Parotidectomy in patients with head and neck cutaneous melanoma with cervical lymph node involvement

Background: Parotidectomy in melanoma of the coronal scalp and face with clinically involved cervical lymph node metastasis is based on predicted cervical lymphatic drainage described by O'Brien. Methods: In total, 40 parotidectomies with en bloc therapeutic neck dissection were retrospectively analyzed. Results: Lymphatic spread of melanoma to the parotid lymph nodes was observed in 10 of 40 specimens (25%). Eight of the 10 parotid-positive patients developed a recurrence vs 17 of the 30 parotid-negative patients (P = 0.28). There were no differences in overall survival, melanoma-specific survival, and disease-free survival between the parotid-positive and parotid-negative patients. Conclusion: Although in this series no survival differences were found, parotidectomy still merits a sustained role in therapeutic neck dissection procedures to improve regional control and to prevent facial nerve damage after surgery for a second relapse from occult metastases in the parotid

External validation of the American Joint Committee on Cancer 8th edition melanoma staging system: who needs adjuvant treatment?

Now effective adjuvant therapy has arrived in melanoma, accurate staging and patient selection to optimize its risk/ benefit ratio is crucial. The American Joint Committee on Cancer staging system is the most widely used and validated melanoma staging system, which recently released its 8th edition. We aimed to externally validate the prognostic and discriminatory ability for survival of the 8th edition compared to the 7th edition and evaluate prognostic factors. Prospective database of stage III melanoma (2000-2016). Prognostic factors for melanomaspecific survival and distant metastasis-free survival were analyzed. Survival differentiation of the 7th and 8th edition was assessed with log-rank tests and Cox proportional hazards models. Discriminatory ability was compared using the receiver operating characteristic and Akaike's Information Criterion. Six hundred forty patients were included (median follow-up 59 months). Median melanoma-specific survival was 138 months, distant metastasis-free survival 96 months. Age, Breslow thickness, ulceration of the primary tumor and number of positive lymph nodes (N) were independent prognostic parameters for distant metastasis-free survival and melanoma-specific survival. The 8th edition performed slightly better than the 7th edition in terms of survival discrimination but showed slightly worse distant metastasis-free survival and melanoma-specific survival differentiation between stage IIIA and IIIB. Sentinel node (SN) metastasis size cutoff of 1 mm differentiated survival in both 7th and 8th edition stage IIIA, showing excellent distant metastasis-free survival and melanoma-specific survival for patients with a SN metastasis size <1 mm. The 8th edition performed at least comparably, if not better than the 7th in terms of survival discrimination. However, survival in both 7th and 8th edition stage IIIA melanoma remains heterogeneous. EORTC SN tumor burden criteria can further stratify survival and help patient selection for adjuvant therapy

Reversal of pre-existing NGFR-driven tumor and immune therapy resistance

Melanomas can switch to a dedifferentiated cell state upon exposure to cytotoxic T cells. However, it is unclear whether such tumor cells pre-exist in patients and whether they can be resensitized to immunotherapy. Here, we chronically expose (patient-derived) melanoma cell lines to differentiation antigen-specific cytotoxic T cells and observe strong enrichment of a pre-existing NGFRhi population. These fractions are refractory also to T cells recognizing non-differentiation antigens, as well as to BRAF + MEK inhibitors. NGFRhi cells induce the neurotrophic factor BDNF, which contributes to T cell resistance, as does NGFR. In melanoma patients, a tumor-intrinsic NGFR signature predicts anti-PD-1 therapy resistance, and NGFRhi tumor fractions are associated with immune exclusion. Lastly, pharmacologic NGFR inhibition restores tumor sensitivity to T cell attack in vitro and in melanoma xenografts. These findings demonstrate the existence of a stable and pre-existing NGFRhi multitherapy-refractory melanoma subpopulation, which ought to be eliminated to revert intrinsic resistance to immunotherapeutic intervention

Rationale, design, and baseline characteristics in Evaluation of LIXisenatide in Acute Coronary Syndrome, a long-term cardiovascular end point trial of lixisenatide versus placebo

BACKGROUND: Cardiovascular (CV) disease is the leading cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). Furthermore, patients with T2DM and acute coronary syndrome (ACS) have a particularly high risk of CV events. The glucagon-like peptide 1 receptor agonist, lixisenatide, improves glycemia, but its effects on CV events have not been thoroughly evaluated. METHODS: ELIXA (www.clinicaltrials.gov no. NCT01147250) is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study of lixisenatide in patients with T2DM and a recent ACS event. The primary aim is to evaluate the effects of lixisenatide on CV morbidity and mortality in a population at high CV risk. The primary efficacy end point is a composite of time to CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. Data are systematically collected for safety outcomes, including hypoglycemia, pancreatitis, and malignancy. RESULTS: Enrollment began in July 2010 and ended in August 2013; 6,068 patients from 49 countries were randomized. Of these, 69% are men and 75% are white; at baseline, the mean ± SD age was 60.3 ± 9.7 years, body mass index was 30.2 ± 5.7 kg/m(2), and duration of T2DM was 9.3 ± 8.2 years. The qualifying ACS was a myocardial infarction in 83% and unstable angina in 17%. The study will continue until the positive adjudication of the protocol-specified number of primary CV events. CONCLUSION: ELIXA will be the first trial to report the safety and efficacy of a glucagon-like peptide 1 receptor agonist in people with T2DM and high CV event risk