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The hypoxia and profound inflammatory response associated with the pneumonitis observed with the severe acute respiratory virus coronavirus-2 (SARS-COV-2) virus responsible for the recent COVID-19 pandemic has overwhelmed intensive care facilities in the epicenters of infection including Wuhan

Background Metastatic uveal melanoma is a highly fatal disease; most patients die from their hepatic metastasis within 1 year. A major drawback in the development of new treatments for metastatic uveal melanoma is the difficulty in obtaining appropriate cell lines and the lack of appropriate animal models. Patient-derived xenograft (PDX) tumor models, bearing ectopically implanted tumors at a subcutaneous site, have been developed. However, these ectopically implanted PDX models have obstacles to translational research, including a low engraftment rate, slow tumor growth, and biological changes after multiple passages due to the different microenvironment. To overcome these limitations, we developed a new method to directly transplant biopsy specimens to the liver of immunocompromised mice. Results By using two metastatic uveal melanoma cell lines, we demonstrated that the liver provides a more suitable microenvironment for tumor growth compared to subcutaneous sites and that surgical orthotopic implantation (SOI) of tumor pieces allows the creation of a liver tumor in immunocompromised mice. Subsequently, 10 of 12 hepatic metastasis specimens from patients were successfully xenografted into the immunocompromised mice (83.3% success rate) using SOI, including 8 of 10 needle biopsy specimens (80%). Additionally, four cryopreserved PDX tumors were re-implanted to new mice and re-establishment of PDX tumors was confirmed in all four mice. The serially passaged xenograft tumors as well as the re-implanted tumors after cryopreservation were similar to the original patient tumors in histologic, genomic, and proteomic expression profiles. CT imaging was effective for detecting and monitoring PDX tumors in the liver of living mice. The expression of Ki67 in original patient tumors was a predictive factor for implanted tumor growth and the success of serial passages in PDX mice. Conclusions Surgical orthotopic implantation of hepatic metastasis from uveal melanoma is highly successful in the establishment of orthotopic PDX models, enhancing their practical utility for research applications. By using CT scan, tumor growth can be monitored, which is beneficial to evaluate treatment effects in interventional studies. Electronic supplementary material The online version of this article (doi:10.1186/s12967-017-1247-z) contains supplementary material, which is available to authorized users.

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.

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.

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

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...

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: 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.

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.

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...

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.

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.

The patient with surgically incurable melanoma presents a difficult problem for the medical oncologist. Single chemotherapeutic agents at conventional doses produce bona fide but infrequent remissions. The most active single agent for the treatment of metastatic melanoma is dacarbazine (DTIC). Until recently, combinations of drugs yielded no real improvement over treatment with the individual components. The combination of DTIC + carmustine (BCNU) + cisplatin + tamoxifen (the "Dartmouth regimen") appears to be more effective than DTIC alone, but prospective randomized trials comparing the two are still in progress. The contribution of tamoxifen to the observed results continues to be evaluated. Biological agents, such as interferon and interleukin-2, have lower overall response rates compared to chemotherapy regimens, but response duration appears to be longer. Chemotherapy combined with biotherapy offers the promise of higher response rates and long-term durable remissions. The results from high-dose regimens that use autologous bone marrow or peripheral stem cell support have not been sufficient to justify the added toxicity. Although advanced melanoma often is not curable with systemic therapy, the considered use of currently available regimens can induce clinically significant remissions and, possibly, prolong life in some patients.

PURPOSE To determine whether treatment with an autologous whole-cell vaccine modified with the hapten dinitrophenyl (DNP vaccine) is an effective postsurgical adjuvant treatment for melanoma patients with clinically evident nodal metastases. PATIENTS AND METHODS Eligible patients had regional nodal metastases that were large enough (> or = 3 cm diameter) to prepare vaccine. Following standard lymphadenectomy, patients were treated with DNP vaccine on a monthly or weekly schedule. RESULTS Of 62 patients with metastasis in a single lymph node bed (stage III), 36 are alive after a median follow-up time of 55 months (range, 29 to 76); the projected 5-year relapse-free and overall survival rates are 45% and 58%, respectively. Of 15 patients with metastases in two nodal sites, five are alive with a median follow-up time of 73 months. An unexpected finding was the significantly better survival of older patients; the projected 5-year survival of patients greater than 50 versus < or = 50 years was 71% and 47%, respectively (P = .011, log-rank test). The development of a positive delayed-type hypersensitivity (DTH) response to unmodified autologous melanoma cells was associated with significantly longer 5-year survival (71% v 49%; P = .031). Finally, the median survival time from date of first recurrence was significantly longer for patients whose subcutaneous recurrence exhibited an inflammatory response (> 19.4 v 5.9 months; P < .001). CONCLUSION Postsurgical adjuvant therapy with autologous DNP-modified vaccine appears to produce survival rates that are markedly higher than have been reported with surgery alone. Moreover, this approach has some intriguing immunobiologic features that might provide insights into the human tumor-host relationship.

