Following wide excision of Merkel cell carcinoma (MCC), postoperative radiation therapy (RT) is typically recommended. Controversy remains as to whether RT can be avoided in selected cases, such as those with negative margins. Additionally, there is evidence that RT can influence survival.

Purpose/Objective(s)Following wide excision of Merkel Cell Carcinoma (MCC), adjuvant radiation therapy (RT) is typically recommended although its influence on overall survival (OS) is uncertain. There also remains controversy as to whether RT can be avoided in selected cases, such as those with negative margins and/or node-negative disease.Materials/MethodsWe reviewed 300 patients treated for non-metastatic MCC from 1989 through 2012 at a single institution. Most patients were treated with wide local excision with or without adjuvant radiation therapy. Median follow-up was 27 months. The median age was 75 years (range 13-96), median pathologic tumor size 1.5 cm (range 0.2-12.5) and the majority of patients were male (70%), with node-negative (70%), head and neck primary (48%), and margin negative (88%) MCC. Patients treated with adjuvant RT were significantly younger (median age 73 vs. 77 years, respectively), more often had involved nodal disease (35% vs. 20%, respectively), and more often were treated with chemotherapy (16% vs. 4%, respectively). The median radiation dose was 5,000 cGy delivered in 25 daily fractions. Clinicopathologic and treatment variables were assessed regarding their role in local control (LC), locoregional control (LRC), disease-free survival (DFS), and OS.ResultsTreatment with adjuvant RT was associated with improved LC (91% vs. 70% at 3-years, respectively; p<0.001), LRC (71.5% vs. 37.8% at 3 years, respectively; p<0.001), DFS (57.0% vs. 30.2% at 3 years, respectively; p<0.001), and OS (73% vs. 66%, respectively; p=0.02). On multivariate analysis, adjuvant RT was independently associated with improved LC (hazard ratio [HR] 0.14, 95% confidence interval [CI] 0.06-0.29, p<0.001), LRC (HR 0.25, 95% CI 0.16-0.39, p<0.001), DFS (HR 0.38, 95% CI 0.27-0.54, p=0.001), and OS (HR 0.62, 95% CI 0.41-0.94, p=0.03). Even patients with negative margins and node-negative disease had significant improvements in LC (93% vs. 82%, respectively, p=0.03) and LRC (75% vs. 52%, respectively, p<0.001) with adjuvant RT.ConclusionAdjuvant RT for MCC was independently associated with improved LC, LRC, DFS, and OS. RT was beneficial regardless of margin status and nodal status. Purpose/Objective(s)Following wide excision of Merkel Cell Carcinoma (MCC), adjuvant radiation therapy (RT) is typically recommended although its influence on overall survival (OS) is uncertain. There also remains controversy as to whether RT can be avoided in selected cases, such as those with negative margins and/or node-negative disease. Following wide excision of Merkel Cell Carcinoma (MCC), adjuvant radiation therapy (RT) is typically recommended although its influence on overall survival (OS) is uncertain. There also remains controversy as to whether RT can be avoided in selected cases, such as those with negative margins and/or node-negative disease. Materials/MethodsWe reviewed 300 patients treated for non-metastatic MCC from 1989 through 2012 at a single institution. Most patients were treated with wide local excision with or without adjuvant radiation therapy. Median follow-up was 27 months. The median age was 75 years (range 13-96), median pathologic tumor size 1.5 cm (range 0.2-12.5) and the majority of patients were male (70%), with node-negative (70%), head and neck primary (48%), and margin negative (88%) MCC. Patients treated with adjuvant RT were significantly younger (median age 73 vs. 77 years, respectively), more often had involved nodal disease (35% vs. 20%, respectively), and more often were treated with chemotherapy (16% vs. 4%, respectively). The median radiation dose was 5,000 cGy delivered in 25 daily fractions. Clinicopathologic and treatment variables were assessed regarding their role in local control (LC), locoregional control (LRC), disease-free survival (DFS), and OS. We reviewed 300 patients treated for non-metastatic MCC from 1989 through 2012 at a single institution. Most patients were treated with wide local excision with or without adjuvant radiation therapy. Median follow-up was 27 months. The median age was 75 years (range 13-96), median pathologic tumor size 1.5 cm (range 0.2-12.5) and the majority of patients were male (70%), with node-negative (70%), head and neck primary (48%), and margin negative (88%) MCC. Patients treated with adjuvant RT were significantly younger (median age 73 vs. 77 years, respectively), more often had involved nodal disease (35% vs. 20%, respectively), and more often were treated with chemotherapy (16% vs. 4%, respectively). The median radiation dose was 5,000 cGy delivered in 25 daily fractions. Clinicopathologic and treatment variables were assessed regarding their role in local control (LC), locoregional control (LRC), disease-free survival (DFS), and OS. ResultsTreatment with adjuvant RT was associated with improved LC (91% vs. 70% at 3-years, respectively; p<0.001), LRC (71.5% vs. 37.8% at 3 years, respectively; p<0.001), DFS (57.0% vs. 30.2% at 3 years, respectively; p<0.001), and OS (73% vs. 66%, respectively; p=0.02). On multivariate analysis, adjuvant RT was independently associated with improved LC (hazard ratio [HR] 0.14, 95% confidence interval [CI] 0.06-0.29, p<0.001), LRC (HR 0.25, 95% CI 0.16-0.39, p<0.001), DFS (HR 0.38, 95% CI 0.27-0.54, p=0.001), and OS (HR 0.62, 95% CI 0.41-0.94, p=0.03). Even patients with negative margins and node-negative disease had significant improvements in LC (93% vs. 82%, respectively, p=0.03) and LRC (75% vs. 52%, respectively, p<0.001) with adjuvant RT. Treatment with adjuvant RT was associated with improved LC (91% vs. 70% at 3-years, respectively; p<0.001), LRC (71.5% vs. 37.8% at 3 years, respectively; p<0.001), DFS (57.0% vs. 30.2% at 3 years, respectively; p<0.001), and OS (73% vs. 66%, respectively; p=0.02). On multivariate analysis, adjuvant RT was independently associated with improved LC (hazard ratio [HR] 0.14, 95% confidence interval [CI] 0.06-0.29, p<0.001), LRC (HR 0.25, 95% CI 0.16-0.39, p<0.001), DFS (HR 0.38, 95% CI 0.27-0.54, p=0.001), and OS (HR 0.62, 95% CI 0.41-0.94, p=0.03). Even patients with negative margins and node-negative disease had significant improvements in LC (93% vs. 82%, respectively, p=0.03) and LRC (75% vs. 52%, respectively, p<0.001) with adjuvant RT. ConclusionAdjuvant RT for MCC was independently associated with improved LC, LRC, DFS, and OS. RT was beneficial regardless of margin status and nodal status. Adjuvant RT for MCC was independently associated with improved LC, LRC, DFS, and OS. RT was beneficial regardless of margin status and nodal status.

