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9586 Background: Despite successful treatment of primary uveal melanoma (UM), tumors with monosomy 3 and 8q amplification (M3 + 8q amp) or DecisionDx-UM Class 2 have high metastatic death rates. We report the final analysis of Cohort 1 in the randomized phase II clinical trial of 6 months of adjuvant sunitinib or valproic acid (VPA) in high-risk UM patients. Methods: High risk for systemic metastasis was defined as the following: A) M3 + 8q amp; B) Class 2. Patients within 6 months of initial treatment of primary UM were randomized 1:1 to receive either sunitinib 25 mg daily or VPA 750 mg daily for 6 consecutive months. The primary endpoint was to evaluate the improvement of 2-year overall survival (OS) rate from 70% (historical references) to 85% in each arm. Secondary endpoints included 1) systemic relapse-free survival (RFS) rate at 18 months, 2) ability to complete adjuvant treatment and, 3) toxicity assessment. Results: Eighty-eight patients were included in the final analysis. There were no differences in tumor size or T stage between the two treatment arms. Nine of 45 patients in the sunitinib arm and 4 of 43 patients in the VPA arm could not complete the 6-month treatment due to toxicity (sunitinib n = 6, VPA n = 2) or systemic progression (sunitinib n = 3, VPA n = 2). All but 9 patients (death due to metastasis, sunitinib n =4, VPA n = 5) were followed for at least 2 years. With a median follow-up of 52.6 months, both drugs met the primary end point with 2-year OS rates of 95.6% (sunitinib, 90% CI 86.5-98.6%) and 90.7% (VPA, 90% CI 80.1-95.8%). The 18-month RFS rates were 75.6% (sunitinib, 90% CI 63.1-84.3%) and 62.8% (VPA, 90% CI 49.4-73.5%). Although not statistically significant, there was a trend of superior RFS with sunitinib over VPA in primary UM with T-stage 3-4 (p=0.131) or >12mm (p=0.129). There was no significant difference in median RFS in HLA-A*02:01 positive or negative status (24.6 vs. 24.8 months). It is of note that the potential survival benefit of sunitinib over VPA diminished after 3 years, indicating longer duration of sunitinib administration might be required. In the multivariable Cox analysis, the RFS was not significantly different in the two treatment arms, but increase of tumor diameter was associated with increase hazard of progression (HR=1.23, 95% CI: 1.13, 1.33; p

Purpose To compare overall survival in high-risk patients with primary uveal melanoma who received adjuvant sunitinib with institutional controls. Design Retrospective cohort. Participants Selection criteria were (1) monosomy 3 and 8q amplification by cytogenetic or DecisionDx-UM Class 2 and (2) monosomy 3 and large tumor size (T3-4 by American Joint Committee on Cancer classification). Exclusion criteria were date of diagnosis before 2007 or after 2013 and age Methods A cohort of patients who intended to receive adjuvant sunitinib for 6 months was compared with institutional historical controls with the same risk factors. Kaplan–Meier and Cox proportional hazards models were used to analyze the outcome. Propensity score was used to adjust for nonrandom assignment to sunitinib. Main Outcome Measures Overall survival. Results From the Wills Eye Hospital Oncology Service Uveal Melanoma Cytogenetic Database (N = 1172), 128 patients fulfilled the selection and exclusion criteria. Median follow-up was 52.7 months (range, 0.26–108 months). A total of 54 patients received sunitinib. Their median age was 56 years (range, 29–81 years), and 48% were men. A total of 74 historical controls in the same risk category were identified. Their median age was 62 years (21–80 years), and 48% were men. Patients in the sunitinib group had worse cytogenetic or molecular features (monosomy 3 and 8q amplification or class 2 87% vs. 57%; P P = 0.001), and were younger. There were 51 deaths, 14 (26%) in the sunitinib group and 37 (50%) in the control group. In the univariate analysis, the sunitinib group had longer overall survival (hazard ratio, 0.53; 95% confidence interval, 0.29–0.99; P = 0.041). In multivariate Cox regression analysis, interaction between use of sunitinib and age as a dichotomous variable was highly significant ( P = 0.003). The following variables were statistically associated with prediction of overall survival: cytogenetic/molecular status ( P = 0.015), T-size category ( P = 0.022), gender ( P = 0.040), and adjuvant sunitinib in patients aged P = 0.004). Results were confirmed by propensity score analysis. Conclusions In this retrospective study, the use of sunitinib in the adjuvant setting was associated with better overall survival.

Patients with stage II melanoma have a considerable risk for recurrence. Current guidelines are imprecise as to optimal follow-up. We hypothesized that by examining recurrence patterns, we could help to better inform guidelines.We queried IRB-approved melanoma databases of Thomas Jefferson University and University of North Carolina, identifying 581 patients with stage II melanoma between 1996 and 2015 with at least 1 year of follow-up. Data included location of first recurrence and how recurrence was detected (ie patient symptom, physician examination, or routine surveillance imaging). Cox regression with backward elimination was used for multivariable analysis.One hundred and seventy-one patients had a recurrence (29.4%), the incidence increased considerably by stage sub-group. Significant predictors of recurrence included male sex (p = 0.003), ulceration (p = 0.03), and stage (p0.001). On multivariable analysis, male sex and stage continued to be significant (p0.01). For overall survival, regression, ulceration, stage, and age were significant predictors of survival. Stage, regression, and age remained significant by multivariable analysis. Patient symptoms were the most frequent mode of detection (40%), followed by physician examination (30%) and surveillance imaging (26%)-this did not differ significantly by stage. Regional nodes were the most common site of recurrence (30%), followed by lung (27%) and in-transit (18%).The majority of recurrences in stage II melanoma are detected by patients and their physicians and rarely by routine imaging. As such, clinical follow-up and patient education are critical factors in detection of recurrence. With the prevalence of regional nodal recurrences, ultrasound might prove to be an important strategy in early recurrence detection.

