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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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. 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. 2001;6:393-406. 12. Wang SC, Hung MC. HER2 overexpression and cancer target-ing. Semin Oncol. 2001;28:115-124. 13. Schechter AL, Stern DF, Vaidyanathan L, et al. The neu onco-gene: an erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature. 1984;312:513-516. 14. Arcila ME, Chaft JE, Nafa K, et al. Prevalence, clinicopatho-logic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas. Clin Cancer Res. 2012;18:4910-4918. 15. Wang SE, Narasanna A, Perez-Torres M, et al. HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyro-sine kinase inhibitors. Cancer Cell. 2006;10:25-38. 16. Li D, Ambrogio L, Shimamura T, et al. BIBW2992, an irre-versible EGFR/HER2 inhibitor highly


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Surgery_Schwartz. of HER2 and EGFR and resistance to EGFR tyro-sine kinase inhibitors. Cancer Cell. 2006;10:25-38. 16. Li D, Ambrogio L, Shimamura T, et al. BIBW2992, an irre-versible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene. 2008;27:4702-4711. 17. Shimamura T, Ji H, Minami Y, et al. Non-small-cell lung cancer and Ba/F3 transformed cells harboring the ERBB2 G776insV_G/C mutation are sensitive to the dual-specific epi-dermal growth factor receptor and ERBB2 inhibitor HKI-272. Cancer Res. 2006;66:6487-6491. 18. Ma CX, Bose R, Gao F, et al. Neratinib efficacy and circu-lating tumor DNA detection of HER2 mutations in HER2 nonamplified metastatic breast cancer. Clin Cancer Res. 2017;23:5687-5695. 19. Kim R, Tanabe K, Uchida Y, Emi M, Inoue H, Toge T. Cur-rent status of the molecular mechanisms of anticancer drug-induced apoptosis. The contribution of molecular-level analysis to cancer chemotherapy. Cancer Chemother Phar-macol. 2002;50:343-352. 20. Igney FH, Krammer


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Surgery_Schwartz. the molecular mechanisms of anticancer drug-induced apoptosis. The contribution of molecular-level analysis to cancer chemotherapy. Cancer Chemother Phar-macol. 2002;50:343-352. 20. Igney FH, Krammer PH. Death and anti-death: tumour resis-tance to apoptosis. Nat Rev Cancer. 2002;2:277-288. 21. Levy JMM, Towers CG, Thorburn A. Targeting autophagy in cancer. Nat Rev Cancer. 2017;17:528-542. 22. Folkman J, Merler E, Abernathy C, Williams G. Isolation of a tumor factor responsible for angiogenesis. J Exp Med. 1971;133:275-288. 23. McCarty MF, Liu W, Fan F, et al. Promises and pitfalls of anti-angiogenic therapy in clinical trials. Trends Mol Med. 2003;9:53-58. 24. Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell. 1998;92:735-745. 25. Stacker SA, Achen MG, Jussila L, Baldwin ME, Alitalo K. Lymphangiogenesis and cancer metastasis. Nat Rev Cancer.


Surgery_Schwartz

Surgery_Schwartz. receptor for vascular endothelial growth factor. Cell. 1998;92:735-745. 25. Stacker SA, Achen MG, Jussila L, Baldwin ME, Alitalo K. Lymphangiogenesis and cancer metastasis. Nat Rev Cancer. 2002;2:573-583. 26. He Y, Kozaki K, Karpanen T, et al. Suppression of tumor lym-phangiogenesis and lymph node metastasis by blocking vas-cular endothelial growth factor receptor 3 signaling. J Natl Cancer Inst. 2002;94:819-825. 27. Steeg PS. Metastasis suppressors alter the signal transduction of cancer cells. Nat Rev Cancer. 2003;3:55-63. 28. Naumov GN, MacDonald IC, Weinmeister PM, et al. Per-sistence of solitary mammary carcinoma cells in a second-ary site: a possible contributor to dormancy. Cancer Res. 2002;62:2162-2168. 29. Demichelu R. Tumour dormancy: findings and hypotheses from clinical research on breast cancer. Semin Cancer Biol. 2001;11:297-306. 30. Tohme S, Simmons RL, Tsung A. Surgery for cancer: a trigger for metastases. Cancer Res. 2017;77:1548-1552. 31. Chambers AF, Groom AC,


Surgery_Schwartz

Surgery_Schwartz. on breast cancer. Semin Cancer Biol. 2001;11:297-306. 30. Tohme S, Simmons RL, Tsung A. Surgery for cancer: a trigger for metastases. Cancer Res. 2017;77:1548-1552. 31. Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer. 2002;2:563-572. 32. Stadler ZK, Come SE. Review of gene-expression profiling and its clinical use in breast cancer. Crit Rev Oncol Hematol. 2009;69:1-11. 33. De Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013;13:97-110. 34. Alderton GK. Metastasis: epithelial to mesenchymal and back again. Nat Rev Cancer. 2013;13:3. 35. Ocana OH, Corcoles R, Fabra A, et al. Metastatic colonization requires the repression of the epithelial-mesenchymal transi-tion inducer Prrx1. Cancer Cell. 2012;22:709-724. 36. Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J. Spatio-temporal regulation of epithelial-mesenchymal transition is essential for squamous cell