A total of 116 patients, all of whom had systemic metastases from posterior uveal melanoma, were evaluated to identify potential indicators for time to systemic metastasis. In the multivariate Cox proportional hazards model with clinically available variables, the age at initial treatment for uveal melanoma, gender and diameter of the primary tumor were revealed to be independent predictive factors for time to systemic metastasis. Age older than 60 years, male gender, and diameter of the primary uveal melanoma more than 10 mm were proved to be independent unfavorable factors. The estimated median time to systemic metastasis for the most unfavorable group (age60, male, diameter10 mm) was 20.2 months in contrast with 76.1 months for the most favorable group (ageor = 60, female, diameteror = 10 mm). Although the results of this study cannot be applied to all patients with posterior uveal melanoma, predictive factors for time to systemic metastasis in those patients who have recurred supplement the information obtained from prognostic factors for the likelihood of metastasis or survival. They contribute not only to our understanding of the biology of metastasizing posterior uveal melanoma, but also in developing appropriate strategies for follow-up and treatment.

The prognosis of metastatic uveal melanoma (UM) is extremely poor. Approximately 90% of patients with metastatic UM die from hepatic metastasis. Controlling hepatic metastases has been a rational approach to extend survival. This raises an urgent need to develop a novel mouse model for further investigation. Patient-derived tumor xenograft (PDX) mouse model provides potential benefit through a personalized medicine approach. This model may be useful for predictions of clinical outcomes, drug efficacy and biomarker identification. Most PDX models, including UM PDX models, are made by ectopic subcutaneous implantation. Subcutaneous PDX models have some obstacles in translational research due to differences in anatomic microenvironment from tumor origin, low engraftment rate, and slow tumor growth. Our goal was to develop an orthotopic PDX model of liver metastatic UM which would overcome these difficulties. In developing our model, we first compared the differences in growth in a liver with a subcutaneous site using two UM cell lines (UM001 and UM004) in NSG mice, to ascertain which site is a more suitable tumor microenvironment. Second, we investigated the feasibility of surgical orthotopic implantation (SOI) of tumor masses to develop a practical liver tumor xenograft mouse model with UM cell lines in 20 mice. Finally, we tried to establish an orthotopic PDX mouse model of liver metastatic UM in 5 mice. We also evaluated concordance for tumor characteristics between pre-implant and post-implant tumors. Our results showed that the liver was a more suitable microenvironment to grow the two UM cell lines compared to the subcutaneous site. UM001 engrafted in the liver, whereas it did not engraft in the subcutaneous site. UM004 displayed more rapid growth in the liver compared to the subcutaneous site. A new SOI of tumor chunk was created to develop a practical liver tumor xenograft model. Donor tumors, which were generated in the liver after injecting UM cell lines, were surgically transplanted into the liver of recipient mice. The new SOI was successfully performed in all 20 mice without adverse events. Recipient mice formed tumors in the liver after SOI. For comparison, the tumor chunks of UM cell lines were also implanted subcutaneously, in which we were able to show that the growth was more rapid in the liver. Both donor and recipient tumors had matching tumor characteristics in histological and proteomic analysis. We established an orthotopic PDX mouse model of liver metastatic UM with a new SOI method. The success rate of engraftment was 80% (4/5) within 6 months. Tumor characteristics of both patient's original tumors and xenograft mouse tumors matched in histological, genomic and proteomic analysis. This new SOI method can establish a patient-derived liver metastatic uveal melanoma xenograft model in NSG mouse at a highly successful rate. Citation Format: Ken Kageyama, Masahiro Ohara, Kengo Saito, Shinji Ozaki, Mizue Terai, Andrew E. Aplin, Michael J. Mastrangelo, Takami Sato. Feasibility of surgical orthotopic implantation for establishment of patient-derived liver metastatic uveal melanoma xenograft model in NSG mouse. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 623.