Purpose The main purpose of this paper was to describe the unique accumulation of cases of uveal melanoma (UM). All patients were white and did not have known occupational risk factors. From the authors' standpoint, there were no lifestyle factors in common in the reported cases. Results of more extensive analyses, including geospatial analysis, are currently being conducted and will be presented in a separate paper. Design Observational case series. Methods Descriptive data from medical records, patient interviews, and questionnaires were obtained from 5 patients from North Carolina, 6 patients from Alabama, and 14 patients from New York. Standard incidence ratio (SIR) calculations were provided by the respective states' cancer registries. UM is the most common primary malignant eye tumor in adults, although it is rare, with 2,500 cases diagnosed annually in the United States. Despite a growing understanding of the molecular characteristics, there remains uncertainty regarding epidemiologic trends and environmental risk factors. This study identified 3 geographic accumulations of UM: 1) Huntersville, NC; 2) Auburn, AL; and 3) Broome and Tioga Counties, New York. Investigation of these groups will guide ongoing efforts to discover potential risk factor and assist with future treatment and prevention. Results In North Carolina, 5 females who were identified as living in Huntersville, NC, were diagnosed with UM at ages 20, 22, 24, 30, and 31. The SIR calculations considering the observed and expected incidence ratios was 0.7 (95% confidence interval [CI], 0.5-0.9) in Mecklenburg County. In Alabama, 6 individuals who were identified as either attending Auburn University or employed there from 1989 to 1993 had diagnoses of UM. Initial SIR calculations for white females of all ages was 1.15 (95% CI, 0.989-1.328). In New York, SIR for Broome and Tioga counties were 0.93 and not significant. However, in Tioga county, for males and females and females alone, SIRs were 2.00 (P = .04) and 3.33 (P = .006). Conclusions Although most of the conclusions that the SIR does not meet statistical criteria that defines these accumulations as true “cancer clusters,” considering the incidence and demographics of UM, these accumulations of cases is unexpected and worth additional exploration. Further investigation into these cases with additional geospatial analyses and blood and tumor testing is ongoing. Information learned from the study of these unique populations may inform a better understanding of the pathogenesis of UM.

9583 Background: Recent studies have shown 5-yr recurrence rates for Stage IIB and IIC melanoma of up to 46%. These high-risk patients currently have few options for adjuvant therapy to prevent this inevitable recurrence, with the only FDA approved therapy being high-dose interferon-alfa, which is quite toxic. However, there are now immunotherapies (anti-PD1) and targeted therapies (anti-BRAF and anti-MEK combinations) which are approved as adjuvants for Stage III patients, some of whom will have a lower baseline recurrence risk than those with Stage IIB/IIC melanoma. We sought to determine if adjuvant PD1 inhibition with nivolumab (N) would improve the recurrence free survival (RFS) compared to historical RFS rates. Methods: Our study (NCT03405155) is a single-arm, open label, multi-center, phase 2 clinical trial evaluating RFS at 24 months in patients with Stage IIB/IIC melanoma on treatment with N at 480 mg IV every 4 weeks for 12 cycles. Overall survival is a secondary endpoint. Associated translational research includes circulating tumor cell DNA and immune correlates. Results: Twenty three patients with Stage IIB and three patients with Stage IIC melanoma were enrolled onto the study and received at least one dose of N. At data cutoff, 22 patients remain in follow up, as four patients withdrew consent at different time points in the study – one patient after one dose who wished to discontinue, one due to concern for COVID and need for repeat visits, one due to insurance issues, and one due to recurrence and wish to discontinue (which was captured in study data and RFS calculations). Seventeen patients have been on the clinical trial for at least two years with nine patients having finished treatment but with less than two years follow-up; the median follow-up is currently 21.9 months. Two patients demonstrated melanoma recurrence, one after receiving cycle six of N and another one year after completing treatment, resulting in a 87.8% RFS (90% CI (64.2%-96.3%) at 2 years, compared to the historical RFS at 2 years of 70%. No N related serious adverse events (SAEs) were observed, with only 2% Grade 3 AEs observed (varied and unrelated to treatment) and all others were Grade 1-2, including 21% GI, 18% cutaneous, and 10% musculoskeletal, respiratory, and fatigue, each; overall, 2% of these Grade 1-2 AEs were treatment related. Conclusions: Our preliminary results show a trend towards improved RFS in patients with Stage IIB/IIC melanoma treated with nivolumab. The cohort has not reached a minimum follow up of at least 2 years for RFS; patients are continuing to be monitored. On study, we observed the expected adverse events, without evidence of new toxicities. Data maturation will reveal the full effect of adjuvant N on disease relapse and overall survival and distant metastasis-free survival in stage IIB/IIC melanoma patients. Clinical trial information: NCT03405155.

TPS9588 Background: Despite successful treatment of primary uveal melanomas (UM), up to 50% of patients subsequently develop systemic metastasis, with the liver involved in up to 90% of patients. Currently there is no US FDA-approved treatment for metastatic uveal melanoma (MUM). Activating mutations in genes encoding alpha subunits of the heterotrimeric G proteins, GNAQ and GNA11, are found in 80-90% of UM. Recent information suggests that GNAQ/GNA11-oncogenic signaling involves a non-canonical pathway conferring the activation of YAP1, distinct from the activation of PLCβ and PKC-MEK-ERK, which may explain the failure of MEK inhibitors in MUM patients. Focal Adhesion Kinase (FAK) is a tyrosine kinase that provides a direct link between Gαq and tyrosine phosphorylation networks controlling YAP and UM growth. Interestingly, UM represents the human cancer harboring the highest level of FAK overexpression. Recent kinome-wide CRISPR-Cas9 screens revealed that FAK and RAF/MEK co-targeting may provide a new network-based precision therapeutic strategy for MUM treatment. Methods: This is an investigator-initiated, prospective, single arm, single-institution, phase II trial evaluating the combination of a FAK inhibitor (defactinib, VS-6063) with a RAF/MEK inhibitor (VS-6766, CH5126766) for the treatment of patients with metastatic uveal melanoma [NCT04720417]. The primary endpoint of the study is disease control rate (DCR) of 50% including complete response (CR), partial response (PR), and stable disease (SD) as determined by RECIST criteria version 1.1. Secondary endpoints include progression free survival, overall survival, and causality of adverse events. Exploratory endpoints include analysis of the pharmacodynamic profile, mechanism of resistance to the combination, and investigation of circulating free DNA as a biomarker. The efficacy of this combination treatment will be assessed using the Simon’s two stage design. In stage I, a total number of 8 patients are accrued and if there are 2 or fewer overall responses among these 8 patients, further enrollment of patients may be stopped with the conclusion that DCR cannot be 50% or greater. Otherwise, an additional 10 patients will be accrued in stage II, resulting in a total sample size of 18 patients. Patients at 18 years or older with metastases from uveal melanoma will be eligible (any line of therapy). Defactinib (200 mg) will be administered orally twice a day in combination with VS-6766 (3.2 mg) administered orally twice a week for 3 weeks, in 28-day cycles. Dose modification will be considered based on toxicity. Treatment will be continued until maximum clinical benefit is obtained; disease progression or the development of intolerable side effects. Enrollment to stage 1 began in February 2021. Clinical trial information: NCT04720417.