BACKGROUNDThe purposes of this study were 1) to determine the impact of primary tumor‐related factors on the prediction of the sentinel lymph node (SLN) status and 2) to identify clinical and pathologic factors associated with survival in Merkel cell carcinoma (MCC).METHODSAn institutional review board–approved, retrospective review of patients with MCC treated between 1988 and 2011 at a single center was performed. Patients were categorized into 5 groups: 1) negative SLN, 2) positive SLN, 3) clinically node‐negative but SLN biopsy not performed, 4) regional nodal disease without a known primary tumor, and 5) primary MCC with synchronous clinically evident regional nodal disease. Factors predictive of the SLN status were analyzed with logistic regressions, and overall survival (OS) and disease‐specific survival (DSS) were analyzed with Cox models and competing risk models assuming proportional hazards, respectively.RESULTSThree hundred seventy‐five patients were analyzed, and 70% were male; the median age was 75 years. The median tumor diameter was 1.5 cm (range, 0.2‐12.5 cm), and the median tumor depth was 4.8 mm (range, 0.3‐45.0 mm). One hundred ninety‐one patients underwent SLN biopsy, and 59 (31%) were SLN‐positive. Increasing primary tumor diameter and increasing tumor depth were associated with SLN positivity (P = .007 and P = .017, respectively). Age and sex were not associated with the SLN status. Immunosuppression, increasing tumor diameter, and increasing tumor depth were associated with worse OS (P = .007, P = .003, and P = .025, respectively). DSS differed significantly by group and was best for patients with a negative SLN and worst for those with primary MCC and synchronous clinically evident nodal disease (P = .018).CONCLUSIONFor patients with MCC, increasing primary tumor diameter and increasing tumor depth are independently predictive of a positive SLN, worse OS, and worse DSS. Tumor depth should be routinely reported when primary MCC specimens are being evaluated histopathologically. Cancer 2015;121:3252–3260. © 2015 American Cancer Society.

