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Purpose: Two phase I dose-escalation studies were conducted to determine the maximum tolerated dose (MTD) and safety profile of the G2 checkpoint abrogator CBP501, as a single agent and in combination with cisplatin. Experimental Design: Patients with advanced solid tumors were treated with CBP501 alone (D1/D8/D15, q4w, from 0.9 mg/m2), or with cisplatin (both on D1, q3w, from 3.6 mg/m2 CBP501, 50 mg/m2 cisplatin). Dose escalation proceeded if dose-limiting toxicity (DLT) was observed in 1 or less of 3 to 6 patients; CBP501 dose increments were implemented according to the incidence of toxicity. MTD was determined from DLTs occurring during the first two cycles. Results: In the combination study, the DLT was a histamine-release syndrome (HRS) occurring 10 to 60 minutes after initiating infusion that was attenuated by prophylaxis comprising dexamethasone, diphenhydramine, ranitidine, and loratadine. The MTD was 25 mg/m2 CBP501 and 75 mg/m2 cisplatin, with two patients at the highest dose (36.4 mg/m2 CBP501, 75 mg/m2 cisplatin) experiencing grade 3 HRS. The only DLT with monotherapy was transient G3 rise of troponin in one patient. Grade 3 to 4 treatment–related events were rare. Promising activity was observed with CBP501/cisplatin, mainly in ovarian and mesothelioma patients who had previously progressed on platinum-containing regimens. Among ovarian cancer patients, low expression of DNA repair proteins was associated with partial response or stable disease. Conclusions: CBP501 is well tolerated in patients as monotherapy and with cisplatin. At the recommended phase II dose (RP2D), the combination is feasible and HRS manageable with prophylaxis. Evidence of antitumor activity was observed in platinum-resistant patients. Clin Cancer Res; 17(10); 3431–42. ©2011 AACR.

BACKGROUND: On the basis of potential additive or synergistic immunostimulatory antitumor effects, in this phase 1 study, the authors evaluated the combination of sunitinib and tremelimumab (CP-675206; an antibody against cytotoxic T-lymphocyte–associated antigen 4 [CTLA4]) in patients with metastatic renal cell carcinoma (mRCC) was evaluated. METHODS: Adult patients with mRCC who had received ≤1 previous systemic treatment received tremelimumab (6 mg/kg, 10 mg/kg, or 15 mg/kg) intravenously once every 12 weeks and oral sunitinib (50 mg daily for 4 weeks then 2 weeks off or 37.5 mg daily as a continuous dose). The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives were to assess antitumor activity, safety, and pharmacokinetics. RESULTS: Twenty-eight patients were enrolled. Two of 5 patients who received 50 mg sunitinib plus tremelimumab 6 mg/kg experienced dose-limiting toxicities (DLTs), and no further enrollment to the combination with sunitinib 50 mg dosing was pursued. Among patients who received continuous sunitinib 37.5 mg daily, 1 of 7 patients who received tremelimumab 10 mg/kg plus sunitinib suffered a sudden death, and 3 of 6 patients who received tremelimumab 15 mg/kg plus sunitinib experienced DLTs. An expansion cohort (n = 7) was enrolled at tremelimumab 10 mg/kg plus sunitinib 37.5 mg daily; 3 of those patients experienced DLTs. Overall, rapid-onset renal failure was the most common DLT. Nine of 21 patients who were evaluable for response achieved partial responses (43%; 95% confidence interval, 22%-66%), and 4 of those responses were ongoing at the time of the current report. CONCLUSIONS: In this study of tremelimumab plus sunitinib, rapid-onset acute renal failure was observed unexpectedly, and further investigation of tremelimumab doses >6 mg/kg plus sunitinib 37.5 mg daily is not recommended. Preclinical investigation may be warranted to understand the mechanism of renal toxicity. Cancer 2011. © 2010 American Cancer Society.

Background: This is an update of the safety and efficacy of durvalumab monotherapy in pts with locally advanced/metastatic urothelial carcinoma (UC) from an ongoing, phase 1/2 open-label study (NCT01693562). Methods: Pts received 10 mg/kg every 2 weeks up to 12 months or until unacceptable toxicity, progression, or starting another anticancer therapy. Pts were stratified by tumor PD-L1 expression (Ventana PD-L1 [SP263] Assay [PD-L1 cutoff: ≥25% of tumor cells and/or immune cells with membrane staining]) and treatment line. Results: As of the data cutoff (16Oct2017), 201 UC pts with Stage IV disease received treatment, with a median follow-up of 16.9 months (range, 0.4-37.7). Across treatment lines, objective response rate (ORR) by blinded independent central review was 17.4% (95% CI, 12.4, 23.4) in all pts; 27.5% in the PD-L1 ≥25% group vs 5.8% in the PD-L1 Conclusions: With extended follow-up, durvalumab continues to show durable clinical activity in UC pts, especially in the PD-L1 ≥25% group with an acceptable toxicity profile. PD-L1 ≥25%PD-L1 Citation Format: Peter O'Donnell, Christophe Massard, Bhumsuk Keam, Sang-We Kim, Terry Friedlander, Myung-Ju Ahn, Michael Ong, Michael Gordon, Marcus Butler, Scott Antonia, Gerardo Colon-Otero, Martin Gutierrez, Sumati Gupta, Alexander Spira, Alexandra Drakaki, Michele Maio, Feng Xiao, Natasha Angra, Shaad Abdullah, Thomas Powles. Updated efficacy and safety profile of durvalumab monotherapy in urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT031.