Surgery_Schwartz

Surgery_Schwartz. inducer Prrx1. Cancer Cell. 2012;22:709-724. 36. Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J. Spatio-temporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell. 2012;22:725-736. 37. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105-111. 38. Stratton MR, Campbell PJ, Futreal PA. The cancer genome. Nature. 2009;458:719-724.Brunicardi_Ch10_p0305-p0354.indd 35022/02/19 2:14 PM 351ONCOLOGYCHAPTER 10 39. Olivier M, Hussain SP, Caron de Fromentel C, Hainaut P, Harris CC. TP53 mutation spectra and load: a tool for gen-erating hypotheses on the etiology of cancer. IARC Sci Publ. 2004:247-270. 40. Kennedy RD, D’Andrea AD. DNA repair pathways in clini-cal practice: lessons from pediatric cancer susceptibility syn-dromes. J Clin Oncol. 2006;24:3799-3808. 41. Hanks S, Rahman N. Aneuploidy-cancer predisposition syn-dromes: a new link between the mitotic spindle checkpoint


Surgery_Schwartz

Surgery_Schwartz. from pediatric cancer susceptibility syn-dromes. J Clin Oncol. 2006;24:3799-3808. 41. Hanks S, Rahman N. Aneuploidy-cancer predisposition syn-dromes: a new link between the mitotic spindle checkpoint and cancer. Cell Cycle. 2005;4:225-227. 42. Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature. 1998;396:643-649. 43. Futreal PA, Coin L, Marshall M, et al. A census of human cancer genes. Nat Rev Cancer. 2004;4:177-183. 44. Forbes SA, Tang G, Bindal N, et al. COSMIC (the Catalogue of Somatic Mutations in Cancer): a resource to investigate acquired mutations in human cancer. Nucleic Acids Res. 2010;38:D652-D657. 45. Meric-Bernstam F, Mills GB. Overcoming implementa-tion challenges of personalized cancer therapy. Nat Rev Clin Oncol. 2012;9:542-548. 46. Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747-752. 47. Sorlie T, Tibshirani R, Parker J, et al. Repeated observation of breast tumor subtypes in


Surgery_Schwartz

Surgery_Schwartz. CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747-752. 47. Sorlie T, Tibshirani R, Parker J, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sciences USA. 2003;100:8418-8423. 48. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sciences USA. 2001;98:10869-10874. 49. Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor het-erogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366:883-892. 50. Michailidou K, Lindström S, Dennis J. Association anal-ysis identifies 65 new breast cancer risk loci. Nature. 2017;551:92-94. 51. Vahteristo P, Tamminen A, Karvinen P, et al. p53, CHK2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition. Cancer Res.


Surgery_Schwartz

Surgery_Schwartz. P, Tamminen A, Karvinen P, et al. p53, CHK2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition. Cancer Res. 2001;61:5718-5722. 52. DiCiommo D, Gallie BL, Bremner R. Retinoblastoma: the disease, gene and protein provide critical leads to understand cancer. Semin Cancer Biol. 2000;10:255-269. 53. Knudson AG. Two genetic hits (more or less) to cancer. Nat Rev Cancer. 2001;1:157-162. 54. Li FP, Fraumeni JF, Jr. Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med. 1969;71:747-752. 55. Li FP, Fraumeni JF, Jr., Mulvihill JJ, et al. A cancer fam-ily syndrome in twenty-four kindreds. Cancer Res. 1988;48:5358-5362. 56. Birch JM, Hartley AL, Tricker KJ, et al. Prevalence and diver-sity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res. 1994;54:1298-1304. 57. Birch JM, Alston RD, McNally RJ, et al. Relative frequency and morphology of cancers in


Surgery_Schwartz

Surgery_Schwartz. of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res. 1994;54:1298-1304. 57. Birch JM, Alston RD, McNally RJ, et al. Relative frequency and morphology of cancers in carriers of germline TP53 muta-tions. Oncogene. 2001;20:4621-4628. 58. Birch JM, Blair V, Kelsey AM, et al. Cancer phenotype cor-relates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome. Oncogene. 1998;17:1061-1068. 59. Loman N, Johannsson O, Kristoffersson U, Olsson H, Borg A. Family history of breast and ovarian cancers and BRCA1 and BRCA2 mutations in a population-based series of early-onset breast cancer. J Natl Cancer Inst. 2001;93:1215-1223. 60. Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE. Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet. 1994;343:692-695. 61. Ford D, Easton DF, Stratton M, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer


Surgery_Schwartz

Surgery_Schwartz. Consortium. Lancet. 1994;343:692-695. 61. Ford D, Easton DF, Stratton M, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consor-tium. Am J Hum Genet. 1998;62:676-689. 62. The Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst. 1999;91: 1310-1316. 63. Venkitaraman AR. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002;108:171-182. 64. Liu Y, West SC. Distinct functions of BRCA1 and BRCA2 in double-strand break repair. Breast Cancer Res. 2002;4:9-13. 65. Venkitaraman AR. Functions of BRCA1 and BRCA2 in the biological response to DNA damage. J Cell Sci. 2001;114:3591-3598. 66. Hedenfalk I, Duggan D, Chen Y, et al. Gene-expression pro-files in hereditary breast cancer. N Engl J Med. 2001;344: 539-548. 67. Sieber OM, Tomlinson IP, Lamlum H. The adenomatous pol-yposis coli (APC) tumour suppressor–genetics, function and disease. Mol Med Today.


