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We present the results of spectroscopy and multi-wavelength photometry of luminous and variable star candidates in the nearby spiral galaxies NGC 2403 and M81. We discuss specific classes of stars, the Luminous Blue Variables (LBVs), B[e] supergiants (sgB[e]), and the high luminosity yellow hypergiants. We identify two new LBV candidates, and three sgB[e] stars in M81. We also find that some stars previously considered LBV candidates are actually field stars. The confirmed and candidate LBVs and sgB[e] stars together with the other confirmed members are shown on the HR Diagrams for their respective galaxies. We also present the HR Diagrams for the two "SN impostors", V37 (SN2002kg) and V12(SN1954J) in NGC 2403 and the stars in their immediate environments., Comment: To appear in the Astronomical Journal

Background Despite several drugs approved in advanced renal cell carcinoma (RCC), new targets are needed as patients frequently experience progression on current approved therapies. TIM-1 is highly upregulated in RCC. CDX-014 combines a tumour targeting antibody against the mucin stalk of TIM-1 with potent cytotoxic microtubule inhibitor monomethyl E (MMAE) using a valine-citrulline peptide linker. Methods In this first-in-human phase I trial, patients with advanced clear cell or papillary RCC with at least 2 prior therapies including one vascular endothelial growth factor targeted therapy received CDX-014 every 3 weeks with tumor assessment every 6 weeks. Starting dose was 0.15 mg/kg to be escalated to 1.2 mg/kg in single patient cohorts. Further dose escalations up to 2.4 mg/kg was to follow traditional 3 + 3 design. Protocol was amended after escalation through 2 mg/kg to allow for 1.2 mg/kg dose given every 2 weeks in attempt to improve efficacy without increase in toxicity. Results Sixteen patients were enrolled (Table); median number of prior therapies was 4 (range 2-9.) Median number of doses received was 4; 9 patients were on treatment 1 year. Overall response rate was 6.25% with a partial response (PR) seen at 0.30 mg/kg dose lasting 21 months. Tumor shrinkage and progressive disease (PD) as best response occurred in 5 and 6 patients respectively. Clinical benefit rate (PR or Stable disease (SD) ≥6 months) was 25%. TIM-1 expression was noted in > 10% of tumour cells in 13 patients; none of the remaining 3 patients had any tumour shrinkage. 5 dose limiting toxicities were observed in 2 patients, both at 2 mg/kg. Single grade 5 serious adverse event was associated with high free levels of MMAE. Most common Grade ≥ 3 treatment related adverse event was hyperglycemia occurring in 3 patients. Table . 953P Dose (mg/kg) every 3 weeks unless specified # patients enrolled Best overall response 0.15 1 PD 0.3 1 PR 0.6 1 PD 1.2 1 SD 1.8 6 5 SD 1 PD 2 4 2 SD 1 PD 1 NE 1.2 q2wks 2 2 PD NE=not evaluable. Conclusions TIM-1 is a novel target in the treatment of RCC. Optimal dosing strategy of CX-104 has not yet been defined. Clinical trial identification NCT02837991. Legal entity responsible for the study Celldex Pharmaceuticals. Funding Celldex Pharmaceuticals. Disclosure B.A. McGregor: Honoraria (self), Advisory / Consultancy: EMD Serrano; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Seattle Genetics; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Genentech; Honoraria (self), Advisory / Consultancy: Janssen; Research grant / Funding (institution): BMS. N. Agarwal: Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Argos; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Clovis; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Exelixis; Honoraria (self), Advisory / Consultancy: EMD Serono; Honoraria (self), Advisory / Consultancy: Ely Lilly; Honoraria (self), Advisory / Consultancy: Genentech; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Medivation; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Nektar; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Pharmacyclics. S. George: Honoraria (self), Research grant / Funding (institution): BMS; Honoraria (self), Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Novartis; Honoraria (self): Exelixis; Honoraria (self): Janssen; Honoraria (self), Research grant / Funding (institution): Corvus; Honoraria (self): Genentech; Honoraria (self): Sanofi/Genzyme; Honoraria (self), Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Acceleron; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Eisai; Honoraria (self): EMD Serono. D.I. Quinn: Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self): BMS; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Dendreon; Honoraria (self), Advisory / Consultancy: Exelixis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Honoraria (self): Janssen; Honoraria (self): Novartis; Honoraria (self): Mundipharma; Honoraria (self): Pharmacyclics; Honoraria (self), Advisory / Consultancy: Clovis; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Amgen; Advisory / Consultancy: Eisai; Advisory / Consultancy: Novartis; Research grant / Funding (institution), in addition to Millennium: GlaxoSmithKline. M. Rogalski: Full / Part-time employment: Celldex Pharmaceuticals. T. Keler: Full / Part-time employment: Celldex Pharmaceuticals. T. Hawthorne: Full / Part-time employment: Celldex Pharmaceuticals. T.K. Choueiri: Honoraria (self): AstraZeneca; Honoraria (self): Alexion; Honoraria (self): Bayer; Honoraria (self): Bristol Myers-Squibb; Honoraria (self): Cerulean; Honoraria (self): Eisai; Honoraria (self): foundation medication; Honoraria (self): Exelixis; Honoraria (self): Ipsen; Honoraria (self): Tracon; Honoraria (self): Genentech; Honoraria (self): Roche; Honoraria (self): GlaxoSmithKline; Honoraria (self): Lilly; Honoraria (self): Merck; Honoraria (self): Novartis; Honoraria (self): Peloton; Honoraria (self): Pfizer; Honoraria (self): Prometheus labs; Honoraria (self): Corvus. All other authors have declared no conflicts of interest.

Individuals on probation and parole are disproportionately at high risk for HIV infection and experience significant barriers to accessing health care. This study was a two-group randomized controlled trial conducted at a community corrections office and was designed to link HIV positive probationers/parolees to HIV treatment in the community. HIV positive participants were assigned to one of the two treatment conditions: (1) Project Bridge (PB), an intensive case-management intervention; or (2) treatment as usual (TAU), involving standard referral to treatment. We hypothesized that PB would be more effective than TAU in terms of initiating individuals in community HIV treatment. We found no difference in rates of, or time to, treatment initiation when comparing the PB to TAU (all ns > 0.05). Additionally, there was no statistically significant difference between HIV medication regiment initiation by treatment condition (p > 0.05). Despite limitations, we found that probationers and parolees were willing to be screened and linked to treatment.

We report the fifth confirmed Luminous Blue Variable/S Doradus variable in M31. In 2006, J004526.62+415006.3 had the spectrum of hot Fe ii emission line star with strong P Cygni profiles in the Balmer lines. In 2010, its absorption line spectrum resembled an early A-type supergiant with H and Fe ii emission lines with strong P Cygni profiles, and in 2013, the spectrum had fully transitioned to an F-type supergiant due to the formation of the optically thick, cool wind which characterizes LBVs at maximum light. The photometric record supports the LBV/S Doradus nature of the variability. Its bolometric luminosity of ~-9.65 mag places it on the H-R diagram near the known LBVs, AE And, Var C in M33, and S Dor.

Background Pharmacotherapy studies involving buprenorphine have rarely been conducted with US community corrections populations. This is one of the first reports of buprenorphine treatment outcomes of adult opioid-dependent probationers and parolees. Methods This longitudinal study examined the 3-month treatment outcomes for a sample of probation and parole clients ( N = 64) who received community-based buprenorphine treatment. Results Approximately two thirds of the sample (67%) were still in treatment at 3 months post baseline. Furthermore, there was a significant decline in the number of self-reported heroin use days and crime days from baseline to 3 months post baseline. Although there was not a significant reduction in reincarcerations, there was no evidence that they had increased. Conclusions Given that buprenorphine is approved by the Food and Drug Administration (FDA) as a safe, effective treatment for opioid use disorders, individuals on parole or probation should have the opportunity to benefit from it through community-based programs.

Background: Type 1 insulin-like growth factor receptor (IGF-IR) signaling is often dysregulated in cancer. Cixutumumab, a fully human IgG1 monoclonal antibody, blocks IGF-IR and inhibits downstream signaling. The current study determined the recommended dose, safety, and pharmacokinetic (PK) profile of weekly or every-2-week dosing of cixutumumab. Patients and Methods: Two open-label, multicenter phase I studies evaluated weekly (3–15 mg/kg) or every-2-weeks (6–15 mg/kg) dosing of cixutumumab in patients with advanced solid tumors. Serial blood samples for PK were collected up to 168–336 h (day 8–15) following the first administration of cixutumumab. Efficacy was evaluated as best overall tumor response. Results: A total of 24 and 16 patients were enrolled in the weekly and every-2-week dosing studies, respectively. Treatment-emergent adverse events (≥10 %) included hyperglycemia, fatigue, anemia, nausea, and vomiting. Severe adverse events (AE) were infrequent; one serious AE (grade 3 electrocardiogram QT prolongation) was deemed possibly cixutumumab-related (10 mg/kg every-2-weeks). One death occurred due to disease progression (6 mg/kg weekly cohort). Maximum serum concentrations increased with dose. A maximum tolerated dose was not identified; pre-determined target serum minimum concentrations (60 μg/mL) were achieved with ≥6 mg/kg weekly and ≥10 mg/kg every-2-week dosing. Cixutumumab terminal elimination half-life is approximately a week (individual range, t1/2 = 4.58–9.33 days based upon 10 mg/kg every 2 weeks). Overall, stable disease was achieved in 25 % of all patients. Conclusions: Cixutumumab was associated with favorable safety and PK profiles. A dosing regimen of 10 mg/kg every 2 weeks was recommended for subsequent disease-focused clinical trials.