117 Background: Neoadjuvant chemoradiation therapy (NT) has become standard of care for patients with locally advanced esophageal cancer. In selected patients, robotic-assisted Ivor Lewis esophagectomy (RAIL) is a safe and feasible operative strategy in the management of esophageal cancer. This study was designed to determine potential differences in peri-operative morbidity and short term outcomes in patients with esophageal cancer treated with RAIL with or without NT. Methods: A retrospective review of consecutive patients with esophageal cancer who underwent RAIL esophagectomy between October 2010 and June 2012 with and without NT was performed. Clinical and pathological variables were analyzed with two-sided student t-test assuming equal variance. Data were considered significant at a p-value <0.05. Results: Eighty-nine patients underwent RAIL during the study period. Seventy-seven patients (87%) received NT and twenty-two patients did not (13%). The median age was 66 years (range 44 – 84) and the median BMI was 28 kg/m 2 (range 16.7 – 40.1). All patients had a R0 resection. There were no differences in the mean estimated blood loss (149 vs.153 mL; p = 0.52) and mean operative times (434 vs. 427 minutes; p = 1.0). There were no differences in the incidence of pneumonia or atrial fibrillation, lengths of stay in the ICU, or length of hospitalization. In total, there were two anastomotic leaks and one leak from the gastric conduit. The anastomotic leaks occurred in the group that did not receive NT and the gastric conduit leak occurred in the group that received NT. There were no mortalities in either group. There was no difference in the mean number of lymph nodes harvested in the NT group (22 ± 11 vs. 20 ± 8, p = 0.41). Conclusions: RAIL can be safely performed following neoadjuvant chemoradiation therapy.In this series there were similar perioperative, morbidity and short-term mortality outcomes in patients who received NT compared with RAIL alone. Longer follow-up is required in order to determine long term oncologic outcome.

Objectives: Although refractory to chemotherapy, metastatic melanoma may respond to adoptive immunotherapy. As novel treatments evolve, surgeons may be asked to perform metastasectomy not only for palliation or potential cure but also for isolation of tumor-infiltrating lymphocytes. This study was undertaken to examine outcomes of patients with melanoma undergoing thoracic metastasectomy in preparation for investigational immunotherapy.Methods: A retrospective review identified 107 consecutive patients who underwent 116 thoracic metastasectomy procedures from April 1998 to July 2009. Indications for surgical intervention included procurement of tumor-infiltrating lymphocytes, rendering of patients to no evaluable disease status, palliation, and diagnosis. Response Evaluation Criteria in Solid Tumors criteria were used to assess tumor response.Results: Thoracotomy, lobectomy, and video-assisted thoracoscopic surgery with nonanatomic resection were the most common procedures. Major complications included 1 death and 1 coagulopathy-induced hemothorax. Seventeen patients were rendered to no evaluable disease status. Virtually all patients with residual disease had tumor specimens cultured for tumor-infiltrating lymphocytes; approximately 70% of tumor-infiltrating lymphocyte cultures exhibited antitumor reactivity. Of the 91 patients with residual or recurrent disease, 24 (26%) underwent adoptive cell transfer of tumor-infiltrating lymphocytes, of whom 7 exhibited objective responses (29% response rate and 8% based on intent to treat). Rapid disease progression precluded tumor-infiltrating lymphocyte therapy in most cases. Actuarial 1- and 5-year survival rates for patients rendered to no evaluable disease status or receiving or not receiving tumor-infiltrating lymphocytes were 93% and 76%, 64% and 33%, and 43% and 0%, respectively.Conclusions: Relatively few patients currently having thoracic metastasectomy undergo adoptive cell transfer. Continued refinement of tumor-infiltrating lymphocyte expansion protocols and improved patient selection might increase the number of patients with melanoma benefiting from these interventions. (J Thorac Cardiovasc Surg 2010;140:1276-82)

Adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) can mediate objective tumor regression in 49% to 72% of patients with many long-term durable responses. To undergo treatment a patient must have (1) a resectable tumor from which (2) TIL can be generated that (3) exhibit tumor-specific reactivity. From July 2002 to July 2007, 787 tumors from 402 patients were processed for possible use in the generation of TIL, leading to the eventual treatment of 107 patients (27%). Viable TILs were generated in 376 patients (94%), and active, specific TILs were identified in 269 patients (67%). Patient demographics and tumor characteristics were analyzed for possible prognostic factors for growth and activity. Gastrointestinal-derived TIL grew less frequently, whereas lymph node and lung-derived TIL exhibited specific activity more often. TIL that grew and exhibited specific reactivity were from tumors that were larger in diameter and digests that had a higher percentage of lymphocytes. Despite these considerations, active, specific TIL could be generated from almost any site of metastasis. As more centers begin exploring the use of adoptive transfer with TIL, this compendium may provide a framework for therapeutic decision making and future investigation.

Adoptive cell therapy (ACT) for metastatic melanoma involves the ex vivo expansion and reinfusion of tumor infiltrating lymphocytes (TIL) obtained from resected specimens. With an overall objective response rate of 56%, this T-cell immunotherapy provides an appealing alternative to other therapies, including conventional therapies with lower response rates. However, there are significant regulatory and logistical concerns associated with the ex vivo activation and large-scale expansion of these cells. The best current practice uses a rapid expansion protocol (REP) consisting of an ex vivo process that occurs in tissue culture flasks (T-flasks) and gas-permeable bags, utilizes OKT3 (anti-CD3 monoclonal antibody), recombinant human interleukin-2, and irradiated peripheral blood mononuclear cells to initiate rapid lymphocyte growth. A major limitation to the widespread delivery of therapy to large numbers of melanoma patients is the open system in which a REP is initiated. To address this problem, we have investigated the initiation, expansion and harvest at clinical scale of TIL in a closed-system continuous perfusion bioreactor. Each cell product met all safety criteria for patient treatment and by head-to-head comparison had a similar potency and phenotype as cells grown in control T-flasks and gas-permeable bags. However, the currently available bioreactor cassettes were limited in the total cell numbers that could be generated. This bioreactor may simplify the process of the rapid expansion of TIL under stringent regulatory conditions thereby enabling other institutions to pursue this form of ACT.

A patient with metastatic melanoma who had progressive disease after prior surgical resections, high dose interleukin-2. and anti-cytotoxic T lymphocyte antigen-4 antibody received sequential treatments with autologous tumor infiltrating lymphocytes that recognized the gp100 melanocyte differentiation antigen. Although no clinical response was seen when cells were administered alone, an objective clinical response to therapy was seen with tumor infiltrating lymphocytes administered together with a highly immunogenic fowlpox vaccine expressing a gp100: 209-217 (210M) epitope. Persistence of the transferred antigen-specific lymphocytes in the peripheral blood was observed only after adoptive cell therapy plus administration of vaccine. Cell proliferation in vitro was further stimulated by additional vaccine and interleukin-2. The patient has an ongoing partial response at 10 months after the last treatment.

AbstractBACKGROUND.The treatment of metastatic renal cell carcinoma (RCC) with high‐dose interleukin‐2 (HD IL‐2) has resulted in durable tumor regression in a minority of patients. The current study presents the authors' 20‐year experience administering this immunotherapeutic agent.METHODS.Patients with metastatic RCC (n = 259) were treated with HD IL‐2 alone from January 13, 1986 through December 31, 2006 at the Surgery Branch of the National Cancer Institute. Potential predictive factors for response and survival, both pretreatment and treatment‐related, were first subjected to univariate analysis and then to multivariate logistic regression or a Cox proportional hazards model. Finally, the authors investigated Memorial Sloan‐Kettering Cancer Center (MSKCC) prognostic factors for survival to assess their predictive value in the patient population in the current study.RESULTS.A total of 23 patients experienced a complete response and 30 patients achieved a partial response, for an overall objective response rate of 20%. All partial responders had developed disease recurrence at the time of last follow‒up, but only 4 complete responders had experienced disease recurrence by that time. Despite toxicities, only 2 patients developed treatment‐related mortalities over this same time period. A higher baseline weight (P = .05) and MSKCC prognostic factors (P = .02) were found to be the variables most associated with response. For survival >4 years and overall survival, several pretreatment and treatment‒related factors maintained significance, but none more so than response (P < .0001).CONCLUSIONS.HD IL‐2 can induce complete tumor regression in a small number of patients, and many patients have experienced extended disease‐free intervals. Given its relative safety, HD IL‐2 should still be considered a first‐line therapy in patients with metastatic RCC who have an overall good performance status. Cancer 2008. Published 2008 American Cancer Society.