e22059 Background: Uveal melanoma is the most common primary intraocular cancer in adults. Despite successful treatment of primary tumors, up to 50% of patients later die of distant metastases. Currently, no effective adjuvant treatment is available. Presence of both monosomy 3 and 8q amplification (M3 + 8q amp) or DecisionDx-UM Class 2 in the primary uveal melanoma characterizes a group of patients with high metastatic death rates with reported 2-year survival rates ranging from 50% to 78%. This study aims to decrease or delay the death from metastatic uveal melanoma. Methods: Uveal melanoma patients with high risk for systemic metastasis defined as any of the following were eligible: A) M3 + 8q amp; B) Class 2. Patients must show no evidence of systemic metastasis and they need to be enrolled within 6 months of initial treatment of primary uveal melanoma. Patients were randomized to receive either sunitinib 25 mg daily or valproic acid (VPA) 750 mg daily as adjuvant treatment for 6 consecutive months. Improvement of 2-year overall survival (OS) rate from historical reference (70%) to 85% was the primary endpoint. The secondary endpoints included 1) systemic relapse-free survival (RFS) rate at 18 months, 2) ability to complete adjuvant treatment and, 3) toxicity assessment. The study was not powered to compare the efficacy between each arm. Results: A total of 90 patients were enrolled in this study. Two patients were excluded from the study including one in the sunitinib arm (did not start treatment after randomization) and one in the VPA arm (refused to stop VPA at 6 months). Nine of 45 patients in the sunitinib arm and 4 of 43 patients in the VPA arm could not complete the 6-month treatment due to toxicity (sunitinib n = 6, VPA n = 2) or systemic progression (sunitinib n = 3, VPA n = 2). The rest of patients completed the 6-month course of study treatments and all patients were followed at least for 2 years. With a median follow-up of 40.2 months, the 2-year OS rates of the sunitinib and VPA group were 95.6% (90% CI 86.5-98.6) and 90.7% (90% CI 80.1 - 95.8), respectively. The 18-month RFS rates of the sunitinib and VPA group were 75.6% (90% CI 63.1 - 84.3) and 62.8% (90% CI 49.4 - 73.5), respectively. Conclusions: Although the study is still ongoing, adjuvant sunitinib and VPA were considered to be safe and tolerable treatments for high-risk uveal melanoma. Sunitinib showed a tendency for a better outcome, thus a Cohort 2 was created to investigate the safety and potential improvement of 18-month RFS rate with 12 months of treatment with sunitinib. Clinical trial information: NCT02068586.

e22049 Background: Immune checkpoint inhibitors (ICI) have become a mainstay of treatment for patients with metastatic cutaneous melanoma. Currently, there are no reliable biomarkers to predict which patients will benefit from ICI therapy. K1505Ac immunohistochemistry (IHC) signal loss is equivalent to loss of functional PBRM1 protein, which has previously been shown to predict response to ICI therapy in metastatic renal cell carcinoma. We hypothesized that loss of K1505Ac IHC expression in patients’ tumors may predict benefit to ICI therapy. Methods: An exploratory study was conducted in patients with metastatic cutaneous melanoma (n = 25) who were treated with ICI therapy at Thomas Jefferson University. Retrospective chart review was performed to determine best clinical response using RECIST 1.1 criteria. Tumor samples from these patients were tested for loss of K1505Ac IHC signals to determine the correlation to best clinical response to ICI therapy. The pathologist was blinded to clinical responses during IHC analysis. Results: The chart below demonstrates the percentage of patients with K1505Ac IHC signal loss ≥ 40% and their correlating best clinical response to ICI therapy. Four of five patients (80%) with complete or partial response displayed K1505Ac IHC signal loss ≥ 40%. Fifteen of twenty patients (75%) with stable disease or progression of disease displayed K1505Ac IHC signal loss < 40%. Conclusions: Loss of K1505Ac IHC signal was associated with better clinical response to ICI therapy for patients with metastatic cutaneous melanoma. These findings suggest that K1505Ac IHC signal loss may serve as a biomarker to help determine which patients will benefit from ICI therapy. A larger cohort of patients is currently under investigation to better evaluate this association. [Table: see text]

Uveal melanoma (UM) is a rare type of melanoma, although it is the most common primary ocular malignant tumor in adults. Nearly one-half the patients with primary UM subsequently develop systemic metastasis, preferentially to the liver. Currently, no treatment is effective for UM hepatic metastasis, and the prognosis is universally poor. The main challenge in designing a treatment strategy for UM hepatic metastasis is the lack of suitable animal models. We developed two orthotopic mouse models for human UM hepatic metastases: direct hepatic implantation model (intrahepatic dissemination model) and splenic-implantation model (hematogenous dissemination model) and investigated the tumorgenesis in the liver. A human UM cell line, established from a hepatic metastasis and nonobese diabetic severe combined immunodeficient γ mice, were used for development of in vivo tumor models. In the direct hepatic implantation model, a localized tumor developed in the liver in all cases and intrahepatic dissemination was subsequently seen in about one-half of cases. However, in the splenic implantation model, multiple hepatic metastases were observed after splenic implantation. Hepatic tumors subsequently seeded intra-abdominal metastasis; however, lung metastases were not seen. These findings are consistent with those observed in human UM hepatic metastases. These orthotopic mouse models offer useful tools to investigate the biological behavior of human UM cells in the liver.

Intratumoral therapy with bacteria/bacterial products dates to at least the 1890s. Over the decades this has expanded beyond the use of microbes and microbial products to include chemicals, cancer chemotherapeutic agents, cytokines, recombinant organisms, and hybrid molecules. The appeal of this method of delivery is the ability to deliver high concentrations of the therapeutic agent directly to the tumor, often with minimal side effects. This article summarizes the use and efficacy of the various agents used in the past and present in the treatment of in-transit and satellite metastases in melanoma.