Background Extended-release naltrexone (XR-NTX, Vivitrol®; Alkermes Inc.) is an injectable monthly sustained-release mu opioid receptor antagonist. XR-NTX is a potentially effective intervention for opioid use disorders and as relapse prevention among criminal justice system (CJS) populations. Methods This 5-site open-label randomized controlled effectiveness trial examines whether XR-NTX reduces opioid relapse compared with treatment as usual (TAU) among community dwelling, non-incarcerated volunteers with current or recent CJS involvement. The XR-NTX arm receives 6 monthly XR-NTX injections at Medical Management visits; the TAU group receives referrals to available community treatment options. Assessments occur every 2 weeks during a 24-week treatment phase and at 12- and 18-month follow-ups. The primary outcome is a relapse event, defined as either self-report or urine toxicology evidence of ≥ 10 days of opioid use in a 28-day (4 week) period, with a positive or missing urine test counted as 5 days of opioid use. Results We describe the rationale, specific aims, and design of the study. Alternative design considerations and extensive secondary aims and outcomes are discussed. Conclusions XR-NTX is a potentially important treatment and relapse prevention option among persons with opioid dependence and CJS involvement. ClinicalTrials.gov: NCT00781898 Language: en

We report low-energy proton and alpha particle SEE data on a 32 nm silicon-on-insulator (SOI) complementary metal oxide semiconductor (CMOS) static random access memory (SRAM) that demonstrates the criticality of understanding and using low-energy protons for SEE testing of highly-scaled technologies

BACKGROUND Epidermal growth factor receptor (EGFR) alterations are associated with multiple cancers. Current EGFR‐directed therapies have led to increased efficacy but are associated with specific side effects. The antibody‐drug conjugate depatuxizumab mafodotin (depatux‐m) targets EGFR with a monoclonal antibody linked to a cytotoxin, and is highly tumor‐specific. METHODS This phase 1/2 study evaluated the safety, pharmacokinetics, and efficacy of depatux‐m in patients who had advanced solid tumors with known wild‐type EGFR overexpression, amplification, or mutated EGFR variant III. A 3 + 3 dose escalation was used, and 2 dosing schedules were evaluated. Depatux‐m also was manufactured under an alternate process to reduce the drug load and improve the safety profile, and it was tested at the maximum tolerated dose (MTD). In another cohort, prolonged infusion time of depatux‐m was evaluated; and a cohort with confirmed EGFR amplification also was evaluated at the MTD. RESULTS Fifty‐six patients were treated. The MTD and the recommended phase 2 dose for depatux‐m was 3.0 mg/kg. Common adverse events (AEs) were blurred vision (48%) and fatigue (41%). A majority of patients (66%) experienced 1 or more ocular AEs. Grade 3 or 4 AEs were observed in 43% of patients. One patient with EGFR‐amplified, triple‐negative breast cancer had a partial response. Stable disease was observed in 23% of patients. Pharmacokinetics revealed that depatux‐m exposures were approximately dose‐proportional. CONCLUSIONS Depatux‐m resulted in infrequent nonocular AEs but increased ocular AEs. Patient follow‐up confirmed that ocular AEs were reversible. Lowering the drug‐antibody ratio did not decrease the number of ocular AEs. A partial response in 1 patient with EGFR‐amplified disease provides the opportunity to study depatux‐m in diseases with a high incidence of EGFR amplification. Cancer 2018;124:2174‐83. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes., This phase 1 study evaluates the safety, pharmacokinetics, and efficacy of depatuxizumab mafodotin (depatux‐m), an antibody‐drug conjugate targeting epidermal growth factor receptor in patients with solid tumors. Depatux‐m is associated with generally reversible ocular side effects, and 1 patient with EGFR‐amplified breast cancer had a partial response, suggesting an opportunity for further study of depatux‐m.

The U.S. female criminal justice (CJ) population is rapidly growing, yet large-scale studies exploring gender-specific HIV risk behaviors in the CJ population are lacking. This analysis uses baseline data on adults with a CJ history from eight U.S. studies in an NIH-funded "Seek, Test, Treat, Retain" harmonization consortium. Data were collected using a standardized HIV risk behavior assessment tool and pooled across studies to describe participants' characteristics and risk behaviors. Multilevel mixed-effects logistic regression models were used to test for gender-based behavior differences. Among 784 HIV-positive (21.4% female) and 5521 HIV-negative (8.5% female) participants, HIV-positive women had higher odds than HIV-positive men of engaging in condomless sexual intercourse (AOR 1.84 [1.16-2.95]) with potentially sero-discordant partners (AOR 2.40 [1.41-4.09]) and of sharing injection equipment (AOR 3.36 [1.31-8.63]). HIV risk reduction interventions targeting CJ-involved women with HIV are urgently needed as this population may represent an under-recognized potential source of HIV transmission.

An estimated one in seven HIV-infected individuals pass through U.S. correctional facilities each year. Transitioning from correctional to community settings may increase HIV treatment interruptions and increase the risk of continued HIV transmission in the community. This study assessed access to HIV providers in the community, antiretroviral treatment, and viral suppression to inform the development of interventions to improve HIV treatment outcomes among individuals involved in community corrections. The sample included 100 individuals under community supervision (probation or parole) in Baltimore, Maryland. While a large proportion of the study sample had undetectable HIV viral loads, 39% did not, and this represents a significant HIV transmission risk. Given the large proportion of individuals involved in the criminal justice system who are under community supervision, community corrections may be an important point of intervention to engage or reengage HIV-positive individuals who are currently out of care.

Background The STTR treatment cascade provides a framework for research aimed at improving the delivery of services, care and outcomes of PLWH. The development of effective approaches to increase HIV diagnoses and engage PLWH in subsequent steps of the treatment cascade could lead to earlier and sustained ART treatment resulting in viral suppression. There is an unmet need for research applying the treatment cascade to improve outcomes for those with criminal justice involvement. Methods The Seek, Test, Treat, and Retain (STTR) criminal justice (CJ) cohort combines data from 11 studies across the HIV treatment cascade that focused on persons involved in the criminal justice system, often but not exclusively for reasons related to substance use. The studies were conducted in a variety of CJ settings and collected information across 11 pre-selected domains: demographic characteristics, CJ involvement, HIV risk behaviors, HIV and/or Hepatitis C infections, laboratory measures of CD4 T-cell count (CD4) and HIV RNA viral load (VL), mental illness, health related quality of life (QoL), socioeconomic status, health care access, substance use, and social support. Results The STTR CJ cohort includes data on 11,070 individuals with and without HIV infection who range in age from 18 to 77 years, with a median age at baseline of 37 years. The cohort reflects racial, ethnic and gender distributions in the U.S. CJ system, and 64% of participants are African-American, 12% are Hispanic and 83% are men. Cohort members reported a wide range of HIV risk behaviors including history of injection drug use and, among those who reported on pre-incarceration sexual behaviors, the prevalence of unprotected sexual intercourse ranged across studies from 4% to 79%. Across all studies, 53% percent of the STTR CJ cohort reported recent polysubstance use. Conclusions The STTR CJ cohort is comprised of participants from a wide range of CJ settings including jail, prison, and community supervision who report considerable diversity in their characteristics and behavioral practices. We have developed harmonized measures, where feasible, to improve the integration of these studies together to answer questions that cannot otherwise be addressed.

Concerns persist that individuals with substance use disorders who are under community criminal justice supervision experience circumstances that might compromise their provision of valid, informed consent for research participation. These concerns include the possibilities that desire to obtain access to treatment might lead individuals to ignore important information about research participation, including information about risks, or that cognitive impairment associated with substance use might interfere with attending to important information. We report results from a consent quiz (CQ) administered in a multisite randomized clinical trial of long-acting naltrexone to prevent relapse to opioid use disorder among adults under community criminal justice supervision-a treatment option difficult to access by this population of individuals. Participants were required to answer all 11 items correctly before randomization. On average, participants answered 9.8 items correctly (89%) at baseline first attempt (n=306). At week 21 (n=212), participants scored 87% (9.5 items correct) without review. Performance was equivalent to, or better than, published results from other populations on a basic consent quiz instrument across multiple content domains. The consent quiz is an efficient method to screen for adequate knowledge of consent information as part of the informed consent process. Clinical researchers who are concerned about these issues should consider using a consent quiz with corrected feedback to enhance the informed consent process. Overall, while primarily useful as an educational tool, employing a CQ as part of the gateway to participation in research may be particularly important as the field continues to advance and tests novel experimental treatments with significant risks and uncertain potential for benefit.

