Faculty Bibliography

Surgery with or without radiation has always been the mainstay of treatment for patients with non-melanoma skin cancers, including basal cell carcinoma, squamous cell carcinoma, and Merkel cell carcinoma. Until recently, there were no effective systemic therapies for patients with advanced disease. This review will focus on the landmark clinical trials that led to Food and Drug Administration (FDA) approval of Vismodegib for advanced basal cell carcinoma (ERIVANCE BCC) and pembrolizumab for advanced Merkel cell carcinoma (KEYNOTE-017). These trials have not only changed the landscape for patients with metastatic disease but also notably for patients with locally advanced disease that is either unresectable or resectable with high morbidity. Additional mention is made for the clinical trial that led to FDA approval of cemiplimab for advanced cutaneous squamous cell carcinoma (EMPOWER-CSCC-1), which is already changing practice patterns, but for which longer-term data are still needed.

INTRODUCTION: Cholecystectomy remains one of the most common surgical procedures in the United States with a rate of greater than 750,000 annually. Of these cases, approximately 1-2% are complicated by a bile leak. Although the rate of bile leaks is relatively low, the morbidity and mortality can be very high with patients rapidly deteriorating after presentation usually due to sepsis. Endoscopic retrograde cholangiopancreatography (ERCP) can detect greater than 95% of leaks and provide therapeutic intervention aimed at eliminating the pressure gradient across the Sphincter of Oddi which promotes the flow of bile into the duodenum to heal the injured portion of the biliary tree. This case aims to show the significant clinical benefit of endoscopic management of bile leaks, although with the novel use of direct cholangioscopy. CASE DESCRIPTION/METHODS: This is a case of a 45-year-old woman with no significant past medical history who presented to an outside hospital with cholecystitis and underwent open cholecystectomy. Surgery was complicated by duodenal injury which was primary repaired and a Jackson- Pratt (JP) drain was left in place. Bilious fluid returned from the JP drain on post-operative day two and she underwent an ERCP which confirmed a bile leak and a sphincterotomy was performed and a stent was placed. She was referred to our center for stent removal four months later and at the time her cholangiogram was negative for leak so a stent was not replaced (Figure 1).Within a week of the procedure she had bilious return from the JP drain and a tube study preformed via the JP drain was read as a ?normal T-tube? cholangiogram (Figure 2). As there was suspected erosion of the JP drain into the biliary tree and high concern for creating a biliary injury when removing the drain, direct cholangioscopy was used for safe removal and identification of the leak (Figure 3). The biliary injury was sealed with a fully covered self-expanding metal stent with excellent results and no further evidence of ongoing leak. DISCUSSION: ERCP remains the preferred treatment option for bile leaks and prevents patients from having to undergo corrective operation.4 In this case there was high concern for creating a biliary injury when removing the drain, thereby direct cholangioscopy was used for safe removal and identification of the leak. To our knowledge this is the first report of JP drain erosion into the CBD with use of direct cholangioscopy and ERCP as endoscopic management for removal and treatment of biliary injury. (Figure Presented)

Background: Efforts to identify targeted therapies that can improve treatment outcome in metastatic ALM have been unsuccessful. In a previous genomic screening, we identified copy number amplification of the histone methyltransferase EZH2 in 47% of ALM cases, a higher frequency than previously reported in cutaneous melanomas (CM) (5%). Here, we tested the hypothesis that increased EZH2 expression contributes to ALM progression and may confer selective sensitivity to EZH2 inhibition. Methods: EZH2 expression was examined by immunohistochemistry (IHC) in 51 primary (21 stage I, 13 Stage II and 17 Stage III) and 23 metastatic (11 in transit, 8 nodal and 4 visceral) ALM cases with extensive clinicopathological data and protocol-driven follow up. Colony formation and cell proliferation was assessed following treatment of ALM and CM cell lines with three EZH2 inhibitors, including GSK126, currently in clinical trials. The effect of GSK126 on H3K27me3 and downstream EZH2 targets was analyzed by western blotting. Results: EZH2 is commonly overexpressed in both primary (30/51; 65%) and metastatic (20/23; 87%) ALM cases, with a significant increase in mean IHC score between primary and metastatic tumors (1.9 vs. 2.7, respectively, p = 0.047). EZH2 expression increased in 6/10 metastatic ALM tumors compared to their matched primary tumors. ALM tumors with EZH2 gene amplification showed increased EZH2 protein expression; however more cases showed overexpression with no amplification suggesting a potential epigenetic component of EZH2 regulation. GSK126 significantly suppressed ALM colony formation at lower doses compared to CM (1 muM vs. 5 muM, respectively). EZH2 inhibition also increased expression of the downstream tumor suppressor E-cadherin in ALM but not in CM cell lines. Finally, ALM cell lines had significantly lower basal H3K27me3 levels than CM cell lines, suggesting an additional, histone methyltransferase-independent function of EZH2 in ALM. Conclusions: Our data demonstrate thatEZH2 upregulation is common in ALM, and suggest that it may play a role in ALM's metastatic progression that requires further investigation. Selective sensitivity of ALM cell lines to EZH2 inhibitors supports the therapeutic potential of EZH2-targeted therapy in ALM