PurposeApoptosis ligand 2/tumor necrosis factor–related apoptosis-inducing ligand (Apo2L/TRAIL)—a member of the tumor necrosis factor cytokine family—induces apoptosis by activating the extrinsic pathway through the proapoptotic death receptors DR4 and DR5. Recombinant human Apo2L/TRAIL (rhApo2L/TRAIL) has broad potential as a cancer therapy. To the best of our knowledge, this is the first in-human clinical trial to assess the safety, tolerability, pharmacokinetics, and antitumor activity of multiple intravenous doses of rhApo2L/TRAIL in patients with advanced cancer.Patients and MethodsThis phase I, open-label, dose-escalation study treated patients with advanced cancer with rhApo2L/TRAIL doses ranging from 0.5 to 30 mg/kg/d, with parallel dose escalation for patients without liver metastases and with normal liver function (cohort 1) and for patients with liver metastases and normal or mildly abnormal liver function (cohort 2). Doses were given daily for 5 days, with cycles repeating every 3 weeks. Assessments included adverse events (AEs), laboratory tests, pharmacokinetics, and imaging to evaluate antitumor activity.ResultsSeventy-one patients received a mean of 18.3 doses; seven patients completed all eight treatment cycles. The AE profile of rhApo2L/TRAIL was similar in cohorts 1 and 2. The most common AEs were fatigue (38%), nausea (28%), vomiting (23%), fever (23%), anemia (18%), and constipation (18%). Liver enzyme elevations were concurrent with progressive metastatic liver disease. Two patients with sarcoma (synovial and undifferentiated) experienced serious AEs associated with rapid tumor necrosis. Two patients with chondrosarcoma experienced durable partial responses to rhApo2L/TRAIL.ConclusionAt the tested schedule and dose range, rhApo2L/TRAIL was safe and well tolerated. Dose escalation achieved peak rhApo2L/TRAIL serum concentrations equivalent to those associated with preclinical antitumor efficacy.

e24160Background: The degree of tumor infiltration by CD8 T cells is associated with favorable outcomes to immunotherapy. Biopsies to assess T cell infiltration are invasive and may not capture het...

4532Background: In Study 1108, durvalumab showed meaningful clinical activity in patients with UC, with an objective response rate (ORR) of 17.8% (PD-L1–positive patients: 27.6%) [Powles 2017, JAMA...

1032Background: Matrix metalloproteinase-9 (MMP-9) is highly expressed in several advanced cancers, including metastatic breast cancer, and confers an adverse prognosis. In a preclinical breast can...

3540Background: Monalizumab (IPH2201) is a humanized IgG4 antibody targeting CD94/NKG2a to suppress inhibitory signaling by tumors on NK cells. The combination of monalizumab and durvalumab (anti-P...

2547Background: Citarinostat is an oral, selective histone deacetylase 6 inhibitor that inhibits growth of solid tumor cell lines and exhibits potent synergy with Pac in preclinical studies. We con...

11511Background: GIST is driven by primary and secondary driver mutations in KIT/PDGFRα and cell-free tumor (ct) DNA may provide the opportunity to assess disease status and response to therapy. Th...

We investigate the sputtering behavior and depth resolution upon low energy ion irradiation during Secondary Ion Mass Spectrometry (SIMS) depth profiling of GaAs. We present a systematic and quantitative study of the impact of ion species, primary ion impact energy, and incident angle on the evolution of depth resolution, using a well-defined InGaAs/GaAs multilayer structure with highly abrupt hetero-interfaces. We demonstrate that for low energy O2+ ion beam irradiation, SIMS depth resolution becomes progressively degraded by (transient) incorporation of high surface O-concentration levels in the altered layer, leading to detrimental ion-beam induced formation of topography. In case of low energy oblique Cs+ ion beam irradiation, sputtering behavior of GaAs is well-behaved with no significant transient yield changes and a constant depth resolution. This enables SIMS depth profiling of sharp hetero-epitaxial III-V compound semiconductor structures and shallow dopant profiles with sufficiently good depth resolution with good detection efficiency.

272 Background: Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancers, making it an ideal imaging and therapeutic target of interest. The utility of the PSMA-targeted imaging agent 99mTc-EC0652 is being evaluated, along with biomarker analysis of circulating tumor cells (CTCs), in pts with mCRPC in a PSMA-targeted chemotherapeutic study. We now report the PSMA heterogeneity via CTC vs. imaging in the pt population treated to date. Methods: Patients were enrolled in 1 of 2 cohorts: mCRPC taxane naïve or taxane exposed. A total of 48 pts evaluated at the time of the data cut had baseline CT & bone scans performed in addition to a 99mTc-EC0652 SPECT/CT as a measure of imaging-based PSMA expression. 40 of 48 pts provided pre-treatment blood samples evaluable for CTC biomarker analysis, which included PSMA expression & were given percent homologous recombination deficiency (%HRD) scores. Four of the best and four of the worst responders were evaluated in more detail for imaging and CTC-based biomarker analysis as it related to clinical outcome. Results: 35 of 40 pts (88%) had detectable CTCs in their samples. 15 of the 35 (43%) pts had PSMA-positive CTCs. The 4 “non-responders” were on study for an average of 41 days and the 4 “responders” for an average of 256 days. Each group contained 2 taxane exposed & 2 taxane naïve patients. Of the 335 bone lesions analyzed by MDP, CT, 99mTc-EC0652, 333 (99.4%) were characterized as PSMApos based on their 99mTc-EC0652 SPECT/CT scan. Of the 26 soft tissue lesions analyzed by CT, all were characterized as PSMApos based on their 99mTc-EC0652 SPECT/CT scan. Seven (26.9%) of those lesions were CT positive (observed on CT scan). Each group had 2 pts that were CTC-based PSMApos & 2 that were PSMAneg. Their percent homologous recombination deficiency (%HRD) scores were of 0.60 [0.333, 1.0] for “non-responders” & 0.01 [0.0, 0.039] for “responders”. Conclusions: PSMA-based imaging showed a high percentage of positive lesions whereas CTC-based PMSA positivity is lower by comparison (43%). The discordance between the imaging results & CTC-based biomarkers, & the relative therapeutic predictive value, requires additional exploration. Clinical trial information: NCT02202447.