Surgery_Schwartz

Surgery_Schwartz. breast cancer. N Engl J Med. 2001;344: 539-548. 67. Sieber OM, Tomlinson IP, Lamlum H. The adenomatous pol-yposis coli (APC) tumour suppressor–genetics, function and disease. Mol Med Today. 2000;6:462-469. 68. Caspari R, Olschwang S, Friedl W, et al. Familial adenomatous polyposis: desmoid tumours and lack of ophthalmic lesions (CHRPE) associated with APC mutations beyond codon 1444. Hum Mol Genet. 1995;4:337-340. 69. Davies DR, Armstrong JG, Thakker N, et al. Severe Gardner syndrome in families with mutations restricted to a specific region of the APC gene. Am J Hum Genet. 1995;57:1151-1158. 70. Lynch HT, Smyrk TC, Watson P, et al. Genetics, natural his-tory, tumor spectrum, and pathology of hereditary nonpolypo-sis colorectal cancer: an updated review. Gastroenterology. 1993;104:1535-1549. 71. Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical cri-teria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on


Surgery_Schwartz

Surgery_Schwartz. HF, Watson P, Mecklin JP, Lynch HT. New clinical cri-teria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology. 1999;116:1453-1456. 72. Leach FS, Nicolaides NC, Papadopoulos N, et al. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell. 1993;75:1215-1225. 73. Fishel R, Lescoe MK, Rao MR, et al. The human mutator gene homolog MSH2 and its association with hereditary nonpol-yposis colon cancer. Cell. 1993;75:1027-1038. 74. Miyaki M, Konishi M, Tanaka K, et al. Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nat Genet. 1997;17:271-272. 75. Bronner CE, Baker SM, Morrison PT, et al. Mutation in the DNA mismatch repair gene homologue hMLH1 is associ-ated with hereditary non-polyposis colon cancer. Nature. 1994;368:258-261. 76. Papadopoulos N, Nicolaides NC, Wei YF, et al. Mutation of a mutL homolog in hereditary colon cancer. Science.


Surgery_Schwartz

Surgery_Schwartz. is associ-ated with hereditary non-polyposis colon cancer. Nature. 1994;368:258-261. 76. Papadopoulos N, Nicolaides NC, Wei YF, et al. Mutation of a mutL homolog in hereditary colon cancer. Science. 1994;263:1625-1629. 77. Nicolaides NC, Papadopoulos N, Liu B, et al. Mutations of two PMS homologues in hereditary nonpolyposis colon can-cer. Nature. 1994;371:75-80. 78. Pearlman R, Frankel WL, Swanson. Prevalence and spec-trum of germline cancer susceptibility gene mutations among patients with early-onset colorectal cancer. JAMA Oncol. 2017;3:464-471. 79. Steck PA, Pershouse MA, Jasser SA, et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet. 1997;15:356-362. 80. Liaw D, Marsh DJ, Li J, et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet. 1997;16:64-67. 81. Eng C. Will the real Cowden syndrome please stand up: revised


Surgery_Schwartz

Surgery_Schwartz. al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet. 1997;16:64-67. 81. Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med Genet. 2000;37:828-830.Brunicardi_Ch10_p0305-p0354.indd 35122/02/19 2:14 PM 352BASIC CONSIDERATIONSPART I 82. Greene MH. The genetics of hereditary melanoma and nevi. 1998 update. Cancer. 1999;86:2464-2477. 83. Goldstein AM, Fraser MC, Struewing JP, et al. Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations. N Engl J Med. 1995;333:970-974. 84. Fitzgerald RC, Caldas C. E-cadherin mutations and heredi-tary gastric cancer: prevention by resection? Dig Dis. 2002;20:23-31. 85. Berx G, Van Roy F. The E-cadherin/catenin complex: an important gatekeeper in breast cancer tumorigenesis and malignant progression. Breast Cancer Res. 2001;3:289-293. 86. Alsanea O, Clark OH. Familial thyroid cancer. Curr Opin Oncol.


