorbed correlates with the energy of the beam. The basic unit is the amount of energy absorbed per unit of mass (joules per kilogram) and is known as a gray (Gy). One gray is equivalent to 100 rads, the unit of radiation measurement used in the past.Biologic
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is the amount of energy absorbed per unit of mass (joules per kilogram) and is known as a gray (Gy). One gray is equivalent to 100 rads, the unit of radiation measurement used in the past.Biologic Basis of Radiation TherapyRadiation deposition results in DNA damage manifested by singleand double-strand breaks in the sugar phosphate back-bone of the DNA molecule.168 Cross-linking between the DNA strands and chromosomal proteins also occurs. The mecha-nism of DNA damage differs by the type of radiation deliv-ered. Electromagnetic radiation is indirectly ionizing through the actions of short-lived hydroxyl radicals, which are pro-duced primarily by the ionization of cellular hydrogen perox-ide (H2O2).168 Protons and other heavy particles are directly ionizing and directly damage DNA.Table 10-12General mechanisms of drug resistanceCellular and biochemical mechanisms Decreased drug accumulation Decreased drug influx Increased drug efflux Altered intracellular trafficking of
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Surgery_Schwartz. is the amount of energy absorbed per unit of mass (joules per kilogram) and is known as a gray (Gy). One gray is equivalent to 100 rads, the unit of radiation measurement used in the past.Biologic Basis of Radiation TherapyRadiation deposition results in DNA damage manifested by singleand double-strand breaks in the sugar phosphate back-bone of the DNA molecule.168 Cross-linking between the DNA strands and chromosomal proteins also occurs. The mecha-nism of DNA damage differs by the type of radiation deliv-ered. Electromagnetic radiation is indirectly ionizing through the actions of short-lived hydroxyl radicals, which are pro-duced primarily by the ionization of cellular hydrogen perox-ide (H2O2).168 Protons and other heavy particles are directly ionizing and directly damage DNA.Table 10-12General mechanisms of drug resistanceCellular and biochemical mechanisms Decreased drug accumulation Decreased drug influx Increased drug efflux Altered intracellular trafficking of
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DNA.Table 10-12General mechanisms of drug resistanceCellular and biochemical mechanisms Decreased drug accumulation Decreased drug influx Increased drug efflux Altered intracellular trafficking of drug Decreased drug activation Increased inactivation of drug or toxic intermediate Increased repair of drug-induced damage to: DNA Protein Membranes Alteration of drug targets (quantitatively or qualitatively) Alteration of cofactor or metabolite levels Alteration of gene expression DNA mutation, amplification, or deletion Altered transcription, posttranscription processing, or translation Altered stability of macromoleculesMechanisms relevant in vivo Pharmacologic and anatomic drug barriers (tumor sanctuaries) Host-drug interactions Increased drug inactivation by normal tissues Decreased drug activation by normal tissues Relative increase in normal tissue drug sensitivity (toxicity)Host-tumor interactionsReproduced with permission from Bast R, Kufe D, Pollock R: Cancer
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Surgery_Schwartz. DNA.Table 10-12General mechanisms of drug resistanceCellular and biochemical mechanisms Decreased drug accumulation Decreased drug influx Increased drug efflux Altered intracellular trafficking of drug Decreased drug activation Increased inactivation of drug or toxic intermediate Increased repair of drug-induced damage to: DNA Protein Membranes Alteration of drug targets (quantitatively or qualitatively) Alteration of cofactor or metabolite levels Alteration of gene expression DNA mutation, amplification, or deletion Altered transcription, posttranscription processing, or translation Altered stability of macromoleculesMechanisms relevant in vivo Pharmacologic and anatomic drug barriers (tumor sanctuaries) Host-drug interactions Increased drug inactivation by normal tissues Decreased drug activation by normal tissues Relative increase in normal tissue drug sensitivity (toxicity)Host-tumor interactionsReproduced with permission from Bast R, Kufe D, Pollock R: Cancer
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drug activation by normal tissues Relative increase in normal tissue drug sensitivity (toxicity)Host-tumor interactionsReproduced with permission from Bast R, Kufe D, Pollock R: Cancer Medicine. Hamilton: BC Decker, Inc; 2000.Brunicardi_Ch10_p0305-p0354.indd 34622/02/19 2:14 PM 347ONCOLOGYCHAPTER 10Radiation damage is manifested primarily by the loss of cellular reproductive integrity. Most cell types do not show signs of radiation damage until they attempt to divide, so slowly proliferating tumors may persist for months and appear viable. Some cell types, however, undergo apoptosis.The extent of DNA damage after radiation exposure is dependent on several factors. The most important of these is cellular oxygen. Hypoxic cells are significantly less radiosensi-tive than aerated cells. The presence of oxygen is thought to pro-long the half-life of free radicals produced by the interaction of X-rays and cellular H2O2, and thus indirectly ionizing radiation is less efficacious in
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Surgery_Schwartz. drug activation by normal tissues Relative increase in normal tissue drug sensitivity (toxicity)Host-tumor interactionsReproduced with permission from Bast R, Kufe D, Pollock R: Cancer Medicine. Hamilton: BC Decker, Inc; 2000.Brunicardi_Ch10_p0305-p0354.indd 34622/02/19 2:14 PM 347ONCOLOGYCHAPTER 10Radiation damage is manifested primarily by the loss of cellular reproductive integrity. Most cell types do not show signs of radiation damage until they attempt to divide, so slowly proliferating tumors may persist for months and appear viable. Some cell types, however, undergo apoptosis.The extent of DNA damage after radiation exposure is dependent on several factors. The most important of these is cellular oxygen. Hypoxic cells are significantly less radiosensi-tive than aerated cells. The presence of oxygen is thought to pro-long the half-life of free radicals produced by the interaction of X-rays and cellular H2O2, and thus indirectly ionizing radiation is less efficacious in
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The presence of oxygen is thought to pro-long the half-life of free radicals produced by the interaction of X-rays and cellular H2O2, and thus indirectly ionizing radiation is less efficacious in tumors with areas of hypoxia.168 In contrast, radiation damage from directly ionizing radiation is independent of cellular oxygen levels.The extent of DNA damage from indirectly ionizing radiation is dependent on the phase of the cell cycle. The most radiation-sensitive phases are G2 and M, whereas G1 and late S phases are less sensitive. Thus, irradiation of a population of tumor cells results in killing of a greater proportion of cells in G2 and M phases. However, delivery of radiation in divided doses, a concept referred to as fractionation, allows the surviv-ing G1 and S phase cells to progress to more sensitive phases, a process referred to as reassortment. In contrast to DNA dam-age after indirectly ionizing radiation, that after exposure to directly ionizing radiation is less dependent
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Surgery_Schwartz. The presence of oxygen is thought to pro-long the half-life of free radicals produced by the interaction of X-rays and cellular H2O2, and thus indirectly ionizing radiation is less efficacious in tumors with areas of hypoxia.168 In contrast, radiation damage from directly ionizing radiation is independent of cellular oxygen levels.The extent of DNA damage from indirectly ionizing radiation is dependent on the phase of the cell cycle. The most radiation-sensitive phases are G2 and M, whereas G1 and late S phases are less sensitive. Thus, irradiation of a population of tumor cells results in killing of a greater proportion of cells in G2 and M phases. However, delivery of radiation in divided doses, a concept referred to as fractionation, allows the surviv-ing G1 and S phase cells to progress to more sensitive phases, a process referred to as reassortment. In contrast to DNA dam-age after indirectly ionizing radiation, that after exposure to directly ionizing radiation is less dependent
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to more sensitive phases, a process referred to as reassortment. In contrast to DNA dam-age after indirectly ionizing radiation, that after exposure to directly ionizing radiation is less dependent on the cell-cycle phase.169Several chemicals can modify the effects of ionizing radia-tion. These include hypoxic cell sensitizers such as metronida-zole and misonidazole, which mimic oxygen and increase cell kill of hypoxic cells.168 A second category of radiation sensitiz-ers are the thymidine analogues iododeoxyuridine and bromo-deoxyuridine. These molecules are incorporated into the DNA in place of thymidine and render the cells more susceptible to radiation damage; however, they are associated with consid-erable acute toxicity. Several other chemotherapeutic agents sensitize cells to radiation through various mechanisms, includ-ing 5-fluorouracil, actinomycin D, gemcitabine, paclitaxel, topotecan, doxorubicin, and vinorelbine.168 The development of novel radiosensitizers is an active
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Surgery_Schwartz. to more sensitive phases, a process referred to as reassortment. In contrast to DNA dam-age after indirectly ionizing radiation, that after exposure to directly ionizing radiation is less dependent on the cell-cycle phase.169Several chemicals can modify the effects of ionizing radia-tion. These include hypoxic cell sensitizers such as metronida-zole and misonidazole, which mimic oxygen and increase cell kill of hypoxic cells.168 A second category of radiation sensitiz-ers are the thymidine analogues iododeoxyuridine and bromo-deoxyuridine. These molecules are incorporated into the DNA in place of thymidine and render the cells more susceptible to radiation damage; however, they are associated with consid-erable acute toxicity. Several other chemotherapeutic agents sensitize cells to radiation through various mechanisms, includ-ing 5-fluorouracil, actinomycin D, gemcitabine, paclitaxel, topotecan, doxorubicin, and vinorelbine.168 The development of novel radiosensitizers is an active
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through various mechanisms, includ-ing 5-fluorouracil, actinomycin D, gemcitabine, paclitaxel, topotecan, doxorubicin, and vinorelbine.168 The development of novel radiosensitizers is an active area of research and mul-tiple small molecules as well as novel nanomaterials are under investigation.170Radiation Therapy PlanningRadiation therapy is delivered in a homogeneous dose to a well-defined region that includes tumor and/or surrounding tissue at risk for subclinical disease. The first step in planning is to define the target to be irradiated as well as the dose-limiting organs in the vicinity.171 Treatment planning includes evaluation of alter-native treatment techniques, which is done through a process referred to as simulation. Once the beam distribution that will best achieve homogeneous delivery to the target volume and minimize the dose to the normal tissue is determined, immo-bilization devices and markings or tattoos on the patient’s skin are used to ensure that each daily
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Surgery_Schwartz. through various mechanisms, includ-ing 5-fluorouracil, actinomycin D, gemcitabine, paclitaxel, topotecan, doxorubicin, and vinorelbine.168 The development of novel radiosensitizers is an active area of research and mul-tiple small molecules as well as novel nanomaterials are under investigation.170Radiation Therapy PlanningRadiation therapy is delivered in a homogeneous dose to a well-defined region that includes tumor and/or surrounding tissue at risk for subclinical disease. The first step in planning is to define the target to be irradiated as well as the dose-limiting organs in the vicinity.171 Treatment planning includes evaluation of alter-native treatment techniques, which is done through a process referred to as simulation. Once the beam distribution that will best achieve homogeneous delivery to the target volume and minimize the dose to the normal tissue is determined, immo-bilization devices and markings or tattoos on the patient’s skin are used to ensure that each daily
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delivery to the target volume and minimize the dose to the normal tissue is determined, immo-bilization devices and markings or tattoos on the patient’s skin are used to ensure that each daily treatment is given in the same way. Conventional fractionation is 1.8 to 2 Gy/d, administered 5 days each week for 3 to 7 weeks.Radiation therapy may be used as the primary modality for palliation in certain patients with metastatic disease, pri-marily patients with bony metastases. In these cases, radiation is recommended for symptomatic metastases only. However, lytic metastases in weight-bearing bones such as the femur, tibia, or humerus also are considered for irradiation. Another circumstance in which radiation therapy might be appropriate is spinal cord compression due to metastases to the vertebral body that extend posteriorly to the spinal canal.The goal of adjuvant radiation therapy is to decrease local-regional recurrence rates. Adjuvant radiation therapy can be given before surgery,