Circulating tumor cells (CTCs) have been shown to be a prognostic marker in breast cancer1. We hypothesize that circulating melanoma cell (CMC) detection could be utilized in the management of uveal melanoma, including early intervention. Prior methodologies for circulating uveal melanoma cell (CUMC) detection have been fraught with poor sensitivity, limiting their clinical utility2. Development of an improved method is necessary to establish the clinical utility of CUMC monitoring. Photoacoustics, also referred to as laser-induced ultrasound, is a novel platform for the detection and capture of CMCs. Photoacoustics uses short duration pulsed light to create ultrasonic acoustic waves in an optically absorbing medium, in this case melanin within melanoma3. As light is absorbed by irradiated chromophores, the optical energy gets converted into kinetic thermal energy trapped within the chromophore and subsequent thermal expansion ensues. Transient thermoelastic expansion of the absorbent cell results in the propagation of ultrasonic acoustic waves which can be detected and analyzed using a piezoelectric response mechanism. In addition, detected CMCs can be isolated by a two-phase flow cell separation technique4. Due to the low cost and melanoma specific capabilities of photoacoustics, we evaluated this technology for the purpose of CUMC detection. Methods: Cells from uveal melanoma cell line UM002B, established at Thomas Jefferson, were titrated to various cell concentrations and analyzed in a neutral density solution utilizing the photoacoustic method. Uveal melanoma cells of differing concentrations were spiked into isolated healthy donor peripheral blood mononuclear cells (PBMCs) and healthy whole blood samples. PBMC isolates were analyzed for CUMCs. Results: CUMCs were successfully quantified by the photoacoustic method including single cell detection. Recovery rates of cultured cells in a neutral density solution approached 25%. Recovery rates for CUMCs in whole blood averaged 10% of expected cell yield (56/540 cells detected) with a higher detection rate at lower cell concentrations. Photoacoustics offers a viable method for the detection of CUMCs with an accuracy that meets or exceeds previously reported CUMC yields. Studies analyzing CUMCs from patients with metastatic disease are ongoing. 1. Cristofanilli, M, et al., Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med, 2004. 351(8): 781-91. 2. Bidard FC, et al., Detection rate and prognostic value of circulating tumor cells and circulating tumor DNA in metastatic uveal melanoma. Int J Cancer. 2014 Mar 1;134(5):1207-13. 3. Weight RM, et al. Photoacoustic detection of metastatic melanoma cells in the human circulatory system. Opt Lett. 2006 Oct 15;31(20):2998-3000. 4. O’Brien CM, et al. Capture of circulating tumor cells using photoacoustic flowmetry and two phase flow. J Biomed Opt. 2012 Jun;17(6):061221. Citation Format: Ryan M. Weight, Shingo Sato, Masahiro Ohara, Mizue Terai, Michael Mastrangelo, Marlana Orloff, Benjamin Goldschmidt, John Viator, Takami Sato. Detection of circulating tumor cells in high-risk primary uveal melanoma by the photoacoustic method. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 471.

We have reported that patients with metastatic melanoma treated with an autologous, dinitrophenol-modified vaccine develop inflammatory responses at tumor sites. Histologically, these inflamed lesions are characterized by T cell infiltration, which is sometimes associated with tumor cell destruction. We tested biopsy specimens of eight subcutaneous metastases that had developed inflammation following vaccine treatment for expression of mRNA for interferon gamma (IFN gamma), interleukin-4 (IL-4), tumor necrosis factor alpha (TNF alpha), and IL-10. Post-vaccine, inflamed biopsies contained mRNA for IFN gamma (5/8), IL-4 (4/8) or both (3/8), and for TNF alpha (4/7). In contrast, IFN gamma mRNA was detected in only 1/17 and TNF alpha mRNA in 2/16 control specimens (pre-treatment lymph node metastases or non-inflamed subcutaneous metastases). mRNA for IL-10, a cytokine with anti-inflammatory properties, was detected in 24/25 melanoma metastases and was independent of lymphoid content; in situ the reverse transcriptase/polymerase chain reaction confirmed that melanoma cells were the major source. These findings may provide a new parameter by which to measure the effects of cancer immunotherapy.

e14536Background: Checkpoint inhibitors have been shown to improve outcomes in patients with metastatic cutaneous melanoma. Thyroid-related laboratory abnormalities are one of the most common abnor...