Surgery_Schwartz

Surgery_Schwartz. complex: an important gatekeeper in breast cancer tumorigenesis and malignant progression. Breast Cancer Res. 2001;3:289-293. 86. Alsanea O, Clark OH. Familial thyroid cancer. Curr Opin Oncol. 2001;13:44-51. 87. Redmond DE, Jr. Tobacco and cancer: the first clinical report, 1761. N Engl J Med. 1970;282:18-23. 88. International Agency for Research on Cancer (IARC). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Complete List of Agents Evaluated and Their Clas-sification. Avaialable at: http://monographs.iarc.fr/ENG/Clas-sification/index.php. Accessed July 1, 2018. 89. Baan R, Grosse Y, Straif K, et al. A review of human car-cinogens–part F: chemical agents and related occupations. Lancet Oncol. 2009;10:1143-1144. 90. Timblin C, Jannsen-Heininger Y, Mossman B. Physical agents in human carcinogenesis. In: Coleman W, Tsongalis G, eds. The Molecular Basis of Human Cancer. Totowa, NJ: Humana Press; 2002:223. 91. Stanton MF, Layard M, Tegeris A, et al. Relation of


Surgery_Schwartz

Surgery_Schwartz. agents in human carcinogenesis. In: Coleman W, Tsongalis G, eds. The Molecular Basis of Human Cancer. Totowa, NJ: Humana Press; 2002:223. 91. Stanton MF, Layard M, Tegeris A, et al. Relation of par-ticle dimension to carcinogenicity in amphibole asbestoses and other fibrous minerals. J Natl Cancer Inst. 1981;67: 965-975. 92. Rous P. A transmissible avian neoplasm. (Sarcoma of the com-mon fowl.) J Exp Med. 1910;12(5):696-705. 93. Butel JS. Viral carcinogenesis: revelation of molecular mechanisms and etiology of human disease. Carcinogenesis. 2000;21:405-426. 94. El-Serag HB. Hepatocellular carcinoma and hepatitis C in the United States. Hepatology. 2002;36:S74-S83. 95. Ault KA. Effect of prophylactic human papillomavirus L1 virus-like-particle vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3, and adenocarcinoma in situ: a combined analysis of four randomised clinical trials. Lancet. 2007;369:1861-1868. 96. Chaturvedi AK, Graubard BI, Broutian T, et al. Effect of


Surgery_Schwartz

Surgery_Schwartz. grade 2, grade 3, and adenocarcinoma in situ: a combined analysis of four randomised clinical trials. Lancet. 2007;369:1861-1868. 96. Chaturvedi AK, Graubard BI, Broutian T, et al. Effect of pro-phylactic human papillomavirus (HPV) vaccination on oral HPV infections among young adults in the United States. J Clin Oncol. 2018;36(3):262-267. 97. Smith RA, Brooks D, Cokkinides V, Saslow D, Brawley OW. Cancer screening in the United States, 2013: a review of current American Cancer Society guidelines, current issues in cancer screening, and new guidance on cervical cancer screening and lung cancer screening. CA Cancer J Clin. 2013;63:87-105. 98. Whitman G, Stelling C. Stereotactic core needle biopsy of breast lesions: experience at the University of Texas M. D. Anderson Cancer Center. In: Singletary S, ed. Breast Cancer. New York: Springer-Verlag; 1999:4. 99. Claus EB, Risch N, Thompson WD. Autosomal dominant inheritance of early-onset breast cancer. Implications for risk prediction.


Surgery_Schwartz

Surgery_Schwartz. Singletary S, ed. Breast Cancer. New York: Springer-Verlag; 1999:4. 99. Claus EB, Risch N, Thompson WD. Autosomal dominant inheritance of early-onset breast cancer. Implications for risk prediction. Cancer. 1994;73:643-651. 100. Tyrer J, Duffy SW, Cuzick J. A breast cancer prediction model incorporating familial and personal risk factors. Stat Med. 2004;23:1111-1130. 101. Berry DA, Iversen ES, Jr, Gudbjartsson, et al. BRCAPRO vali-dation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes. J Clin Oncol. 2002;20:2701-2712. 102. Antoniou AC, Pharoah PP, Smith P, Easton DF. The BOA-DICEA model of genetic susceptibility to breast and ovarian cancer. Br J Cancer. 2004;91:1580-1590. 103. Gail MH, Brinton LA, Byar DP, et al. Projecting individu-alized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst. 1989;81:1879-1886. 104. National Cancer Institute. Breast Cancer Risk


Surgery_Schwartz

Surgery_Schwartz. individu-alized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst. 1989;81:1879-1886. 104. National Cancer Institute. Breast Cancer Risk Assessment Tool. Available at: http://www.cancer.gov/bcrisktool. Accessed July 1, 2018. 105. Bach PB, Kattan MW, Thornquist MD, et al. Variations in lung cancer risk among smokers. J Natl Cancer Inst. 2003;95:470-478. 106. Bassett L, Hendrick R, Bassford T. Quality determinants of mammography. In: Agency for Health Care Policy and Research PHS, ed. Clinical Practice Guideline No 13. Rockville, MD: US Department of Health and Human Services; 1994. 107. Saslow D, Boetes C, Burke W, et al. American Cancer Soci-ety guidelines for breast screening with MRI as an adjunct to mammography. Cancer J Clin. 2007;57:75-89. 108. Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365:395-409. 109. Wender R, Fontham ET,