Research suggests that buprenorphine treatment may be a promising intervention for incarcerated individuals with heroin addiction histories. However, its implementation varies from corrections-based methadone because of unique challenges regarding dosing, administration, and regulation. Describing the first randomized clinical trial of prison-initiated buprenorphine treatment in the United States, this manuscript focuses on how these obstacles were overcome through collaboration among correctional, treatment, and research personnel. Building on the present authors' work in developing prison-based methadone treatment, and considering the lack of experience in implementing corrections-based buprenorphine programs in the United States, this manuscript may serve as a guide for interested corrections officials, treatment providers, and researchers.

Background: We report dose escalation results from a phase 1/2 trial of ASTX660 (NCT02503423). This non-peptidomimetic, dual XIAP and cIAP antagonist inhibits tumor cell lines at nanomolar concentrations and is active against xenografts. Methods: Study ASTX660-01, an open-label, multi-center, dose-escalation study in subjects with advanced cancers and lymphomas, used a 3+3 dose escalation design. Study drug was administered orally once daily in 28 day cycles of alternating 7 days on, then 7 days off therapy. Dose escalation was planned from a starting fixed 15 mg dose until the maximum tolerated dose (MTD) was reached. Endpoints included safety, MTD, recommended phase 2 dose (RP2D), pharmacokinetics, pharmacodynamics, and antitumor effects. Results: Forty-five subjects received at least 1 dose of ASTX660 (range 15 mg - 270 mg). Mean age was 62 years (range 36-77); 60% of subjects were female. Median duration of study therapy was 2 cycles (range 1-8). Four dose-limiting toxicities (DLTs) were observed: 3 at 270 mg QD (grade 3/4 lipase increased), and 1 at 210 mg QD (grade 3 lipase increased). These lipasemia DLTs were all asymptomatic. Most declined after dose interruption and did not recur after dose reduction. The MTD was 210 mg QD, and the RP2D was 180 mg QD. Common adverse events (AEs) included fatigue, lipasemia, and vomiting (29%); nausea and lymphopenia (27%); anemia (24%); rash and edema (20%); ALT increase and pruritus (18%); AST increase (16%); appetite decrease and diarrhea (13%); and amylasemia and hyponatremia (11%). Lipasemia and amylasemia appeared to be dose-related. Most AEs were CTCAE grades 1-2 and manageable with supportive treatment. Median time to peak plasma concentration (tmax) was 1 hour. ASTX660 t ½ was 15.3 hours at the RP2D. Day 1 and 7 AUC0-24h plasma exposures after 180 mg ASTX660 were 1450 (67%) and 2080 (62%) ng*hr/mL (geometric mean [CV]), respectively. Modest accumulation (1.4 fold) at Day 7 vs Day 1 was observed for ASTX660 AUC0-24h exposures but not for Cmax. Human RP2D exposure levels reached the biologically active exposure range seen in preclinical models. ASTX660 at all dose levels suppressed cIAP1 in peripheral blood mononuclear cells (PBMCs). At 180 mg cIAP1 suppression was sustained beyond the off-therapy week. A clinical response in cutaneous T cell lymphoma was observed at the 180-mg dose level. Conclusions: In phase 1, ASTX660 caused manageable toxicities, achieved target study drug exposures, and demonstrated both biologic and clinical activity at the RP2D. Enrollment to phase 2 expansion cohorts in lymphoma and other selected cancers is ongoing. Citation Format: Monica Mita, Patricia LoRusso, Michael S. Gordon, Aram Oganesian, Xiaoping Zhang, Roberta Ferraldeschi, Simone Jueliger, Harold N. Keer, Purvee Kumar, Chihche Lin, Edwin P. Rock, Alain Mita, Anthony W. Tolcher. Phase 1 study of IAP inhibitor ASTX660 in adults with advanced cancers and lymphomas [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A091.

Purpose Patients with advanced papillary renal cell cancer (pRCC) have poor survival after systemic therapy; the reported median survival time is 7 to 17 months. In this trial, we evaluated the efficacy of erlotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor in patients with advanced pRCC, a tumor type associated with wild-type von Hippel Lindau gene. Patients and Methods Patients with histologically confirmed, advanced, or metastatic pRCC were treated with erlotinib 150 mg orally once daily. A RECIST (Response Evaluation Criteria in Solid Tumors) response rate (RR) of ≥ 20% was considered a promising outcome. Secondary end points included overall survival and 6-month probability of treatment failure. Results Of 52 patients registered, 45 were evaluable. The overall RR was 11% (five of 45 patients; 95% CI, 3% to 24%), and the disease control rate was 64% (ie five partial response and 24 stable disease). The median overall survival time was 27 months (95% CI, 13 to 36 months). Probability of freedom from treatment failure at 6 months was 29% (95% CI, 17% to 42%). There was one grade 5 adverse event (AE) of pneumonitis, one grade 4 thrombosis, and nine other grade 3 AEs. Conclusion Although the RECIST RR of 11% did not exceed prespecified estimates for additional study, single-agent erlotinib yielded disease control and survival outcomes of interest with an expected toxicity profile. The design of future trials of the EGFR axis in pRCC should be based on preclinical or molecular data that define appropriate patient subgroups, new drug combinations, or potentially more active alternative schedules.

This study examined the impact of prison-initiated methadone maintenance at 12 months postrelease. Males with pre-incarceration heroin dependence (N = 204) were randomly assigned to (a) Counseling Only: counseling in prison, with passive referral to treatment upon release; (b) Counseling + Transfer: counseling in prison with transfer to methadone maintenance treatment upon release; and (c) Counseling + Methadone: counseling and methadone maintenance in prison, continued in the community upon release. The mean number of days in community-based drug abuse treatment were, respectively, Counseling Only, 23.1; Counseling + Transfer, 91.3; and Counseling + Methadone, 166.0 (p < .01); all pairwise comparisons were statistically significant (all ps < .01). Counseling + Methadone participants were also significantly less likely than participants in each of the other two groups to be opioid-positive or cocaine-positive according to urine drug testing. These results support the effectiveness of prison-initiated methadone for males in the United States. Further study is required to confirm the findings for women.