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Surgery_Schwartz. delivery to the target volume and minimize the dose to the normal tissue is determined, immo-bilization devices and markings or tattoos on the patient’s skin are used to ensure that each daily treatment is given in the same way. Conventional fractionation is 1.8 to 2 Gy/d, administered 5 days each week for 3 to 7 weeks.Radiation therapy may be used as the primary modality for palliation in certain patients with metastatic disease, pri-marily patients with bony metastases. In these cases, radiation is recommended for symptomatic metastases only. However, lytic metastases in weight-bearing bones such as the femur, tibia, or humerus also are considered for irradiation. Another circumstance in which radiation therapy might be appropriate is spinal cord compression due to metastases to the vertebral body that extend posteriorly to the spinal canal.The goal of adjuvant radiation therapy is to decrease local-regional recurrence rates. Adjuvant radiation therapy can be given before surgery,
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body that extend posteriorly to the spinal canal.The goal of adjuvant radiation therapy is to decrease local-regional recurrence rates. Adjuvant radiation therapy can be given before surgery, after surgery, or, in selected cases, during surgery. Preoperative radiation therapy has several advantages. It may minimize seeding of the tumor during surgery and it allows for smaller treatment fields because the operative bed has not been contaminated with tumor cells. Also, radiation therapy for inoperable tumors may achieve adequate reduction to make them operable. The disadvantages of preoperative therapy are an increased risk of postoperative wound healing problems and the difficulty in planning subsequent radiation therapy in patients who have positive surgical margins. If radiation therapy is given postoperatively, it is usually given 3 to 4 weeks after surgery to allow for wound healing. The advantage of postoperative radia-tion therapy is that the surgical specimen can be evaluated
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Surgery_Schwartz. body that extend posteriorly to the spinal canal.The goal of adjuvant radiation therapy is to decrease local-regional recurrence rates. Adjuvant radiation therapy can be given before surgery, after surgery, or, in selected cases, during surgery. Preoperative radiation therapy has several advantages. It may minimize seeding of the tumor during surgery and it allows for smaller treatment fields because the operative bed has not been contaminated with tumor cells. Also, radiation therapy for inoperable tumors may achieve adequate reduction to make them operable. The disadvantages of preoperative therapy are an increased risk of postoperative wound healing problems and the difficulty in planning subsequent radiation therapy in patients who have positive surgical margins. If radiation therapy is given postoperatively, it is usually given 3 to 4 weeks after surgery to allow for wound healing. The advantage of postoperative radia-tion therapy is that the surgical specimen can be evaluated
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is given postoperatively, it is usually given 3 to 4 weeks after surgery to allow for wound healing. The advantage of postoperative radia-tion therapy is that the surgical specimen can be evaluated histo-logically and radiation therapy can be reserved for patients who are most likely to benefit from it. Further, the radiation therapy can be modified on the basis of margin status. The disadvantages of postoperative radiation therapy are that the volume of nor-mal tissue requiring irradiation may be larger owing to surgical contamination of the tissue planes and that the tumor may be less sensitive to radiation owing to poor oxygenation. Postlapa-rotomy adhesions may decrease the mobility of the small bowel loops, increasing the risk for radiation injury in abdominal or pel-vic irradiation. Given the potential advantages and disadvantages of both approaches, the roles of preoperative and postoperative radiation therapy are being actively evaluated and compared for many cancer
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Surgery_Schwartz. is given postoperatively, it is usually given 3 to 4 weeks after surgery to allow for wound healing. The advantage of postoperative radia-tion therapy is that the surgical specimen can be evaluated histo-logically and radiation therapy can be reserved for patients who are most likely to benefit from it. Further, the radiation therapy can be modified on the basis of margin status. The disadvantages of postoperative radiation therapy are that the volume of nor-mal tissue requiring irradiation may be larger owing to surgical contamination of the tissue planes and that the tumor may be less sensitive to radiation owing to poor oxygenation. Postlapa-rotomy adhesions may decrease the mobility of the small bowel loops, increasing the risk for radiation injury in abdominal or pel-vic irradiation. Given the potential advantages and disadvantages of both approaches, the roles of preoperative and postoperative radiation therapy are being actively evaluated and compared for many cancer
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Given the potential advantages and disadvantages of both approaches, the roles of preoperative and postoperative radiation therapy are being actively evaluated and compared for many cancer types.Another mode of postoperative radiation therapy is brachytherapy. In brachytherapy, unlike in external beam therapy, the radiation source is in contact with the tissue being irradiated. The radiation source may be cesium, gold, iridium, or radium. Brachytherapy is administered via temporary or per-manent delivery implants such as needles, seeds, or catheters. Temporary brachytherapy catheters are placed either during open surgery or percutaneously soon after surgery. The implants are loaded interstitially, and treatment usually is given postop-eratively for a short duration, such as 1 to 3 days. Although brachytherapy has the disadvantages of leaving scars at the cath-eter insertion site and requiring special facilities for inpatient brachytherapy, the advantage of patient convenience owing to
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Surgery_Schwartz. Given the potential advantages and disadvantages of both approaches, the roles of preoperative and postoperative radiation therapy are being actively evaluated and compared for many cancer types.Another mode of postoperative radiation therapy is brachytherapy. In brachytherapy, unlike in external beam therapy, the radiation source is in contact with the tissue being irradiated. The radiation source may be cesium, gold, iridium, or radium. Brachytherapy is administered via temporary or per-manent delivery implants such as needles, seeds, or catheters. Temporary brachytherapy catheters are placed either during open surgery or percutaneously soon after surgery. The implants are loaded interstitially, and treatment usually is given postop-eratively for a short duration, such as 1 to 3 days. Although brachytherapy has the disadvantages of leaving scars at the cath-eter insertion site and requiring special facilities for inpatient brachytherapy, the advantage of patient convenience owing to
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brachytherapy has the disadvantages of leaving scars at the cath-eter insertion site and requiring special facilities for inpatient brachytherapy, the advantage of patient convenience owing to the shorter treatment duration has made intracavitary treatment approaches popular for the treatment of breast cancer.Another short delivery approach is intraoperative radio-therapy (IORT), often used in combination with external beam therapy. The oncologic consequences of the limited treatment volume and duration associated with brachytherapy and IORT are not well understood. Accelerated partial breast irradiation with interstitial brachytherapy, intracavitary brachytherapy (MammoSite), IORT, and three-dimensional conformal external beam radiotherapy is being compared with whole breast irra-diation in an intergroup phase 3 trial (NSABP B-39/Radiation Therapy Oncology Group 0413). Several additional studies of adjuvant IORT also are ongoing internationally. There has also been increased interest
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Surgery_Schwartz. brachytherapy has the disadvantages of leaving scars at the cath-eter insertion site and requiring special facilities for inpatient brachytherapy, the advantage of patient convenience owing to the shorter treatment duration has made intracavitary treatment approaches popular for the treatment of breast cancer.Another short delivery approach is intraoperative radio-therapy (IORT), often used in combination with external beam therapy. The oncologic consequences of the limited treatment volume and duration associated with brachytherapy and IORT are not well understood. Accelerated partial breast irradiation with interstitial brachytherapy, intracavitary brachytherapy (MammoSite), IORT, and three-dimensional conformal external beam radiotherapy is being compared with whole breast irra-diation in an intergroup phase 3 trial (NSABP B-39/Radiation Therapy Oncology Group 0413). Several additional studies of adjuvant IORT also are ongoing internationally. There has also been increased interest
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in an intergroup phase 3 trial (NSABP B-39/Radiation Therapy Oncology Group 0413). Several additional studies of adjuvant IORT also are ongoing internationally. There has also been increased interest in utilizing intensity-modulated radiation therapy (IMRT). IMRT is a complex technique for the delivery of radiation therapy preferentially to target structures while mini-mizing doses to adjacent normal critical structures.172 It is widely utilized for the treatment of a variety of tumor types, including Brunicardi_Ch10_p0305-p0354.indd 34722/02/19 2:14 PM 348BASIC CONSIDERATIONSPART Ithe central nervous system, head and neck, breast, prostate, gas-trointestinal tract, and gynecologic organs, as well as in patients where previous radiation therapy has been delivered. Stereotac-tic radiosurgery uses extremely accurate image-guidance and patient positioning to deliver a high dose of radiation to a small tumor with well-defined margins. In this manner, the dose of radiation being
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Surgery_Schwartz. in an intergroup phase 3 trial (NSABP B-39/Radiation Therapy Oncology Group 0413). Several additional studies of adjuvant IORT also are ongoing internationally. There has also been increased interest in utilizing intensity-modulated radiation therapy (IMRT). IMRT is a complex technique for the delivery of radiation therapy preferentially to target structures while mini-mizing doses to adjacent normal critical structures.172 It is widely utilized for the treatment of a variety of tumor types, including Brunicardi_Ch10_p0305-p0354.indd 34722/02/19 2:14 PM 348BASIC CONSIDERATIONSPART Ithe central nervous system, head and neck, breast, prostate, gas-trointestinal tract, and gynecologic organs, as well as in patients where previous radiation therapy has been delivered. Stereotac-tic radiosurgery uses extremely accurate image-guidance and patient positioning to deliver a high dose of radiation to a small tumor with well-defined margins. In this manner, the dose of radiation being
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radiosurgery uses extremely accurate image-guidance and patient positioning to deliver a high dose of radiation to a small tumor with well-defined margins. In this manner, the dose of radiation being applied to normal tissues can be minimized. It is most commonly used for the treatment of brain and spinal tumors. Protons are a charged particle that can be also used in external beam radiation therapy. Proton therapy employs a beam of protons as a means of delivering radiation to a tumor. In con-trast to photons, which deposit energy continuously during their passage through tissue, protons deposit a large amount of their energy near the end of their path (known as the Bragg peak) and release less energy along the way. Thus, proton therapy could theoretically reduce the exposure of normal tissue to radiation, allowing the delivery of higher doses of radiation to a tumor. It is thought that chemotherapy given concurrently with radiation improves survival rates. Chemotherapy before