Surgery_Schwartz

Surgery_Schwartz. J Clin. 2007;57:75-89. 108. Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365:395-409. 109. Wender R, Fontham ET, Barrera E, Jr., et al. American Can-cer Society lung cancer screening guidelines. Cancer J Clin. 2013;63:106-117. 110. Jacobs TW, Connolly JL, Schnitt SJ. Nonmalignant lesions in breast core needle biopsies: to excise or not to excise? Am J Surg Pathol. 2002;26:1095-1110. 111. Krop I, Ismaila N, Andre F, Bast RC, et al. Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology clinical practice guideline focused update. J Clin Oncol. 2017;35:2838-2847. 112. Sepulveda AR, Hamilton SR, Allegra CJ et al. Molecular biomarkers for the evaluation of colorectal cancer: Guideline from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology,


Surgery_Schwartz

Surgery_Schwartz. et al. Molecular biomarkers for the evaluation of colorectal cancer: Guideline from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and the American Society of Clinical Oncology. J Clin Oncol. 2017;35:1453-1486. 113. Way BA, Kessler G. Tumour marker overview. Lab Med News-letter. 1996;4:1-7. 114. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351:2817-2826. 115. van ‘t Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415:530-536. 116. Cardoso F, van ‘t Veer LJ, Bogaerts J, et al; MINDACT Inves-tigators. Gene signature as an aid to treatment decisions in early-stage breast cancer. N Engl J Med. 2016;375:717-729. 117. Moyer VA. Screening for prostate cancer: U.S. Preventive Ser-vices Task Force recommendation statement. Ann Intern Med.


Surgery_Schwartz

Surgery_Schwartz. decisions in early-stage breast cancer. N Engl J Med. 2016;375:717-729. 117. Moyer VA. Screening for prostate cancer: U.S. Preventive Ser-vices Task Force recommendation statement. Ann Intern Med. 2012;157:120-134. 118. Wolf AM, Wender RC, Etzioni RB, et al. American Cancer Society guideline for the early detection of prostate cancer: update 2010. Cancer J Clin. 2010;60:70-98. 119. Alpha-Fetoprotein (AFP), Serum, Tumor Marker (Serial Monitor), Laboratory Corporation of America. Available at: http://www.labcorp.com/datasets/labcorp/html/chapter/mono/ri000600.htm. Accessed December 26, 2008. 120. Nguyen MH, Keeffe EB. Screening for hepatocellular carci-noma. J Clin Gastroenterol. 2002;35:S86-S91. 121. Chan DW, Beveridge RA, Muss H, et al. Use of Truquant BR radioimmunoassay for early detection of breast cancer recur-rence in patients with stage II and stage III disease. J Clin Oncol. 1997;15:2322-2328.Brunicardi_Ch10_p0305-p0354.indd 35222/02/19 2:14 PM 353ONCOLOGYCHAPTER


Surgery_Schwartz

Surgery_Schwartz. detection of breast cancer recur-rence in patients with stage II and stage III disease. J Clin Oncol. 1997;15:2322-2328.Brunicardi_Ch10_p0305-p0354.indd 35222/02/19 2:14 PM 353ONCOLOGYCHAPTER 10 122. Outcomes of cancer treatment for technology assessment and cancer treatment guidelines. American Society of Clinical Oncology. J Clin Oncol. 1996;14:671-679. 123. Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351:781-791. 124. Lucci A, Hall CS, Lodhi AK, et al. Circulating tumour cells in non-metastatic breast cancer: a prospective study. Lancet Oncol. 2012;13:688-695. 125. Rack B, Schindlbeck C, Jückstock J, et al. Circulating tumor cells predict survival in early average-to-high risk breast cancer patients. J Natl Cancer Inst. 2014;106(5). pii: dju066. 126. Huang SK, Hoon DS. Liquid biopsy utility for the surveil-lance of cutaneous malignant melanoma patients. Mol Oncol.


Surgery_Schwartz

Surgery_Schwartz. risk breast cancer patients. J Natl Cancer Inst. 2014;106(5). pii: dju066. 126. Huang SK, Hoon DS. Liquid biopsy utility for the surveil-lance of cutaneous malignant melanoma patients. Mol Oncol. 2016;10:450-463. 127. Scoggins CR, Ross MI, Reintgen DS, et al. Prospective multi-institutional study of reverse transcriptase polymerase chain reaction for molecular staging of melanoma. J Clin Oncol. 2006;24:2849-2857. 128. Braun S, Vogl FD, Naume B, et al. A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med. 2005;353:793-802. 129. Giuliano AE, Hawes D, Ballman KV, et al. Association of occult metastases in sentinel lymph nodes and bone marrow with survival among women with early-stage invasive breast cancer. JAMA. 2011;306:385-393. 130. Janni W, Rack B, Lindemann K, Harbeck N. Detection of micrometastatic disease in bone marrow: is it ready for prime time? Oncologist. 2005;10:480-492. 131. Grau A, Spitz F, Bouvet M. Pancreatic adenocarcinoma. In: Feig B, Berger