9541Background: Programmed death-ligand 1 (PD-L1) is expressed by various cells such as dendritic cells and tumor cells. In cancer, tumors evade the immune system by the interaction of PD-L1 with P...

The incidence of melanoma is increasing rapidly in the United States. Sentinel lymph node biopsy is an important diagnostic tool in the treatment and staging of melanoma. However, many patients with melanoma will have had lymph node surgery for previous melanoma or breast cancer. We set out to examine alterations in drainage patterns in patients with previous axillary dissection for breast cancer. We reviewed four patients with truncal and/or extremity melanomas and examined their lymphoscintigraphy and drainage patterns. Three patients with truncal melanoma mapped to cervical lymph nodes and a fourth patient with an arm melanoma mapped to her previously dissected axilla. Sentinel lymph node mapping is still an important adjunct in patients with melanoma despite previous axillary dissection.

IL-10 is an immunomodulatory cytokine that is frequently upregulated in various types of cancer. The biological role of IL-10 in cancer is quite complex; however, the presence of IL-10 in advanced metastases and the positive correlation between serum IL-10 levels and progression of disease indicates a critical role of IL-10 in the tumor microenvironment. IL-10 has been shown to directly affect the function of antigen-presenting cells by inhibiting the expression of MHC and costimulatory molecules, which in turn induces immune suppression or tolerance. Additionally, IL-10 downregulates the expression of Th1 cytokines and induces T-regulatory responses. Taken together, a combination of IL-10 antagonism and immunostimulatory treatments such as cancer vaccines, Toll-like receptor agonists, Th1 cytokines, and chemokines would be a logical approach to enhance an antitumor immune response.

We previously reported that substantial amounts of IL-10, an immunomodulatory cytokine, are produced by cell suspensions of fresh human metastatic melanoma tissues. Production diminished with continuous culturing of cells, which suggests a pivotal interactive role between melanoma cells and the tumor microenvironment. In this study, we found that the culture media obtained from LPS-stimulated peripheral blood mononuclear cells induced IL-10 production by metastatic melanoma cells. Of the multiple cytokines present in the conditioned culture media, IL-6 was identified as the inducer of IL-10 production. A neutralizing antibody against IL-6 completely blocked the conditioned medium-induced IL-10 production. Metastatic melanoma cells that constitutively produce low amount of IL-10 increased IL-10 production in response to recombinant human IL-6 in a dose-dependent fashion. The response to exogenously added IL-6 was less significant in melanoma cells that produced high amounts of IL-6, probably due to pre-existing autocrine stimulation of IL-10 by endogenous IL-6. On the other hand, metastatic melanoma cells that do not constitutively produce IL-10 protein did not respond to exogenous IL-6. In IL-6-responsive melanoma cells, IL-6 increased STAT3 phosphorylation and inhibition of STAT3 signaling using siRNA or inhibitors for JAKs diminished IL-6-induced IL-10 production. In addition, inhibition of MEK and PI3K, but not mTOR, interfered with IL-10 production. Taken together, the data suggest that blocking of these signals leading to IL-10 production is a potential strategy to enhance an anti-melanoma immune response in metastatic melanoma.

Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer. © 2011 Fox et al; licensee BioMed Central Ltd.