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Surgery_Schwartz. radiosurgery uses extremely accurate image-guidance and patient positioning to deliver a high dose of radiation to a small tumor with well-defined margins. In this manner, the dose of radiation being applied to normal tissues can be minimized. It is most commonly used for the treatment of brain and spinal tumors. Protons are a charged particle that can be also used in external beam radiation therapy. Proton therapy employs a beam of protons as a means of delivering radiation to a tumor. In con-trast to photons, which deposit energy continuously during their passage through tissue, protons deposit a large amount of their energy near the end of their path (known as the Bragg peak) and release less energy along the way. Thus, proton therapy could theoretically reduce the exposure of normal tissue to radiation, allowing the delivery of higher doses of radiation to a tumor. It is thought that chemotherapy given concurrently with radiation improves survival rates. Chemotherapy before
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tissue to radiation, allowing the delivery of higher doses of radiation to a tumor. It is thought that chemotherapy given concurrently with radiation improves survival rates. Chemotherapy before radiation has the advantage of reducing the tumor burden, which facilitates radia-tion therapy. On the other hand, some chemotherapy regimens, when given concurrently with radiation, may sensitize the cells to radiation therapy. Chemoradiation is being investigated in many tumor types, including rectal cancer, pancreatic cancer, and esophageal cancer.173-175 In a Cochrane review of six ran-domized controlled trials, it was demonstrated that in patients with T3/4 rectal cancer, chemoradiation was associated with a significantly lower local recurrence rate compared with radiation therapy alone (OR 0.56, 95% CI 0.42–0.75, P <0.0001) but was not associated with improved survival.173Side EffectsBoth tumor and normal tissue have radiation dose-response rela-tionships that can be plotted as a
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Surgery_Schwartz. tissue to radiation, allowing the delivery of higher doses of radiation to a tumor. It is thought that chemotherapy given concurrently with radiation improves survival rates. Chemotherapy before radiation has the advantage of reducing the tumor burden, which facilitates radia-tion therapy. On the other hand, some chemotherapy regimens, when given concurrently with radiation, may sensitize the cells to radiation therapy. Chemoradiation is being investigated in many tumor types, including rectal cancer, pancreatic cancer, and esophageal cancer.173-175 In a Cochrane review of six ran-domized controlled trials, it was demonstrated that in patients with T3/4 rectal cancer, chemoradiation was associated with a significantly lower local recurrence rate compared with radiation therapy alone (OR 0.56, 95% CI 0.42–0.75, P <0.0001) but was not associated with improved survival.173Side EffectsBoth tumor and normal tissue have radiation dose-response rela-tionships that can be plotted as a
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(OR 0.56, 95% CI 0.42–0.75, P <0.0001) but was not associated with improved survival.173Side EffectsBoth tumor and normal tissue have radiation dose-response rela-tionships that can be plotted as a sigmoidal curve (Fig. 10-16).171 A minimum dose of radiation must be given before any response is seen. The response to radiation then increases slowly with an increase in dose. At a certain dose level the curves become exponential, with increases in tumor response and normal tissue toxicity with each incremental dose increase. The side effects of radiation therapy can be acute, occurring during or 2 to 3 weeks after therapy, or chronic, occurring weeks to years after therapy. The side effects depend on the tissue included in the target volume. Some of the major acute and chronic sequelae of radiation are summarized in Table 10-13.171,176 In addition to these effects, a small increase in the risk for secondary malignancies is attribut-able to radiation therapy.CANCER PREVENTIONThe truth of
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Surgery_Schwartz. (OR 0.56, 95% CI 0.42–0.75, P <0.0001) but was not associated with improved survival.173Side EffectsBoth tumor and normal tissue have radiation dose-response rela-tionships that can be plotted as a sigmoidal curve (Fig. 10-16).171 A minimum dose of radiation must be given before any response is seen. The response to radiation then increases slowly with an increase in dose. At a certain dose level the curves become exponential, with increases in tumor response and normal tissue toxicity with each incremental dose increase. The side effects of radiation therapy can be acute, occurring during or 2 to 3 weeks after therapy, or chronic, occurring weeks to years after therapy. The side effects depend on the tissue included in the target volume. Some of the major acute and chronic sequelae of radiation are summarized in Table 10-13.171,176 In addition to these effects, a small increase in the risk for secondary malignancies is attribut-able to radiation therapy.CANCER PREVENTIONThe truth of
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are summarized in Table 10-13.171,176 In addition to these effects, a small increase in the risk for secondary malignancies is attribut-able to radiation therapy.CANCER PREVENTIONThe truth of the old axiom “An ounce of prevention is worth a pound of cure” is being increasingly recognized in oncology. Cancer prevention can be divided into three categories: (a) pri-mary prevention (i.e., prevention of initial cancers in healthy indi-viduals), (b) secondary prevention (i.e., prevention of cancer in individuals with premalignant conditions), and (c) tertiary pre-vention (i.e., prevention of second primary cancers in patients cured of their initial disease).The systemic or local administration of therapeutic agents to prevent the development of cancer, called chemoprevention, is being actively explored for several cancer types. In breast can-cer, the NSABP Breast Cancer Prevention Trial demonstrated that tamoxifen administration reduces the risk of breast cancer by one half and reduces the
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Surgery_Schwartz. are summarized in Table 10-13.171,176 In addition to these effects, a small increase in the risk for secondary malignancies is attribut-able to radiation therapy.CANCER PREVENTIONThe truth of the old axiom “An ounce of prevention is worth a pound of cure” is being increasingly recognized in oncology. Cancer prevention can be divided into three categories: (a) pri-mary prevention (i.e., prevention of initial cancers in healthy indi-viduals), (b) secondary prevention (i.e., prevention of cancer in individuals with premalignant conditions), and (c) tertiary pre-vention (i.e., prevention of second primary cancers in patients cured of their initial disease).The systemic or local administration of therapeutic agents to prevent the development of cancer, called chemoprevention, is being actively explored for several cancer types. In breast can-cer, the NSABP Breast Cancer Prevention Trial demonstrated that tamoxifen administration reduces the risk of breast cancer by one half and reduces the
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explored for several cancer types. In breast can-cer, the NSABP Breast Cancer Prevention Trial demonstrated that tamoxifen administration reduces the risk of breast cancer by one half and reduces the risk of estrogen receptor-positive tumors by 69% in high-risk patients.177 Therefore, tamoxifen has been approved by the FDA for breast cancer chemoprevention. The subsequent NSABP P-2 trial demonstrated that raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and is associated with a lower risk of thromboembolic events and cataracts but a nonstatistically significant higher risk of noninvasive breast cancer; these findings led the FDA to approve raloxifene for prevention as well. Several other agents are also under investigation.178 Celecoxib (a cyclooxygenase 2 [COX-2] inhibitor) has been shown to reduce polyp number and polyp burden in patients with FAP, which led to its approval by the FDA for these patients. However, celecoxib is no longer widely
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Surgery_Schwartz. explored for several cancer types. In breast can-cer, the NSABP Breast Cancer Prevention Trial demonstrated that tamoxifen administration reduces the risk of breast cancer by one half and reduces the risk of estrogen receptor-positive tumors by 69% in high-risk patients.177 Therefore, tamoxifen has been approved by the FDA for breast cancer chemoprevention. The subsequent NSABP P-2 trial demonstrated that raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and is associated with a lower risk of thromboembolic events and cataracts but a nonstatistically significant higher risk of noninvasive breast cancer; these findings led the FDA to approve raloxifene for prevention as well. Several other agents are also under investigation.178 Celecoxib (a cyclooxygenase 2 [COX-2] inhibitor) has been shown to reduce polyp number and polyp burden in patients with FAP, which led to its approval by the FDA for these patients. However, celecoxib is no longer widely
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2 [COX-2] inhibitor) has been shown to reduce polyp number and polyp burden in patients with FAP, which led to its approval by the FDA for these patients. However, celecoxib is no longer widely used as a primary preventative treatment in this setting due to the association between COX-2 inhibitors and coronary artery disease. In head and neck cancer, 13-cis-retinoic acid has been shown both to reverse oral leukoplakia and to reduce sec-ond primary tumor development.179,180 However, a large phase 3 clinical trial that utilized low-dose 13-cis-retinoic acid in patients with early stage squamous cell carcinoma of the head and neck showed no significant difference in the incidence of tumor recurrence or the second primary tumors between the pla-cebo and chemoprevention arms.181 Thus, the chemoprevention trials completed so far have had mixed results. Much remains to be done over the next few years to improve outcomes and decrease therapy-related toxic effects. It is important for
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Surgery_Schwartz. 2 [COX-2] inhibitor) has been shown to reduce polyp number and polyp burden in patients with FAP, which led to its approval by the FDA for these patients. However, celecoxib is no longer widely used as a primary preventative treatment in this setting due to the association between COX-2 inhibitors and coronary artery disease. In head and neck cancer, 13-cis-retinoic acid has been shown both to reverse oral leukoplakia and to reduce sec-ond primary tumor development.179,180 However, a large phase 3 clinical trial that utilized low-dose 13-cis-retinoic acid in patients with early stage squamous cell carcinoma of the head and neck showed no significant difference in the incidence of tumor recurrence or the second primary tumors between the pla-cebo and chemoprevention arms.181 Thus, the chemoprevention trials completed so far have had mixed results. Much remains to be done over the next few years to improve outcomes and decrease therapy-related toxic effects. It is important for
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the chemoprevention trials completed so far have had mixed results. Much remains to be done over the next few years to improve outcomes and decrease therapy-related toxic effects. It is important for sur-geons to be aware of these preventive options because they are likely to be involved in the diagnosis of premalignant and malig-nant conditions and will be the ones to counsel patients about their chemopreventive options.In selected circumstances, the risk of cancer is high enough to justify surgical prevention. These high-risk settings include hereditary cancer syndromes such as hereditary breast-ovarian cancer syndrome, hereditary diffuse gastric cancer, multiple endocrine neoplasia type 2, FAP, and hereditary non-polyposis colorectal cancer, as well as some nonhereditary Tumor controlComplicationsABDosePercentFigure 10-16. The probability of tumor control and of complica-tions at different radiation doses. A. At lower doses, the probability of complications is low, with a moderate
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Surgery_Schwartz. the chemoprevention trials completed so far have had mixed results. Much remains to be done over the next few years to improve outcomes and decrease therapy-related toxic effects. It is important for sur-geons to be aware of these preventive options because they are likely to be involved in the diagnosis of premalignant and malig-nant conditions and will be the ones to counsel patients about their chemopreventive options.In selected circumstances, the risk of cancer is high enough to justify surgical prevention. These high-risk settings include hereditary cancer syndromes such as hereditary breast-ovarian cancer syndrome, hereditary diffuse gastric cancer, multiple endocrine neoplasia type 2, FAP, and hereditary non-polyposis colorectal cancer, as well as some nonhereditary Tumor controlComplicationsABDosePercentFigure 10-16. The probability of tumor control and of complica-tions at different radiation doses. A. At lower doses, the probability of complications is low, with a moderate
