TH-MYCN tumors, but not tumor-derived cell lines, are adrenergic lineage, GD2+, and responsive to anti-GD2 antibody therapy.

Neuroblastoma is a commonly lethal solid tumor of childhood and intensive chemoradiotherapy treatment cures ~50% of children with high-risk disease. The addition of immunotherapy using dinutuximab, a monoclonal antibody directed against the GD2 disialoganglioside expressed on neuroblasts, improves survival when incorporated into front-line therapy and shows robust activity in regressing relapsed disease when combined with chemotherapy. Still, many children succumb to neuroblastoma progression despite receiving dinutuximab-based immunotherapy, and efforts to counteract the immune suppressive signals responsible are warranted. Animal models of human cancers provide useful platforms to study immunotherapies. TH-MYCN transgenic mice are immunocompetent and develop neuroblastomas at autochthonous sites due to enforced MYCN expression in developing neural crest tissues. However, GD2-directed immunotherapy in this model has been underutilized due to the prevailing notion that TH-MYCN neuroblasts express insufficient GD2 to be targeted. We demonstrate that neuroblasts in TH-MYCN-driven tumors express GD2 at levels comparable to human neuroblastomas but rapidly lose GD2 expression when explanted ex vivo to establish tumor cell lines. This occurs in association with a transition from an adrenergic to mesenchymal differentiation state. Importantly, not only is GD2 expression retained on tumors in situ, treatment with a murine anti-GD2 antibody, 14G2a, markedly extends survival in such mice, including durable complete responses. Tumors in 14G2a-treated mice have fewer macrophage and myeloid-derived suppressor cells in their tumor microenvironment. Our findings support the utility of this model to inform immunotherapy approaches for neuroblastoma and potential opportunities to investigate drivers of adrenergic to mesenchymal fate decisions.

Economic impact of preventing brain metastases with alectinib in ALK-positive non-small cell lung cancer.

OBJECTIVES: Despite improved progression-free survival, most patients treated with the first generation ALK inhibitor crizotinib ultimately experience central nervous system (CNS) progression. Brain metastases (BM) are associated with high clinical burden in patients with advanced anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC). In this study we estimate the real-world economic burden of BM in newly diagnosed ALK+ NSCLC patients and investigate whether alectinib, a second generation ALK inhibitor that delays CNS progression, may help reduce healthcare costs in patients with ALK+ NSCLC. MATERIALS AND METHODS: Cost of BM was measured in ALK+ NSCLC patients identified from a stacked PharMetrics Plus and MarketScan claims database from January 2008 to March 2016 and December 2015, respectively. Per patient per month (PPPM) cost of BM was calculated as the difference in baseline-adjusted total costs in patients with and without BM over a variable follow-up period of up to 24 months. Cumulative incidence of new BM was derived from 88 alectinib-treated and 93 crizotinib-treated patients without baseline BM in a randomized phase III clinical trial, ALEX (NCT02075840). Costs of BM per patient were then calculated by applying the PPPM BM cost to the number of incident BM patients in each treatment cohort. RESULTS: 207 patients with no BM and 198 with BM were selected from the claims database. Total cost of BM was estimated at $6,029 PPPM. 24-month cumulative incidence rates of BM from the clinical trial were 7.2% and 45.3% for alectinib and crizotinib, respectively. Over follow-up, alectinib was estimated to reduce BM-related costs by $41,434 per patient compared to crizotinib. CONCLUSION: BM is associated with substantial economic burden. Alectinib was estimated to reduce BM-related costs by preventing or delaying the occurrence of BM compared to crizotinib.

Experiences and treatment patterns of hypogonadal men in a U.S. health system.

OBJECTIVE: To examine self-reported experiences with hypogonadism (HG) and patterns of testosterone replacement therapy (TRT) in men seeking care in a U.S. healthcare system. METHODS: Men ≥ 18 years old with HG were identified from the 2008-2010 Reliant electronic medical records database. Surveys, including validated instruments for measuring symptoms of HG, were collected and evaluated for demographic and behavioural data. RESULTS: Surveys were mailed to 133 men with HG in 2012. Of the 107 surveys returned, 95 were included in the final analysis. Most respondents were Caucasian (90.5%). Men reported developing symptoms of HG, as well as being diagnosed, at a median age of 50 years. The most common symptoms reported as reasons for seeking treatment were erectile dysfunction (66.3%), fatigue (59.0%) and decreased sex drive (57.9%). These continued to be the most bothersome symptoms at the time of the survey regardless of whether the patient received treatment, although men who were currently taking TRT reported less severe symptoms. Approximately 88% of men reported taking TRT at some point, with 61.9% on therapy at the time of the survey. CONCLUSIONS: This study examined men's experiences with HG, including symptoms, quality of life, and treatments. Some symptoms continued despite treatment, and therapy was discontinued at a high rate, which men generally attributed to cost and perceptions of efficacy. In light of this lack of adherence, patients may benefit from appropriate expectation setting regarding reasonable timelines for symptom improvement, the strengths and challenges of various TRT formulations, the importance of adherence and the benefits and risks of TRT.