PURPOSEThe two approved treatments for patients with metastatic melanoma, interleukin (IL)-2 and dacarbazine, mediate objective response rates of 12% to 15%. We previously reported that adoptive cell therapy (ACT) with autologous antitumor lymphocytes in lymphodepleted hosts mediated objective responses in 51% of 35 patients. Here, we update that study and evaluate the safety and efficacy of two increased-intensity myeloablative lymphodepleting regimens.PATIENTS AND METHODSWe performed two additional sequential trials of ACT with autologous tumor-infiltrating lymphocytes (TIL) in patients with metastatic melanoma. Increasing intensity of host preparative lymphodepletion consisting of cyclophosphamide and fludarabine with either 2 (25 patients) or 12 Gy (25 patients) of total-body irradiation (TBI) was administered before cell transfer. Objective response rates by Response Evaluation Criteria in Solid Tumors (RECIST) and survival were evaluated. Immunologic correlates of effective treatment were studied.RESULTSAlthough nonmyeloablative chemotherapy alone showed an objective response rate of 49%, when 2 or 12 Gy of TBI was added, the response rates were 52% and 72% respectively. Responses were seen in all visceral sites including brain. There was one treatment-related death in the 93 patients. Host lymphodepletion was associated with increased serum levels of the lymphocyte homeostatic cytokines IL-7 and IL-15. Objective responses were correlated with the telomere length of the transferred cells.CONCLUSIONHost lymphodepletion followed by autologous TIL transfer and IL-2 results in objective response rates of 50% to 70% in patients with metastatic melanoma refractory to standard therapies.

BACKGROUND:The treatment of metastatic renal cell carcinoma (RCC) with high-dose interleukin-2 (HD IL-2) has resulted in durable tumor regression in a minority of patients. The current study presents the authors' 20-year experience administering this immunotherapeutic agent.METHODS:Patients with metastatic RCC (n = 259) were treated with HD IL-2 alone from January 13, 1986 through December 31, 2006 at the Surgery Branch of the National Cancer Institute. Potential predictive factors for response and survival, both pretreatment and treatment-related, were first subjected to univariate analysis and then to multivariate logistic regression or a Cox proportional hazards model. Finally, the authors investigated Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic factors for survival to assess their predictive value in the patient population in the current study.RESULTS:A total of 23 patients experienced a complete response and 30 patients achieved a partial response, for an overall objective response rate of 20%. All partial responders had developed disease recurrence at the time of last follow-up, but only 4 complete responders had experienced disease recurrence by that time. Despite toxicities, only 2 patients developed treatment-related mortalities over this same time period. A higher baseline weight (P = .05) and MSKCC prognostic factors (P = .02) were found to be the variables most associated with response. For survival >4 years and overall survival, several pretreatment and treatment-related factors maintained significance, but none more so than response (P < .0001).CONCLUSIONS:HD IL-2 can induce complete tumor regression in a small number of patients, and many patients have experienced extended disease-free intervals. Given its relative safety, HD IL-2 should still be considered a first-line therapy in patients with metastatic RCC who have an overall good performance status.

Purpose: To identify prognostic factors associated with survival beyond 4 years and overall response in patients with metastatic melanoma treated with high-dose bolus i.v. interleukin-2 (IL-2) given either alone or in combination with a variety of melanoma vaccines. Study Design: 684 consecutive patients with metastatic melanoma received high-dose bolus i.v. IL-2 either alone or in conjunction with a variety of melanoma vaccines. Treatments occurred between August 1, 1985 and January 1, 2006. Results: The overall objective response rate was 13% for patients receiving IL-2 alone and 16% for patients who received IL-2 with vaccine. In patients treated with IL-2 alone (n = 305) and IL-2 with vaccine (n = 379), having an objective response was associated with survival beyond 4 years (P < 0.0001). No pretreatment factors could be identified that were strongly associated with increased rate of objective response or long-term survival in patients receiving IL-2 alone. In patients receiving IL-2 with vaccines, there were increased response rates in patients with s.c. or cutaneous disease only and lower response rates with visceral disease only. Patients who received the gp100:209-217(210M) peptide plus IL-2 showed a strong trend to increased objective responses compared with IL-2 alone (22% versus 12.8%; P = 0.01) and also compared with patients who received a variety of vaccines that did not include this immunogenic peptide (13.8%; P = 0.009). Conclusion: IL-2 can produce a modest response rate in patients with metastatic melanoma including patients with durable complete responses. S.c. or cutaneous disease only and vaccination with gp100:209-217(210M) peptide was associated with significant increase in response rates.