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10-16. The probability of tumor control and of complica-tions at different radiation doses. A. At lower doses, the probability of complications is low, with a moderate chance of tumor control. B. Increasing the dose may gain a higher chance of tumor control at the price of significantly higher complication risks. (Reproduced with permission from Eisbruch A, Lichter AS. What a surgeon needs to know about radiation, Ann Surg Oncol. 1997 Sep;4(6):516-522.)Brunicardi_Ch10_p0305-p0354.indd 34822/02/19 2:14 PM 349ONCOLOGYCHAPTER 10conditions such as chronic ulcerative colitis. Most prophy-lactic surgeries are large ablative surgeries (e.g., bilateral risk-reducing mastectomy or total proctocolectomy). There-fore, it is important that the patient be completely informed about potential surgical complications as well as long-term lifestyle consequences. Further, the conservative options of close surveillance and chemoprevention need to be discussed. The patient’s cancer risk needs to be
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Surgery_Schwartz. 10-16. The probability of tumor control and of complica-tions at different radiation doses. A. At lower doses, the probability of complications is low, with a moderate chance of tumor control. B. Increasing the dose may gain a higher chance of tumor control at the price of significantly higher complication risks. (Reproduced with permission from Eisbruch A, Lichter AS. What a surgeon needs to know about radiation, Ann Surg Oncol. 1997 Sep;4(6):516-522.)Brunicardi_Ch10_p0305-p0354.indd 34822/02/19 2:14 PM 349ONCOLOGYCHAPTER 10conditions such as chronic ulcerative colitis. Most prophy-lactic surgeries are large ablative surgeries (e.g., bilateral risk-reducing mastectomy or total proctocolectomy). There-fore, it is important that the patient be completely informed about potential surgical complications as well as long-term lifestyle consequences. Further, the conservative options of close surveillance and chemoprevention need to be discussed. The patient’s cancer risk needs to be
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complications as well as long-term lifestyle consequences. Further, the conservative options of close surveillance and chemoprevention need to be discussed. The patient’s cancer risk needs to be assessed accurately and implications for survival discussed. Ultimately, the decision to proceed with surgical prevention should be individualized and made with caution.TRENDS IN ONCOLOGYCancer Screening and DiagnosisIt is clear that the practice of oncology will change dramati-cally over the next few decades because our understanding of the molecular basis of cancer and available technologies are evolving rapidly. One of the critical changes expected is earlier detection of cancers. With improvements in available imaging modalities and development of newer functional imaging tech-niques, it is likely that many tumors will be detected at earlier, more curable stages in the near future.Another area of rapid development is the identification of serum markers. High-throughput technologies such as
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Surgery_Schwartz. complications as well as long-term lifestyle consequences. Further, the conservative options of close surveillance and chemoprevention need to be discussed. The patient’s cancer risk needs to be assessed accurately and implications for survival discussed. Ultimately, the decision to proceed with surgical prevention should be individualized and made with caution.TRENDS IN ONCOLOGYCancer Screening and DiagnosisIt is clear that the practice of oncology will change dramati-cally over the next few decades because our understanding of the molecular basis of cancer and available technologies are evolving rapidly. One of the critical changes expected is earlier detection of cancers. With improvements in available imaging modalities and development of newer functional imaging tech-niques, it is likely that many tumors will be detected at earlier, more curable stages in the near future.Another area of rapid development is the identification of serum markers. High-throughput technologies such as
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that many tumors will be detected at earlier, more curable stages in the near future.Another area of rapid development is the identification of serum markers. High-throughput technologies such as matrix-assisted laser desorption ionization time-of-flight mass spec-troscopy and liquid chromatography ion-spray tandem mass spectroscopy have revolutionized the field of proteomics and are now being used to compare the serum protein profiles of patients with cancer with those of individuals without cancer. Identification of unique proteins as well as unique proteomic profiles for most cancer types is being pursued actively by many researchers and, if successful, could dramatically enhance our ability to detect cancers early.182DNA fragments that are derived from tumors and are circulating in the blood stream are referred to as circulating tumor DNA (ctDNA). Analysis of ctDNA can potentially pro-vide information on the entire tumor genome and has poten-tial clinical utility as a so-called
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Surgery_Schwartz. that many tumors will be detected at earlier, more curable stages in the near future.Another area of rapid development is the identification of serum markers. High-throughput technologies such as matrix-assisted laser desorption ionization time-of-flight mass spec-troscopy and liquid chromatography ion-spray tandem mass spectroscopy have revolutionized the field of proteomics and are now being used to compare the serum protein profiles of patients with cancer with those of individuals without cancer. Identification of unique proteins as well as unique proteomic profiles for most cancer types is being pursued actively by many researchers and, if successful, could dramatically enhance our ability to detect cancers early.182DNA fragments that are derived from tumors and are circulating in the blood stream are referred to as circulating tumor DNA (ctDNA). Analysis of ctDNA can potentially pro-vide information on the entire tumor genome and has poten-tial clinical utility as a so-called
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the blood stream are referred to as circulating tumor DNA (ctDNA). Analysis of ctDNA can potentially pro-vide information on the entire tumor genome and has poten-tial clinical utility as a so-called “liquid biopsy” when blood samples are obtained during important junctures of a clinical scenario. ctDNA may originate directly from the tumor or from circulating tumor cells, which refers to intact tumor cells that are shed from primary tumors and enter the bloodstream. The precise mechanism of ctDNA release has not been determined; however, there is evidence to show that the length of the DNA fragments are similar to those seen during the process of apop-tosis. ctDNA can be reliably procured from peripheral blood and analyzed via a number of advanced techniques, including next generation sequencing. The main advantages of using ctDNA in genomic studies is the ability to obtain information on the entire tumor genome, thus avoiding the difficulties of tumor heteroge-neity that are
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Surgery_Schwartz. the blood stream are referred to as circulating tumor DNA (ctDNA). Analysis of ctDNA can potentially pro-vide information on the entire tumor genome and has poten-tial clinical utility as a so-called “liquid biopsy” when blood samples are obtained during important junctures of a clinical scenario. ctDNA may originate directly from the tumor or from circulating tumor cells, which refers to intact tumor cells that are shed from primary tumors and enter the bloodstream. The precise mechanism of ctDNA release has not been determined; however, there is evidence to show that the length of the DNA fragments are similar to those seen during the process of apop-tosis. ctDNA can be reliably procured from peripheral blood and analyzed via a number of advanced techniques, including next generation sequencing. The main advantages of using ctDNA in genomic studies is the ability to obtain information on the entire tumor genome, thus avoiding the difficulties of tumor heteroge-neity that are
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sequencing. The main advantages of using ctDNA in genomic studies is the ability to obtain information on the entire tumor genome, thus avoiding the difficulties of tumor heteroge-neity that are encountered with needle biopsies, and the ability to obtain multiple samples with much less risk to the patient.181Surgical TherapyThe current trend in surgery is toward more conservative resec-tions. With earlier identification of tumors, more conservative operations may be possible. The goal, however, is always to remove the tumor en bloc with wide negative margins. Another interesting area being explored is the destruction of tumors by techniques such as radiofrequency ablation, cryoablation, and heat-producing technologies like lasers, microwaves, or focused ultrasound.The debate over how to manage the regional lymph node basins for certain cancer types continues. With an increasing understanding of the metastatic process, surgeons may be able to stratify patients on the basis of the
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Surgery_Schwartz. sequencing. The main advantages of using ctDNA in genomic studies is the ability to obtain information on the entire tumor genome, thus avoiding the difficulties of tumor heteroge-neity that are encountered with needle biopsies, and the ability to obtain multiple samples with much less risk to the patient.181Surgical TherapyThe current trend in surgery is toward more conservative resec-tions. With earlier identification of tumors, more conservative operations may be possible. The goal, however, is always to remove the tumor en bloc with wide negative margins. Another interesting area being explored is the destruction of tumors by techniques such as radiofrequency ablation, cryoablation, and heat-producing technologies like lasers, microwaves, or focused ultrasound.The debate over how to manage the regional lymph node basins for certain cancer types continues. With an increasing understanding of the metastatic process, surgeons may be able to stratify patients on the basis of the
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to manage the regional lymph node basins for certain cancer types continues. With an increasing understanding of the metastatic process, surgeons may be able to stratify patients on the basis of the likelihood that their disease will spread metastatically, based on the gene expression profile of their primary tumors, and offer regional therapy accordingly. There is also a growing interest in minimally invasive surgical treatments for a variety of cancer types.Systemic TherapyThe current trend in systemic therapy is toward individual-ized therapy. Therefore, the intent is to determine the under-lying biology of each tumor to tailor therapy accordingly. Genomic, transcriptional, and proteomic profiling approaches are being used to identify molecular signatures that correlate Table 10-13Local effects of radiationORGANACUTE CHANGESCHRONIC CHANGESSkinErythema, wet or dry desquamation, epilationTelangiectasia, subcutaneous fibrosis, ulcerationGI tractNausea, diarrhea, edema, ulceration,
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Surgery_Schwartz. to manage the regional lymph node basins for certain cancer types continues. With an increasing understanding of the metastatic process, surgeons may be able to stratify patients on the basis of the likelihood that their disease will spread metastatically, based on the gene expression profile of their primary tumors, and offer regional therapy accordingly. There is also a growing interest in minimally invasive surgical treatments for a variety of cancer types.Systemic TherapyThe current trend in systemic therapy is toward individual-ized therapy. Therefore, the intent is to determine the under-lying biology of each tumor to tailor therapy accordingly. Genomic, transcriptional, and proteomic profiling approaches are being used to identify molecular signatures that correlate Table 10-13Local effects of radiationORGANACUTE CHANGESCHRONIC CHANGESSkinErythema, wet or dry desquamation, epilationTelangiectasia, subcutaneous fibrosis, ulcerationGI tractNausea, diarrhea, edema, ulceration,
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effects of radiationORGANACUTE CHANGESCHRONIC CHANGESSkinErythema, wet or dry desquamation, epilationTelangiectasia, subcutaneous fibrosis, ulcerationGI tractNausea, diarrhea, edema, ulceration, hepatitisStricture, ulceration, perforation, hematocheziaKidney—Nephropathy, renal insufficiencyBladderDysuriaHematuria, ulceration, perforationGonadsSterilityAtrophy, ovarian failureHematopoietic tissueLymphopenia, neutropenia, thrombocytopeniaPancytopeniaBoneEpiphyseal growth arrestNecrosisLungPneumonitisPulmonary fibrosisHeart—Pericarditis, vascular damageUpper aerodigestive tractMucositis, xerostomia, anosmiaXerostomia, dental cariesEyeConjunctivitisCataract, keratitis, optic nerve atrophyNervous systemCerebral edemaNecrosis, myelitisBrunicardi_Ch10_p0305-p0354.indd 34922/02/19 2:14 PM 350BASIC CONSIDERATIONSPART Iwith response to certain agents. It is likely that in the near future all tumors can be tested and treatments individualized. Patients who will respond to conventional