Aims This study examines the frequency and severity of arrest charges among heroin addicts randomly assigned to either interim methadone (IM) maintenance or to remain on a waiting list for methadone treatment. It was hypothesized that IM participants would have a: (1) lower number of arrests at 6 and 12 months and (2) lower mean crime severity scores at 6 and 12 months post-baseline. Methods Available official arrest data were obtained for all 319 study participants for a period of 2 years before and after study enrollment. Crime severity ratings of charges were made using an established measure of crime severity. Findings Participants randomly assigned to IM as compared to those on a waiting list had a significant reduction in number of arrests at 6 but not at 12 months from study enrollment. There were no significant differences in whether participants were arrested for a more severe crime but frequency of severe crime was relatively low in both groups. Additional post hoc analyses based on whether participants were in methadone treatment at 4 and 10 months after original random assignment to treatment condition revealed that those participants not in treatment at these follow-up assessment points were significantly more likely to be arrested and to have a higher mean crime severity rating at 12 and 24 months post-baseline assessment. Conclusions IM as compared to the waiting list condition, had a significant reduction in number of officially recorded arrests from baseline to 6 months post-baseline. Those who were enrolled in methadone treatment at the 4- and 10-month follow-up assessment, regardless of initial assignment, had fewer arrests at 12 and 24 months post-baseline.

BACKGROUND. ABT-510 is a substituted nonapeptide that mimics the antiangiogenic activity of the endogenous protein thrombospondin-1 (TSP-1). The current study was designed to establish the safety of ABT-510 in the treatment of patients with advanced malignancies on a once-daily (QD) and twice-daily dosing schedule. METHODS. Patients were randomly assigned to 1 of 6 dosing regimens: 20 mg, 50mg, or 100 mg QD or 10 mg, 25 mg, or 50 mg twice daily. ABT-510 was administered by subcutaneous bolus injection in cycles of 28 days. Tumor response and disease progression were monitored at 8-week intervals by computed tomography scan or magnetic resonance imaging. RESULTS. Thirty-six patients were randomly assigned in equal numbers to the 6 study regimens, with an additional 13 patients randomized to the 10-mg-twice-daily and 50-mg-twice-daily ABT-510 regimens. The expected pharmacokinetic target was achieved at all dose levels tested. The majority of adverse events were grade 1 or 2 (according to National Cancer Institute Common Toxicity Criteria [version 2]) and were not found to be dose related. The most frequently reported adverse events that were possibly related to ABT-510 included injection site reactions, asthenia, headache, and nausea. Grade 3 events considered to possibly be related included nausea, dyspnea, bone pain, constipation, vomiting, asthenia, and chills and tremors. One partial response was observed in a patient with carcinosarcoma who received 20 mg QD. The 6-month progression-free survival rate was 6%. Approximately 42% of patients (21 of 50 patients) had stable disease for ≥3 months. CONCLUSIONS. ABT-510 can be administered at doses of 20 mg/day to 100 mg/day without significant toxicity. In the current study, minimal antitumor activity was observed, which was similar to observations in other single-agent antiangiogenic trials. Cancer 2008. © 2008 American Cancer Society.

This study examined benefits of methadone maintenance among prerelease prison inmates. Incarcerated males with preincarceration heroin dependence ( n = 197) were randomly assigned to (a) group educational counseling (counseling only); (b) counseling, with opportunity to begin methadone maintenance on release (counseling + transfer); or (c) counseling and methadone maintenance in prison, with opportunity to continue methadone maintenance on release (counseling + methadone). At 90-day follow-up, counseling + methadone participants were significantly more likely than counseling-only and counseling + transfer participants to attend drug treatment ( p = .0001) and less likely to be reincarcerated ( p = .019). Counseling + methadone and counseling + transfer participants were significantly less likely (all ps < .05) to report heroin use, cocaine use, and criminal involvement than counseling-only participants. Follow-up is needed to determine whether these findings hold over a longer period.

Purpose This phase I study examined whether a heat shock protein (Hsp) 90 inhibitor tanespimycin (17-AAG; KOS-953) could be administered safely in combination with trastuzumab at a dose that inhibits Hsp90 function in vivo in lymphocytes. Patients and Methods Patients with an advanced solid tumor progressing during standard therapy were eligible. Patients were treated with weekly trastuzumab followed by intravenous tanespimycin, assessed in escalating dose levels. Results Twenty-five patients were enrolled onto four tanespimycin dose levels: 225 (n = 4), 300 (n = 3), 375 (n = 8), and 450 mg/m2 (n = 10). Dose-limiting toxicity (DLT) was observed at the third and fourth cohort (1 patient each): more than 2-week delay for grade 4 fatigue/grade 2 nausea and anorexia (375 mg/m2); more than 2-week delay for thrombocytopenia (450 mg/m2). Drug-related grade 3 toxicity included emesis, increased ALT, hypersensitivity reactions (two patients each), and drug-induced thrombocytopenia (n = 1). Common mild to moderate toxicities included fatigue, nausea, diarrhea, emesis, headache, rash/pruritus, increased AST/ALT, and anorexia. Pharmacokinetic analysis demonstrated no difference in tanespimycin kinetics with or without trastuzumab. Pharmacodynamic testing showed reactive induction of Hsp70 (a marker of Hsp90 inhibition) in lymphocytes at all dose levels. Antitumor activity was noted (partial response, n = 1; minor response, n = 4; stable disease ≥ 4 months, n = 4). Tumor regressions were seen only in patients with human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer. Conclusion Tanespimycin plus trastuzumab is well tolerated and has antitumor activity in patients with HER-2+ breast cancer whose tumors have progressed during treatment with trastuzumab. These data suggest that Hsp90 function can be inhibited in vivo to a degree sufficient to cause inhibition of tumor growth.