Aim: To compare PD-L1 expression between metastatic uveal melanoma (MUM) and metastatic cutaneous melanoma (MCM). Materials & methods: A total of 295 MCM and 78 MUM specimens were analyzed for tumor cell PD-L1 expression. Additionally, 91 MCM and 45 MUM specimens were analyzed for PD-1 expression on tumor-infiltrating lymphocytes. Results: A total of 77/295 (26.1%) MCM specimens expressed PD-L1 as compared to 4/78 (5.1%) MUM specimens (p

To compare overall survival in high-risk patients with primary uveal melanoma who received adjuvant sunitinib with institutional controls.Retrospective cohort.Selection criteria were (1) monosomy 3 and 8q amplification by cytogenetic or DecisionDx-UM Class 2 and (2) monosomy 3 and large tumor size (T3-4 by American Joint Committee on Cancer classification). Exclusion criteria were date of diagnosis before 2007 or after 2013 and age18 years.A cohort of patients who intended to receive adjuvant sunitinib for 6 months was compared with institutional historical controls with the same risk factors. Kaplan-Meier and Cox proportional hazards models were used to analyze the outcome. Propensity score was used to adjust for nonrandom assignment to sunitinib.Overall survival.From the Wills Eye Hospital Oncology Service Uveal Melanoma Cytogenetic Database (N = 1172), 128 patients fulfilled the selection and exclusion criteria. Median follow-up was 52.7 months (range, 0.26-108 months). A total of 54 patients received sunitinib. Their median age was 56 years (range, 29-81 years), and 48% were men. A total of 74 historical controls in the same risk category were identified. Their median age was 62 years (21-80 years), and 48% were men. Patients in the sunitinib group had worse cytogenetic or molecular features (monosomy 3 and 8q amplification or class 2 87% vs. 57%; P0.001), had smaller tumor sizes (T3-4 56% vs. 83%; P = 0.001), and were younger. There were 51 deaths, 14 (26%) in the sunitinib group and 37 (50%) in the control group. In the univariate analysis, the sunitinib group had longer overall survival (hazard ratio, 0.53; 95% confidence interval, 0.29-0.99; P = 0.041). In multivariate Cox regression analysis, interaction between use of sunitinib and age as a dichotomous variable was highly significant (P = 0.003). The following variables were statistically associated with prediction of overall survival: cytogenetic/molecular status (P = 0.015), T-size category (P = 0.022), gender (P = 0.040), and adjuvant sunitinib in patients aged60 years (P = 0.004). Results were confirmed by propensity score analysis.In this retrospective study, the use of sunitinib in the adjuvant setting was associated with better overall survival.

We investigated the importance of the insulin-like growth factor-1 receptor (IGF-1R) in hepatic metastases of uveal melanoma. The expression pattern of IGF-1R in archival tissue samples of hepatic metastasis from 24 patients was analyzed by immunohistochemistry. All the samples of hepatic metastases stained positive for IGF-1R. To investigate the biological role of IGF-1R on the growth of metastatic uveal melanoma, a long-term cell line obtained from a hepatic metastasis (TJU-UM001) was evaluated. TJU-UM001 expressed cell surface IGF-1R (>90%) and proliferated in response to exogenous and endogenous insulin-like growth factor-1 (IGF-1). Correlatively, anti-IGF-1R antibody completely blocked IGF-1-induced growth of TJU-UM001 cells. IGF-1 preferentially induced phosphorylation of Akt (S473) in quiescent TJU-UM001 cells, and this was blocked by anti-IGF-1R antibody. This study suggests that autocrine and paracrine mechanisms underlie IGF-1-induced growth of metastatic uveal melanoma and underscore the potential benefit of IGF-1 or IGF-1R antagonism in treatment for metastatic uveal melanoma.

Purpose We performed a phase 1 study to determine the maximum tolerable dose and safety of ipilimumab with stereotactic radiosurgery (SRS) or whole brain radiation therapy (WBRT) in patients with brain metastases from melanoma. Methods and Materials Based on the intracranial disease burden, patients underwent WBRT (arm A) or SRS (arm B). The ipilimumab starting dose was 3 mg/kg every 3 weeks, starting on day 3 of WBRT or 2 days after SRS. The ipilimumab dose was escalated to 10 mg/kg using a 2-stage, 3+3 design. The primary endpoint was to determine the maximum tolerable dose of ipilimumab combined with radiation therapy. The secondary endpoints were overall survival, intracranial and extracranial control, progression-free survival, and toxicity. The ClinicalTrials.gov registration number is NCT01703507 . Results The characteristics of the 16 patients enrolled between 2011 and 2014 were mean age, 60 years; median number of brain metastases, 2 (range 1->10); and number with EC disease, 13 (81%). Treatment included WBRT (n=5), SRS (n=11), and ipilimumab 3 mg/kg (n=7) or 10 mg/kg (n=9). The median follow-up was 8 months (arm A) and 10.5 months (arm B). A total of 21 grade 1 to 2 neurotoxic effects occurred, with no dose-limiting toxicities. One patient experienced grade 3 neurotoxicity before ipilimumab administration. Ten additional grade 3 toxicities were reported, with gastrointestinal toxicities (n=5; 31%) the most common. No patient developed grade 4 or 5 toxicity. The median progression-free survival and overall survival in arm A was 2.5 months and 8 months and in arm B was 2.1 months and not reached, respectively. Conclusions Concurrent ipilimumab 10 mg/kg with SRS is safe. The WBRT arm was closed early because of slow accrual but demonstrated safety with ipilimumab 3 mg/kg. No patient experienced dose-limiting toxicity. Larger studies, including those with combination checkpoint inhibitor therapy and SRS, are warranted.

The prognosis of patients with metastatic uveal melanoma is poor and there are limited therapeutic options. C-kit is expressed in the majority of patients with metastatic uveal melanoma. In this pilot trial, we examined the toxicity and efficacy of sunitinib malate, a multitarget tyrosine kinase inhibitor, in patients with metastatic uveal melanoma. Twenty patients with metastatic uveal melanoma expressing c-kit, 17 of whom failed previous treatments, were included in this study. Patients received sunitinib malate 37.5 mg daily continuously in 4-week cycles. The evaluation of response was carried out every 8 weeks. The overall survival (OS) and progression-free survival (PFS) were evaluated using Kaplan-Meier survival curves and differences in survivals were tested using the log-rank test. There was one partial response and 12 stable disease (SD) after sunitinib treatment. The median OS and PFS were 8.2 and 4.2 months, respectively. Three patients had SD for more than 12 months with sunitinib after failing previous treatments. The most common adverse events were fatigue (90%), diarrhea (60%), hemorrhage (55%), anorexia (45%), hand-foot syndrome (25%), hypothyroidism (25%), and rash (25%). Eleven patients required a dose reduction to 25 mg daily secondary to grade 3 adverse events. The degree of c-kit expression in melanoma cells was not associated with longer PFS or OS. Patients who developed systemic metastases after more than 5 years of their initial diagnosis had better PFS (median PFS: 5.8 vs. 2.6 months, P=0.005). Sunitinib was safely administered and showed potential clinical benefit in patients with metastatic uveal melanoma. The lack of a correlation between c-kit expression and clinical outcomes requires further investigation on the mechanism of sunitinib in metastatic uveal melanoma.