PURPOSE: Pathologic stage II melanoma patients have variable outcomes when divided by substage. We hypothesized that an understanding of the patterns of initial relapse by substage will better inform follow-up guidelines. METHODS: We performed a retrospective review of 738 adult patients with pathologic stage II cutaneous melanoma treated at Memorial Sloan Kettering Cancer Center between 1993 and 2013. Clinical records were reviewed to determine time, location, and method of detection of initial relapse. RESULTS: At a median follow-up of 52 months, 219 patients relapsed. Relapses were detected more frequently in higher substages. Initial relapses were most commonly local/in-transit for IIA and IIB and systemic for IIC. Lung and brain were the most frequent sites of systemic relapse. Patient-detection was the most common method of relapse detection (59%) in all substages. The 5-year cumulative incidence for patient-detected relapse was 13.6% for IIA, 18.9% for IIB, and 23.3% for IIC and for image-detected relapse was 3.4, 7.9, and 16.6%, respectively. The 5-year cumulative incidence for physician-detected relapse was less than 10% across all substages and leveled off at 3 years for stage IIA and IIB and 2 years for stage IIC. CONCLUSIONS: Relapses were most frequently patient-detected in all stage II substages, highlighting the importance of patient education and self-examination. The highest yield for routine imaging is in stage IIC patients during the first 4 years. Physician examination is unlikely to detect relapses beyond 3 years for stage IIA and IIB and beyond 2 years for stage IIC patients.

Most extremity soft tissue sarcomas present as a painless mass. Work-up should generally involve cross-sectional imaging with MRI and a core biopsy for pathologic diagnosis. Limb-sparing surgery is the standard of care, and may be supplemented with radiation for histologic subtypes at higher risk for local recurrence and chemotherapy for those at higher risk for distant metastases. This article reviews the work-up and surgical approach to extremity soft tissue sarcomas, and the role for radiation and chemotherapy, with particular attention given to the distinguishing characteristics of some of the most common subtypes.

Myxofibrosarcoma is a common mesenchymal malignancy with complex genomics and heterogeneous clinical outcomes. Through gene-expression profiling of 64 primary high-grade myxofibrosarcomas, we defined an expression signature associated with clinical outcome. The gene most significantly associated with disease-specific death and distant metastasis was ITGA10 (integrin-alpha10). Functional studies revealed that myxofibrosarcoma cells strongly depended on integrin-alpha10, whereas normal mesenchymal cells did not. Integrin-alpha10 transmitted its tumor-specific signal via TRIO and RICTOR, two oncoproteins that are frequently co-overexpressed through gene amplification on chromosome 5p. TRIO and RICTOR activated RAC/PAK and AKT/mTOR to promote sarcoma cell survival. Inhibition of these proteins with EHop-016 (RAC inhibitor) and INK128 (mTOR inhibitor) had antitumor effects in tumor-derived cell lines and mouse xenografts, and combining the drugs enhanced the effects. Our results demonstrate the importance of integrin-alpha10/TRIO/RICTOR signaling for driving myxofibrosarcoma progression and provide the basis for promising targeted treatment strategies for patients with high-risk disease. SIGNIFICANCE: Identifying the molecular pathogenesis for myxofibrosarcoma progression has proven challenging given the highly complex genomic alterations in this tumor type. We found that integrin-alpha10 promotes tumor cell survival through activation of TRIO-RAC-RICTOR-mTOR signaling, and that inhibitors of RAC and mTOR have antitumor effects in vivo, thus identifying a potential treatment strategy for patients with high-risk myxofibrosarcoma. Cancer Discov; 6(10); 1148-65. (c)2016 AACR.This article is highlighted in the In This Issue feature, p. 1069.