Purpose: Angiogenesis is a characteristic of renal cell carcinoma. ABT-510 is an angiogenesis inhibitor that mimics the antiangiogenic properties of thrombospondin-1. This study was designed to assess the safety and efficacy of ABT-510 in patients with advanced renal cell carcinoma. Experimental Design: Patients with previously untreated metastatic or unresectable renal cell carcinoma were randomized to treatment with one of two doses of ABT-510, self-administered s.c. twice daily in 28-day treatment periods without intervening rest periods. End points were progression-free survival (PFS), objective response rate, overall survival, and toxicity. Results: The objective response rate was 4% in the 10 mg twice daily group, and there were two unconfirmed PRs in the 100 mg twice daily group. Respective median PFS was 4.2 and 3.3 months, with a 6-month PFS of 39% and 32%. Median overall survival was 27.8 months (10 mg twice daily) and 26.1 months (100 mg twice daily). The most frequent adverse events were injection site reactions (84%), fatigue (50%), headache (20%), and nausea (19%). The incidence of treatment-related, grade 3/4 adverse events was low and included three bleeding episodes (gastrointestinal hemorrhage, intracranial hemorrhage, and hemoptysis) and one thrombotic event (deep vein thrombosis). No deaths were attributed to ABT-510. Conclusions: There was little evidence of clinical activity for ABT-510, and further evaluation as a single agent for treating advanced renal cell carcinoma is not warranted. The evidence of a favorable safety profile may justify further evaluation in combination therapy.

The following study, conducted in Puerto Rico, examined the feasibility of providing daily buprenorphine-naloxone (bup-nx) in prison and on release to 45 male inmates with histories of heroin addiction. Participants were assessed at study entry and at 1 month after release (N = 42; 93.3% follow-up rate). Treatment completers compared with noncompleters had significantly greater reductions in self-reported heroin use, cocaine use, and crime and were less likely to be opioid-positive according to urine drug testing. Despite study limitations, the short-term outcomes of this study suggest that bup-nx may contribute to reductions in readdiction to heroin and in criminal activities among re-entering male prisoners.

Integrins are heterodimeric cell adhesion receptors that mediate intercellular communication through cell-extracellular matrix interactions and cell-cell interactions. Integrins have been demonstrated to play a direct role in cancer progression, specifically in tumor cell survival, tumor angiogenesis, and metastasis. Therefore, agents targeted against integrin function have potential as effective anticancer therapies. Numerous anti-integrin agents, including monoclonal antibodies and small-molecule inhibitors, are in clinical development for the treatment of solid and hematologic tumors. This review focuses on the role of alpha(v) integrins in cancer progression, the current status of integrin-targeted agents in development, and strategies for the clinical development of anti-integrin therapies.

We tested specific gene polymorphisms known to be involved in the irinotecan (CPT-11) metabolic pathway. The combination of at least one SLCO1B1 521 T allele, one ABCB1 1236 C allele and one UGT1A1*28 variant 7 repeat demonstrated a statistically significant association with Grade 3/4 toxicities in metastatic colorectal cancer patients.

Background In a previously reported randomized controlled trial, formerly opioid-dependent prisoners were more likely to enter community drug abuse treatment when they were inducted in prison onto buprenorphine/naloxone (hereafter called buprenorphine) than when they received counseling without buprenorphine in prison (47.5% vs. 33.7%, p = 0.012) ( Gordon et al., 2014 ). In this communication we report on the results of the induction schedule and the adverse event profile seen in pre-release prisoners inducted onto buprenorphine. Method This paper examines the dose induction procedure, a comparison of the proposed versus actual doses given per week, and side effects reported for 104 adult participants who were randomized to buprenorphine treatment in prison. Self-reported side effects were analyzed using generalized estimated equations to determine changes over time in side effects. Results Study participants were inducted onto buprenorphine at a rate faster than the induction schedule. Of the 104 (72 males, 32 females) buprenorphine recipients, 64 (37 males, 27 females) remained on medication at release from prison. Nine participants (8.6%) discontinued buprenorphine because of unpleasant opioid side effects. There were no serious adverse events reported during the in-prison phase of the study. Constipation was the most frequent symptom reported (69 percent). Conclusion Our findings suggest that buprenorphine administered to non-opioid-tolerant adults should be started at a lower, individualized dose than customarily used for adults actively using opioids, and that non-opioid-tolerant pre-release prisoners can be successfully inducted onto therapeutic doses prior to release.

ABSTRACT Aims: To evaluate the safety and maximum tolerated dose (MTD) of afatinib combined with nintedanib. Materials & methods: Patients received afatinib 10–20 mg daily plus nintedanib 150–200 mg twice daily (28-day cycle). Dose escalation followed a 3+3 design. Results: Patients received afatinib/nintedanib: 10/150 mg (n = 11); 10/200 mg (n = 13; MTD); 20/200 mg (n = 4). Four patients had dose-limiting toxicities (all grade 3): increased alanine aminotransferase (afatinib/nintedanib: 10/150 mg), diarrhea (10/200 mg), dehydration (20/200 mg), diarrhea with elevated liver enzymes (20/200 mg). Frequent treatment-related adverse events were diarrhea, nausea, anorexia, fatigue and vomiting. In total, 14 patients (46.2%) had objective responses at the MTD. Conclusion: The MTD, afatinib 10 mg daily plus nintedanib 200 mg twice daily, had a manageable safety profile, but was considered subtherapeutic for Phase II evaluation.

Measurements of the soft error upset cross section for SOI FinFET SRAMs are compared to earlier generation PDSOI SRAMs, with the FinFET circuit showing 2–3 orders of magnitude lower soft error susceptibility. This improvement is shown by simulations to be due to the better electrostatic control of the channel in the FinFET.