Introduction The incidence of melanoma is dramatically increasing worldwide. We hypothesized that the ratio of metastatic to examined lymph node ratio (LNR) would be the most important prognostic factor for stage III patients. Methods We retrospectively reviewed our institutional database of melanoma patients and identified 168 patients who underwent lymph node dissection (LND) for stage III disease between 1993 and 2007. Patients were divided into three groups based on LNR (≤10%, n = 93; 10–≤25%, n = 45; and >25%, n = 30). Univariate and multivariate analysis was performed using Cox proportional hazards model. Results The median survival time of the entire group of patients was 34 months. The median number of positive nodes was 2 (range = 1, 55), and the median number of examined nodes was 22 (range = 5–123). Tumor characteristics of the primary melanoma (such as thickness, ulceration, and primary site) were not significant predictors of survival in this analysis. By univariate analysis, LNR was an important prognostic factor. Patients with LNR 10–25% and >25% had decreased survival compared to those patients with LNR ≤10% (HR = hazard ratio = 2.0 and 3.1, respectively; P ≤ 0.005). The number of positive lymph nodes also impacted on survival (P = 0.001). In multivariate analysis, LNR of 10–25% and >25% predicted survival (HR = 2.5 and 4.0, respectively). Conclusion LNR is an important prognostic factor in patients undergoing LND for stage III melanoma. It can be used to stratify patients being considered for adjuvant therapy trials and should be evaluated using a larger prospective database. J. Surg. Oncol. 2012; 105:15–20. © 2011 Wiley Periodicals, Inc.

Interleukin-10 (IL-10) downregulates T-cell-mediated immune responses. We studied the association between IL-10 production by freshly isolated melanoma cell suspensions in vitro and overall survival in patients undergoing adjuvant treatment with a vaccine prepared from the same autologous melanoma cells modified with a hapten, dinitrophenyl (DNP). Forty-four patients with cutaneous melanoma (29 stage III and 15 stage IV) were prospectively evaluated. Tumor cells were extracted from metastatic deposits for production of DNP-modified autologous melanoma cell vaccine. Small aliquots of the melanoma cell suspensions were separated prior to vaccine processing and cultured overnight for IL-10 production. Based on a blind assessment of the distribution of IL-10 levels in the culture supernatants, a cutoff of 200 pg/ml was used to define high versus low IL-10 producers. Cox regression model was used for multivariate analysis. Overall survival was calculated using the Kaplan–Meier method, and survival curves were compared with the log-rank test. Out of 44 patients, 29 were low and 15 were high IL-10 producers. The median OS was significantly worse for high compared with low IL-10 producers (10.5 months vs. 42 months; P = 0.022). In stage III patients, the multivariate hazard ratio for high versus low IL-10 producers was 2.92 (95% CI, 1.04–8.20; P = 0.041). The corresponding hazard ratio in stage IV patients was 0.92 (95% CI, 1.04–8.20; P = 0.888). High IL-10 production in the tumor microenvironment could be a determinant of clinical outcomes in stage III melanoma patients receiving autologous melanoma cell vaccine.

9592Background: Despite successful treatment of primary uveal melanomas, up to 50% of patients subsequently develop systemic metastasis, with the liver involved in up to 90% of patients. At our ins...

Purpose: To retrospectively evaluate prognostic factors for survival in patients with uveal melanoma who received chemoembolization (CE) with 1,3-bis (2-chloroethyl)-1-nitrosourea or immunoembolization (IE) with granulocyte-macrophage colony-stimulating factor (GM-CSF) for hepatic metastases. Materials and Methods: Fifty-three consecutive patients with uveal melanoma were treated by using CE or IE in clinical trials approved by the Institutional Review Board. Prognostic factors associated with overall survival (OS) and progression-free survival (PFS) in the liver and extrahepatic (systemic) organs were retrospectively evaluated. Covariates of age, sex, preexisting extrahepatic metastases, liver enzyme levels, tumor volume, radiologic response in hepatic metastases, and treatment type were analyzed. Results: Compared with CE, high-dose (≥1500 μg of GM-CSF) IE resulted in significantly better OS (20.4 vs 9.8 months, P = .005) and systemic PFS (12.4 vs 4.8 months, P = .001) at univariate analysis. Overall, w...

Interleukin 10 (IL-10) is produced by various types of human cancer, including malignant melanoma, and plays an important role in negative regulation of cell-mediated immune responses against tumors. We have developed chimeric molecules (immunoadhesins), combining the extracellular domain of human interleukin 10 receptor 1 (IL-10R1) with the Fc regions of human IgG1 heavy chain and investigated their capability of blocking the biological activities of human IL-10. Monomeric and dimeric immunoadhesins (IL-10R1/IgG1) constructs were tested for capturing human IL-10 and blocking its biological activities. Plasmid vectors that contained the IL-10 immunoadhesin constructs were directly transfected into human melanoma cell lines. Transfection of plasmid vectors into melanoma cell lines resulted in capturing of exogenously added as well as endogeneously produced IL-10. The supernatants obtained from an IL-10 non-producing melanoma cell line transfected with monomeric IL-10 immunoadhesin plasmids most efficiently captured exogenously added IL-10, compared to those obtained with the dimeric IL-10R1/IgG1 plasmid vector. Transfection of IL-10-producing melanoma cells with the monomeric IL-10 immunoadhesin plasmids totally captured endogenously produced IL-10 and enhanced T cell responses against allogeneic melanoma cells. Furthermore, purified monomeric IL-10 immunoadhesin protein showed IL-10 capturing efficacy compatible with that of IL-10-specific monoclonal antibodies. Collectively, these studies indicate that IL-10 immunoadhesins, especially in monomeric form, are potent inhibitors of biological activities of IL-10 and suggest that these molecules, alone or in conjunctions with other immunotherapeutic approaches, can be utilized for the immuno-targeting of IL-10 producing tumors.