Purpose: CTL-associated antigen 4 (CTLA-4) can inhibit T-cell activation and helps maintain peripheral self-tolerance. Previously, we showed immune-related adverse events (IRAE) and objective, durable clinical responses in patients with metastatic melanoma treated with CTLA-4 blockade. We have now treated 139 patients in two trials and have sufficient follow-up to examine factors associated with clinical response. Experimental Design: A total of 139 patients with metastatic melanoma were treated: 54 patients received ipilimumab in conjunction with peptide vaccinations and 85 patients were treated with intra-patient dose escalation of ipilimumab and randomized to receive peptides in accordance with HLA-A*0201 status. Results: Three patients achieved complete responses (CR; ongoing at 29+, 52+, and 53+ months); an additional 20 patients achieved partial responses (PR) for an overall objective response rate of 17%. The majority of patients (62%, 86 of 139) developed some form of IRAE, which was associated with a greater probability of objective antitumor response (P = 0.0004); all patients with CR had more severe IRAEs. Prior therapy with IFNα-2b was a negative prognostic factor, whereas prior high-dose interleukin-2 did not significantly affect the probability of response. There were no significant differences in the rate of clinical response or development of IRAEs between the two trials. The duration of tumor response was not affected by the use of high-dose steroids for abrogation of treatment-related toxicities (P = 0.23). There were no treatment-related deaths. Conclusion: In patients with metastatic melanoma, ipilimumab can induce durable objective clinical responses, which are related to the induction of IRAEs.

To the Editor: The Surgery Branch at the National Cancer Institute has had extensive experience with the intravenous administration of high-dose interleukin-2 (IL-2) and anti-CTLA 4 antibody (MDX010, Ipilimumab) in patients with metastatic melanoma or metastatic renal cell cancer as standard cancer therapy or in clinical trials. The purpose of this letter is to report a possible increase in a rare IL-2 toxicity after therapy with anti-CTLA 4 antibody. Twenty-two patients in the Surgery Branch received intravenous antiCTLA 4 antibody while participating in experimental therapies and at some later point received treatment with high-dose IL-2 therapy at 720,000U/ kg every 8 hours. Retrospective analysis of our data showed that 3 of these 22 patients developed bowel perforations during their treatment with highdose IL-2 and subsequently required emergency laparotomy (Table 1). There did not seem to be a temporal relationship between the anti-CTLA 4 antibody administration and the dosing with IL-2. There was an average of 86 days between the last dose of anti-CTLA 4 antibody and the start of IL-2 therapy. All 3 patients were asymptomatic before starting IL-2 therapy. Although the numbers are small, this incidence of 13.6% contrasts significantly with our experience with bowel perforations in patients treated with high-dose IL-2 alone of less than 1%. In a retrospective analysis done in the Surgery Branch of patients treated between November 1, 1998 and May 1, 2002 with IL-2 alone there were 8 perforations out of 1797 patients (0.45%; P2=0.002 compared with patients treated with anti-CTLA 4 antibody followed by IL-2). In 198 patients treated in the Surgery Branch with anti-CTLA 4 antibody alone between March 19, 2002 and July 15, 2005 there were 4 perforations (2%; P2=0.024 compared with patients treated with anti-CTLA 4 followed by IL-2). Two of the 3 patients who developed bowel perforation while receiving IL-2, had autoimmune colitis after treatment with anti-CTLA 4 antibody. The third patient had no symptoms of colitis. The pathology from all 3 patients demonstrated active chronic colonic colitis with intraepithelial lymphocytosis. To reduce the risk of this complication it is our recommendation that patients who have received prior anti-CTLA 4 antibody, and who plan to receive treatment with IL-2 undergo diagnostic colonoscopy before initiating IL-2 to rule out chronic active colitis. This should be considered regardless of whether the patients have experienced colitis due to anti-CTLA 4 antibody or not. In the Surgery Branch this has led to increased interest in further studying the immunologic and pathologic mechanisms of the colitis due to IL-2 and anti-CTLA 4 antibody.