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Surgery_Schwartz. effects of radiationORGANACUTE CHANGESCHRONIC CHANGESSkinErythema, wet or dry desquamation, epilationTelangiectasia, subcutaneous fibrosis, ulcerationGI tractNausea, diarrhea, edema, ulceration, hepatitisStricture, ulceration, perforation, hematocheziaKidney—Nephropathy, renal insufficiencyBladderDysuriaHematuria, ulceration, perforationGonadsSterilityAtrophy, ovarian failureHematopoietic tissueLymphopenia, neutropenia, thrombocytopeniaPancytopeniaBoneEpiphyseal growth arrestNecrosisLungPneumonitisPulmonary fibrosisHeart—Pericarditis, vascular damageUpper aerodigestive tractMucositis, xerostomia, anosmiaXerostomia, dental cariesEyeConjunctivitisCataract, keratitis, optic nerve atrophyNervous systemCerebral edemaNecrosis, myelitisBrunicardi_Ch10_p0305-p0354.indd 34922/02/19 2:14 PM 350BASIC CONSIDERATIONSPART Iwith response to certain agents. It is likely that in the near future all tumors can be tested and treatments individualized. Patients who will respond to conventional
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PM 350BASIC CONSIDERATIONSPART Iwith response to certain agents. It is likely that in the near future all tumors can be tested and treatments individualized. Patients who will respond to conventional therapies can be treated with these regimens, whereas patients who will not respond will not, which spares them the toxicity. Instead, the latter patients can be offered novel therapies. Furthermore, with the advent of effec-tive immune-based therapies, it is likely that patients may be given treatments that can specifically target the alterations driv-ing tumor growth in combination with drugs that can enhance the anticancer immune response. Patients can be genotyped for critical alleles that may affect drug metabolism and thus, may influence the efficacy as well as the side effects of the drugs given. Finally, stratification of patients by gene expression pro-file for prognosis may assist in determining which patients are at higher risk of relapse so that patients whose tumors have less
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Surgery_Schwartz. PM 350BASIC CONSIDERATIONSPART Iwith response to certain agents. It is likely that in the near future all tumors can be tested and treatments individualized. Patients who will respond to conventional therapies can be treated with these regimens, whereas patients who will not respond will not, which spares them the toxicity. Instead, the latter patients can be offered novel therapies. Furthermore, with the advent of effec-tive immune-based therapies, it is likely that patients may be given treatments that can specifically target the alterations driv-ing tumor growth in combination with drugs that can enhance the anticancer immune response. Patients can be genotyped for critical alleles that may affect drug metabolism and thus, may influence the efficacy as well as the side effects of the drugs given. Finally, stratification of patients by gene expression pro-file for prognosis may assist in determining which patients are at higher risk of relapse so that patients whose tumors have less
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given. Finally, stratification of patients by gene expression pro-file for prognosis may assist in determining which patients are at higher risk of relapse so that patients whose tumors have less aggressive biologic characteristics can be spared further therapy.REFERENCESEntries highlighted in bright blue are key references. 1. Siegel R, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7-30. 2. Ravdin PM, Cronin KA, Howlader N, et al. The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med. 2007;356:1670-1674. 3. Siegel R, Miller KD, Jemal A. Cancer statistics, 2016. CA: Cancer J Clin. 2016;66:7-30. 4. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM; International Agency for Research on Cancer. GLO-BOCAN 2008 v2.0, Cancer incidence and mortality world-wide. Available at: https://www.iarc.fr/en/media-centre/iarcnews/2010/globocan2008.php. Accessed July 1, 2018. 5. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics,
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Surgery_Schwartz. given. Finally, stratification of patients by gene expression pro-file for prognosis may assist in determining which patients are at higher risk of relapse so that patients whose tumors have less aggressive biologic characteristics can be spared further therapy.REFERENCESEntries highlighted in bright blue are key references. 1. Siegel R, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7-30. 2. Ravdin PM, Cronin KA, Howlader N, et al. The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med. 2007;356:1670-1674. 3. Siegel R, Miller KD, Jemal A. Cancer statistics, 2016. CA: Cancer J Clin. 2016;66:7-30. 4. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM; International Agency for Research on Cancer. GLO-BOCAN 2008 v2.0, Cancer incidence and mortality world-wide. Available at: https://www.iarc.fr/en/media-centre/iarcnews/2010/globocan2008.php. Accessed July 1, 2018. 5. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics,
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and mortality world-wide. Available at: https://www.iarc.fr/en/media-centre/iarcnews/2010/globocan2008.php. Accessed July 1, 2018. 5. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74-108. 6. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57-70. 7. Hanahan D, Weinberg RA. Hallmarks of cancer: the next gen-eration. Cell. 2011;144:646-674. 8. Pelengaris S, Khan M, Evan G. c-MYC: more than just a mat-ter of life and death. Nat Rev Cancer. 2002;2:764-776. 9. Li C-J, Zhang, X, Fan G-W. Updates in colorectal cancer stem cell research. J Cancer Res Ther. 2014;10:233-239. 10. Kastan M, Skapek S. Molecular biology of cancer: the cell cycle. In: DeVita V, Hellman S, Rosenberg S, eds. Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2005. 11. Eccles SA. The role of c-erbB-2/HER2/neu in breast cancer progression and metastasis. J Mammary Gland Biol Neopla-sia.
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Surgery_Schwartz. and mortality world-wide. Available at: https://www.iarc.fr/en/media-centre/iarcnews/2010/globocan2008.php. Accessed July 1, 2018. 5. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74-108. 6. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57-70. 7. Hanahan D, Weinberg RA. Hallmarks of cancer: the next gen-eration. Cell. 2011;144:646-674. 8. Pelengaris S, Khan M, Evan G. c-MYC: more than just a mat-ter of life and death. Nat Rev Cancer. 2002;2:764-776. 9. Li C-J, Zhang, X, Fan G-W. Updates in colorectal cancer stem cell research. J Cancer Res Ther. 2014;10:233-239. 10. Kastan M, Skapek S. Molecular biology of cancer: the cell cycle. In: DeVita V, Hellman S, Rosenberg S, eds. Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2005. 11. Eccles SA. The role of c-erbB-2/HER2/neu in breast cancer progression and metastasis. J Mammary Gland Biol Neopla-sia.
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Surgery_Schwartz. exci-sion in the management of rectal cancer. Surg Clin North Am. 2002;82:995-1007. 135. Meric F, Hunt KK. Surgical options for breast cancer. In: Hunt KK, Robb GL, Strom EA, Ueno NT, eds. MD Anderson Cancer Care Series—Breast Cancer. New York: Springer-Verlag; 2001:187-222. 136. Cabanas RM. An approach for the treatment of penile carci-noma. Cancer. 1977;39:456-466. 137. Querzoli P, Pedriali M, Rinaldi R, et al. Axillary lymph node nanometastases are prognostic factors for disease-free survival and metastatic relapse in breast cancer patients. Clin Cancer Res. 2006;12:6696-6701. 138. Mocellin S, Pilati P, Lise M, Nitti D. Meta-analysis of hepatic arterial infusion for unresectable liver metastases from colorectal cancer: the end of an era? J Clin Oncol. 2007;25:5649-5654. 139. Faries MB, Thompson JF, Cochran AJ, et al. Completion dis-section or observation for sentinel-node metastasis in mela-noma. N Engl J Med. 2017;376:2211-2222. 140. Pearson AS, Izzo F, Fleming RY, et al.
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MB, Thompson JF, Cochran AJ, et al. Completion dis-section or observation for sentinel-node metastasis in mela-noma. N Engl J Med. 2017;376:2211-2222. 140. Pearson AS, Izzo F, Fleming RY, et al. Intraoperative radiofre-quency ablation or cryoablation for hepatic malignancies. Am J Surg. 1999;178:592-599. 141. Curley SA, Izzo F. Radiofrequency ablation of primary and met-astatic hepatic malignancies. Int J Clin Oncol. 2002;7:72-81. 142. Fisher B, Bryant J, Wolmark N, et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol. 1998;16:2672-2685. 143. Meric F, Hess KR, Varma DG, et al. Radiographic response to neoadjuvant chemotherapy is a predictor of local control and survival in soft tissue sarcomas. Cancer. 2002;95:11201126. 144. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the
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Surgery_Schwartz. MB, Thompson JF, Cochran AJ, et al. Completion dis-section or observation for sentinel-node metastasis in mela-noma. N Engl J Med. 2017;376:2211-2222. 140. Pearson AS, Izzo F, Fleming RY, et al. Intraoperative radiofre-quency ablation or cryoablation for hepatic malignancies. Am J Surg. 1999;178:592-599. 141. Curley SA, Izzo F. Radiofrequency ablation of primary and met-astatic hepatic malignancies. Int J Clin Oncol. 2002;7:72-81. 142. Fisher B, Bryant J, Wolmark N, et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol. 1998;16:2672-2685. 143. Meric F, Hess KR, Varma DG, et al. Radiographic response to neoadjuvant chemotherapy is a predictor of local control and survival in soft tissue sarcomas. Cancer. 2002;95:11201126. 144. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the
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P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205-216. 145. Page R. Principles of chemotherapy. In: Pazdur R, Hoskins W, Coia L, eds. Cancer Management: A Multidisciplinary Approach. Melville, NY: PRR Inc; 2001:21. 146. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer. 1981;47:207-214. 147. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516. 148. McAuliffe PF, Meric-Bernstam F, Mills GB, Gonzalez-Angulo AM. Deciphering the role of PI3K/Akt/mTOR pathway in breast cancer biology and pathogenesis. Clin Breast Cancer. 2010;10(suppl 3):S59-S65. 149. Mocellin S, Rossi CR, Lise M, Marincola FM. Adjuvant immunotherapy for
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Surgery_Schwartz. P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205-216. 145. Page R. Principles of chemotherapy. In: Pazdur R, Hoskins W, Coia L, eds. Cancer Management: A Multidisciplinary Approach. Melville, NY: PRR Inc; 2001:21. 146. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer. 1981;47:207-214. 147. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516. 148. McAuliffe PF, Meric-Bernstam F, Mills GB, Gonzalez-Angulo AM. Deciphering the role of PI3K/Akt/mTOR pathway in breast cancer biology and pathogenesis. Clin Breast Cancer. 2010;10(suppl 3):S59-S65. 149. Mocellin S, Rossi CR, Lise M, Marincola FM. Adjuvant immunotherapy for
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the role of PI3K/Akt/mTOR pathway in breast cancer biology and pathogenesis. Clin Breast Cancer. 2010;10(suppl 3):S59-S65. 149. Mocellin S, Rossi CR, Lise M, Marincola FM. Adjuvant immunotherapy for solid tumors: from promise to clinical application. Cancer Immunol Immunother. 2002;51:583-595. 150. Perales MA, Wolchok JD. Melanoma vaccines. Cancer Invest. 2002;20:1012-1026. 151. Lizee G, Cantu MA, Hwu P. Less yin, more yang: confront-ing the barriers to cancer immunotherapy. Clin Cancer Res. 2007;13:5250-5255. 152. Dermime S, Armstrong A, Hawkins RE, Stern PL. Cancer vac-cines and immunotherapy. Br Med Bull. 2002;62:149-162. 153. Berinstein NL. Enhancing cancer vaccines with immunomod-ulators. Vaccine. 2007;25 Suppl 2:B72-B88. 154. Cranmer LD, Hersh E. The role of the CTLA4 blockade in the treatment of malignant melanoma. Cancer Invest. 2007;25:613-631. 155. Balar AV, Weber JS. PD-1 and PD-L1 antibodies in cancer: current status and future directions. Cancer Immunol Immu-nother.
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Surgery_Schwartz. the role of PI3K/Akt/mTOR pathway in breast cancer biology and pathogenesis. Clin Breast Cancer. 2010;10(suppl 3):S59-S65. 149. Mocellin S, Rossi CR, Lise M, Marincola FM. Adjuvant immunotherapy for solid tumors: from promise to clinical application. Cancer Immunol Immunother. 2002;51:583-595. 150. Perales MA, Wolchok JD. Melanoma vaccines. Cancer Invest. 2002;20:1012-1026. 151. Lizee G, Cantu MA, Hwu P. Less yin, more yang: confront-ing the barriers to cancer immunotherapy. Clin Cancer Res. 2007;13:5250-5255. 152. Dermime S, Armstrong A, Hawkins RE, Stern PL. Cancer vac-cines and immunotherapy. Br Med Bull. 2002;62:149-162. 153. Berinstein NL. Enhancing cancer vaccines with immunomod-ulators. Vaccine. 2007;25 Suppl 2:B72-B88. 154. Cranmer LD, Hersh E. The role of the CTLA4 blockade in the treatment of malignant melanoma. Cancer Invest. 2007;25:613-631. 155. Balar AV, Weber JS. PD-1 and PD-L1 antibodies in cancer: current status and future directions. Cancer Immunol Immu-nother.