Melanoma metastatic to the gallbladder is rare. When present, it is often part of a widespread complex of metastases. Primary gallbladder melanomas are also extremely rare and can sometimes be difficult to distinguish from metastatic lesions. The optimal treatment for malignant melanoma of the gallbladder remains unclear, and prognosis is generally poor. We present here two cases of patients with metastatic lesions to the gallbladder. One patient presented with symptomatic cholelithiasis and was found incidentally to have a metastasis. Another patient had known a metastasis, but underwent curative resection of the only site of disease. We review the published literature for gallbladder melanoma, both primary and metastatic to determine the role of surgery in this disease.

The Melanoma Staging Committee of the American Joint Committee on Cancer (AJCC) promulgated in 2001 major revisions of the melanoma tumor-node-metastasis (TNM) categories and stage grouping criteria, for a new staging system of cutaneous melanoma. The Committee invited data analyses relevant to the proposed new melanoma staging for validation of the system. Validation studies that were published subsequently confirmed most of the parameters of the new staging system, identified new prognostic factors that had not been included in the revised AJCC staging, whereas the prognostic power of some parameters could not be confirmed in the data of other institutions. This article provides an in-depth analysis of the current AJCC staging for melanoma, addresses areas of controversy, and offers proposals for consideration at the next revision of the system.

Background: The definitive criteria for assessing competence remain elusive. In our study, we aimed to identify the determinants of competence assessment used by individual laparoscopic surgeons. Methods: In a blinded fashion, five laparoscopic surgeons rated 27 subjects on three laparoscopic simulations in four skill categories: clinical judgment, dexterity, serial/simultaneous complexity, and spatial orientation. The raters then assessed overall subject competence for each procedure. Point-biserial correlational analyses and cluster analyses were performed to ascertain the relationships among the various scales. Results: All of the correlations between the skills’ ratings and competence judgments were statistically significant (p < .05). No skill rating was consistently more highly correlated with the competence rating. There were no distinct patterns of correlations for each rater or each procedure. One factor emerged from each cluster analysis of the skills measures. Conclusions: The results suggest that the four skills scored in the study are highly correlated with each other and are important in determining competence. The cluster analyses revealed that the surgeon raters shared a common perception of competence.

Background The purpose of our study was to evaluate the construct validity of laparoscopic technical performance measures and the face validity of three laparoscopic simulations. Materials and methods Subjects (N = 27) of varying levels of surgical experience performed three laparoscopic simulations, representing appendectomy (LA), cholecystectomy (LC), and inguinal hemiorrhaphy (LH). Five laparoscopic surgeons, blinded to the identity of the subjects, rated the subjects on procedural competence on a binary scale and in four skills categories on a 5-point scale: clinical judgment, dexterity, serial/simultaneous complexity, and spatial orientation. Using a task-specific checklist, non-clinical staff assessed the technical errors. The level of surgical experience was correlated with the ratings, the technical errors, and the time for each procedure. Subject responses to a survey regarding the utility of the inanimate models were evaluated. Results Years of experience directly correlated with the skills ratings (all P Conclusion The laparoscopic simulations demonstrated both face and construct validity. Regardless of the level of surgical experience, the subjects found the models to be suitable representations of actual laparoscopic procedures. Task speed improved with surgical experience. More importantly, the quality of performance increased with experience, as shown by the improvement in the skills assessments by expert laparoscopic surgeons.

Background: Laparoscopic live donor nephrectomy is becoming increasingly popular as it has been shown to minimize donor morbidity, length of hospital stay and length of time to return to work. Initial experience suggestedthat kidneys procured laparoscopically had higher rates of delayed graft function and ureteric complications but with increasing experience. these complications have become less common. Methods: Retrospective chart review of all patients who underwent living donor kidney transplant using kidneys procured laparoscopically at our centre was performed. From the initiation of the laparoscopic donor nephrectomy programme at our institution in November 1998 until February 2002. we performed 71 living donor kidney transplants (69 kidneys procured laparoseopically and two procured by open donor nephrectomy after failed laparoscopic approach). Donor left kidney was used in all except in one patient. Mean duration of warm ischaemia time was 206 ′ 79 s. Results: The mean age of the recipients was 42 ′ 15 years (range 1-68) including five paediatric recipients (age < 18 years). There were 48 males and 23 females. Nine (13%) were retransplants (seven second transplants and one each of third and fourth transplants). Two patients died with functioning grafts and four patients lost the graft (three thrombosis one anastomotic rupture). No patient developed ureteric complications. The incidence of delayed graft function (need for dialysis in the first week post-transplant) was 4%. Patient and graft survival rates (actual) were 97% and 91%, respectively. Mean length of hospital stay was 9 ′ 7 days (median 7 days). Conclusions: Recipient outcome is not compromised and excellent results can be achieved with living donor kidney transplantation using laparoscopically procured kidneys.

Monoclonal rat anti-idiotypic antibody (Ab2) BR3E4 mimicking the colorectal carcinoma (CRC)-associated epitope CO17-1A induced antigen-specific humoral and cellular immune responses in mice and rabbits. Ab2 BR3E4 was administered in a phase I trial to CRC patients either as intact IgG or as F(ab′) 2 coupled to keyhole limpet hemocyanin (KLH). There was a trend for the F(ab′) 2 -KLH-immunized patients to show higher immune response rates (18/21 and 5/15 patients with anti-anti-idiotypic antibodies and T cells, respectively) than the IgG-immunized patients (15/23 and 3/15 patients positive). Clinical responses were rare in these patients with liver metastases.

Since the advent of the laparoscopic cholecystectomy in the last 2 decades, minimally invasive surgery (MIS) has evolved through advances in videoscopic technology, instrumentation, and surgical techniques. As surgeons have gained experience with the laparoscopic approach, conditions once considered contraindications to laparoscopic cholecystectomy, such as the inflammation of acute cholecystitis and common bile duct obstruction, are now frequently treated with MIS. The following serves as a review of the basic technique of laparoscopic cholecystectomy.