The objective of this study was to evaluate the potential for a pharmacokinetic (PK) drug-drug interaction (DDI) between trastuzumab and carboplatin and to evaluate the potential effect of trastuzumab on the electrocardiogram QT interval. Here, we report the results of the PK DDI assessment and an interim safety analysis. Patients with metastatic or locally advanced, inoperable, human epidermal growth factor receptor 2-positive cancer received docetaxel and carboplatin on cycle 1, day 1 and then on day 1 of each subsequent 3-weekly treatment cycle. Trastuzumab was administered by intravenous infusion, with an accelerated loading dose on cycle 1, day 2 and cycle 1, day 8, and then a maintenance dose on day 1 of each subsequent 3-weekly treatment cycle. Blood was collected at various time points to assess free (unbound) plasma carboplatin and serum trastuzumab PK. The study enrolled 59 patients. Carboplatin concentrations in the presence and absence of trastuzumab were similar, as demonstrated by the geometric mean ratios for PK parameters, which were close to 1.0 (no effect). The observed trastuzumab concentrations were similar to the values predicted by population PK modelling on the basis of a prediction-corrected visual predictive check, computed using the actual sampling time. In this interim safety analysis, 84.5% of patients had experienced adverse events of grade three or higher, the most common of which were hematologic and as expected. The results suggest that there is no clinically relevant PK DDI between carboplatin and trastuzumab. The safety profile of trastuzumab plus carboplatin and docetaxel was consistent with the known safety profile of this combination.

While prison-initiated methadone maintenance treatment is effective, it is largely unknown as to what patient and program factors are related to outcomes. These issues were studied in a secondary analysis of data from 67 male prerelease prison inmates with preincarceration heroin addiction. Three outcomes are examined: completed prison treatment; completed 1 year of community treatment; and number of days in community treatment. Being employed (p = .045) during the three years prior to index incarceration was significantly and positively related to community treatment completion. Increased frequency of urine tests taken was significantly associated with a greater number of days in community treatment (p < .001). Limitations, policy implications, and directions for future research are discussed.

Keywords: Diabetes, PPAR-gamma, Thiazolidinedione, Renin-angiotensin system Abstract Background. Thiazolidinediones (TZD) have been reported to improve early stages of diabetic nephropathy independent of glycaemic control. Since blockade of the renin-angiotensin system (RAS) is known to reduce the risk of nephropathy, we hypothesised that the renal effect of TZDs might be related to a favourable effect on the intrarenal RAS.We aimed to determine if the TZD rosiglitazone could reduce RAS activation. Methods. We studied adult type 2 diabetic patients and placed them on rosiglitazone for three months.We have previously used the renal haemodynamic response to angiotensin-converting enzyme (ACE) inhibition to demonstrate the state of RAS activation, and thus measured renal plasma flow (RPF) and glomerular filtration rate (GFR) before and after administration of captopril at 0 month and at three months. Plasma renin activity (PRA), active renin, aldosterone and natriuretic peptides were analysed. Results. The RPF response to ACE inhibition was not altered.There was no change in GFR, PRA, active renin and aldosterone levels.Two patients developed oedema - one had an elevated baseline active renin and another had an elevated baseline aldosterone level. Conclusion. The favourable effects of TZDs on diabetic nephropathy is likely not related to an influence on the RAS.

The present study examined the attitudes and beliefs of 189 correctional officers at four Maryland State prisons representing various security levels regarding the control of inmates (i.e., control ideology) using the Correctional Control Ideology Scale (CCIS). Correctional officers reported moderate levels of custodialism. In the bivariate analysis, African American and female officers reported lower CCIS scores. In the multivariate analysis, being African American and working the evening shift were predictors of CCIS. These findings indicate that a more thorough understanding of race, shift, gender, and to some degree, education, are important in conceptualizing workforce motivation within the prison environment. The sampling procedure consisted of a convenience sample; thus data are not representative of all officers employed (excluding officers absent at shift because of vacation, illness, days off, court appearances) at the four sampled facilities. Finally, a more comprehensive investigation of corre...

To assess the individual and team skills acquired from an interactive training program to prepare emergency personnel to respond to terrorist acts.We developed a 16-hour, two-day, multimedia- and simulation-enhanced course that places learners in realistic situations using the equipment required to respond to various chemical, biologic, radiologic, and explosive acts of terrorism. Small-group sessions and drills were conducted. Errors in skill performance were corrected immediately, and then skills were repeated to achieve mastery. Participants included emergency medical technicians, paramedics, nurses, and physicians. Team performance was assessed over four successive scenarios using a 100-mm visual analog scale. Individual learner skill acquisition was assessed with precourse and postcourse evaluation of selected skills in a randomized sampling of consenting learners.Nearly all teams achieved mastery of the required skills by the second assessment rotation. Individual learners demonstrated significant gains in the ability to emergently don personal protective equipment and administer a nerve agent antidote kit.An interactive, simulation-enhanced curriculum of terrorism response training for emergency responders can produce significant, quantifiable individual and team skill gain. Future studies should further address performance benchmarks for these newly acquired skills.

Purpose To investigate whether mRNA expression levels of cyclin D1 (CCND1), cyclooxygenase 2 (Cox-2), epidermal growth factor receptor (EGFR), interleukin 8 (IL-8), and vascular endothelial growth factor (VEGF), all members of the EGFR signaling pathway, are associated with clinical outcome in patients with EGFR-expressing metastatic colorectal cancer (CRC) treated with cetuximab. Patients and Methods Thirty-nine patients with metastatic CRC, refractory to both irinotecan and oxaliplatin, were enrolled on IMCL-0144 and treated with single-agent cetuximab. The intratumoral mRNA levels of CCND1, Cox-2, EGFR, IL-8, and VEGF were assessed from paraffin-embedded tissue samples using laser-capture microdissection and quantitative real-time polymerase chain reaction. Results There were 21 women and 18 men with a median age of 64 years (range, 35 to 83 years). Higher gene expression levels of VEGF were associated with resistance to cetuximab (P = .038; Kruskal-Wallis test). The combination of low gene expression levels of Cox-2, EGFR, and IL-8 was significantly associated with overall survival (13.5 v 2.3 months; P = .028; log-rank test). Both findings were independent of skin toxicity that was itself significantly correlated to survival. Patients with a lower mRNA amount of EGFR had a longer overall survival compared with patients that had a higher mRNA amount (7.3 v 2.2 months; P = .09; log-rank test). Patients with lower expression of Cox-2 had a significantly higher rate of grade 2 to 3 skin reactions under cetuximab treatment. Conclusion This pilot study suggests that gene expression levels of Cox-2, EGFR, IL-8, and VEGF in patients with metastatic CRC may be useful markers of clinical outcome in single-agent cetuximab treatment.