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in the treatment of malignant melanoma. Cancer Invest. 2007;25:613-631. 155. Balar AV, Weber JS. PD-1 and PD-L1 antibodies in cancer: current status and future directions. Cancer Immunol Immu-nother. 2017;6:551-564. 156. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. The N Engl J Med. 2010;363:711-723. 157. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517-2526. 158. Jacquelot N, Roberti MP, Enot DP, et al. Predictors of responses to immune checkpoint blockade in advanced mela-noma. Nat Commun. 2017;8:592. 159. Cusack JC, Jr., Tanabe KK. Introduction to cancer gene ther-apy. Surg Oncol Clin N Am. 2002;11:497-519. 160. Morrow C, Cowan K. Drug resistance and its clinical circum-vention. In: Bast R, Kufe D, Pollock R, eds. Cancer Medicine. Hamilton: B.C. Decker, Inc; 2000:539. 161. Mittendorf EA, Wu Y, Scaltriti M, et al. Loss of
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Surgery_Schwartz. in the treatment of malignant melanoma. Cancer Invest. 2007;25:613-631. 155. Balar AV, Weber JS. PD-1 and PD-L1 antibodies in cancer: current status and future directions. Cancer Immunol Immu-nother. 2017;6:551-564. 156. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. The N Engl J Med. 2010;363:711-723. 157. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517-2526. 158. Jacquelot N, Roberti MP, Enot DP, et al. Predictors of responses to immune checkpoint blockade in advanced mela-noma. Nat Commun. 2017;8:592. 159. Cusack JC, Jr., Tanabe KK. Introduction to cancer gene ther-apy. Surg Oncol Clin N Am. 2002;11:497-519. 160. Morrow C, Cowan K. Drug resistance and its clinical circum-vention. In: Bast R, Kufe D, Pollock R, eds. Cancer Medicine. Hamilton: B.C. Decker, Inc; 2000:539. 161. Mittendorf EA, Wu Y, Scaltriti M, et al. Loss of
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K. Drug resistance and its clinical circum-vention. In: Bast R, Kufe D, Pollock R, eds. Cancer Medicine. Hamilton: B.C. Decker, Inc; 2000:539. 161. Mittendorf EA, Wu Y, Scaltriti M, et al. Loss of HER2 amplification following trastuzumab-based neoadjuvant systemic therapy and survival outcomes. Clin Cancer Res. 2009;15:7381-7388. 162. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2:e73. 163. Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplifi-cation leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316:1039-1043.Brunicardi_Ch10_p0305-p0354.indd 35322/02/19 2:14 PM 354BASIC CONSIDERATIONSPART I 164. Bean J, Brennan C, Shih JY, et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci USA.
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Surgery_Schwartz. K. Drug resistance and its clinical circum-vention. In: Bast R, Kufe D, Pollock R, eds. Cancer Medicine. Hamilton: B.C. Decker, Inc; 2000:539. 161. Mittendorf EA, Wu Y, Scaltriti M, et al. Loss of HER2 amplification following trastuzumab-based neoadjuvant systemic therapy and survival outcomes. Clin Cancer Res. 2009;15:7381-7388. 162. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2:e73. 163. Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplifi-cation leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316:1039-1043.Brunicardi_Ch10_p0305-p0354.indd 35322/02/19 2:14 PM 354BASIC CONSIDERATIONSPART I 164. Bean J, Brennan C, Shih JY, et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci USA.
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J, Brennan C, Shih JY, et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci USA. 2007;104:20932-20937. 165. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3:75ra26. 166. Takezawa K, Pirazzoli V, Arcila ME, et al. HER2 amplifica-tion: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation. Cancer Discov. 2012;2:922-933. 167. Misale S, Yaeger R, Hobor S, et al. Emergence of KRAS muta-tions and acquired resistance to anti-EGFR therapy in colorec-tal cancer. Nature. 2012;486:532-536. 168. Mundt A, Roeske J, Weichelbaum R. Principles of radiation oncology. In: Bast R, Kuff D, Pollock R, eds. Cancer Medi-cine. Hamilton: B.C. Decker Inc; 2000:465. 169. Raju MR, Carpenter SG. A heavy
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Surgery_Schwartz. J, Brennan C, Shih JY, et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci USA. 2007;104:20932-20937. 165. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3:75ra26. 166. Takezawa K, Pirazzoli V, Arcila ME, et al. HER2 amplifica-tion: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation. Cancer Discov. 2012;2:922-933. 167. Misale S, Yaeger R, Hobor S, et al. Emergence of KRAS muta-tions and acquired resistance to anti-EGFR therapy in colorec-tal cancer. Nature. 2012;486:532-536. 168. Mundt A, Roeske J, Weichelbaum R. Principles of radiation oncology. In: Bast R, Kuff D, Pollock R, eds. Cancer Medi-cine. Hamilton: B.C. Decker Inc; 2000:465. 169. Raju MR, Carpenter SG. A heavy
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A, Roeske J, Weichelbaum R. Principles of radiation oncology. In: Bast R, Kuff D, Pollock R, eds. Cancer Medi-cine. Hamilton: B.C. Decker Inc; 2000:465. 169. Raju MR, Carpenter SG. A heavy particle comparative study. Part IV: acute and late reactions. Br J Radiol. 1978;51:720-727. 170. Wang H, Mu X, He H, Zhang XD. Cancer radiosensitizers. Trends Pharmacol Sci. 2018;39:24-48. 171. Eisbruch A, Lichter AS. What a surgeon needs to know about radiation. Ann Surg Oncol. 1997;4:516-522. 172. Hartford AC, Galvin JM, Beyer DC, et al. American College of Radiology (ACR) and American Society for Radiation Oncology (ASTRO) Practice Guideline for Intensity-modulated Radiation Therapy (IMRT). Am J Clin Oncol. 2012;35:612-617. 173. McCarthy K, Pearson K, Fulton R, Hewitt J. Pre-operative chemoradiation for non-metastatic locally advanced rectal cancer. Cochrane Database Syst Rev. 2012;12:CD008368. 174. Evans DB, Varadhachary GR, Crane CH, et al. Preoperative gemcitabine-based chemoradiation for
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Surgery_Schwartz. A, Roeske J, Weichelbaum R. Principles of radiation oncology. In: Bast R, Kuff D, Pollock R, eds. Cancer Medi-cine. Hamilton: B.C. Decker Inc; 2000:465. 169. Raju MR, Carpenter SG. A heavy particle comparative study. Part IV: acute and late reactions. Br J Radiol. 1978;51:720-727. 170. Wang H, Mu X, He H, Zhang XD. Cancer radiosensitizers. Trends Pharmacol Sci. 2018;39:24-48. 171. Eisbruch A, Lichter AS. What a surgeon needs to know about radiation. Ann Surg Oncol. 1997;4:516-522. 172. Hartford AC, Galvin JM, Beyer DC, et al. American College of Radiology (ACR) and American Society for Radiation Oncology (ASTRO) Practice Guideline for Intensity-modulated Radiation Therapy (IMRT). Am J Clin Oncol. 2012;35:612-617. 173. McCarthy K, Pearson K, Fulton R, Hewitt J. Pre-operative chemoradiation for non-metastatic locally advanced rectal cancer. Cochrane Database Syst Rev. 2012;12:CD008368. 174. Evans DB, Varadhachary GR, Crane CH, et al. Preoperative gemcitabine-based chemoradiation for
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for non-metastatic locally advanced rectal cancer. Cochrane Database Syst Rev. 2012;12:CD008368. 174. Evans DB, Varadhachary GR, Crane CH, et al. Preoperative gemcitabine-based chemoradiation for patients with resect-able adenocarcinoma of the pancreatic head. J Clin Oncol. 2008;26:3496-3502. 175. Courrech Staal EF, Aleman BM, Boot H, van Velthuysen ML, van Tinteren H, van Sandick JW. Systematic review of the ben-efits and risks of neoadjuvant chemoradiation for oesophageal cancer. Br J Surg. 2010;97:1482-1496. 176. Daly J, Bertagnolli M, DeCosse J. Oncology. In: Schwartz S, Spencer F, Galloway A, eds. Principles of Surgery. New York: McGraw-Hill; 1999:297. 177. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90:1371-1388. 178. Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamox-ifen vs raloxifene on the risk of developing invasive
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Surgery_Schwartz. for non-metastatic locally advanced rectal cancer. Cochrane Database Syst Rev. 2012;12:CD008368. 174. Evans DB, Varadhachary GR, Crane CH, et al. Preoperative gemcitabine-based chemoradiation for patients with resect-able adenocarcinoma of the pancreatic head. J Clin Oncol. 2008;26:3496-3502. 175. Courrech Staal EF, Aleman BM, Boot H, van Velthuysen ML, van Tinteren H, van Sandick JW. Systematic review of the ben-efits and risks of neoadjuvant chemoradiation for oesophageal cancer. Br J Surg. 2010;97:1482-1496. 176. Daly J, Bertagnolli M, DeCosse J. Oncology. In: Schwartz S, Spencer F, Galloway A, eds. Principles of Surgery. New York: McGraw-Hill; 1999:297. 177. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90:1371-1388. 178. Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamox-ifen vs raloxifene on the risk of developing invasive
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Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90:1371-1388. 178. Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamox-ifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006;295:2727-2741. 179. Lippman SM, Batsakis JG, Toth BB, et al. Comparison of low-dose isotretinoin with beta carotene to prevent oral carcino-genesis. N Engl J Med. 1993;328:15-20. 180. Hong WK, Lippman SM, Itri LM, et al. Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med. 1990;323:795-801. 181. Bettegowda C, Sausen M, Leary RJ, et al. Detection of circu-lating tumor DNA in earlyand late-stage human malignan-cies. Sci Transl Med. 2014;6:224ra24. 182. Sidransky D. Emerging molecular markers of cancer. Nat Rev Cancer. 2002;2:210-219. 183. Meric-Bernstam F, Hung MC. Advances in targeting human epi-dermal growth factor
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Surgery_Schwartz. Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90:1371-1388. 178. Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamox-ifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006;295:2727-2741. 179. Lippman SM, Batsakis JG, Toth BB, et al. Comparison of low-dose isotretinoin with beta carotene to prevent oral carcino-genesis. N Engl J Med. 1993;328:15-20. 180. Hong WK, Lippman SM, Itri LM, et al. Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med. 1990;323:795-801. 181. Bettegowda C, Sausen M, Leary RJ, et al. Detection of circu-lating tumor DNA in earlyand late-stage human malignan-cies. Sci Transl Med. 2014;6:224ra24. 182. Sidransky D. Emerging molecular markers of cancer. Nat Rev Cancer. 2002;2:210-219. 183. Meric-Bernstam F, Hung MC. Advances in targeting human epi-dermal growth factor
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Med. 2014;6:224ra24. 182. Sidransky D. Emerging molecular markers of cancer. Nat Rev Cancer. 2002;2:210-219. 183. Meric-Bernstam F, Hung MC. Advances in targeting human epi-dermal growth factor receptor-2 signaling for cancer therapy. Clin Cancer Res. 2006;12:6326-6330. 184. Pao W, Hutchinson KE. Chipping away at the lung cancer genome. Nat Med. 2012;18:349-351.Brunicardi_Ch10_p0305-p0354.indd 35422/02/19 2:14 PM patients awaiting a transplant and the limited number of organs available is one of the field’s biggest challenges (Fig. 11-1). In 2017 alone, according to the United Network for Organ Shar-ing (UNOS), about 115,000 patients in the United States were awaiting a transplant, yet the number of transplants performed approached only about 35,000 (Fig. 11-2).DEFINITIONSIn addition to being the overall name of this relatively new field of medicine, transplantation is the process of transferring an organ, tissue, or cell from one place to another. An organ transplant is a
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Surgery_Schwartz. Med. 2014;6:224ra24. 182. Sidransky D. Emerging molecular markers of cancer. Nat Rev Cancer. 2002;2:210-219. 183. Meric-Bernstam F, Hung MC. Advances in targeting human epi-dermal growth factor receptor-2 signaling for cancer therapy. Clin Cancer Res. 2006;12:6326-6330. 184. Pao W, Hutchinson KE. Chipping away at the lung cancer genome. Nat Med. 2012;18:349-351.Brunicardi_Ch10_p0305-p0354.indd 35422/02/19 2:14 PM patients awaiting a transplant and the limited number of organs available is one of the field’s biggest challenges (Fig. 11-1). In 2017 alone, according to the United Network for Organ Shar-ing (UNOS), about 115,000 patients in the United States were awaiting a transplant, yet the number of transplants performed approached only about 35,000 (Fig. 11-2).DEFINITIONSIn addition to being the overall name of this relatively new field of medicine, transplantation is the process of transferring an organ, tissue, or cell from one place to another. An organ transplant is a