UNLABELLED Since the first description by Ratner and collegues in 1996, laparoscopic live-donor nephrectomy is gaining wide acceptance in an attempt to minimize the donor morbidity, length of hospital stay and length of time to return to work. It is unknown whether multiple renal arteries pose additional problems with laparoscopic donor nephrectomy. In November 1998, our institution initiated laparoscopic donor nephrectomy program. In the ensuing 19 months, we performed 25 living donor renal transplants, 24 of them using laparoscopic donor nephrectomy. The left kidney was procured in all cases. Eight donor candidates (33%) had two or more renal arteries (two arteries in five patients and three patients). RESULTS In six cases (25%), findings at surgery differed from the CT angography results (in four cases, CT angiogram reported fewer arteries than were found at surgery and in two cases it reported more). We found no significant differences in both donor outcomes and recipient, based on the presence or absence of multiple renal arteries. Among donor outcomes, we found equivalent results for donor warm ischemia time total donor operating time, and donor length of stay. For recipient outcomes, we found no significant differences between groups for the incidence of acute tubular necrosis (ATN), graft survival and most recent serum creatinine. In one case, we constructed two arteries into a single conduit on the backtable prior to transplantation. However, in most cases with multiple arteries, we implanted the arteries separately into the recipient external iliac artery. Based on this experience, we do not find the presence of multiple renal arteries to be a barrier to the successful use of kidney grafts procured by laparoscopic donor nephrectomy.

Background. We have previously shown that oxidative stress alone can promote transformation of human B cells infected with Epstein-Barr virus (EBV) in vitro, an accepted model mimicking posttransplant lymphoproliferative disorders (PTLDs). Our laboratory has investigated the direct effects of cyclosporine A (CyA) as an oxidant promoting B-cell transformation and we have proposed that CyA directly promotes B-cell transformation and that this effect can be blocked by antioxidants. Methods. Human splenocytes were prepared by centrifugation and plating technique to provide a greater than 80% pure preparation of B cells that was used for the direct oxidative stress experiments. These cells were cocultured with CyA (500 ng/ml) and hydrogen peroxide (H 2 O 2 , 0.15 mM) with or without antioxidant vitamin E (40 μM). Oxidative stress was evaluated by using a commercial lipid hydroperoxide (LPO) assay kit. In another set of three separate experiments, human B lymphocytes infected with EBV were cultured with CyA (500 ng/ml), H 2 O 2 (0.15 mM), and vitamin E (40 μM). B-Cell transformation by EBV was evaluated by counting colony number and [ 3 H]-thymidine incorporation. Results. At therapeutic concentrations, CyA (500 ng/ mL) had an oxidative effect on human splenocytes in vitro, similar to the effect of H 2 O 2 (90 and 97% increases, respectively in LPO production over control P < 0.005), which was abrogated by the addition of vitamin E. Similarly, both CyA and H 2 O 2 promoted transformation of B cells infected with EBV(75 and 108% increases respectively in colony counts over control, P < 0.005). This effect was also blocked by vitamin E. Conclusions. Both CyA and H 2 O 2 have a direct oxidative effect on human B cells and cause promotion of EBV-induced transformation of B cells. These effects are blocked by the antioxidant vitamin E. These findings may have future therapeutic implications for PTLDs.

Purpose: Vaccinia virus is a DNA poxvirus previously used as a vaccine to eradicate smallpox. The virus has a high efficiency of infection, replicates in the cytoplasm without chromosomal integration and can transport a large amount of recombinant DNA without losing infectivity. Therefore, it is an excellent choice as a vector for gene delivery in vivo. Large quantities of vaccinia have been injected into dermal, subcutaneous and peripheral lymph node melanoma metastases without significant side effects, and with efficient infection of the tumor cells and recombinant gene transfection. To determine if vaccinia, when given intravesically, can effectively infect bladder mucosa and tumor with acceptable toxicity, we performed a phase I trial of intravesical vaccinia in patients with muscle invasive transitional cell carcinoma before radical cystectomy.Materials and Methods: After documenting immune competence and demonstration of a major reaction after revaccination, patients received 3 increasing doses of i...

The colorectal carcinoma (CRC)-associated CO17-1A/GA733 antigen (Ag) has been the target of a phase II/III randomized trial of passive immunotherapy with monoclonal antibody CO17-1A (Ab1), and phase I active immunotherapy trials with polyclonal anti-idiotypic antibodies (Ab2) mimicking the CO17-1A or GA733 epitope of the Ag. However, monoclonal rat Ab2 BR3E4 directed against Ab1 CO17-1A was superior to polyclonal Ab2 in inducing antigen-specific humoral and cellular immune responses in mice and rabbits. Various forms of Ab2 BR3E4, i.e., BR3E4-F(ab')2 precipitated with aluminum-hydroxide (alum), BR3E4-F(ab')2 coupled to KLH and precipitated or non-precipitated with alum, and BR3E4-IgG in alum or incomplete Freund's adjuvant were compared for their capacity to induce in rabbits anti-anti-idiotypic antibodies (Ab3) that specifically bind to the CO17-1A Ag. BR3E4-F(ab')2 coupled to KLH and precipitated with alum was shown to induce the highest Ab3 titers, followed by Ab2 BR3E4-IgG in alum. Therefore Ab2 BR3E4 as intact IgG (IgG group) or as F(ab')2 coupled to KLH (KLH group), was administered in a phase I trial to 45 patients with CRC, stage Dukes'D (UICC stage IV), with the goal to modulate patients' immune responses to their tumors. Fifteen of 23 patients in the IgG group developed Ab3 binding specifically to Ab2, and in four of these patients the Ab3 also specifically bound to Ag-positive CRC cells. Lymphoproliferative responses to Ab2 and/or GA733-2E Ag stimulation were observed in three of these patients. Eighteen of the 22 KLH group patients tested developed Ab3 and the Ab3 bound specifically to CRC cells in eight patients. Five of the 15 KLH group patients tested developed lymphoproliferative responses to Ab2 and/or GA733-2E Ag. Thus, there was a trend for the KLH group demonstrating higher immune response rates than the IgG group. Clinical responses were rare in these patients with liver metastases.

Purpose Minimally Invasive Surgery (MIS) has impacted patient care as well as medical training. New medical education opportunities have emerged with MIS. In this pilot study we explore the role of live, interactive MIS to augment and strengthen specific segments of the undergraduate medical curriculum.

The authors provide an overview of laparoscopic dissecting instruments and discuss early development, surgical options, and special features. End effectors of different shapes and functions are described. A comparison of available energy sources for laparoscopic instruments includes discussion of thermal dissection, ultrasonic dissection, and water-jet dissection. The ergonomic risks and challenges inherent in the use of current laparoscopic instruments are outlined, as well as ergonomic issues for the design of future instruments. New directions that laparoscopic instrumentation may take are considered in connection with developing technology in robotics, haptic feedback, and MicroElectroMechanical Systems. Copyright © 2001 by W.B. Saunders Company.