Purpose Pertuzumab, a recombinant humanized monoclonal antibody (2C4), binds to extracellular domain II of the HER-2 receptor and blocks its ability to dimerize with other HER receptors. Pertuzumab represents a new class of targeted therapeutics known as HER dimerization inhibitors. A clinical study was conducted to investigate safety and pharmacokinetics of pertuzumab and to perform a preliminary assessment of HER dimerization inhibition as a treatment strategy. Patients and Methods Patients with incurable, locally advanced, recurrent or metastatic solid tumors that had progressed during or after standard therapy were recruited to a dose-escalation study of pertuzumab (0.5 to 15 mg/kg) given intravenously every 3 weeks. Results Twenty-one patients received pertuzumab and 19 completed at least two cycles. Pertuzumab was well tolerated. Overall, 365 adverse events were reported and 122 considered to be possibly drug related. Of these, 116 were of grade 1 to 2 intensity. The pharmacokinetics of pertuzumab were similar to other humanized immunoglobulin G antibodies, supporting a 3-week dosing regimen. Trough plasma concentrations were in excess of target concentrations at doses greater than 5 mg/kg. Two patients, one with ovarian cancer (5.0 mg/kg) and one with pancreatic islet cell carcinoma (15.0 mg/kg), achieved a partial response. Responses were documented by Response Evaluation Criteria in Solid Tumors after 1.5 and 6 months of pertuzumab therapy, and lasted for 11 and 10 months, respectively. Stable disease lasting for more than 2.5 months (range, 2.6 to 5.5 months) was observed in six patients. Conclusion These results demonstrate that pertuzumab is well tolerated, has a pharmacokinetic profile which supports 3-week dosing, and is clinically active, suggesting that inhibition of dimerization may be an effective anticancer strategy.

Since appropriate treatment of patients in the first few hours of ischemic stroke may decrease the risk of long-term disability, prehospital providers should recognize, assess, manage and communicate about stroke patients in an effective and time-efficient manner. This requires the instruction and evaluation of a wide range of competencies including clinical skills, patient investigation and management and communication skills. The authors developed and assessed the effectiveness of a simulation-enhanced stroke course that incorporates several different learning strategies to evaluate competencies in the care of acute stroke patients. The one-day, interactive, emergency stroke course features a simulation-enhanced, blended-learning approach that includes didactic lectures, tabletop exercises, and focused-examination training and small-group sessions led by paramedic instructors as standardized patients portraying five key neurological syndromes. From January to October 2000, 345 learners were assessed using multiple-choice tests as were randomly selected group of 73 learners using skills' checklists during two pre- and two post-course simulated patient encounters. Among all learners there was a significant gain in knowledge (pre: 53.9%+/-13.9 and post: 85.4%+/-8.5; p0.001), and for the 73 learners a significant improvement in their clinical and communication skills (p0.0001 for all). By using a simulation-enhanced, blended-learning approach, pre-hospital paraprofessionals were successfully trained and evaluated in a wide range of competences that will lead to the more improved recognition and management of acute stroke patients.

Because retention of adolescents in substance abuse treatment is critical to treatment effectiveness, factors that predict length of time in treatment were examined among youth ( N =173) admitted to five outpatient clinics. At admission, youth received a comprehensive psychosocial assessment. Relevant predictors of length of treatment were determined using Poisson regression analyses. Factors positively associated with treatment duration included use of drugs in addition to alcohol and marijuana, having less deviant peers, absence of substance-caused emotional problems, and viewing counselor's skills more positively. In contrast, pressure to enter treatment was unrelated to treatment duration. Results suggest that the counselor–client relationship and peer influences be explicitly considered in treatment.

Purpose: The purpose of this study was to investigate the safety and tolerability of Zosuquidar.3HCl, a potent inhibitor of P-glycoprotein (Pgp), when administered p.o. alone and in combination with doxorubicin and to determine whether Zosuquidar.3HCl affects doxorubicin pharmacokinetics and inhibits Pgp function in peripheral blood natural killer lymphocytes. Experimental Design: Patients with advanced nonhematological malignancies were eligible for this Phase I trial. Zosuquidar.3HCl and doxorubicin were administered separately during the first cycle of therapy and then administered concurrently. Zosuquidar.3HCl was administered over 4 days, with doses escalated until the occurrence of dose-limiting toxicity. Subsequently, doxorubicin doses were increased from 45 to 75 mg/m 2 . Zosuquidar.3HCl, doxorubicin, and doxorubicinol pharmacokinetics were analyzed, and dual fluorescence cytometry was used to determine the effects of Zosuquidar.3HCl on Pgp function in natural killer cells. Results: A total of 38 patients were treated at nine dose levels. Neurotoxicity was dose-limiting for oral Zosuquidar.3HCl, characterized by cerebellar dysfunction, hallucinations, and palinopsia. The maximum-tolerated dose for oral Zosuquidar.3HCl administered every 12 h for 4 days is 300 mg/m 2 . Zosuquidar.3HCl did not affect doxorubicin myelosuppression or pharmacokinetics, and Zosuquidar.3HCl pharmacokinetics were similar in the absence and presence of doxorubicin. Higher plasma concentrations of Zosuquidar.3HCl were associated with greater Pgp inhibition in natural killer cells. Conclusion: Zosuquidar.3HCl can be coadministered with doxorubicin using a 4-day oral dosing schedule, with little effect on doxorubicin toxicity or pharmacokinetics. Further refinement in Zosuquidar.3HCl dosing and scheduling should be explored to optimize Pgp inhibition while minimizing cerebellar toxicity.