New MMT/MIRAC (9-11 {\mu}m), SOFIA/FORCAST (11-37 {\mu}m), and Herschel/PACS (70 and 160 {\mu}m) infrared (IR) imaging and photometry is presented for three famous OH/IR red supergiants (NML Cyg, VX Sgr, and S Per) and two normal red supergiants (RS Per and T Per). We model the observed spectral energy distributions (SEDs) using radiative transfer code DUSTY. Azimuthal average profiles from the SOFIA/FORCAST imaging, in addition to dust mass distribution profiles from DUSTY, constrain the mass-loss histories of these supergiants. For all of our observed supergiants, the DUSTY models suggest that constant mass-loss rates do not produce enough dust to explain the observed infrared emission in the stars' SEDs. Combining our results with Shenoy et al. (2016) (Paper I) we find mixed results with some red supergiants showing evidence for variable and high mass-loss events while others have constant mass loss over the past few thousand years., Comment: 29 pages, 15 figures, 3 tables. Accepted to AJ

The development of human cancer is a multistep process characterized by the accumulation of genetic and epigenetic alterations that drive or reflect tumour progression. These changes distinguish cancer cells from their normal counterparts, allowing tumours to be recognized as foreign by the immune system. However, tumours are rarely rejected spontaneously, reflecting their ability to maintain an immunosuppressive microenvironment. Programmed death-ligand 1 (PD-L1; also called B7-H1 or CD274), which is expressed on many cancer and immune cells, plays an important part in blocking the 'cancer immunity cycle' by binding programmed death-1 (PD-1) and B7.1 (CD80), both of which are negative regulators of T-lymphocyte activation. Binding of PD-L1 to its receptors suppresses T-cell migration, proliferation and secretion of cytotoxic mediators, and restricts tumour cell killing. The PD-L1-PD-1 axis protects the host from overactive T-effector cells not only in cancer but also during microbial infections. Blocking PD-L1 should therefore enhance anticancer immunity, but little is known about predictive factors of efficacy. This study was designed to evaluate the safety, activity and biomarkers of PD-L1 inhibition using the engineered humanized antibody MPDL3280A. Here we show that across multiple cancer types, responses (as evaluated by Response Evaluation Criteria in Solid Tumours, version 1.1) were observed in patients with tumours expressing high levels of PD-L1, especially when PD-L1 was expressed by tumour-infiltrating immune cells. Furthermore, responses were associated with T-helper type 1 (TH1) gene expression, CTLA4 expression and the absence of fractalkine (CX3CL1) in baseline tumour specimens. Together, these data suggest that MPDL3280A is most effective in patients in which pre-existing immunity is suppressed by PD-L1, and is re-invigorated on antibody treatment.

Well-differentiated thyroid carcinoma (WDTC) generally has a favorable prognosis. However, patients with distant metastatic disease experience progression of disease with a higher mortality. A subset of patients not previously described may challenge the conventional dogma regarding the progressive nature of all metastatic WDTC. Through analysis of our database, we identified patients with distant metastatic WDTC and persistent, minimally progressive disease. In all patients, persistent metastatic disease was confirmed via tissue biopsy, abnormal PET scan, and/or biochemical elevations in thyroglobulin or antibody levels. Progression of disease was monitored clinically and with repeat imaging. We describe five patients with WDTC and pulmonary metastases, aged 8–43 years at diagnosis. All patients underwent initial surgery and radioactive iodine (RAI) ablation, with some receiving multiple treatments. Persistent pulmonary metastatic disease was confirmed over decades (mean 22 years, range 8–42 years) with minimal progression despite no further treatment beyond thyroid hormone suppression. Persistent disease was biopsy-proven in all patients at a mean of 9.6 years from last RAI treatment. All patients had elevated thyroglobulin or anti-thyroglobulin antibody levels, while three demonstrated metabolically active disease with positive FDG uptake on PET scan, and one patient with persistent radioactive iodine avid pulmonary metastasis 36 years after her last RAI treatment. This case series demonstrates that some patients with distant metastases, even if metabolically active and radioactive iodine resistant, remain stable for decades without further treatment. Clinical awareness of such patients and continual reassessment of disease risk following initial therapy are crucial as aggressive treatment may not be necessary.

Trametinib (Mekinist®) is a selective inhibitor of mitogen-activated protein kinase kinase (MEK) approved in the United States as a single agent and in combination with dabrafenib (Tafinlar®) for treatment of patients with unresectable or metastatic melanoma with a positive BRAF V600E/V600K mutation for which a pediatric oral solution formulation is being developed. This open-label, two-period, two-treatment, randomized, crossover study assessed the relative bioavailability of the trametinib pediatric oral solution compared to the tablet formulation after a single-dose administration to adult patients with solid tumors. Primary pharmacokinetic endpoints derived from standard non-compartmental methods were AUC0-inf , AUC0-t , and Cmax . As expected, Cmax was higher and Tmax earlier for the pediatric oral solution compared to the tablet formulation. Administration of the trametinib pediatric oral solution resulted in a 12%, 10%, 18%, and 71% higher AUC0-inf , AUC0-last , AUC0-24 , and Cmax , respectively, as compared to the tablet formulation. Safety results were aligned with the known safety profile of trametinib. No serious or non-serious adverse events resulted in study drug withdrawal. Palatability of the pediatric oral solution was evaluated and found to be acceptable to most adult patients, but may differ in the pediatric population.

Purpose Cabozantinib (XL184), an oral inhibitor of multiple receptor tyrosine kinases such as MET and VEGFR2, was evaluated in a phase II nonrandomized expansion study in castration-resistant prostate cancer (CRPC). Patients and Methods Patients received open-label cabozantinib at daily starting doses of 100 mg or 40 mg until disease progression or unacceptable toxicity. The primary end point was bone scan response, defined as ≥ 30% reduction in bone scan lesion area. Other efficacy end points included overall survival, pain, analgesic use, and biomarkers. Results One hundred forty-four patients sequentially enrolled in either a 100-mg (n = 93) or 40-mg (n = 51) study cohort. Ninety-one patients (63%) had a bone scan response, often by week 6. Treatment resulted in clinically meaningful pain relief (57% of patients) and reduction or discontinuation of narcotic analgesics (55% of patients), as well as improvements in measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Improvements in each of these outcomes were observed in both cohorts: bone scan response in 73% and 45%, respectively; reductions in measurable soft tissue disease in 80% and 79%, respectively. Median overall survival was 10.8 months for the entire population. Most common grade 3 or 4 adverse events were fatigue (22%) and hypertension (14%). Fewer dose reductions because of toxicity were required in the 40-mg group. Conclusion The evidence suggests that cabozantinib has clinically meaningful activity in CRPC. Cabozantinib resulted in improvements in bone scans, pain, analgesic use, measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Taken together, these phase II observations warrant further development of cabozantinib in prostate cancer.

Buprenorphine is a promising treatment for heroin addiction. However, little is known regarding its provision to pre-release prisoners with heroin dependence histories who were not opioid-tolerant, the relative effectiveness of the post-release setting in which it is provided, and gender differences in treatment outcome in this population.This is the first randomized clinical trial of prison-initiated buprenorphine provided to male and female inmates in the US who were previously heroin-dependent prior to incarceration. A total of 211 participants with 3-9 months remaining in prison were randomized to one of four conditions formed by crossing In-Prison Treatment Condition (received buprenorphine vs. counseling only) and Post-release Service Setting (at an opioid treatment center vs. a community health center). Outcome measures were: entered prison treatment; completed prison treatment; and entered community treatment 10 days post-release.There was a significant main effect (p=.006) for entering prison treatment favoring the In-Prison buprenorphine Treatment Condition (99.0% vs. 80.4%). Regarding completing prison treatment, the only significant effect was Gender, with women significantly (p.001) more likely to complete than men (85.7% vs. 52.7%). There was a significant main effect (p=.012) for community treatment entry, favoring the In-Prison buprenorphine Treatment Condition (47.5% vs. 33.7%).Buprenorphine appears feasible and acceptable to prisoners who were not opioid-tolerant and can facilitate community treatment entry. However, concerns remain with in-prison treatment termination due to attempted diversion of medication.

