Faculty Bibliography

AIMS: Selective vascular endothelial growth factor receptor (VEGFR) inhibitors have the potential for greater potency and less off-target toxicity compared with multikinase tyrosine kinase inhibitors in the treatment of metastatic renal cell carcinoma. We carried out a meta-analysis to determine quantitatively the differences in comparative efficacy and tolerability between these newer, selective agents and the multikinase inhibitors. MATERIALS AND METHODS: We searched four electronic databases for published randomised controlled trials comparing selective VEGFR inhibitors with multikinase tyrosine kinase inhibitors for metastatic renal cell carcinoma and carried out a meta-analysis. Outcomes of interest were progression-free survival, objective response rate (ORR), overall survival, discontinuation of treatment due to adverse events (DAE) and occurrence of specific toxicities. RESULTS: Four trials involving the selective VEGFR inhibitors axitinib, tivozanib and dovitinib were analysed, all using sorafenib as the comparator. There was a 22% reduction in risk of disease progression with selective VEGFR inhibitors (relative risk 0.78; 95% confidence interval 0.69-0.87) compared with sorafenib, the tyrosine kinase inhibitor in all trials, and similar whether the agents were first-line or subsequent therapy. ORR was improved with selective VEGFR inhibitors, with 91% increased odds over sorafenib (odds ratio 1.91; 95% confidence interval 1.35-2.69). Overall survival was similar between groups (relative risk 1.03; 95% confidence interval 0.88-1.21) and DAE differed only in sensitivity analysis with exclusion of dovitinib (odds ratio 0.62; 95% confidence interval 0.41-0.94). Frequencies of the most common toxicities were overall similar, but differences included more frequent grade 3 or 4 fatigue and less frequent palmar-plantar erythrodysesthesia with selective VEGFR therapy. CONCLUSION: Although selective VEGFR inhibitors are associated with similar overall survival as multikinase inhibitor sorafenib, they show significant improvement in progression-free survival, regardless of first-line or later use, and ORR compared with sorafenib. Tolerability due to toxicities is similar.

BACKGROUND: Among the nearly 750,000 inmates in U.S. jails, 12% report using opioids regularly, 8% report use in the month prior to their offense, and 4% report use at the time of their offense. Although ample evidence exists that medications effectively treat Opiate Use Disorder (OUD) in the community, strong evidence is lacking in jail settings. The general lack of medications for OUD in jail settings may place persons suffering from OUD at high risk for relapse to drug use and overdose following release from jail. METHODS: The three study sites in this collaborative are pooling data for secondary analyses from three open-label randomized effectiveness trials comparing: (1) the initiation of extended-release naltrexone [XR-NTX] in Sites 1 and 2 and interim methadone in Site 3 with enhanced treatment-as usual (ETAU); (2) the additional benefit of patient navigation plus medications at Sites 2 and 3 vs. medication alone vs. ETAU. Participants are adults with OUD incarcerated in jail and transitioning to the community. RESULTS: We describe the rationale, specific aims, and designs of three separate studies harmonized to enhance their scientific yield to investigate how to best prevent jail inmates from relapsing to opioid use and associated problems as they transition back to the community. CONCLUSIONS: Conducting drug abuse research during incarceration is challenging and study designs with data harmonization across different sites can increase the potential value of research to develop effective treatments for individuals in jail with OUD.

BACKGROUND:Studies have shown that children with cancer globally lack access to palliative care. Little is known regarding physicians' perceptions of palliative care, treatment access, and self-reported competence in providing palliative care. PROCEDURE/METHODS:Members of the Global Neuroblastoma Network (online tumor board) were surveyed. Eighty-three respondents met inclusion criteria; 53 (64%) completed the survey. RESULTS:Most respondents trained in high-income countries (HIC) but practice in low- and middle-income countries (LMIC), and care for more than five patients with neuroblastoma annually. WHO Essential Medicines in palliative care varied in availability, with incomplete access across LMIC centers. Nonpharmacologic therapies were inconsistently available. Contrary to international definitions, 17% of respondents inappropriately considered palliative care as that initiated only after curative therapy is stopped. Mean physician competence composite score (Likert scale 1-5, 5 = very competent) in providing symptomatic relief and palliative care across phases of care was 2.93 (95% CI 2.71-3.22). Physicians reported significantly greater competence in symptom management during cure-directed therapy than during end-of-life (P = 0.02) or when patients are actively dying (P = 0.007). Practicing in HIC, prior palliative care training, having access to radiotherapy, and not having to turn patients away due to bed shortages were significantly predictive of perceived competence in providing palliative care at end of life. CONCLUSIONS:An international sample identified gaps in treatment and palliative care service availability, in understanding the definition of palliative care, and in self-reported competence in providing palliative care. Increased perceived competence was associated with training, which supports the need for increased palliative care education and advocacy, especially in LMIC.

