Search

We aimed to evaluate the impact of the Pathways to Comorbidity Care (PCC) training program for alcohol and other drugs (AOD) clinicians to improve the management of comorbidity. Methods: A controlled before-and-after study using PCC training was conducted across 6 matched sites in Australia including 35 clinicians. Controls received standard workplace training. PCC training included seminar presentations, workshops conducted by local "clinical champions," individual clinical supervision, and access to an online information portal. We examined (a) identification (screening, assessment) and treatment (treatment, referral) of comorbidity in practice (N = 10 clinical files per clinician), (b) self-efficacy, knowledge, and attitudes of clinicians. Results: Significant improvements were observed in the PCC group but not the control sites with regards to the rate of clinical files showing identification of comorbidity (+50% v -12% change from baseline, respectively; [X2 (1, N = 340) = 35.29, p = .01] with only a trend for improvements in the rate of files demonstrating treatment of comorbidity [X2 (1, N = 340) = 10.45, p = .06]. There were significant improvements in the PCC relative to the control group for clinician self-efficacy, F(1,33) = 6.40, p = .02 and knowledge and attitudes of comorbidity monitoring, F(1,33) = 8.745, p = .01. Conclusions: The PCC training package may help improve identification of comorbidity, self-efficacy, and attitudes toward screening and monitoring of comorbidity in drug and alcohol settings.

Background Radical (chemo)radiotherapy offers potentially curative treatment for patients with locally advanced laryngeal or hypopharyngeal cancer. We aimed to show that dose-escalated intensity-modulated radiotherapy (DE-IMRT) improved locoregional control. Methods We performed a phase III open-label randomised controlled trial in patients with laryngeal or hypopharyngeal cancer (AJCC III-IVa/b, TNM 7). Patients were randomised (1:1) to DE-IMRT or standard dose IMRT (ST-IMRT) using a minimisation algorithm, balancing for centre, tumour site, nodal status and chemotherapy use. DE-IMRT was 67.2 gray (Gy) in 28 fractions (f) to the primary tumour and 56Gy/28f to at-risk nodes; ST-IMRT was 65Gy/30f to primary tumour and 54Gy/30f to at-risk nodes. Suitable patients received 2 cycles of concomitant cisplatin and up to 3 cycles of platinum-based induction chemotherapy. The primary end-point was time to locoregional failure analysed by intention-to-treat analysis using competing risk methodology. Findings Between February 2011 and October 2015, 276 patients (138 ST-IMRT; 138 DE-IMRT) were randomised. A preplanned interim futility analysis met the criterion for early closure. After a median follow-up of 47.9 months (interquartile range 37.5–60.5), there were locoregional failures in 38 of 138 (27.5%) ST-IMRT patients and 42 of 138 (30.4%) DE-IMRT patients; an adjusted subhazard ratio of 1.16 (95% confidence interval: 0.74–1.83, p = 0.519) indicated no evidence of benefit with DE-IMRT. Acute grade 2 pharyngeal mucositis was reported more frequently with DE-IMRT than with ST-IMRT (42% vs. 32%). No differences in grade ≥3 acute or late toxicity rates were seen. Conclusion DE-IMRT did not improve locoregional control in patients with laryngeal or hypopharyngeal cancer. The trial is registered: ISRCTN01483375.

Although effective evidence-based treatments exist for comorbid mental health and substance use disorders, they are not widely implemented. This paper reports a case study of the clinical supervisi...

Background: We have previously reported that the Pathways to Comorbidity Care (PCC) training program for alcohol and other drug (AOD) clinicians improved identification of comorbidity, self-efficacy, and attitudes toward screening and monitoring of comorbidity. We aimed to identify barriers and facilitators of implementation of the PCC training program in drug and alcohol settings.Methods: The PCC training program was implemented across 6 matched sites in Australia as per (1), and 20 clinicians received training. PCC training included seminar presentations, workshops conducted by local “clinical champions,” individual clinical supervision, and access to an online information portal. We examined barriers and facilitators of implementation according to the Consolidated Framework for Implementation Research.Results: Barriers included inner setting (e.g., allocated time for learning) and characteristics of individuals (e.g., resistance). Facilitators included intervention characteristics (e.g., credible sources), inner setting (e.g., leadership), and outer setting domains (e.g., patient needs). Clinical champions were identified as an important component of the implementation process.Conclusions: Barriers included limited specific allocated time for learning. A credible clinical supervisor, strong leadership engagement and an active clinical champion were found to be facilitators of the PCC training program.