Alpha emissivity measurements are important in the semiconductor industry for assessing the suitability of materials for use in production processes. A recently published round-robin study that circulated the same samples to several alpha counting centers showed wide center-to-center variations in measured alpha emissivity. A separate analysis of these results hypothesized that much of the variation might arise from differences in sample-to-entrance window separations. XIA recently introduced an ultra low background counter, the UltraLo-1800 (UltraLo), that operates in a fundamentally different manner from the proportional counters used at most of the centers in the original study. In particular, by placing the sample within the counting volume, it eliminates the sample-to-entrance window separation issue noted above, and so offers an opportunity to test this hypothesis. In this work we briefly review how the UltraLo operates and describe a new round-robin study conducted entirely on UltraLo instruments using a set of standard samples that included two samples used in the original study. This study shows that, for LA (Low Alpha between 2 and 50 alpha/khr-cm$^2$) sample measurements, the only remaining site-to-site variations were due to counting statistics. Variations in ULA (Ultra-Low Alpha < 2 alpha/khr-cm$^2$) sample measurements were reduced three-fold, compared to the earlier study, with the measurements suggesting that residual activity variations now primarily arise from site-to-site differences in the cosmogenic background., 7 pages, 8 figures, 4 tables; Fixed typos, added discussion on potential for positive systematic bias per reviewer comments, quick formatting refresh. Accepted for publication in Nucl. Instr. and Meth. in Phys. Res. A

Amuvatinib is an oral multi-kinase inhibitor that suppresses RAD51, inhibits mutant c-KIT and platelet-derived growth factor receptor alpha, and has synergistic activity with DNA-damaging agents and topoisomerase inhibitors such as etoposide, doxorubicin, and topotecan. We conducted a phase 1B study to estimate the maximum tolerated dose (MTD) levels of amuvatinib with standard chemotherapy regimens and to define the safety profiles of specific amuvatinib + standard regimens.Five therapies each co-administered with amuvatinib 100-800 mg/day every 21 days were evaluated in treatment-naïve or moderately pre-treated subjects: paclitaxel IV followed by carboplatin IV; carboplatin IV followed by etoposide; topotecan IV; docetaxel IV; and erlotinib by mouth.Among 97 treated subjects, no treatment arm reached the MTD. Dose-limiting toxicities included febrile neutropenia and diarrhea. No pharmacokinetic interactions of amuvatinib with any cancer regimens occurred. Of 12/97 (12 %) partial responses overall, 11 were seen in the amuvatinib and paclitaxel/carboplatin or carboplatin/etoposide arms and most commonly in the neuroendocrine (NE), non-small cell lung cancer (NSCLC), and small cell lung cancer (SCLC) tumors. Forty-four subjects (45 %) had stable disease. Adverse events reflected combination treatment and were primarily non-hematologic (fatigue, alopecia, diarrhea, nausea, anorexia) and hematologic (neutropenia, anemia, thrombocytopenia, leukopenia). Pharmacodynamic effects as measured by decreased levels of RAD51 and increased residual DNA damage (53BP1 foci) were seen in skin punch biopsies.Amuvatinib was well tolerated, modulated RAD51, and showed antitumor activity when combined with paclitaxel/carboplatin and carboplatin/etoposide in NE, NSCLC, and SCLC tumors.

Purpose: The angiogenesis inhibitor dalantercept (formerly ACE-041) is a soluble form of activin receptor–like kinase-1 (ALK1) that prevents activation of endogenous ALK1 by bone morphogenetic protein-9 (BMP9) and BMP10 and exhibits antitumor activity in preclinical models. This first-in-human study of dalantercept evaluated its safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity in adults with advanced solid tumors. Experimental Design: Patients in dose-escalating cohorts received dalantercept subcutaneously at one of seven dose levels (0.1–4.8 mg/kg) every 3 weeks until disease progression. Patients in an expansion cohort received dalantercept at 0.8 or 1.6 mg/kg every 3 weeks until disease progression. Results: In 37 patients receiving dalantercept, the most common treatment-related adverse events were peripheral edema, fatigue, and anemia. Edema and fluid retention were dose-limiting toxicities and responded to diuretic therapy. No clinically significant, treatment-related hypertension, proteinuria, gross hemorrhage, or gastrointestinal perforations were observed. One patient with refractory squamous cell cancer of the head and neck had a partial response, and 13 patients had stable disease according to RECISTv1.1, eight of whom had prolonged periods (≥12 weeks) of stable disease. Correlative pharmacodynamic markers included tumor metabolic activity and tumor blood flow, which decreased from baseline in 63% and 82% of evaluable patients, respectively, and telangiectasia in eight patients. Conclusion: Dalantercept was well-tolerated at doses up to 1.6 mg/kg, with a safety profile distinct from inhibitors of the VEGF pathway. Dalantercept displayed promising antitumor activity in patients with advanced refractory cancer, and multiple phase II studies are underway. Clin Cancer Res; 20(2); 480–9. ©2013 AACR.

CDX-1140 is an agonist CD40 mAb intended to promote priming of CD8+ effector T cells through activation of dendritic cells (DC), enhance macrophage tumoricidal activity, and mediate direct killing of CD40-expressing tumor cells. CDX-1140 is a human IgG2 mAb with Fc receptor independent activity and is synergistic with sCD40L, suggesting a potential to enhance CD40L-mediated immune activation. CDX-1140 has a broad dose-dependent activity that may achieve maximal agonist activity at doses that provide significant tumor penetration with minimal toxicities from systemic CD40 activation. CDX-301 (rhFLT3L) is a DC growth factor that markedly increases CD141+ DCs, including in the tumor microenvironment (TME). CD141+ DCs are critical for initiating anti-tumor immune responses and are often depleted within the TME. Preclinical studies have shown that treatment with CDX-301 synergizes with CD40 signaling to enhance anti-tumor immune responses, suggesting that combining CDX-1140 and CDX-301 could result in enhanced clinical benefit. CDX1140-01(NCT03329950) is a Phase I dose-escalation study of CDX-1140 as monotherapy or in combination with CDX-301 evaluating safety, PK, PD, and preliminary clinical activity in patients (pts) with refractory solid tumors and non-Hodgkin lymphoma. CDX-1140 is given iv q 4 weeks at doses from 0.01 to 3 mg/kg utilizing a 3+3 design (first 2 cohorts are single-pts). In combination cohorts (solid tumors only), CDX-301 at 75 μg/kg daily x 5 is administered sc prior to cycles 1 and 2 of escalating doses of CDX-1140 starting at 0.09 mg/kg. Tumor-specific expansion cohorts are planned to further explore the activity of monotherapy or combination treatment. To date, 18 pts across 10 tumor types have been dosed in CDX-1140 monotherapy cohorts with doses ranging from 0.01 to 0.72 mg/kg and without identification of an MTD. There has been one DLT (0.18 mg/kg): grade 3 pneumonitis and hypoxia. One pt (0.72 mg/kg) experienced grade 3 fatigue requiring hospitalization 48 hrs after the first infusion. There have been 3 additional grade 3 treatment-related adverse events: dyspnea (0.18 mg/kg), nausea (0.36 mg/kg), and vomiting (0.36 mg/kg). The first combination cohort (n=5) has been completed. In monotherapy and combination cohorts there have been no significant drug-related changes in liver function tests to date. CDX-1140 PK is quantifiable at doses ≥ 0.09 mg/kg and exposure appears dose proportional. Expected dose-dependent PD effects have shown activation of peripheral blood lymphocytes and increases in pro-inflammatory cytokines and chemokines. Combination with CDX-301 has shown enhanced cytokine responses. The data suggest that CDX-1140 has the expected biologic and safety profile predicted from preclinical studies and may achieve dose levels optimal for systemic exposure. The addition of CDX-301 may enhance the activity of CDX-1140. Citation Format: Rachel E. Sanborn, Nashat Y. Gabrail, Nina Bhardwaj, Michael S. Gordon, Mark O'Hara, Danny Khalil, Thomas Hawthorne, Richard Gedrich, Laura Vitale, Mark Rogalski, Tianshu Li, Tracey Rawls, Tibor Keler, Michael Yellin. First-in-human Phase I study of the CD40 agonist mAb CDX-1140 and in combination with CDX-301 (rhFLT3L) in patients with advanced cancers: Interim results [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-194.