Surgery_Schwartz

Surgery_Schwartz. Harbeck N. Detection of micrometastatic disease in bone marrow: is it ready for prime time? Oncologist. 2005;10:480-492. 131. Grau A, Spitz F, Bouvet M. Pancreatic adenocarcinoma. In: Feig B, Berger D, Fuhrman G, eds. The MD Anderson Surgi-cal Oncology Handbook. Philadelphia: Lippincott Williams & Wilkins; 2003:303. 132. Balch CM, Soong SJ, Smith T, et al. Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1-4 mm melanomas. Ann Surg Oncol. 2001;8:101-108. 133. Moore HG, Riedel E, Minsky BD, et al. Adequacy of 1-cm dis-tal margin after restorative rectal cancer resection with sharp mesorectal excision and preoperative combined-modalitytherapy. Ann Surg Oncol. 2003;10:80-85. 134. Kapiteijn E, van de Velde CJ. The role of total mesorectal 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


Surgery_Schwartz

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.


Surgery_Schwartz

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


Surgery_Schwartz

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


Surgery_Schwartz

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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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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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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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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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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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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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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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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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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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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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


Surgery_Schwartz

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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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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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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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


Surgery_Schwartz

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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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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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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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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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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Surgery_Schwartz. 11-1Transplant historyORGANYEARSURGEONLOCATIONKidney1954Joseph E. MurrayBoston, MALiver1963Thomas E. StarzlDenver, COLung1963James D. HardyJackson, MSPancreas1966Richard C. LilleheiMinneapolis, MNHeart1967Christiaan N. BarnardCape Town, South AfricaSmall intestine1967Richard C. LilleheiMinneapolis, MNHeart/lung1981Bruce ReitzStanford, CAMultivisceral1989Thomas E. StarzlPittsburgh, PAThe gradual increase in the organ shortage led to inno-vative surgical techniques. For example, deceased donor split-liver transplants and living donor liver transplants have helped expand the liver donor pool. Similarly, living donor intestine and pancreas techniques have been developed. The evolution of donor nephrectomy from an open to a minimally invasive procedure (laparoscopic or robotic) has helped increase the pool of living kidney donors.TRANSPLANT IMMUNOBIOLOGYThe outcomes of early transplants were less than satisfactory. The limiting factor was the lack of understanding of immuno-logic


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Surgery_Schwartz. increase the pool of living kidney donors.TRANSPLANT IMMUNOBIOLOGYThe outcomes of early transplants were less than satisfactory. The limiting factor was the lack of understanding of immuno-logic processes, and irreversible rejection was the reason for graft loss in the vast majority of recipients. A better understand-ing of transplant immunobiology led to significant improve-ments in patient and graft survival rates.8,9 The immune system is designed as a defense system to protect the body from foreign pathogens, such as viruses, bacteria, and fungi, but it also acts to reject transplanted cells, tissues, and organs, recognizing them as foreign. It mediates other complex processes as well, such as the body’s response to trauma or to tumor growth. No matter what type of agent, the immune system recognizes it as foreign and triggers a strong response that is designed to either to eradi-cate pathogenic organisms or reject foreign cells or tissue.Brunicardi_Ch11_p0355-p0396.indd


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Surgery_Schwartz. system recognizes it as foreign and triggers a strong response that is designed to either to eradi-cate pathogenic organisms or reject foreign cells or tissue.Brunicardi_Ch11_p0355-p0396.indd 35701/03/19 6:53 PM 358BASIC CONSIDERATIONSPART ITRANSPLANT ANTIGENSTransplants between genetically nonidentical persons lead to recognition and rejection of the organ by the recipient’s immune system, if no intervention is undertaken. The main antigens responsible for this process are part of the major histocompat-ibility complex (MHC). In humans, these antigens make up the human leukocyte antigen (HLA) system. The antigen-encoding genes are located on chromosome 6. Two major classes of HLA antigens are recognized. They differ in their structure, function, and tissue distribution. Class I antigens (HLA-A, HLA-B, and HLA-C) are expressed by all nucleated cells. Class II antigens (HLA-DR, HLA-DP, and HLA-DQ) are expressed by antigen-presenting cells (APCs) such as B lymphocytes, dendritic


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Surgery_Schwartz. (HLA-A, HLA-B, and HLA-C) are expressed by all nucleated cells. Class II antigens (HLA-DR, HLA-DP, and HLA-DQ) are expressed by antigen-presenting cells (APCs) such as B lymphocytes, dendritic cells, macrophages, and other phagocytic cells.The principal function of HLA antigens is to present the fragments of foreign proteins to T lymphocytes. This leads to recognition and elimination of the foreign antigen with great specificity. HLA molecules play a crucial role in transplant recipients as well. They can trigger rejection of a graft via two different mechanisms. The most common mechanism is cellular rejection, in which the damage is caused by acti-vated T lymphocytes. The process of activation and prolifera-tion is triggered by exposure of T lymphocytes to the donor’s HLA molecules. The other mechanism is humoral rejection, in which the damage is mediated by circulating antibodies against the donor’s HLA molecules. The donor-specific anti-bodies can be present either pretransplant,