Childhood trauma is a major precipitating factor in psychiatric disease. Emerging data suggest that stress susceptibility is genetically determined, and that risk is mediated by changes in limbic brain circuitry. There is a need to identify markers of disease vulnerability, and it is critical that these markers be investigated in childhood and adolescence, a time when neural networks are particularly malleable and when psychiatric disorders frequently emerge. In this preliminary study, we evaluated whether a common variant in the brain-derived neurotrophic factor (BDNF) gene (Val66Met; rs6265) interacts with childhood trauma to predict limbic gray matter volume in a sample of 55 youth high in sociodemographic risk. We found trauma-by-BDNF interactions in the right subcallosal area and right hippocampus, wherein BDNF-related gray matter changes were evident in youth without histories of trauma. In youth without trauma exposure, lower hippocampal volume was related to higher symptoms of anxiety. These data provide preliminary evidence for a contribution of a common BDNF gene variant to the neural correlates of childhood trauma among high-risk urban youth. Altered limbic structure in early life may lay the foundation for longer term patterns of neural dysfunction, and hold implications for understanding the psychiatric and psychobiological consequences of traumatic stress on the developing brain.

Testosterone supplementation therapy (TST) has become increasingly popular since the turn of the century. Most prescriptions in the U.S. are written by primary care providers, endocrinologists, or urologists. The FDA has requests pharmaceutical companies provide more long term data on efficacy and safety of testosterone products. Results from these studies will help define the appropriate population for TST going forward. It is hoped that these data combined with physician and public education will minimize inappropriate prescribing and allow those likely to benefit from TST to receive it.

AIM: The goal of this study was to identify progressing periodontal sites by applying linear mixed models (LMM) to longitudinal measurements of clinical attachment loss (CAL). METHODS: 93 periodontally healthy and 236 periodontitis subjects had their CAL measured bi-monthly for 12 months. The proportions of sites demonstrating increases in CAL from baseline above specified thresholds were calculated for each visit. The proportions of sites reversing from the progressing state were also computed. LMM were fitted for each tooth site and the predicted CAL levels used to categorize sites regarding progression or regression. The threshold for progression was established based on the model-estimated error in predictions. RESULTS: Over 12 months, 21.2%, 2.8%, and 0.3% of sites progressed, according to thresholds of 1, 2, and 3mm of CAL increase. However, on average, 42.0%, 64.4% and 77.7% of progressing sites for the different thresholds reversed in subsequent visits. Conversely, 97.1%, 76.9% and 23.1% of sites classified as progressing using LMM had observed CAL increases above 1, 2 and 3mm after 12 months, while mean rates of reversal were 10.6%, 30.2% and 53.0%, respectively. CONCLUSION: LMM accounted for several sources of error in longitudinal CAL measurement, providing an improved method for classifying progressing sites

BACKGROUND: Merkel cell polyomavirus (PyV) is causally related to Merkel cell carcinoma, a rare skin malignancy. Little is known about the serostability of other PyVs over time, or associations with cutaneous squamous cell carcinoma (SCC). METHODS: As part of a US nested case-control study, antibody response against the PyV VP1 capsid proteins of BK and JC was measured using multiplex serology on 113 SCC cases and 229 gender, age, and study center-matched controls who had a prior keratinocyte cancer. Repeated serum samples from controls, and both pre- and post-diagnosis samples from a subset of SCC cases were also tested. Odds ratios (OR) for SCC associated with seropositivity to each PyV type were estimated using conditional logistic regression. RESULTS: Among controls, BK and JC seroreactivity was stable over time, with intraclass correlation coefficients of 0.86 for BK and 0.94 for JC. Among cases, there was little evidence of seroconversion following SCC diagnosis. JC seropositivity prior to diagnosis was associated with an elevated risk of SCC (OR=2.54, 95% CI: 1.23-5.25), and SCC risk increased with increasing quartiles of JC (P-for-trend=0.004) and BK (P-for-trend=0.02) seroreactivity. CONCLUSIONS: PyV antibody levels were stable over time and following an SCC diagnosis. A history of PyV infection may be involved in the occurrence of SCC in a population at high risk for this malignancy. IMPACT: A single measure of PyV seroreactivity appears a reliable indicator of long-term antibody status, and PyV exposure may be a risk factor for subsequent SCC.