Objectives: Ripretinib is a novel, oral kinase switch control inhibitor of KIT and PDGFRα. Encouraging clinical benefit from the phase 1 dose escalation and expansion study as measured by ORR, DCR and PFS in 2nd, 3rd, and >4th line GIST patients with a favorable tolerability profile at doses >100 mg/day has been previously reported (ESMO 2018, abstract #1603O). It has been reported that more than 40% of GIST patients use acid-reducing agents. PPIs are the most potent acid-reducing agents that may impair the absorption of kinase inhibitors 1,2. This retrospective analysis aims to explore whether ripretinib can be used regardless of concomitant PPI use. Methods: The analysis assessed the impact of PPIs on the plasma concentration of ripretinib using PK data from the expansion cohort at the recommended Phase 2 dose of 150 mg QD. Plasma concentrations of ripretinib and its active metabolite DP-5439 obtained from patients who used or did not use PPIs were compared on Cycle 1 Day 1 (C1D1, n=106) and Day 15 (C1D15, n=102). Patients using PPIs were defined as those who continuously took PPIs for at least 4 days prior to C1D1 or C1D15. Patients who did not use PPIs were defined as those who did not take PPIs or any other acid-reducing agents during the study. Results: PK profiles were consistent between patients using and not using PPIs (Table 1), indicating a low likelihood of a clinically significant drug interaction between PPIs and ripretinib. Conclusions: This retrospective PK analysis provides supporting evidence that restriction of co-administration of PPIs with ripretinib may not be necessary. A dedicated drug interaction study is planned to provide a definitive assessment. References: 1. Smelick et al, Mol. Pharmaceutics 2013, 10, 4055−4062 2. Budha et al, Clin Pharmacol Ther. 2012, 92(2):203-13 Table 1.PK Exposure of Ripretinib and DP-5439 in Patients Using or not Using PPIsPK ConcentrationsRipretinib in ng/mL [mean (CV%)]DP-5439 in ng/mL [mean (CV%)]Ripretinib + DP-5439 in ng/mL [mean (CV%)]Using PPIsNot using PPIsUsing PPIsNot using PPIsUsing PPIsNot using PPIsC1D1 6 hr566 (58%) n=24670 (53%) n=82302 (64%) n=23297 (59%) n=82862 (54%) n=24975 (48%) n=82C1D15 pre-dose364 (79%) n= 24344 (63%) n=78960 (80%) n=24889 (86%) n=781350 (72%) n=241260 (75%) n=78C1D15 6 hr834 (51%) n=24871 (47%) n=731170 (69%) n=241060 (67%) n=732040 (53%) n=241960 (49%) n=73Notes: Table 1 is based on data from patients without a history of gastrectomy. A separate analysis in patients with gastrectomy will be published after sufficient data is obtained. Citation Format: Filip Janku, Michael Heinrich, Ping Chi, Albiruni Abdul Razak, Margaret von Mehren, Michael Gordon, Kristen Ganjoo, Jonathan Trent, Robin L. Jones, Hans Gelderblom, Kelli Running, Jing Wang, Rodrigo Ruiz-Soto, Suzanne George. Ripretinib (DCC-2618) pharmacokinetics (PK) in a Phase I study in patients with gastrointestinal stromal tumors (GIST) and other advanced malignancies: A retrospective evaluation of the PK effects of proton pump inhibitors (PPIs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT058.

5511 Background: Preclinical evidence suggests that combining avelumab (A), a human anti-PD-L1 monoclonal antibody, and entinostat (E), a class I selective histone deacetylase (HDAC) inhibitor, may increase tumor immunogenicity and responsivity to checkpoint inhibition. This study evaluated whether A+E would lead to improved progression free survival (PFS) vs A in pts with advanced EOC. Methods: Pts with EOC which had progressed or recurred after 1st-line platinum-based chemotherapy and received 3- 6 lines of therapy were randomized 2:1 to receive A (10 mg/kg IV Q2W) plus E (5 mg PO QW) or A plus placebo (P). Treatment continued until disease progression (PD) or unacceptable toxicity. The primary endpoint was PFS (investigator-assessed, RECIST 1.1), stratifying on the presence/absence of bulky disease (tumor ≥ 50 mm) and platinum-refractory disease. The hypothesis was that the combination would reduce the hazard of PD or death by 43%, representing a 75% improvement in median PFS. 97 events (from 120 pts) provided 90% power with 1-sided significance level of 0.10. Secondary endpoints included ORR, duration and time to response, toxicity, clinical benefit rate, and OS. Results: 126 pts were enrolled, median age 63 yrs (range 43-82), median 4 prior lines, 83% serous histology. Median PFS was 1.64 and 1.51 mos for A+E and A+P, respectively (p = 0.31; HR 0.90, 95% CI: 0.58-1.39). No significant differences in ORR (6% vs 5%), or OS (NE vs 11.3 mos) were observed. 4 pts (3%) had clear cell EOC, with no responses observed. The incidence of related adverse events (AEs) was higher in the A+E arm compared to A+P (any grade: 93% vs 78%, Grade 3/4: 41% vs 10%), and the most frequent (≥20%) related AEs with A+E were fatigue (46%), nausea (31%), diarrhea (26%), anemia (26%), and chills (20%). Grade 3/4 related AEs occurring in ≥5% with A+E were fatigue (9%), and neutropenia (8%). 47% of pts in A+E arm required E dose holds/reductions. Discontinuations due to AEs were similar between arms (21% vs 17.5% for A+E and A+P, respectively), as was duration of study therapy (median 4 and 5 cycles started). Conclusions: In pts with heavily pretreated EOC, median PFS was not prolonged when E was added to A compared to A alone and the combination resulted in greater toxicity. Clinical trial information: NCT02915523.

9565 Background: Nearly 50% of metastatic melanoma patients develop brain metastases, warranting further investigation into the biology of this event. Methods: We analyzed 132 MBM and 745 CM submitted to Caris Life Sciences from 2015-2018, using next generation sequencing of a 44 or 592 cancer-related gene panel, tumor mutational burden (TMB), and PD-L1 expression by IHC. Genomic alterations (GA), including somatic mutations or CNA, were reported. High TMB (TMB-H) was defined as ≥17 mut/Mb. Comparison of molecular profiles, including cancer-related genes and recurrently altered pathways, between tumor sites and by genomic subgroup (BRAF, NRAS, KIT, NF1), was performed using Fisher’s exact test. Results: Among 132 MBM, 72.7% were male, with median age 62 yo (range 25-83). The most common GAs among MBM were: BRAF (52.4%), NRAS (26.6%), CDKN2A (23.3%), NF1 (18.9%), TP53 (18%), ARID2 (13.8%), SETD2 (11.9%), and PBRM1 (7.5%). Compared to CM, MBM were more often TMB-H (53.7% v 38%, p = .025), with higher PD-L1 expression, using both a ≥1% (54.4% v 35.6%, p = .002) and ≥5% cut-off (32.9% v 15.9%, p = .0006). MBM showed higher rates of GAs among: SETD2 (11.9% v 1.9%, p = .0008), BRAF (52.4% v 35.6%, p = .017), PBRM1 (7.5% v 1.6%, p = .018), KRAS (4% v 1%, p = .026), CCND1 (2.9% v 0%, p = .03), and DICER1 (4.4% v 0.6%, p = .04), compared to CM. Alterations of the MAPK (87.9% v 77.8%, p = .015) and SWI/SNF (22.1% v 11.6%, p = .036) pathway were more frequent in MBM, than CM. When analyzed by genomic subgroup, BRAF+ MBM had more GAs involving the PI3K pathway (20% v 5.1%, p = .027), compared to BRAF WT MBM. NRAS+ MBM had higher PD-L1 expression at the ≥1% cutoff (66.7% v 38.6%, p = .05), but not ≥5%, compared to NRAS WT MBM. NF1+ MBM had more GAs involving the SWI/SNF (60% v 11.6%, p = .003) pathway, as opposed to NF1 WT MBM. No significant associations were seen between KIT status, TMB, PD-L1 or other pathways among MBM. Conclusions: In this cross-sectional study, MBM demonstrated higher PD-L1 expression and were more often TMB-H, compared to CM. MBM also featured more GAs involving BRAF and the MAPK pathway. We identified two novel genes, PBRM1 and SETD2, as well as recurrent alterations of the SWI/SNF pathway, supporting future studies of chromatin remodeling pathways in MBM.

HST/STIS spectra of the small clumps and filaments closest to the central star in VY CMa reveal that the very strong K I emission and TiO and VO molecular emission, long thought to form in a dusty circumstellar shell, actually originate in a few small clumps 100's of AU from the star. The K I lines are 10 to 20 times stronger in these nearest ejecta than on the star. The observations also confirm VO as a circumstellar molecule. In this letter we discuss the spectra of the features, their motions and ages, and the identification of the molecular emission. The strength of the atomic and molecular features in the small clumps present an astrophysical problem for the excitation process. We show that the clumps must have a nearly clear line of sight to the star's radiation., Comment: To appear in the Astrophysical Journal

425 Background: Avelumab, a human anti‒PD-L1 IgG1 antibody, is approved for the treatment of metastatic urothelial cancer (mUC) progressing after platinum chemotherapy in the US, Canada, and Israel. Here, we report an updated pooled analysis of 2 cohorts of avelumab-treated patients (pts) with mUC from the JAVELIN Solid Tumor study (NCT01772004). Methods: Pts with mUC whose disease had progressed after platinum-based therapy or were cisplatin ineligible received avelumab 10 mg/kg every 2 weeks. Tumors were assessed every 6 weeks by independent review (RECIST v1.1). Endpoints included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety (NCI CTCAE v4.0). Results: As of April 2018, 249 pts had received avelumab and had been followed for ≥2 years (median 2.7 years). Median treatment duration was 12.0 weeks (IQR, 6.0-32.1), and 12 pts (4.8%) remained on treatment. Confirmed ORR in all evaluable pts (n = 242) was 16.5% (95% CI: 12.1%-21.8%; complete response in 4.1%). Median DOR was 20.5 mo (95% CI: 9.7-not estimable), and the Kaplan-Meier (K-M) estimate of 12-mo DOR was 65.4% (95% CI: 47.0%-78.8%). Median PFS was 1.6 mo (95% CI: 1.4-2.7 mo), median OS was 7.0 mo (95% CI: 5.9-8.5 mo), and the K-M 12-mo and 24-mo OS rates were 35.9% (95% CI: 29.9%-42.0%) and 20.1% (95% CI: 15.2%-25.4%), respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 71.1% of pts (177/249), most commonly infusion-related reactions (24.1%), fatigue (18.1%) and rash (18.1%). Grade ≥3 TRAEs occurred in 11.6% of pts (29/249), most commonly fatigue (1.6%), elevated lipase (1.6%), and pneumonitis (1.2%). Ten pts (4.0%) discontinued avelumab due to a TRAE. There was 1 treatment-related death (pneumonitis). Conclusions: Avelumab showed durable clinical activity and had a manageable safety profile in pts with mUC. A phase 3 trial of avelumab in the maintenance setting after first-line platinum-based therapy for mUC is ongoing. Clinical trial information: NCT01772004.