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Surgery_Schwartz. other mechanism is humoral rejection, in which the damage is mediated by circulating antibodies against the donor’s HLA molecules. The donor-specific anti-bodies can be present either pretransplant, due to previous exposure (because of a previous transplant, pregnancy, blood transfusion, or immunization), or posttransplant. After anti-body binding to the donor’s HLA molecules, the complement cascade is activated, leading to cellular lysis.ALLORECOGNITION AND LYMPHOCYTE ACTIVATIONThe immune system of each person is designed to discriminate between self and nonself cells and tissues. This process is called allorecognition, with T cells playing the crucial role. The recog-nition of foreign HLA antigens by the recipient’s T cells may occur by either a direct or an indirect pathway. Direct recogni-tion occurs when the recipient’s T cells are activated by direct interaction with the donor’s HLA molecules. Indirect recogni-tion occurs when the recipient’s T cells are activated by


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Surgery_Schwartz. Direct recogni-tion occurs when the recipient’s T cells are activated by direct interaction with the donor’s HLA molecules. Indirect recogni-tion occurs when the recipient’s T cells are activated by interac-tion with APCs that have processed and presented the foreign antigen. The foreign antigen can be shed from the graft into the circulation, or it can be identified by the APCs within the graft itself.Independent of the pathway of foreign HLA antigen presentation, the ensuing activation of T cells is similar and involves complex cell surface receptors and markers, i.e., the T-cell receptor (TCR) and an array of cluster differentiation markers (CDs). A two-signal model, T-cell activation begins with the engagement of the TCR/CD3 complex with the foreign molecule. This interaction causes transmission of the signal into the cell, namely signal 1. However, this signal alone is not suf-ficient to activate the T cell. An additional costimulatory signal is required, i.e., signal 2. Two


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Surgery_Schwartz. transmission of the signal into the cell, namely signal 1. However, this signal alone is not suf-ficient to activate the T cell. An additional costimulatory signal is required, i.e., signal 2. Two well-characterized costimula-tory interactions are the CD40/CD154 and B7/CD28 pathways. The “master switch” is turned on by the interaction of CD40 protein with APCs, along with the interaction of CD154 pro-tein with T cells; this ligation induces the upregulation of other costimulatory molecules. Transmission of signal 1 and signal 2 into the cell nucleus leads to upregulation of the transcrip-tion of genes for several cytokines, including the T-cell growth factor interleukin-2 (IL-2). In turn, IL-2 activates a number of pathways, leading to proliferation and differentiation of T cells. Rejection is the result of an attack of activated T cells on the transplanted organ.Although T-cell activation is the main culprit in rejection, B-cell activation and subsequent antibody production also play


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Surgery_Schwartz. is the result of an attack of activated T cells on the transplanted organ.Although T-cell activation is the main culprit in rejection, B-cell activation and subsequent antibody production also play a role. After the foreign HLA antigen is processed by B cells, it interacts with activated helper T cells, leading to differentiation of B cells into plasma cells and subsequently to their prolifera-tion and antibody production.CLINICAL REJECTIONGraft rejection is due to a complex interaction of different com-ponents of the immune system, including B and T lymphocytes, APCs, and cytokines. The end result is graft damage caused by inflammatory injury. According to its onset and pathogenesis, rejection is divided into three main types: hyperacute, acute, and chronic, and each is described in the following sections.HyperacuteHyperacute rejection, a very rapid type of rejection, results in irreversible damage and graft loss within minutes to hours after organ reperfusion. It is triggered by


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Surgery_Schwartz. following sections.HyperacuteHyperacute rejection, a very rapid type of rejection, results in irreversible damage and graft loss within minutes to hours after organ reperfusion. It is triggered by preformed antibodies against the donor’s HLA or ABO blood group antigens. These antibodies activate a series of events that result in diffuse intra-vascular coagulation, causing ischemic necrosis of the graft. Fortunately, pretransplant blood group typing and cross-matching (in which the donor’s cells are mixed with the recipient’s serum, and then the cells are observed for any destruction) have virtu-ally eliminated the incidence of hyperacute rejection.AcuteAcute rejection, the most common type of rejection, usually occurs within a few days or weeks posttransplant. According to the mechanism involved, it is further divided into cellular (T-cell–mediated) rejection, humoral (antibody-mediated) rejection, or a combination of both. The diagnosis is based on the results of biopsies of the


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Surgery_Schwartz. involved, it is further divided into cellular (T-cell–mediated) rejection, humoral (antibody-mediated) rejection, or a combination of both. The diagnosis is based on the results of biopsies of the transplanted organ, special immu-nologic stains, and laboratory tests (such as elevated creatinine levels in kidney transplant recipients, elevated liver test values in liver transplant recipients, and elevated levels of glucose, amylase, and lipase in pancreas transplant recipients).ChronicChronic rejection occurs slowly and usually is progressive. It can manifest within the first year posttransplant but most often takes place gradually over several years. The mechanisms are not well understood, but the pathologic changes eventually lead to tissue fibrosis and loss of graft function. As advances in immunosuppression have diminished the incidence of acute rejection, this form of rejection is becoming more common.CLINICAL IMMUNOSUPPRESSIONA successful transplant hinges upon a balance between