Adolescent substance abuse treatment has been increasingly emphasized as an intervention that could interrupt progression to adult criminal careers. However, information about the pretreatment criminal behavior of adolescent treatment clients has rarely been reported. This study examined the factors associated with the severity of self-reported pretreatment offending of 178 adolescents entering outpatient substance abuse treatment in Baltimore County, Maryland. Results indicated that increased severity of crime was related to male gender, use of drugs other than alcohol and marijuana, bullying and being physically cruel to people, higher levels of deviant behavior among peers, school problems, and having sex without a barrier. Given the rather low level of criminal involvement even among the more serious offenders, the degree to which study findings replicate those on other samples of adolescents is especially noteworthy.

While much is known about criminal behavior patterns of general population and delinquent youth, little is known about the pretreatment criminality of adolescent substance abuse treatment clients. This information is important because of substantial increases in adolescent substance abuse treatment admissions and because adolescents who use substances regularly are more likely than nonusers to be criminally involved. Descriptive information is presented on the lifetime patterns of substance abuse, criminal activity, and justice system involvement of 1,122 youth admitted to nine adolescent treatment programs located throughout the United States, including short- and long-term residential and outpatient programs. Study findings indicate that involvement in illegal activities, other than use and possession of substances, is common among adolescents entering treatment. Most clients in each modality were involved with the justice system prior to treatment, and pressure from the justice system to enter treatment was widely reported. While the severity and frequency of offenses committed by short- and long-term residential clients were considerably greater than outpatient clients, a sizable minority of outpatient clients had also committed serious offenses. In addition to differences among modalities, considerable variation in criminal involvement was found among programs within the same modality. Implications for treatment and research are discussed.

Context At a time of significant changes in medical education world-wide, the international dimensions and global issues relating to the application of new learning technologies have been recognised. Objective The aim of this paper is to describe the adoption and integration within the curriculum in one United Kingdom (UK) medical school of ‘Harvey’, the Cardiology Patient Simulator, and the UMedic multimedia computer-based cardiology curriculum ‐ resources developed in a medical school in the USA. Participants The integration of the resources into the curriculum is described by 3 teachers actively involved in the cardiology curriculum of the UK medical school and 3 teachers associated with the development of resources in the USA. Aspects considered The review considers the adoption of Harvey and UMedic in the UK in programmes in relation to: curricular issues, training needs, learning outcomes, curriculum content and sequences of content, educational strategies, teaching and learning methods, assessment, communication about the curriculum and management of the curriculum. Conclusions Learning resources, in the form of simulators and computer-based learning modules, developed in one country can be successfully adopted and implemented in another. Facets that facilitated the adoption included close liaison between the developers of the resources in the USA and the implementers in the UK, and careful and systematic planning including in-depth integration of the simulation-based resources into the required curriculum rather than their relegation to a peripheral ad hoc position. The successful use of simulators such as Harvey requires the presence of a ‘champion’, a clinician educator and a supporting administrative staff who ensure the simulator’s appropriate use.

Glomerular hemodynamics and the renin-angiotensin system in patients with type 1 diabetes mellitus.BackgroundMany studies have reported that blocking the renin-angiotensin-system (RAS) with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker in the patient with diabetes mellitus leads to an increase in renal plasma flow (RPF), no change in glomerular filtration rate (GFR), and a fall in filtration fraction. This constellation is generally attributed to predominant efferent arteriolar dilation.MethodsThis study examined the renal hemodynamic response to blocking the RAS with both captopril and candesartan on separate days in 31 patients with type 1 diabetes mellitus.ResultsThere was a wide range of changes in RPF and GFR in response to the two agents, each administered at the top of its dose-response range. The RPF response to the two agents was strongly concordant (r = 0.65; P < 0.001), as was the GFR response (r = 0.81; P < 0.001). Moreover, there was a strong correlation between the RPF response and the change in GFR with each agent (r = 0.83 and 0.66; P < 0.01). A significant rise in RPF was followed by a rise in GFR. The RPF dependency of GFR in the type 1 diabetics suggests strongly that glomerular filtration equilibrium exists in the glomeruli of the diabetic kidney: Simple notions of local control based on afferent:efferent arteriolar resistance ratios are too simplistic.ConclusionOur data suggest that the intrarenal RAS is activated in over 80% of patients with type 1 diabetes mellitus. Abundant evidence suggests that this activation predisposes to diabetic nephropathy.

ABSTRACT: Anemia resulting from cancer, or its treatment, is an important clinical problem increasingly treated with the recombinant hematopoietic growth factor erythropoietin. To address uncertainties regarding indications and efficacy, the American Society of Clinical Oncology and the American Society of Hematology developed an evidence-based clinical practice guideline for the use of epoetin in patients with cancer. The guideline panel found good evidence to recommend use of epoetin as a treatment option for patients with chemotherapy-associated anemia with a hemoglobin level less than 10 g/dL. Use of epoetin for patients with less severe anemia (hemoglobin < 12 g/dL but never below 10 g/dL) should be determined by clinical circumstances. Good evidence from clinical trials supports the use of subcutaneous epoetin thrice weekly (150 U/kg tiw) for a minimum of 4 weeks. Less strong evidence supports an alternative weekly (40,000 U/wk) dosing regimen, based on common clinical practice. With either administration schedule, dose escalation should be considered for those not responding to the initial dose. In the absence of response, continuing epoetin beyond 6 to 8 weeks does not appear to be beneficial. Epoetin should be titrated once the hemoglobin concentration reaches 12 g/dL. Evidence from one randomized controlled trial supports use of epoetin for patients with anemia associated with low-risk myelodysplasia not receiving chemotherapy; however, there are no published high-quality studies to support its use for anemia in other hematologic malignancies in the absence of chemotherapy. Therefore, for anemic patients with hematologic malignancies, it is recommended that physicians initiate conventional therapy and observe hematologic response before considering use of epoetin.