Purpose We conducted a phase I study to investigate the feasibility and safety of immunoembolization with granulocyte-macrophage colony-stimulating factor (GM-CSF; sargramostim) for malignant liver tumors, predominantly hepatic metastases from patients with primary uveal melanoma. Patients and Methods Thirty-nine patients with surgically unresectable malignant liver tumors, including 34 patients with primary uveal melanoma, were enrolled. Hepatic artery embolization accompanied an infusion of dose-escalated GM-CSF (25 to 2,000 μg) given every 4 weeks. Primary end points included dose-limiting toxicity and maximum tolerated dose (MTD). Patients who completed two cycles of treatments were monitored for hepatic antitumor response. Survival rates of patients were also monitored. Results MTD was not reached up to the dose level of 2,000 μg, and there were no treatment-related deaths. Thirty-one assessable patients with uveal melanoma demonstrated two complete responses, eight partial responses, and 10 occurrences of stable disease in their hepatic metastases. The median overall survival of intent-to-treat patients who had metastatic uveal melanoma was 14.4 months. Multivariate analyses indicated that female sex, high doses of GM-CSF (≥ 1,500 μg), and regression of hepatic metastases (complete and partial responses) were correlated to longer overall survival. Moreover, high doses of GM-CSF were associated with prolonged progression-free survival in extrahepatic sites. Conclusion Immunoembolization with GM-CSF is safe and feasible in patients with hepatic metastasis from primary uveal melanoma. Encouraging preliminary efficacy and safety results warrant additional clinical study in metastatic uveal melanoma.

We treated 64 patients with metastatic melanoma using a melanoma vaccine preceded by low-dose cyclophosphamide (CY), and monitored immunologic effects and antitumor activity. On day 0, the patients were given CY 300 mg/m2 intravenously. Three days later, they were injected intradermally with vaccine consisting of 10 to 25 x 10(6) autologous, enzymatically dissociated, cryopreserved, irradiated (25 Gy) tumor cells mixed with bacillus Calmette-Guérin (BCG). This treatment sequence was repeated every 28 days. Of 40 assessable patients with measurable metastases, five had responses, four complete and one partial, with a median duration of 10 months (7 to 84+ months). In six additional patients, we observed an antitumor response that seems to be peculiar to this vaccine therapy: the regression of metastatic lesions that appeared after the immunotherapy was begun. Delayed-type hypersensitivity (DTH) to autologous, mechanically dissociated melanoma cells that had not been exposed to extraneous antigens, such as enzymes or fetal calf serum, increased significantly following immunotherapy (day 0 v day 49, P less than .001; day 0 v day 161, P less than .001; day 0 v day 217, P = .021). Antitumor responses to the vaccine were strongly associated with DTH, as indicated by three observations: (1) eight of 10 patients who exhibited tumor regression had positive DTH, (2) in postsurgical adjuvant patients, there was a highly significant linear relationship (P less than .001) between the intensity of DTH to autologous melanoma cells and the time to recurrence of tumor, and (3) nine patients who developed DTH to the autologous melanoma cells in their original vaccine developed new metastases that failed to elicit DTH or elicited a much smaller response. In three cases, we were able to excise regressing tumors for histologic examination; such tumors were characterized by an intense infiltration of lymphocytes. This demonstration that an immune response to melanoma-associated antigens can be elicited in cancer-bearing patients provides some basis for optimism about the prospects for developing active immunotherapy that has practical therapeutic value.

Melanoma is a hypervascular tumor and angiogenesis plays a critical role in the development/progression of metastases. As various pathways are involved in tumor angiogenesis, a combination of agents with different antiangiogenesis activities is a reasonable approach. To determine the efficacy and toxicity of combination treatment with low-dose thalidomide and low-dose interferon (IFN) in patients with stage IV melanoma who failed prior treatment(s), fifteen patients with metastatic melanoma (nine cutaneous, six uveal) received oral thalidomide (200 mg daily) with subcutaneous interferon (IFN)-alpha2b (3 MIU, 3x/week). Stabilization or regression of metastases (as evidenced by computed tomographic measurement) was the primary endpoint of the study. Patients were evaluated monthly for toxicity and every 2 months for clinical response. At a median follow-up of 22.8 months (range, 12-32 months), one patient with metastatic cutaneous melanoma achieved partial response, three patients achieved stable disease (one uveal, two cutaneous), nine patients progressed, and two were not evaluable. The time to progression was 6 months for the patient with partial response, and 2, 5.5+ and 11 months for three patients with stable disease. The estimated median overall survival was 4.7 months (confidence interval, 2.2-9.9 months; range, 0.9-31.5 months), and median progression-free survival was 1.8 months (confidence interval, 1.5-3.0 months; range, 0.5-14 months). Grade 3 toxicities related to treatment included neutropenia (n=5), elevation of transaminases (n=2), and neuropathy (n=1). No treatment-related deaths were experienced. Thalidomide+IFN is a safe and tolerable palliative treatment for previously treated stage IV melanoma.

