Reovirus, a replication competent RNA virus, has preclinical activity against melanoma lines and xenografts. We conducted a phase II trial of reovirus in metastatic melanoma patients. Patients received 3 × 10(10) TCID50 on days 1-5 of each 28 day cycle, administered intravenously. Twenty-one eligible patients were enrolled. Treatment was well tolerated without any dose reductions having to be implemented. Post-treatment biopsy samples were obtained in 15 patients, 13/15 contained adequate tumor for correlative analysis. In two patients, productive reoviral replication (viral antigen coexpression with tubulin) was demonstrated, despite increase in neutralizing antibody titers. There were no objective responses although 75-90% tumor necrosis, consistent with treatment effect, was observed in one patient who had metastatic lesions surgically removed. Median time to progression and survival were 45 days (range 13-96 days) and 165 days (range 15 days-15.8 months) respectively. In conclusion, reovirus treatment was well tolerated in metastatic melanoma patients; viral replication was demonstrated in biopsy samples. Based on preclinical data showing synergy with taxane and platinum compounds, a phase II combination trial in metastatic melanoma patients is ongoing.
PD-1/PD-L1 pathway proteins are highly expressed in ATC tumor samples and appear to represent predictive markers of PFS and OS in multimodality-treated ATC patients.
Screening for the Muir-Torre variant of Lynch Syndrome (LS) using Mismatch Repair (MMR) gene immunohistochemistry (IHC) on sebaceous neoplasms (SNs) is technically feasible. To date, research into the clinical utility of MMR IHC for this indication is limited. We conducted a retrospective chart review of 90 patients with MMR IHC completed on at least one SN from January 2005 to May 2010. SNs included were adenomas, epitheliomas, carcinomas and basal and squamous cell carcinomas with sebaceous differentiation. Of the 90 patients, 13 (14 %) had genetically confirmed or fulfilled clinical criteria for a diagnosis of MTS and 51 patients (57 %) presented with an abnormal MMR IHC result (loss of one or more MMR proteins) on at least one SN. Abnormal IHC had a sensitivity of 85 %, specificity of 48 %, positive predictive value (PPV) of 22 % and negative predictive value (NPV) of 95 % when evaluating for MTS. When personal or family history of colorectal cancer (≥2 family members with a history of colorectal cancer) was taken into consideration, ignoring IHC results, sensitivity was 92 %, specificity was 99 %, PPV was 92 % and NPV was 99 %. MMR IHC on SNs when used to screen for MTS has poor diagnostic utility. We recommend that MMR IHC not be performed routinely on SNs when the patient does not have either personal or family history of colorectal cancer.
Mismatch-repair (MMR) immunohistochemistry is used to detect tumor MMR deficiency associated with high-level microsatellite instability (MSI). Rare tumors show heterogenous loss of mutS homolog 6 (MSH6) with immunohistochemistry, defined by areas of retained staining and separate areas of complete loss of staining. To investigate the clinical interpretation of this phenomenon, we identified 22 cases of heterogenous MSH6 loss interpreted at Mayo Clinic from January 2001 through December 2012 and reviewed histologic features, MSH6 and other MMR immunohistochemistry, and accompanying MSI testing results (n=20). Heterogenous MSH6 loss was seen in colorectal carcinoma (n=18), endometrial carcinoma (n=3), and sebaceous neoplasm (n=1). In the 18 colorectal carcinoma cases, it accompanied complete loss of mutL homolog 1 (MLH1) or PMS2, or both. Heterogenous MSH6 loss was characterized by MSI and MSH6 C8 tract instability in treatment-naive cases and showed mucinous or signet-ring zones in one quarter of cases. Two cases status post neoadjuvant chemoradiation showed heterogenous MSH6 loss but were microsatellite and C8 tract stable. C8 tracts were unstable in 2 of 4 MSH6-associated Lynch syndrome (LS) tumors, but all 4 showed complete MSH6 loss on immunohistochemistry. Further, 12 such MSH6-associated LS cases showed complete MSH6 loss. In conclusion, heterogenous MSH6 loss is uncommon, usually caused by instability in MSH6 exon 5 polycytosine tract, and not associated with germline MSH6 mutation. Although heterogenous MSH6 loss provides evidence against germline MSH6 mutation, patients whose tumors exhibit this immunolabeling pattern may have LS due to a defect in a different MMR gene.
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