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Surgery_Schwartz. in immunosuppression have diminished the incidence of acute rejection, this form of rejection is becoming more common.CLINICAL IMMUNOSUPPRESSIONA successful transplant hinges upon a balance between the extent of the recipient’s immune response, the health and viabil-ity of the donor allograft, and pharmacologic immunosuppres-sion. Immunosuppressive regimens are critical to graft and Brunicardi_Ch11_p0355-p0396.indd 35801/03/19 6:53 PM 359TRANSPLANTATIONCHAPTER 11patient survival posttransplant. Immunosuppression has evolved from the use of azathioprine and steroids in the 1960s and 1970s to the development in the 1980s of cyclosporine, the latter which markedly increased allograft survival.10,11 The intro-duction of tacrolimus and mycophenolate mofetil (MMF) in the 1990s further advanced the field of transplantation, enabling a variety of combinations to be used for immunosuppression often “tailored” for each recipient (Table 11-2).Presently, immunosuppressants are used in


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Surgery_Schwartz. advanced the field of transplantation, enabling a variety of combinations to be used for immunosuppression often “tailored” for each recipient (Table 11-2).Presently, immunosuppressants are used in multidrug regimens aimed at increasing efficacy by targeting multiple pathways to lower the immune response and to decrease the toxicity of individual agents. Certain regimens may involve withdrawal, avoidance, or minimization of certain classes of drugs. Transplant centers generally institute their immunosup-pressive protocols based on experience, risk profiles, cost con-siderations, and outcomes. Immunosuppression is delivered in two phases: induction (starting immediately posttransplant, when the risk of rejection is highest) and maintenance (usu-ally starting within days posttransplant and usually continuing for the life of the graft and the recipient). Thus, the degree of immunosuppression is highest in the first 3 to 6 months posttransplant; during this time, prophylaxis against a


Surgery_Schwartz

Surgery_Schwartz. usually continuing for the life of the graft and the recipient). Thus, the degree of immunosuppression is highest in the first 3 to 6 months posttransplant; during this time, prophylaxis against a number of different bacterial, viral, or even antifungal opportunistic pathogens is administered.12,13A conventional immunosuppressive protocol might include (a) induction with anti-T-lymphocyte–depleting or nondepleting antibodies and (b) maintenance with calcineurin inhibitors, antiproliferative agents, and corticosteroids. Char-acteristics of the most common immunosuppressive agents are listed in Table 11-3.2Table 11-2Immunosuppressive drugs by groupingImmunophilin binders Calcineurin inhibitors Cyclosporine Tacrolimus Noninhibitors of calcineurin SirolimusAntimetabolites Inhibitors of de novo purine synthesis Azathioprine Mycophenolate mofetilBiologic immunosuppression Polyclonal antibodies Atgam Antithymocyte immunoglobulin Monoclonal


Surgery_Schwartz

Surgery_Schwartz. of de novo purine synthesis Azathioprine Mycophenolate mofetilBiologic immunosuppression Polyclonal antibodies Atgam Antithymocyte immunoglobulin Monoclonal antibodies Muromonab-CD3 Basiliximab Belatacept Alemtuzumab Rituximab Bortezomib EculizumabOther CorticosteroidsINDUCTIONInduction includes the use of depleting (polyclonal) antibodies or nondepleting antibodies within the first month posttransplant. Studies have shown that induction with antibody regimens may prevent acute rejection, potentially leading to improved graft survival and the use of less maintenance immunosuppression.Depleting AntibodiesRabbit antithymocyte globulin (Thymoglobulin) is a purified gamma globulin obtained by immunizing rabbits with human thymocytes. Atgam, which has largely been replaced by Thy-moglobulin, is a purified gamma globulin obtained by immu-nizing horses with human thymocytes. These agents contain antibodies to T cells and B lymphocytes (B cells), integrins, and other adhesion


Surgery_Schwartz

Surgery_Schwartz. is a purified gamma globulin obtained by immu-nizing horses with human thymocytes. These agents contain antibodies to T cells and B lymphocytes (B cells), integrins, and other adhesion molecules, thereby resulting in rapid depletion of peripheral lymphocytes. Typically, the total dose of Thymo-globulin is roughly 6 mg/kg, a dose that has been shown to con-fer adequate lymphocyte depletion and better allograft survival. Doses of 3 mg/kg may not effectively prevent acute rejection, but more doses and prolonged administration increase the risk of infection and the potential occurrence of lymphoma. Thymo-globulin administration causes a cytokine release syndrome, so premedications (acetaminophen and diphenhydramine) are usu-ally given. The principal side effects of Thymoglobulin include fever, chills, arthralgias, thrombocytopenia, leukopenia, and an increased incidence of a variety of infections.14,15Nondepleting AntibodiesBasiliximab (Simulect) is an anti-CD25 monoclonal antibody. The