In an effort to better understand the contribution of terrestrial protons to the counter background, we have developed a model to examine the production of protons, within an ionization counter from the interaction of incident neutrons on the counter material. Results of high energy proton irradiation on an UltraLo-1800 XIA alpha-particle counter are shown which indicate that the active signal discrimination is very effective at rejecting most of the detected events. A Poisson model is described which gives guidance on making appropriate measurement times and acceptance criteria for detectors with a range of backgrounds.

Purpose: Heat shock protein 90 (HSP90) is required for the proper folding, function, and stability of various client proteins, two of which (KIT and PDGFRα) are critical in the pathogenesis and progression of gastrointestinal stromal tumors (GIST). This phase I study investigated the safety and maximum tolerated dose (MTD) of retaspimycin hydrochloride (IPI-504), a novel potent and selective HSP90 inhibitor, in patients with metastatic and/or unresectable GIST or other soft-tissue sarcomas (STS). Experimental Design: IPI-504 was administered intravenously at doses ranging from 90 to 500 mg/m2 twice weekly for 2 weeks on/1 week off. Safety, pharmacokinetic, and pharmacodynamic profiles were determined. Response was assessed by Response Evaluation Criteria for Solid Tumors (RECIST) 1.0 and optionally via 18-fluorodeoxyglucose positron emission tomography (18-FDG-PET) imaging. Results: Fifty-four patients received IPI-504; 37 with GIST and 17 with other STS. The MTD was 400 mg/m2 twice weekly for 2 weeks on/1 week off. Common related adverse events were fatigue (59%), headache (44%), and nausea (43%). Exposure to IPI-504, 17-AAG, and 17-AG increased with IPI-504 dose. Stable disease (SD) was observed in 70% (26 of 37) of patients with GIST and 59% (10 of 17) of patients with STS. There was one confirmed partial response (PR) in a patient with GIST and one PR in a patient with liposarcoma. Metabolic partial responses occurred in 11 of 29 (38%) patients with GIST. Conclusions: In this study of advanced GIST or other STS, IPI-504 was generally well-tolerated with some evidence of antitumor activity, serving as a clinical proof-of-concept that HSP90 inhibition remains a promising strategy. Clin Cancer Res; 19(21); 6020–9. ©2013 AACR.

Dabrafenib is a small-molecule inhibitor of BRAF kinase activity that is currently being developed for the treatment of BRAF V600 mutation-positive melanoma. This clinical, open-label, two-cohort (n = 14 per cohort), randomized study was designed to evaluate the effect of drug substance particle size, and food on the plasma pharmacokinetics of a single oral dose of dabrafenib in patients with BRAF V600 mutation-positive solid tumors. In addition, an exploratory cross-cohort comparison of the relative bioavailability of single-dose dabrafenib administered in gelatin and hydroxypropyl methylcellulose (HPMC) capsules was performed. Higher bioavailability was noted with nonmicronized drug substance (larger particle size), under fasting conditions, and with HPMC capsules. Initial dissolution results at pH 1.2 showed higher dissolution of gelatin relative to HPMC capsules inconsistent with clinical data. Subsequent in vitro dissolution studies were conducted in fasted-state simulated gastric fluid over a 24-h period and showed that HPMC capsules reached a higher percentage of dabrafenib dissolved than gelatin capsules. The presence of HPMC is believed to inhibit precipitation of dabrafenib as the freebase, thereby maintaining a supersaturated solution over an extended period of time. Dabrafenib has been administered in pivotal clinical studies on an empty stomach using micronized drug substance in HPMC capsules. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3100–3109, 2013

Aurora kinase inhibitors (AKIs) are a class of antimitotic, small-molecule anticancer agents. MSC1992371A is an AKI being evaluated for the treatment of patients with solid tumors. This phase I, open-label, dose-escalation study determined the maximum tolerated dose (MTD) of MSC1992371A in different dosing schedules in patients with locally advanced or metastatic solid tumors. MSC1992371A was administered on days 1 and 8 (schedule 1) or on days 1, 2, and 3 (schedule 2) of a 21-day cycle. The study was expanded with a third schedule (study drug on days 1-3 and 8-10). Adverse events were monitored throughout the study. Antitumor efficacy, drug pharmacokinetics, and pharmacodynamics were evaluated. Ninety-two patients were enrolled. MSC1992371A was dosed over eight levels in schedules 1 and 2, and the MTD was determined as 74 mg/m(2) per cycle for both schedules and as 60 mg/m(2) in schedule 3, albeit only in three patients due to discontinuation of the study. Overall, the most common grade 3 or 4 treatment-emergent adverse events were neutropenia, febrile neutropenia, thrombocytopenia, anemia, and fatigue. The most frequent dose-limiting toxicity over all schedules was neutropenia. MSC1992371A plasma concentrations tended to increase with increasing dose levels. Although no complete or partial responses were seen, stable disease ≥3 months was observed in 11 patients. Analysis for markers of target modulation and pharmacodynamics effects was unsuccessful. MSC1992371A was generally well tolerated in patients, with mainly transient hematologic toxicities apparent at an MTD of 60-74 mg/m(2)/21-day cycle, independent of dosing frequency.

To determine the recommended/maximum tolerated dose (MTD), pharmacokinetics (PK), and safety profile of tasisulam sodium (hereafter tasisulam), a novel anticancer agent.In this phase I study, tasisulam was administered as a 24-h continuous intravenous infusion on day 1, every 28 days, to patients with advanced solid tumors. A flat-dosing schema was planned for four cohorts of 3-6 patients: 600, 1,200, 2,000, and 2,500 mg.Twenty-six patients were enrolled. No dose-limiting toxicities (DLTs) were observed until cohort 3 (grade 3 hyperbilirubinemia). Interim PK analyses of this and another ongoing phase I study suggested that a lower dose after cycle 1 was necessary for doses ≥2,500 mg because of the long half-life of tasisulam (~14 days). Therefore, a loading dose of 2,500 mg followed by a chronic dose of 1,750 mg was implemented for cohort 4; one patient developed DLT (grade 4 neutropenia), and another developed grade 3 thrombocytopenia in cycles 2 and 3. These findings, together with PK data, which indicated a disproportionate increase in free drug relative to total tasisulam concentrations at doses2,500 mg, led to the determination of the 2,500-/1,750-mg regimen as the MTD. Eight patients had stable disease, and two patients unconfirmed partial responses.When administered as a flat-dose, 24-h infusion, the MTD of tasisulam was a loading dose of 2,500 mg followed by a chronic dose of 1,750 mg, every 28 days. Consistent with the profile of the 2-h infusion in clinical development, bone marrow suppression was the major DLT.

Summary Background This trial evaluated the safety, tolerability and maximum tolerated dose (MTD) of afatinib, a novel ErbB Family Blocker. Methods In this open-label, dose-escalation Phase I study, afatinib was administered continuously, orally, once-daily for 28 days to patients with advanced or metastatic solid tumors. Dose escalation was performed in a 3 + 3 design, with a starting dose of 10 mg/day (d); doses were doubled for each successive cohort until the MTD was defined. The MTD cohort was expanded to a total of 19 patients. Incidence and severity of adverse events (AEs), antitumor activity and pharmacokinetics were assessed. Results Thirty patients received at least one dose of afatinib. Twenty-nine patients were evaluable for response. Dose-limiting toxicities (DLTs) consisting of Grade 3 diarrhea were observed in two out of three patients treated at 60 mg/d. The MTD was determined at 40 mg/d. The most frequent treatment-related AEs were diarrhea and mucosal inflammation reported in 76.7 % and 43.3 % of patients respectively. Five patients had stable disease with a median progression-free survival of 111 days. No objective responses occurred. Pharmacokinetic data showed no deviation from dose-proportionality and steady-state was reached on Day 8 at the latest. Conclusions Afatinib was well tolerated with manageable side effects when administered once-daily, continuously at a dose of 40 mg.