The gastrointestinal (GI) tract is a common site of melanoma metastases although reports of small bowel intussusception are relatively rare. Most patients with intussusception will be symptomatic and resection will provide significant palliation. In rare instances, patients will have solitary metastases to the small intestine, and resection can provide long-term palliation and chance for cure. We describe a case of a patient with a widely metastatic melanoma who presented with crampy abdominal pain and CT findings of small bowel metastases. Exploration revealed jejunojejunal intussusception and resection provided excellent palliation.

Meeting abstracts Ad5-GUCY2C-PADRE is a replication-deficient human type 5 recombinant adenovirus (Ad5) vaccine encoding guanylyl cyclase C (GUCY2C) fused to the PAn DR Epitope (PADRE). GUCY2C, a paracrine hormone receptor producing the second messenger cyclic GMP (cGMP), is selectively expressed

Background: Circulating tumor cells (CTCs) represent a surrogate biomarker for hematogenous metastases. The detection of CTCs has gained increasing interest for prediction of clinical outcome. However, it remains to be determined whether uveal melanoma cells circulating in a peripheral vein predict systemic recurrence and poorer overall prognosis. Uveal melanoma, the most common primary cancer of the eye in adults, is unique in that the uveal tract is devoid of lymphatics. Since systemic recurrence develops exclusively via hematogenous spread, patients with uveal melanomas present a special opportunity to explore the prognostic potential of CTCs. Although the lung is the first organ through which venous drainage from the affected eye passes and indeed the only organ through which all venous blood must pass, 80-95% of systemic metastases are found first in the liver without development of lung metastases. To address these issues, we investigated the numbers of CTCs in paired arterial (femoral) and venous (antecubital) blood specimens obtained from uveal melanoma patients with hepatic metastases. Methods: CTCs in blood specimens were measured in 17 uveal melanoma patients with multiple hepatic metastases, including 10 patients with liver-only metastases and 7 patients with hepatic and extra-hepatic metastases. Peripheral arterial and venous blood specimens were collected at the same time prior to liver directed treatment. CTCs were analyzed using CellTracks Circulating melanoma Cell Kit by CellSearch System. The clinical information and sources of blood specimens were blinded when CTCs were analyzed. Result: CTCs were detectable from all 17 arterial blood specimens (100%) (median 5, range 1 to 168). In contrast, much smaller numbers of CTCs were detectable in 52.9% (9/17) of venous blood specimens (median 1, range 0 to 8) from the same patients. In terms of degree of tumor burden, patients who have hepatic as well as extra-hepatic metastasis showed higher numbers of arterial CTCs (median 12, range 5 to 168), compared to patients who have liver-only metastasis (median 4, range 1 to 11). More importantly, there is no significant correlation between numbers of arterial CTCs and the degree of tumor volume in the liver in patients who have liver-only metastases. Conclusions: Using this technology, the detection of uveal melanoma cells in peripheral blood is feasible. Peripheral capillary beds effectively filter CTCs from venous blood; thus venous blood might not be the best source for measurement of CTCs in patients with metastatic uveal melanoma. The paucity of clinically evident non-hepatic metastases despite the effective filtration by peripheral capillary beds remains unexplained and may be a demonstration of the “seed and soil” hypothesis. CTCs are a non-invasive source of uveal melanoma cells for evaluating tumor biology. Further investigation is warranted. Citation Format: Mizue Terai, Zhaomei Mu, David Eschelman, Carin Gonsalves, Ken Kageyama, Michael J. Mastrangelo, Marlana Orloff, Ryan Weight, Massimo Cristofanilli, Takami Sato. Detection of circulating melanoma cells in paired arterial and venous specimens from uveal melanoma patients with hepatic metastatic. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 384. doi:10.1158/1538-7445.AM2015-384

e20015 Background: Despite promising results in metastatic cutaneous melanoma, ipilimumab has shown a rather disappointing response rate (5%) in metastatic uveal melanoma (MUM). To improve its effi...