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to being the overall name of this relatively new field of medicine, transplantation is the process of transferring an organ, tissue, or cell from one place to another. An organ transplant is a surgical procedure in which a failing organ is replaced by a functioning one. The organ is transplanted either orthotopically (implanted in the same anatomic location in the recipient as it was in the donor) or heterotopically (implanted in TransplantationDavid L. Dunn, Angelika C. Gruessner, and Rainer W.G. Gruessner 11chapterBackground 355Definitions 355History 356Transplant Immunobiology 357Transplant Antigens 358Allorecognition and Lymphocyte Activation 358Clinical Rejection 358Hyperacute / 358Acute / 358Chronic / 358Clinical Immunosuppression 358Induction 359Depleting Antibodies / 359Nondepleting Antibodies / 359Maintenance 359Corticosteroids / 359Azathioprine / 360Mycophenolate Mofetil / 361Sirolimus / 361Cyclosporine / 362Tacrolimus / 362Belatacept / 362Humoral Rejection 362Rituximab /
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Surgery_Schwartz. to being the overall name of this relatively new field of medicine, transplantation is the process of transferring an organ, tissue, or cell from one place to another. An organ transplant is a surgical procedure in which a failing organ is replaced by a functioning one. The organ is transplanted either orthotopically (implanted in the same anatomic location in the recipient as it was in the donor) or heterotopically (implanted in TransplantationDavid L. Dunn, Angelika C. Gruessner, and Rainer W.G. Gruessner 11chapterBackground 355Definitions 355History 356Transplant Immunobiology 357Transplant Antigens 358Allorecognition and Lymphocyte Activation 358Clinical Rejection 358Hyperacute / 358Acute / 358Chronic / 358Clinical Immunosuppression 358Induction 359Depleting Antibodies / 359Nondepleting Antibodies / 359Maintenance 359Corticosteroids / 359Azathioprine / 360Mycophenolate Mofetil / 361Sirolimus / 361Cyclosporine / 362Tacrolimus / 362Belatacept / 362Humoral Rejection 362Rituximab /
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Antibodies / 359Maintenance 359Corticosteroids / 359Azathioprine / 360Mycophenolate Mofetil / 361Sirolimus / 361Cyclosporine / 362Tacrolimus / 362Belatacept / 362Humoral Rejection 362Rituximab / 362Bortezomib / 363Eculizumab / 363Infections and Malignancies 363Infections / 363Malignancies / 364Organ Procurement and Preservation 364Deceased Donors / 364Living Donors / 366Organ Preservation / 366Kidney Transplantation 368Introduction / 368Pretransplant Evaluation / 368Medical Evaluation / 369Surgical Evaluation / 370Recipient Operation / 370Grafts With Multiple Renal Arteries / 372En Bloc Grafts / 372Perioperative Care / 373Results / 373Pancreas Transplantation 374Donor Operation / 374Back Table Preparation of the Pancreas Graft / 375Recipient Operation / 375Complications / 377Living Donor Pancreas Transplants / 377Results / 378Islet versus Pancreas Transplants / 378Islet Transplantation 378Liver Transplantation 379History / 379Indications / 380Recipient Selection /
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Surgery_Schwartz. Antibodies / 359Maintenance 359Corticosteroids / 359Azathioprine / 360Mycophenolate Mofetil / 361Sirolimus / 361Cyclosporine / 362Tacrolimus / 362Belatacept / 362Humoral Rejection 362Rituximab / 362Bortezomib / 363Eculizumab / 363Infections and Malignancies 363Infections / 363Malignancies / 364Organ Procurement and Preservation 364Deceased Donors / 364Living Donors / 366Organ Preservation / 366Kidney Transplantation 368Introduction / 368Pretransplant Evaluation / 368Medical Evaluation / 369Surgical Evaluation / 370Recipient Operation / 370Grafts With Multiple Renal Arteries / 372En Bloc Grafts / 372Perioperative Care / 373Results / 373Pancreas Transplantation 374Donor Operation / 374Back Table Preparation of the Pancreas Graft / 375Recipient Operation / 375Complications / 377Living Donor Pancreas Transplants / 377Results / 378Islet versus Pancreas Transplants / 378Islet Transplantation 378Liver Transplantation 379History / 379Indications / 380Recipient Selection /
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/ 377Living Donor Pancreas Transplants / 377Results / 378Islet versus Pancreas Transplants / 378Islet Transplantation 378Liver Transplantation 379History / 379Indications / 380Recipient Selection / 381Contraindications / 382Surgical Procedure / 382Pediatric Transplants / 383Deceased Donor Split-Liver Transplants / 383Living Donor Transplants / 383Postoperative Care / 383Evaluation of Graft Function / 384Complications / 385Intestine and Multivisceral Transplantation 385Indications and Recipient Selection / 386Surgical Procedure / 386Postoperative Care / 388Heart and Lung Transplantation 388History / 388Heart Transplants / 389Lung Transplants /390Heart-Lung Transplants / 391Xenotransplants 391BACKGROUNDOrgan transplantation is a relatively novel field of medicine that has made significant progress since the second half of the 20th century. Advances in surgical technique and a better under-standing of immunology are the two main reasons that transplants have evolved from experimental
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Surgery_Schwartz. / 377Living Donor Pancreas Transplants / 377Results / 378Islet versus Pancreas Transplants / 378Islet Transplantation 378Liver Transplantation 379History / 379Indications / 380Recipient Selection / 381Contraindications / 382Surgical Procedure / 382Pediatric Transplants / 383Deceased Donor Split-Liver Transplants / 383Living Donor Transplants / 383Postoperative Care / 383Evaluation of Graft Function / 384Complications / 385Intestine and Multivisceral Transplantation 385Indications and Recipient Selection / 386Surgical Procedure / 386Postoperative Care / 388Heart and Lung Transplantation 388History / 388Heart Transplants / 389Lung Transplants /390Heart-Lung Transplants / 391Xenotransplants 391BACKGROUNDOrgan transplantation is a relatively novel field of medicine that has made significant progress since the second half of the 20th century. Advances in surgical technique and a better under-standing of immunology are the two main reasons that transplants have evolved from experimental
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progress since the second half of the 20th century. Advances in surgical technique and a better under-standing of immunology are the two main reasons that transplants have evolved from experimental procedures, just several decades ago, to a widely accepted treatment today for patients with end-stage organ failure. Throughout the world, for a variety of indications, kidney, liver, pancreas, intestine, heart, and lung transplants are now the current standard of care.But the success of transplantation has created new chal-lenges. A better understanding of the pathophysiology of end-stage organ failure as well as advances in critical care medicine and in the treatment of various diseases led to expanding the cri-teria for, and decreasing the contraindications to, transplants. As a result, the discrepancy between the ever-growing number of 1Brunicardi_Ch11_p0355-p0396.indd 35501/03/19 6:53 PM 356Figure 11-1. Patients on the waiting list and the number of organ transplants performed,
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Surgery_Schwartz. progress since the second half of the 20th century. Advances in surgical technique and a better under-standing of immunology are the two main reasons that transplants have evolved from experimental procedures, just several decades ago, to a widely accepted treatment today for patients with end-stage organ failure. Throughout the world, for a variety of indications, kidney, liver, pancreas, intestine, heart, and lung transplants are now the current standard of care.But the success of transplantation has created new chal-lenges. A better understanding of the pathophysiology of end-stage organ failure as well as advances in critical care medicine and in the treatment of various diseases led to expanding the cri-teria for, and decreasing the contraindications to, transplants. As a result, the discrepancy between the ever-growing number of 1Brunicardi_Ch11_p0355-p0396.indd 35501/03/19 6:53 PM 356Figure 11-1. Patients on the waiting list and the number of organ transplants performed,
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discrepancy between the ever-growing number of 1Brunicardi_Ch11_p0355-p0396.indd 35501/03/19 6:53 PM 356Figure 11-1. Patients on the waiting list and the number of organ transplants performed, 2000 to 2009. (U.S. data from the Scientific Registry of Transplant Recipients Annual Report, http://srtr.org)Key Points1 The field of transplantation has made tremendous advances in the last 50 years, mainly due to refinements in surgical technique and development of effective immunosuppressive medications.2 Although immunosuppressive medications are essential for transplantation, they are associated with significant shortand long-term morbidity.3 Opportunistic infections can be significantly lowered by the use of appropriate antimicrobial agents.4 Kidney transplantation represents the treatment of choice for almost all patients with end-stage renal disease. The gap between demand (patients on the waiting list) and supply (available kidneys) continues to widen.5 Pancreas transplantation
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Surgery_Schwartz. discrepancy between the ever-growing number of 1Brunicardi_Ch11_p0355-p0396.indd 35501/03/19 6:53 PM 356Figure 11-1. Patients on the waiting list and the number of organ transplants performed, 2000 to 2009. (U.S. data from the Scientific Registry of Transplant Recipients Annual Report, http://srtr.org)Key Points1 The field of transplantation has made tremendous advances in the last 50 years, mainly due to refinements in surgical technique and development of effective immunosuppressive medications.2 Although immunosuppressive medications are essential for transplantation, they are associated with significant shortand long-term morbidity.3 Opportunistic infections can be significantly lowered by the use of appropriate antimicrobial agents.4 Kidney transplantation represents the treatment of choice for almost all patients with end-stage renal disease. The gap between demand (patients on the waiting list) and supply (available kidneys) continues to widen.5 Pancreas transplantation
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of choice for almost all patients with end-stage renal disease. The gap between demand (patients on the waiting list) and supply (available kidneys) continues to widen.5 Pancreas transplantation represents the most reliable way to achieve euglycemia in patients with poorly controlled diabetes.6 The results of islet transplantation continue to improve but still trail those of pancreas transplantation.7 Liver transplantation has become the standard of care for many patients with end-stage liver failure and/or liver cancer.another anatomic location). Orthotopic transplants require the removal of the diseased organ (heart, lungs, liver, or intestine); in heterotopic transplants, the diseased organ is kept in place (kidney, pancreas).According to the degree of immunologic similarity between the donor and recipient, transplants are divided into three main categories: (a) an autotransplant is the transfer of cells, tissue, or an organ from one part of the body to another part in the same
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Surgery_Schwartz. of choice for almost all patients with end-stage renal disease. The gap between demand (patients on the waiting list) and supply (available kidneys) continues to widen.5 Pancreas transplantation represents the most reliable way to achieve euglycemia in patients with poorly controlled diabetes.6 The results of islet transplantation continue to improve but still trail those of pancreas transplantation.7 Liver transplantation has become the standard of care for many patients with end-stage liver failure and/or liver cancer.another anatomic location). Orthotopic transplants require the removal of the diseased organ (heart, lungs, liver, or intestine); in heterotopic transplants, the diseased organ is kept in place (kidney, pancreas).According to the degree of immunologic similarity between the donor and recipient, transplants are divided into three main categories: (a) an autotransplant is the transfer of cells, tissue, or an organ from one part of the body to another part in the same
