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Immune-Related Tumor Response Dynamics in Melanoma Patients Treated with Pembrolizumab: Identifying Markers for Clinical Outcome and Treatment Decisions

Tuesday, August 15, 2017 -- Purpose: Characterize tumor burden dynamics during PD-1 inhibitor therapy and investigate the association with overall survival (OS) in advanced melanoma. Experimental Design: The study included 107 advanced melanoma patients treated with pembrolizumab. Tumor burden dynamics were assessed on serial CT scans using irRECIST and were studied for the association with OS. Results: Among 107 patients, 96 patients had measurable tumor burden and 11 had nontarget lesions alone at baseline. In the 96 patients, maximal tumor shrinkage ranged from –100% to 567% (median, –18.5%). Overall response rate was 44% (42/96; 5 immune-related complete responses, 37 immune-related partial responses). Tumor burden remained <20% increase from baseline throughout therapy in 57 patients (55%). Using a 3-month landmark analysis, patients with <20% tumor

Feasibility of Ultra-High-Throughput Functional Screening of Melanoma Biopsies for Discovery of Novel Cancer Drug Combinations

Tuesday, August 15, 2017 -- Purpose: Successful development of targeted therapy combinations for cancer patients depends on first discovering such combinations in predictive preclinical models. Stable cell lines and mouse xenograft models can have genetic and phenotypic drift and may take too long to generate to be useful as a personalized medicine tool. Experimental Design: To overcome these limitations, we have used a platform of ultra-high-throughput functional screening of primary biopsies preserving both cancer and stroma cell populations from melanoma patients to nominate such novel combinations from a library of thousands of drug combinations in a patient-specific manner within days of biopsy. In parallel, patient-derived xenograft (PDX) mouse models were created and novel combinations tested for their ability to shrink matched PDXs. Results: The

Epigenetic Regulation of KPC1 Ubiquitin Ligase Affects the NF-{kappa}B Pathway in Melanoma

Tuesday, August 15, 2017 -- Purpose: Abnormal activation of the NF-B pathway induces a more aggressive phenotype of cutaneous melanoma. Understanding the mechanisms involved in melanoma NF-B activation may identify novel targets for this pathway. KPC1, an E3 ubiquitin ligase, is a regulator of the NF-B pathway. The objective of this study was to investigate the mechanisms regulating KPC1 expression and its clinical impact in melanoma. Experimental Design: The clinical impact of KPC1 expression and its epigenetic regulation were assessed in large cohorts of clinically well-annotated melanoma tissues (tissue microarrays; n = 137, JWCI cohort; n = 40) and The Cancer Genome Atlas database (TCGA cohort, n = 370). Using melanoma cell lines, we investigated the functional interactions between KPC1 and NF-B, and the

PD-L1 Expression in Melanoma: A Quantitative Immunohistochemical Antibody Comparison

Tuesday, August 15, 2017 -- Purpose: PD-L1 expression in the pretreatment tumor microenvironment enriches for response to anti-PD-1/PD-L1 therapies. The purpose of this study was to quantitatively compare the performance of five monoclonal anti-PD-L1 antibodies used in recent landmark publications. Experimental Design: PD-L1 IHC was performed on 34 formalin-fixed paraffin-embedded archival melanoma samples using the 5H1, SP142, 28-8, 22C3, and SP263 clones. The percentage of total cells (including melanocytes and immune cells) demonstrating cell surface PD-L1 staining, as well as intensity measurements/H-scores, were assessed for each melanoma specimen using a computer-assisted platform. Staining properties were compared between antibodies. Results: Strong correlations were observed between the percentage of PD-L1(+) cells across all clones studied (R2 = 0.81–0.96). When present, discordant results were attributable to geographic

DNA-based analysis identifies risk factor for metastasis of uveal melanoma

Sunday, August 13, 2017 -- Carol. L. Shields, MD, highlighted the results of collaborative efforts among four Philadelphia institutions: Wills Eye Hospital, Thomas Jefferson Hospital, the Genetics Department of the University of Pennsylvania, and the Wistar Instituate. The findings were published in Ophthalmology (Shields et al. 2017; published online May 7, 2017).

Age of Patients With Thin Melanomas a Consideration in SLNB Recommendations

Wednesday, August 16, 2017 -- Age may be an important factor in estimating lymph node positivity in thin melanoma, according to the results of a recent study.

Changing Treatment Paradigms for Brain Metastases From Melanoma—Part 1: Diagnosis, Prognosis, Symptom Control, and Local Treatment

Tuesday, August 15, 2017 -- Much work has been done recently to try to determine the optimal therapies for brain metastases in melanoma patients, the most effective ways to combine them, and ideal radiation dose and fractions.

Pembrolizumab Prolongs Overall Survival Compared With Ipilimumab in Melanoma

Thursday, August 17, 2017 -- After the second interim analysis, an external data monitoring committee recommended that pembrolizumab be made available to patients receiving ipilimumab whose disease had progressed despite treatment.

[Articles] Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006)

Wednesday, August 16, 2017 -- Substantiating the results of the interim analyses of KEYNOTE-006, pembrolizumab continued to provide superior overall survival versus ipilimumab, with no difference between pembrolizumab dosing schedules. These conclusions further support the use of pembrolizumab as a standard of care for advanced melanoma.

Cytogenetic mutations strongly correlate with metastatic uveal melanoma

Thursday, August 17, 2017 -- During the ASRS 2017 annual meeting, Carol Shields, MD, discussed findings that show cytogenetic abnormalities in chromosomes 3, 6 and 8 are strong predictors of patient prognosis in uveal melanoma.

Older patients at higher risk for class 2 uveal melanoma tumors

Wednesday, August 16, 2017 -- BOSTON — Class 2 uveal melanoma tumors are associated with older age, tumor size, ciliary body involvement and exudative retinal detachment, according to a poster presented at the American Society of Retina Specialists meeting.Duncan Berry, MD, and colleagues presented the multi-institutional study, which consisted of 379 patients with posterior uveal melanoma treated with I-125 plaque brachytherapy. Patients had concurrent tumor biopsies submitted for gene expression profile, which classified 263 patients as having class 1 tumors and 113 as having class 2 tumors.

Cytogenetic abnormalities correlated with clinical features of uveal melanoma

Monday, August 14, 2017 -- BOSTON — It takes teamwork to manage uveal melanoma, Carol L. Shields, MD, told colleagues at the American Society of Retina Specialists meeting,Citing 8-year experience with personalized prognosis of uveal melanoma based on genetic profile in 1,059 patients, recently published in Ophthalmology, Shields said she and coworkers found the strongest predictor of patient prognosis depends on chromosomal status, particularly chromosomes 3, 6 and 8.

Molecular genomics guides targeted uveal melanoma therapy

Tuesday, August 15, 2017 -- BOSTON — Uveal melanoma management is undergoing significant changes that enable improved survival for patients, improved globe retention and excellent visual acuity preservation, a speaker said here.Such management is possible when targeted genomics are evaluated and direct surgical laser ablation that avoids radiotherapy is used, according to Timothy G. Murray, MD, MBA, who spoke on the topic at the American Society of Retina Specialists meeting.