Background This study examined whether starting buprenorphine treatment prior to prison and after release from prison would be associated with better drug treatment outcomes and whether males and females responded differently to the combination of in-prison treatment and post-release service setting. Methods Study design was a 2 (In-Prison Treatment: Condition: Buprenorphine Treatment: vs. Counseling Only) × 2 [Post-Release Service Setting Condition: Opioid Treatment: Program (OTP) vs. Community Health Center (CHC)] × 2 (Gender) factorial design. The trial was conducted between September 2008 and July 2012. Follow-up assessments were completed in 2014. Participants were recruited from two Baltimore pre-release prisons (one for men and one for women). Adult pre-release prisoners who were heroin-dependent during the year prior to incarceration were eligible. Post-release assessments were conducted at 1, 3, 6, and 12-month following prison release. Results Participants (N = 211) in the in-prison treatment condition effect had a higher mean number of days of community buprenorphine treatment compared to the condition in which participants initiated medication after release (P = 0.005). However, there were no statistically significant hypothesized effects for the in-prison treatment condition in terms of: days of heroin use and crime, and opioid and cocaine positive urine screening test results (all Ps > 0.14) and no statistically significant hypothesized gender effects (all Ps > 0.18). Conclusions Although initiating buprenorphine treatment in prison compared to after-release was associated with more days receiving buprenorphine treatment in the designated community treatment program during the 12-months post-release assessment, it was not associated with superior outcomes in terms of heroin and cocaine use and criminal behavior.

The supernova impostor PSN J09132750+7627410 in NGC 2748 reached a maximum luminosity of approximately -14 mag. It was quickly realized that its was not a true supernova, but another example of a non-terminal giant eruption. PSN J09132750+7627410 is distinguished by multiple P Cygni absorption minima in the Balmer emission lines that correspond to outflow velocities of -400, -1100, and -1600 km/s. Multiple outflows have been observed in only a few other objects. In this paper we describe the evolution of the spectrum and the P Cygni profiles for three months past maximum, the post-maximum formation of a cool, dense wind, and the identification of a possible progenitor. One of the possible progenitors is an infrared source. Its pre-eruption spectral energy distribution suggests a bolometric luminosity of -8.3 mag and a dust temperature of 780 degrees K. If it is the progenitor it is above the AGB limit unlike the intermediate luminosity red transients. The three P Cygni profiles could be due to ejecta from the current eruption, the wind of the progenitor, or previous mass loss events. We suggest that they were all formed as part of the same high mass loss event and are due to material ejected at different velocities or energies. We also suggest that multiple outflows during giant eruptions may be more common than reported., To appear in the Astrophysical Journal

Purpose To investigate the safety and efficacy of durvalumab, a human monoclonal antibody that binds programmed cell death ligand-1 (PD-L1), and the role of PD-L1 expression on clinical response in patients with advanced urothelial bladder cancer (UBC). Methods A phase 1/2 multicenter, open-label study is being conducted in patients with inoperable or metastatic solid tumors. We report here the results from the UBC expansion cohort. Durvalumab (MEDI4736, 10 mg/kg every 2 weeks) was administered intravenously for up to 12 months. The primary end point was safety, and objective response rate (ORR, confirmed) was a key secondary end point. An exploratory analysis of pretreatment tumor biopsies led to defining PD-L1–positive as ≥ 25% of tumor cells or tumor-infiltrating immune cells expressing membrane PD-L1. Results A total of 61 patients (40 PD-L1–positive, 21 PD-L1–negative), 93.4% of whom received one or more prior therapies for advanced disease, were treated (median duration of follow-up, 4.3 months). The most common treatment-related adverse events (AEs) of any grade were fatigue (13.1%), diarrhea (9.8%), and decreased appetite (8.2%). Grade 3 treatment-related AEs occurred in three patients (4.9%); there were no treatment-related grade 4 or 5 AEs. One treatment-related AE (acute kidney injury) resulted in treatment discontinuation. The ORR was 31.0% (95% CI, 17.6 to 47.1) in 42 response-evaluable patients, 46.4% (95% CI, 27.5 to 66.1) in the PD-L1–positive subgroup, and 0% (95% CI, 0.0 to 23.2) in the PD-L1–negative subgroup. Responses are ongoing in 12 of 13 responding patients, with median duration of response not yet reached (range, 4.1+ to 49.3+ weeks). Conclusion Durvalumab demonstrated a manageable safety profile and evidence of meaningful clinical activity in PD-L1–positive patients with UBC, many of whom were heavily pretreated.

There is growing interest in the potential role of exercise in the reduction of depressive symptoms. The aim of this meta-analysis was to examine whether exercise reduces depressive symptoms amongst depressed adolescents. The following databases were searched on 30 January 2015: MEDLINE, PsychINFO, SPORTDiscuss and PUBMED. Studies were included if they examined exercise interventions amongst adolescents with clinical levels of depressive symptoms, were published in peer-reviewed journals in the English language and contained a control/comparison group. Of 6631 retrieved studies, eight studies were included in the meta-analysis. Meta-analysis was conducted using a random effects model due to the high level of heterogeneity identified amongst studies ( I

Extended-release naltrexone, a sustained-release monthly injectable formulation of the full mu-opioid receptor antagonist, is effective for the prevention of relapse to opioid dependence. Data supporting its effectiveness in U.S. criminal justice populations are limited.In this five-site, open-label, randomized trial, we compared a 24-week course of extended-release naltrexone (Vivitrol) with usual treatment, consisting of brief counseling and referrals for community treatment programs, for the prevention of opioid relapse among adult criminal justice offenders (i.e., persons involved in the U.S. criminal justice system) who had a history of opioid dependence and a preference for opioid-free rather than opioid maintenance treatments and who were abstinent from opioids at the time of randomization. The primary outcome was the time to an opioid-relapse event, which was defined as 10 or more days of opioid use in a 28-day period as assessed by self-report or by testing of urine samples obtained every 2 weeks; a positive or missing sample was computed as 5 days of opioid use. Post-treatment follow-up occurred at weeks 27, 52, and 78.A total of 153 participants were assigned to extended-release naltrexone and 155 to usual treatment. During the 24-week treatment phase, participants assigned to extended-release naltrexone had a longer median time to relapse than did those assigned to usual treatment (10.5 vs. 5.0 weeks, P0.001; hazard ratio, 0.49; 95% confidence interval [CI], 0.36 to 0.68), a lower rate of relapse (43% vs. 64% of participants, P0.001; odds ratio, 0.43; 95% CI, 0.28 to 0.65), and a higher rate of opioid-negative urine samples (74% vs. 56%, P0.001; odds ratio, 2.30; 95% CI, 1.48 to 3.54). At week 78 (approximately 1 year after the end of the treatment phase), rates of opioid-negative urine samples were equal (46% in each group, P=0.91). The rates of other prespecified secondary outcome measures--self-reported cocaine, alcohol, and intravenous drug use, unsafe sex, and reincarceration--were not significantly lower with extended-release naltrexone than with usual treatment. Over the total 78 weeks observed, there were no overdose events in the extended-release naltrexone group and seven in the usual-treatment group (P=0.02).In this trial involving criminal justice offenders, extended-release naltrexone was associated with a rate of opioid relapse that was lower than that with usual treatment. Opioid-use prevention effects waned after treatment discontinuation. (Funded by the National Institute on Drug Abuse; ClinicalTrials.gov number, NCT00781898.).

Recent supernova and transient surveys have revealed an increasing number of non-terminal stellar eruptions. Though the progenitor class of these eruptions includes the most luminous stars, little is known of the pre-supernova mechanics of massive stars in their most evolved state, thus motivating a census of possible progenitors. From surveys of evolved and unstable luminous star populations in nearby galaxies, we select a sample of yellow and red supergiant candidates in M31 and M33 for review of their spectral characteristics and spectral energy distributions. Since the position of intermediate and late-type supergiants on the color-magnitude diagram can be heavily contaminated by foreground dwarfs, we employ spectral classification and multi-band photometry from optical and near-infrared surveys to confirm membership. Based on spectroscopic evidence for mass loss and the presence of circumstellar dust in their SEDs, we find that $30-40\%$ of the yellow supergiants are likely in a post-red supergiant state. Comparison with evolutionary tracks shows that these mass-losing, post-RSGs have initial masses between $20-40\,M_{\odot}$. More than half of the observed red supergiants in M31 and M33 are producing dusty circumstellar ejecta. We also identify two new warm hypergiants in M31, J004621.05+421308.06 and J004051.59+403303.00, both of which are likely in a post-RSG state., Accepted for publication in ApJ. 34 pages, 11 figures

