; for the Veterans Affairs Keratinocyte Carcinoma Chemoprevention Trial (VAKCC) Group IMPORTANCE Keratinocyte carcinoma (ie, cutaneous basal and squamous cell carcinoma) is the most common cancer in the United States. OBJECTIVE To determine whether topical fluorouracil could prevent surgically treated keratinocyte carcinoma. DESIGN, SETTING, AND PARTICIPANTS The Veterans Affairs Keratinocyte Carcinoma Chemoprevention Trial was a randomized, double-blind, placebo-controlled trial of topical fluorouracil for chemoprevention of keratinocyte carcinoma. Participants were recruited from May 2009 to September 2011 from 12 Veterans Affairs medical centers and followed until June 30, 2013. Participants were veterans (n = 932) with a history of at least 2 keratinocyte carcinomas in the past 5 years; almost all were white males and the median age was 70 years. INTERVENTIONS Application of fluorouracil, 5%, (n = 468) or vehicle control cream (n = 464) to the face and ears twice daily for 2 to 4 weeks upon randomization. MAIN OUTCOMES AND MEASURES Surgically treated keratinocyte, basal cell, and squamous cell carcinoma risk on the face and ears in the first year after enrollment; and time to first surgically treated keratinocyte, basal cell, and squamous cell carcinoma. The a priori hypothesis was that fluorouracil would be effective in preventing these cancers. RESULTS Of 932 participants (916 men [98%]; 926 white [99%]; median age, 70 years), 299 developed a basal cell carcinoma end point (95 in year 1) and 108 developed a squamous cell carcinoma end point (25 in year 1) over 4 years (median follow-up, 2.8 years). Over the entire study, there was no difference between treatment groups in time to first keratinocyte, basal cell, or squamous cell carcinoma. During the first year, however, 5 participants (1%) in the fluorouracil group developed a squamous cell carcinoma vs 20 (4%) in the control group, a 75% (95% CI, 35%-91%) risk reduction (P = .002). The 11% reduction in basal cell carcinoma risk during year 1 (45 [10%] in the fluorouracil group vs 50 [11%] in the control group) was not statistically significant (95% CI, 39% reduction to 31% increase), nor was there a significant effect on keratinocyte carcinoma risk. However, a reduction in keratinocyte carcinomas treated with Mohs surgery was observed. CONCLUSIONS AND RELEVANCE A conventional course of fluorouracil to the face and ears substantially reduces surgery for squamous cell carcinoma for 1 year without significantly affecting the corresponding risk for basal cell carcinoma. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00847912

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Inactivation of the tumor suppressor neurofibromin 1 (NF1) presents a newly characterized melanoma subtype, for which currently no targeted therapies are clinically available. Pre-clinical studies suggest that ERK inhibitors are likely to provide benefit, albeit with limited efficacy as single agent; therefore, there is a need for rationally designed combination therapies. Here, we evaluate the combination of the ERK inhibitor SCH772984 and the biguanide phenformin. Combination of both compounds showed potent synergy in cell viability assays and cooperatively induced apoptosis. Treatment with both drugs was required to fully suppress mTOR signaling, a known effector of NF1 loss. Mechanistically, SCH772984 increased the oxygen consumption rate (OCR), indicating that these cells relied more on oxidative phosphorylation upon treatment. Consistently, SCH772984 increased expression of the mitochondrial transcriptional co-activator PGC1α. In contrast, co-treatment with phenformin, an inhibitor of complex I of the respiratory chain, decreased the OCR. SCH772984 also promoted the expansion of the H3K4 demethylase KDM5B (also known as JARID1B)-positive subpopulation of melanoma cells, which are slow-cycling and treatment-resistant. Importantly, phenformin suppressed this KDM5B-positive population, which reduced the emergence of SCH772984-resistant clones in long-term cultures. Our results warrant the clinical investigation of this combination therapy in patients with NF1 mutant melanoma.

Background Retention in HIV care has important implications. Few studies examining retention include comprehensive and heterogeneous populations, and few examine factors associated with returning to care after gaps in care. We identified reasons for gaps in care and factors associated with returning to care. Methods We extracted medical record and state-wide reporting data from 1865 patients with one HIV visit to a New York facility in 2008 and subsequent 6-month gap in care. Using mixed effect logistic regression, we examined sociodemographic, clinical, and facility characteristics associated with returning to care. Results Most patients were men (63.2%), black (51.4%), had Medicaid (53.9%). Many had CD4 counts >500 cells/mm3 (34.4%) and undetectable viral loads (45.0%). Most (55.9%) had unknown reasons for gaps in care; of those with known reasons, reasons varied considerably. After a gap, 54.6% returned to care. Patients who did (vs. did not) return to care were more likely to have stable housing, longer duration of HIV, high CD4 count, suppressed VL, antiretroviral medications, and had facilities attempt to contact them. Those who returned to care were less likely to be uninsured and have mental health problems or substance use histories. Conclusion Over half of our sample of patients in New York with one HIV visit and subsequent 6-month gap in care returned to care; no major reasons for gaps emerged. Nevertheless, our findings emphasize that stabilizing patients’ psychosocial factors and contacting patients after a gap in care are key strategies to retain HIV-positive patients in care in New York.