BACKGROUND The objective of this study was to evaluate the usefulness of resection of metastatic uveal melanoma and to analyze the characteristics of patients who may benefit from surgical intervention. PATIENTS AND METHODS Twelve patients underwent surgical removal of metastasis between 1976 and 1998. Data regarding primary uveal melanoma, systemic metastasis, surgical procedures, and outcomes were reviewed retrospectively. RESULTS There were seven patients with liver metastases, two with lung metastases, one with brain metastasis, and two patients with metastases in the liver and other organs. Median time to systemic metastasis was 8 years. Seven of 12 patients were asymptomatic when they were found to have metastasis. Ten patients underwent complete resection of metastasis. No significant surgical complications were experienced. Median recurrence free and overall survival periods after complete resection were 19 months (range, 6–78 months) and greater than 27 months (range, 11–86 months), respectively. Recurrence free and overall 5-year survival rates of those patients were 15.6% and 53.3%, respectively. Three of these patients had no further systemic recurrence. All patients whose time to systemic metastasis was within 5 years developed further systemic recurrence within 2 years after surgery. In contrast, in 8 patients whose time to systemic metastases was greater than 5 years, 4 patients either were recurrence free or developed second metastasis more than 4 years after surgery. CONCLUSIONS Complete surgical removal of metastatic uveal melanoma provided unexpectedly long survival without significant morbidity for the selected patients. These results are encouraging and justify a trial in which patients eligible for resection are randomized between standard treatment and surgery. Cancer 2000;89:1561–8. © 2000 American Cancer Society.

When one considers the choice of viral vectors for use in gene therapy systems, candidates usually include adenovirus and retrovirus families and, in the case of retrovirus, most recently the HIV-derived lentiviral vectors. These vectors have been chosen based on criteria such as tropism, duration of expression, and capacity to integrate in the host genome. A number of characteristics of their life cycle make poxviruses poor candidates for long-term expression, and, as a result, they are neglected by investigators and rarely represented in reviews and at conferences. However, vaccinia and its relatives may be ideal in immunotherapy applications, including their use as replicating agents that can be directed against solid tumors. Poxvirus vectors, which enable us, as immunologists, to revisit 1 of our greatest triumphs (Figure ​(Figure1),1), can be used both to deliver recombinant vaccines and to effect in situ gene transfer to provide cytokines that promote the recognition and rejection of tumors.

BACKGROUND In early trials of paclitaxel administered as a 24-hour infusion, an overall response rate of 16% was reported for patients with metastatic melanoma. Paclitaxel is a natural product-based agent and is thus subject to the problem of multidrug resistance (MDR). Tamoxifen is an agent that can abrogate MDR and potentially enhance the effect of paclitaxel. A Phase II trial of the combination was undertaken with previously treated patients. METHODS Patients with metastatic cutaneous or mucosal melanoma who were previously treated with the Dartmouth chemotherapy regimen (dacarbazine, carmustine, cisplatin, and tamoxifen) were evaluated. Paclitaxel was administered at a dose of 225 mg/m2 intravenously over 3 hours every 3 weeks. All patients also took tamoxifen 40 mg orally daily. Treatment continued until disease progression. RESULTS Twenty-one patients completed at least two cycles of paclitaxel and were evaluable for response. Five responses were observed, 1 complete response, and 4 partial responses, for an overall response rate of 24%. The combination was well tolerated. The most common nonhematologic side effects were myalgia and paresthesia. Hematologic toxicity was mild. No patients developed neutropenic fever. CONCLUSIONS This is the first report of a Phase II trial evaluating paclitaxel as a 3-hour infusion in melanoma patients. The 3-hour infusion is well tolerated and results in little myelosuppression and minimal neurotoxicity. The contribution of tamoxifen is difficult to evaluate because plasma levels were not measured. It is possible that a higher response rate might be observed with larger doses of tamoxifen. Further investigation of paclitaxel in the treatment of patients with metastatic melanoma is warranted. Cancer 2000;88:79–87. © 2000 American Cancer Society.

Conventional repairs of incisional hernia are plagued with frequent complications and recurrences. Laparoscopic incision/ventral herniorrhaphy (LIVH) has been reported to be a safe and feasible technique with low morbidity and low early rates of recurrence. In this study, we review our experience with LIVH. All cases of LIVH performed consecutively at St. Joseph's Hospital, Hamilton, Ontario and University of Kentucky Medical Center between November 93 and January 1999 being followed prospectively were reviewed. Seventy-five hernias were repaired in 73 patients (38F, 35M) ranging from 25 to 84 years (mean 57) with a mean American Society of Anesthesiologists (ASA) score of 2.1. Postoperative complications occurred in 14 patients (19%) including seroma (3), wound infection (1), patch infection (2), bowel injury (2), ileus (3), pain (1), atelectasis (1), and congestive heart failure (1). One case was converted to an open procedure and in one case a prosthesis was not placed due to an enterotomy repaired laparoscopically. Postoperative recurrences occurred in 7 (9%) of patients, within two to twelve months. Three of these were repaired laparoscopically. Over the five-year experience, the number of recurrent hernias repaired has increased, operative times have increased, and hospital length of stay has decreased. During that same interval the incidence of recurrence and complications has not changed. In conclusion, LIVH is a safe and feasible technique, applicable to all patient populations including the obese and multi-operated abdomen. Recurrence is low, and may be repaired laparoscopically.

This paper reviews the use of low-dose cyclophosphamide (CY) with active specific immunotherapy in patients with advanced melanoma and other metastatic cancers, and outlines the basic scientific research that supports this use. In various animal models, CY augments delayed-type hypersensitivity responses, increases antibody production, abrogates tolerance, and potentiates antitumor immunity. The mechanism of CY immunopotentiation involves inhibition of a suppressor function, as indicated by extensive work in the MOPC-315 plasmacytoma murine model. Human studies of the immunopotentiating effect of CY have yielded both positive and negative results. Toxicity associated with low-dose CY has been mild in these studies. Results of efficacy have been variable for reasons such as small sample sizes, short follow-up periods, and the weaker immunogenicity of human tumor-associated antigens. Although beneficial clinical outcomes have been observed in historically controlled trials, there are few randomized, controlled trials that evaluate outcome in relation to CY immunopotentiation of active specific immunotherapy. Additional randomized, controlled trials should be done to examine the clinical efficacy of CY immunopotentiation of therapeutic cancer vaccines.