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the donor and recipient, transplants are divided into three main categories: (a) an autotransplant is the transfer of cells, tissue, or an organ from one part of the body to another part in the same person, so no immunosuppression is required; this type of transplant includes skin, artery or vein, bone, carti-lage, nerve, and islet cell transplants; (b) an allotransplant is the transfer of cells, tissue, or an organ from one person to another of the same species; with the exception of identical twins, the immune system of the recipient recognizes the donated organ as a foreign body, so immunosuppression is required in order to avoid rejection; and (c) a xenotransplant is the transfer of cells, tissue, or an organ from one organism to another of a different species. To date, animal-to-human transplants are still experi-mental procedures, given the very complex immunologic and infectious issues that have yet to be solved.HISTORYOver the centuries, many different references to
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Surgery_Schwartz. the donor and recipient, transplants are divided into three main categories: (a) an autotransplant is the transfer of cells, tissue, or an organ from one part of the body to another part in the same person, so no immunosuppression is required; this type of transplant includes skin, artery or vein, bone, carti-lage, nerve, and islet cell transplants; (b) an allotransplant is the transfer of cells, tissue, or an organ from one person to another of the same species; with the exception of identical twins, the immune system of the recipient recognizes the donated organ as a foreign body, so immunosuppression is required in order to avoid rejection; and (c) a xenotransplant is the transfer of cells, tissue, or an organ from one organism to another of a different species. To date, animal-to-human transplants are still experi-mental procedures, given the very complex immunologic and infectious issues that have yet to be solved.HISTORYOver the centuries, many different references to
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transplants are still experi-mental procedures, given the very complex immunologic and infectious issues that have yet to be solved.HISTORYOver the centuries, many different references to transplantation can be found in the world’s literature, yet transplantation as a recognized scientific and medical field began to emerge only in 2000200120022003200420052006200720082009010,00020,00030,00040,00050,00060,00070,00080,00090,000100,000110,000Number of patients# Waiting# Transplantedthe middle of the 20th century. Two major events led to the rise of transplantation.First, the surgical technique of the vascular anastomosis was developed by the French surgeon Alexis Carrel.1 This led to increased transplant activity, especially in animal models. Rus-sian surgeon Yu Yu Voronoy was the first to report a series of human-to-human kidney transplants in the 1940s.2 But the out-comes were dismal, mainly because of the lack of understanding of the underlying immunologic processes.Second, the
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Surgery_Schwartz. transplants are still experi-mental procedures, given the very complex immunologic and infectious issues that have yet to be solved.HISTORYOver the centuries, many different references to transplantation can be found in the world’s literature, yet transplantation as a recognized scientific and medical field began to emerge only in 2000200120022003200420052006200720082009010,00020,00030,00040,00050,00060,00070,00080,00090,000100,000110,000Number of patients# Waiting# Transplantedthe middle of the 20th century. Two major events led to the rise of transplantation.First, the surgical technique of the vascular anastomosis was developed by the French surgeon Alexis Carrel.1 This led to increased transplant activity, especially in animal models. Rus-sian surgeon Yu Yu Voronoy was the first to report a series of human-to-human kidney transplants in the 1940s.2 But the out-comes were dismal, mainly because of the lack of understanding of the underlying immunologic processes.Second, the
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to report a series of human-to-human kidney transplants in the 1940s.2 But the out-comes were dismal, mainly because of the lack of understanding of the underlying immunologic processes.Second, the findings of British scientist Sir Peter B. Medawar in the 1940s were also key.3 In his work with skin grafts in animal models and in human burn patients, he learned that the immune system plays a crucial role in the failure of skin grafts. His research led to a better understanding of the immune system and is considered to be the birth of transplant immunobiology.The first human transplant with long-term success was performed by Joseph Murray in Boston, Massachusetts, in 1954.4 Because it was a living related kidney transplant between identical twins, no immunosuppression was required; the recipi-ent lived for another 8 years before he died of issues unrelated to the transplanted kidney. Other centers performed similar trans-plants and could reproduce similar good results.Ultimately,
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Surgery_Schwartz. to report a series of human-to-human kidney transplants in the 1940s.2 But the out-comes were dismal, mainly because of the lack of understanding of the underlying immunologic processes.Second, the findings of British scientist Sir Peter B. Medawar in the 1940s were also key.3 In his work with skin grafts in animal models and in human burn patients, he learned that the immune system plays a crucial role in the failure of skin grafts. His research led to a better understanding of the immune system and is considered to be the birth of transplant immunobiology.The first human transplant with long-term success was performed by Joseph Murray in Boston, Massachusetts, in 1954.4 Because it was a living related kidney transplant between identical twins, no immunosuppression was required; the recipi-ent lived for another 8 years before he died of issues unrelated to the transplanted kidney. Other centers performed similar trans-plants and could reproduce similar good results.Ultimately,
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recipi-ent lived for another 8 years before he died of issues unrelated to the transplanted kidney. Other centers performed similar trans-plants and could reproduce similar good results.Ultimately, attempts were made to perform kidney trans-plants between nonidentical individuals. For immunosup-pression, total-body radiation and an anticancer agent called Brunicardi_Ch11_p0355-p0396.indd 35601/03/19 6:53 PM 357TRANSPLANTATIONCHAPTER 11Figure 11-2. Patients on the waiting list and the number of organ transplants performed, 2009. KP = kidney and pancreas. (U.S. data from the Scientific Registry of Transplant Recipients Annual Report, http://srtr.org)TotalKidneyPancreas and KPLiverIntestineHeartLungsHeart/Lung010,00020,00030,00040,00050,00060,00070,00080,00090,000100,000110,000Number of patients# Waiting# Transplanted6-mercaptopurine were used, but given the profound toxicity of both those methods of immunosuppression, results were dis-couraging. A breakthrough was achieved in the
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Surgery_Schwartz. recipi-ent lived for another 8 years before he died of issues unrelated to the transplanted kidney. Other centers performed similar trans-plants and could reproduce similar good results.Ultimately, attempts were made to perform kidney trans-plants between nonidentical individuals. For immunosup-pression, total-body radiation and an anticancer agent called Brunicardi_Ch11_p0355-p0396.indd 35601/03/19 6:53 PM 357TRANSPLANTATIONCHAPTER 11Figure 11-2. Patients on the waiting list and the number of organ transplants performed, 2009. KP = kidney and pancreas. (U.S. data from the Scientific Registry of Transplant Recipients Annual Report, http://srtr.org)TotalKidneyPancreas and KPLiverIntestineHeartLungsHeart/Lung010,00020,00030,00040,00050,00060,00070,00080,00090,000100,000110,000Number of patients# Waiting# Transplanted6-mercaptopurine were used, but given the profound toxicity of both those methods of immunosuppression, results were dis-couraging. A breakthrough was achieved in the
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patients# Waiting# Transplanted6-mercaptopurine were used, but given the profound toxicity of both those methods of immunosuppression, results were dis-couraging. A breakthrough was achieved in the early 1960s with the introduction of maintenance immunosuppression through a combination of corticosteroids and a less toxic derivative of 6-mercaptopurine, azathioprine.5,6Increasing experience with kidney transplants and the better results achieved with maintenance immunosuppression paved the way for the era of nonrenal transplants (Table 11-1). In 1963, the first liver transplant was performed by Thomas Starzl in Denver, Colorado, and the first lung transplant was performed by James Hardy in Jackson, Mississippi. In 1966, the first pancreas transplant was performed by William Kelly and Richard Lillehei in Minneapolis, Minnesota. In 1967, the first successful heart transplant was performed by Christiaan Barnard in Cape Town, South Africa. The early years of trans-plantation were marked by
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Surgery_Schwartz. patients# Waiting# Transplanted6-mercaptopurine were used, but given the profound toxicity of both those methods of immunosuppression, results were dis-couraging. A breakthrough was achieved in the early 1960s with the introduction of maintenance immunosuppression through a combination of corticosteroids and a less toxic derivative of 6-mercaptopurine, azathioprine.5,6Increasing experience with kidney transplants and the better results achieved with maintenance immunosuppression paved the way for the era of nonrenal transplants (Table 11-1). In 1963, the first liver transplant was performed by Thomas Starzl in Denver, Colorado, and the first lung transplant was performed by James Hardy in Jackson, Mississippi. In 1966, the first pancreas transplant was performed by William Kelly and Richard Lillehei in Minneapolis, Minnesota. In 1967, the first successful heart transplant was performed by Christiaan Barnard in Cape Town, South Africa. The early years of trans-plantation were marked by
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Lillehei in Minneapolis, Minnesota. In 1967, the first successful heart transplant was performed by Christiaan Barnard in Cape Town, South Africa. The early years of trans-plantation were marked by high mortality, mainly because of irreversible rejection. However, dramatic advances occurred with the further development of new forms of immunosup-pression. The groundbreaking event was the introduction of the first anti-T lymphocyte (T cell) drug, cyclosporine, in the early 1980s.7 Since then, with an even better understanding of immunologic processes, many other drugs have been introduced that target specific pathways that lead to rejection. As a result, rejection rates have decreased substantially, allowing a 1-year graft survival rate in excess of 80% in all types of transplants.Table 11-1Transplant historyORGANYEARSURGEONLOCATIONKidney1954Joseph E. MurrayBoston, MALiver1963Thomas E. StarzlDenver, COLung1963James D. HardyJackson, MSPancreas1966Richard C. LilleheiMinneapolis,
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Surgery_Schwartz. Lillehei in Minneapolis, Minnesota. In 1967, the first successful heart transplant was performed by Christiaan Barnard in Cape Town, South Africa. The early years of trans-plantation were marked by high mortality, mainly because of irreversible rejection. However, dramatic advances occurred with the further development of new forms of immunosup-pression. The groundbreaking event was the introduction of the first anti-T lymphocyte (T cell) drug, cyclosporine, in the early 1980s.7 Since then, with an even better understanding of immunologic processes, many other drugs have been introduced that target specific pathways that lead to rejection. As a result, rejection rates have decreased substantially, allowing a 1-year graft survival rate in excess of 80% in all types of transplants.Table 11-1Transplant historyORGANYEARSURGEONLOCATIONKidney1954Joseph E. MurrayBoston, MALiver1963Thomas E. StarzlDenver, COLung1963James D. HardyJackson, MSPancreas1966Richard C. LilleheiMinneapolis,
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