Purpose The objective was to determine the safety and clinical activity of atezolizumab (MPDL3280A), a humanized programmed death-ligand 1 (PD-L1) antibody, in renal cell carcinoma (RCC). Exploratory biomarkers were analyzed and associated with outcomes. Patients and Methods Seventy patients with metastatic RCC, including clear cell (ccRCC; n = 63) and non–clear cell (ncc; n = 7) histologies, received atezolizumab intravenously every 3 weeks. PD-L1 expression was scored at four diagnostic levels (0/1/2/3) that were based on PD-L1 staining on tumor cells and tumor-infiltrating immune cells (IC) with the SP142 assay. Primary end points were safety and toxicity; secondary end points assessed clinical activity per Response Evaluation Criteria in Solid Tumors version 1.1 and immune-related response criteria. Plasma and tissue were analyzed for potential biomarkers of atezolizumab response. Results Grade 3 treatment-related and immune-mediated adverse events occurred in 17% and 4% of patients, respectively, and there were no grade 4 or 5 events. Sixty-three patients with ccRCC were evaluable for overall survival (median, 28.9 months; 95% CI, 20.0 months to not reached) and progression-free survival (median, 5.6 months; 95% CI, 3.9 to 8.2 months), and 62 patients were evaluable for objective response rate (ORR; 15%; 95% CI, 7% to 26%). ORR was evaluated on the basis of PD-L1 IC expression (IC1/2/3: n = 33; 18%; 95% CI, 7% to 35%; and IC0: n = 22; 9%; 95% CI, 1% to 29%). The ORR for patients with Fuhrman grade 4 and/or sarcomatoid histology was 22% (n = 18; 95% CI, 6% to 48%). Decreases in circulating plasma markers and acute-phase proteins and an increased baseline effector T-cell–to–regulatory T-cell gene expression ratio correlated with response to atezolizumab. Conclusion Atezolizumab demonstrated a manageable safety profile and promising antitumor activity in patients with metastatic RCC. Correlative studies identified potential predictive and pharmacodynamic biomarkers. These results have guided ongoing studies and combinations with atezolizumab in RCC.

Etiologies of a thickened stalk include inflammatory, neoplastic, and idiopathic origins, and the underlying diagnosis may remain occult. We report a patient with a thickened pituitary stalk (TPS) and papillary thyroid carcinoma (PTC) whose diagnosis remained obscure until a skin lesion appeared. The patient presented with PTC, status postthyroidectomy, and I131therapy. PTC molecular testing revealed BRAF mutant (V600E, GTC>GAG). She had a 5-year history of polyuria/polydipsia. Overnight dehydration study confirmed diabetes insipidus (DI). MRI revealed TPS with loss of the posterior pituitary bright spot. Evaluation showed hypogonadotropic hypogonadism and low IGF-1. Chest X-ray and ACE levels were normal. Radiographs to evaluate for extrapituitary sites of Langerhans Cell Histiocytosis (LCH) were unremarkable. Germinoma studies were negative: normal serum and CSF beta-hCG, alpha-fetoprotein, and CEA. Three years later, the patient developed vulvar labial lesions followed by inguinal region skin lesions, biopsy of which revealed LCH. Reanalysis of thyroid pathology was consistent with concurrent LCH, PTC, and Hashimoto’s thyroiditis within the thyroid. This case illustrates that one must be vigilant for extrapituitary manifestations of systemic diseases to diagnose the etiology of TPS. An activating mutation of the protooncogene BRAF is a potential unifying etiology of both PTC and LCH.

We present high-angular (0.17$-$0.35 arcsec) resolution imaging polarimetric observations of Mrk 231 in the 3.1 $\mu$m filter using MMT-Pol on the 6.5-m MMT, and in the 8.7 $\mu$m, 10.3 $\mu$m, and 11.6 $\mu$m filters using CanariCam on the 10.4-m Gran Telescopio CANARIAS. In combination with already published observations, we compile the 1$-$12 $\mu$m total and polarized nuclear spectral energy distribution (SED). The total flux SED in the central 400 pc is explained as the combination of 1) a hot (731 $\pm$ 4 K) dusty structure, directly irradiated by the central engine, which is at 1.6 $\pm$ 0.1 pc away and attributed to be in the pc-scale polar region, 2) an optically-thick, smooth and disk-like dusty structure (`torus') with an inclination of 48 $\pm$ 23$^{\circ}$ surrounding the central engine, and 3) an extinguished (A$_{\mbox{V}} =$ 36 $\pm$ 5 mag) starburst component. The polarized SED decreases from 0.77 $\pm$ 0.14 per cent at 1.2 $\mu$m to 0.31 $\pm$ 0.15 per cent at 11.6 $\mu$m and follows a power-law function, $\lambda^{\sim0.57}$. The polarization angle remains constant ($\sim$108$^{\circ}$) in the 1$-$12 $\mu$m wavelength range. The dominant polarization mechanism is explained as scattering off hot dust grains in the pc-scale polar regions., Comment: 9 pages, 2 figures. Accepted for publication in MNRAS

In a recent paper, Smith and Tombleson (2015) state that the Luminous Blue Variables (LBVs) in the Milky Way and the Magellanic Clouds are isolated; that they are not spatially associated with young O-type stars. They propose a novel explanation that would overturn the standard view of LBVs. In this paper we test their hypothesis for the LBVs in M31 and M33 as well as the LMC and SMC. In M31 and M33, the LBVs are associated with luminous young stars and supergiants appropriate to their luminosities and positions on the HR Diagram. Moreover, in the Smith and Tombleson scenario most of the LBVs should be runaway stars, but the stars' velocities are consistent with their positions in the respective galaxies. In the Magellanic Clouds, those authors' sample was a mixed population. We reassess their analysis, removing seven stars that have no clear relation to LBVs. When we separate the more massive classical and the less luminous LBVs, the classical LBVs have a distribution similar to the late O-type stars, while the less luminous LBVs have a distribution like the red supergiants. None of the confirmed LBVs have high velocities or are candidate runaway stars. These results support the accepted description of LBVs as evolved massive stars that have shed a lot of mass, and are now close to their Eddington limit., Comment: To appear in the Astrophysical Journal With an expanded discussion of statistical errors

Purpose: TRC105 is a chimeric IgG1 monoclonal antibody that binds CD105 (endoglin). This first-in-human, phase I, open-label study assessed safety, pharmacokinetics, and antitumor activity of TRC105 in patients with advanced refractory solid tumors. Patients and Methods: Patients received escalating doses of intravenous TRC105 until disease progression or unacceptable toxicity using a standard 3 + 3 phase I design. Results: Fifty patients were treated with escalating doses of TRC105. The maximum tolerated dose (MTD) was exceeded at 15 mg/kg every week because of dose-limiting hypoproliferative anemia. TRC105 exposure increased with increasing dose, and continuous serum concentrations that saturate CD105 receptors were maintained at 10 mg/kg weekly (the MTD) and 15 mg/kg every 2 weeks. Common adverse events including anemia, telangiectasias, and infusion reactions reflected the mechanism of action of the drug. Antibodies to TRC105 were not detected in patients treated with TRC105 from Chinese hamster ovary cells being used in ongoing phase Ib and phase II studies. Stable disease or better was achieved in 21 of 45 evaluable patients (47%), including two ongoing responses at 48 and 18 months. Conclusion: TRC105 was tolerated at 10 mg/kg every week and 15 mg/kg every 2 weeks, with a safety profile that was distinct from that of VEGF inhibitors. Evidence of clinical activity was seen in a refractory patient population. Ongoing clinical trials are testing TRC105 in combination with chemotherapy and VEGF inhibitors and as a single agent in prostate, ovarian, bladder, breast, and hepatocellular cancer. Clin Cancer Res; 18(17); 4820–9. ©2012 AACR.

Background This secondary analysis examined the impact of methadone initiated in prison on post-release HIV risk behaviors. The parent study was a three-group randomized clinical trial in which participants received drug abuse counseling in prison and were randomly assigned to: (1) passive referral to substance abuse treatment upon release; (2) guaranteed methadone treatment admission upon release; and (3) methadone in prison and guaranteed continuation of methadone upon release.

A manufacturable platform of CMOS, RF and opto-electronic devices fully PDK enabled to demonstrate a 4×25 Gb/s reference design is presented. With self-aligned fiber attach, this technology enables low-cost O-band data-com transceivers. In addition, this technology can offer enhanced performance and yield in hybrid-assembly for applications at 25 Gbaud and beyond.

Creating, implementing and evaluating substance abuse interventions, especially medication-assisted treatments, for prisoners, parolees, and probationers with histories of heroin addiction is an especially challenging endeavor because of the difficulty in coordinating and achieving cooperation among diverse criminal justice, substance abuse treatment, research, and social service agencies, each with its own priorities and agenda. In addition, there are special rules that must be followed when conducting research with criminal justice-involved populations, particularly prisoners. The following case studies will explore the authors' experience of over 10 years conducting pharmacotherapy research using methadone, buprenorphine, and naltrexone with criminal justice populations. The major obstacles and how they were overcome are presented. Finally, recommendations are provided with regard to implementing and conducting research with criminal justice populations.