Purpose: This phase I trial assessed the safety, tolerability, and preliminary antitumor activity of lifastuzumab vedotin (LIFA), an antibody–drug conjugate of anti-NaPi2b mAb (MNIB2126A) and a potent antimitotic agent (monomethyl auristatin E). Patients and Methods: LIFA was administered to patients with non–small cell lung cancer (NSCLC) and platinum-resistant ovarian cancer (PROC), once every 3 weeks, by intravenous infusion. The starting dose was 0.2 mg/kg in this 3+3 dose-escalation design, followed by cohort expansion at the recommended phase II dose (RP2D). Results: Overall, 87 patients were treated at doses between 0.2 and 2.8 mg/kg. The MTD was not reached; 2.4 mg/kg once every 3 weeks was selected as the RP2D based on overall tolerability profile. The most common adverse events of any grade and regardless of relationship to study drug were fatigue (59%), nausea (49%), decreased appetite (37%), vomiting (32%), and peripheral sensory neuropathy (29%). Most common treatment-related grade ≥3 toxicities among patients treated at the RP2D (n = 63) were neutropenia (10%), anemia (3%), and pneumonia (3%). The pharmacokinetic profile was dose proportional. At active doses ≥1.8 mg/kg, partial responses were observed in four of 51 (8%) patients with NSCLC and 11 of 24 (46%) patients with PROC per RECIST. All RECIST responses occurred in patients with NaPi2b-high by IHC. The CA-125 biomarker assessed for patients with PROC dosed at ≥1.8 mg/kg showed 13 of 24 (54%) had responses (≥50% decline from baseline). Conclusions: LIFA exhibited dose-proportional pharmacokinetics and an acceptable safety profile, with encouraging activity in patients with PROC at the single-agent RP2D of 2.4 mg/kg.

Physical educators play a key role in role modeling to students within the school context. Therefore, there is a need to understand whether current physical education teacher education (PETE) provides sufficient knowledge and practice to prepare preservice educators to be successful. Thirty PETE preservice teachers (23 males, 7 females, aged 19–26) participated in this study. Participants performed tests in physical fitness and motor performance and completed an online questionnaire about cognitive factors (e.g., knowledge and understanding). In addition, a 7-day walking step total was recorded as daily activity in accordance with the Canadian Assessment of Physical Literacy testing battery. Each participant’s performance was compared with the achievement level of a 12-year-old child. Participants had significantly better performance in muscular strength (measured as handgrip test) and flexibility (measured as sit-and-reach test) than a 12-year-old. However, participants had significantly poorer performance in aerobic fitness (measured as PACER), motor performance (measured as obstacle course test), and muscular endurance (measured as plank test) than a 12-year-old. In addition, participants had significantly lower knowledge and understanding of health and physical activity than a 12-year-old. A positive relationship between physical competence (i.e., overall performance in physical fitness and motor performance) and cognitive factor was shown among participants. Growth and maturation may explain participants’ better performance in muscular strength and flexibility. Excessive weight status and low level of knowledge may have contributed to their poor performance in the physical competence domain. The positive relationship may indicate that cognitive factors are a strong predictor of the performance of physical fitness and motor performance. Therefore, for physical educators to promote a healthy lifestyle in education settings, the current PETE curriculum needs to be reviewed and relevant information delivered to promote physical literacy in PETE preservice teachers. Subscribe to TPE

IntroductionMilitary veterans are at heightened risk of problem gambling. Little is known about the costs of problem gambling and related harm among United Kingdom (UK) Armed Forces (AF) veterans. We investigated the social and economic costs of gambling among a large sample of veterans through differences in healthcare and social service resource use compared with age-matched and gender-matched non-veterans from the UK AF Veterans’ Health and Gambling Study.MethodsAn online survey measured sociodemographic characteristics, gambling experience and problem severity, mental health and healthcare resource utilisation. Healthcare provider, personal social service and societal costs were estimated as total adjusted mean costs and utility, with cost-consequence analysis of a single timepoint.ResultsVeterans in our sample had higher healthcare, social service and societal costs and lower utility. Veterans had greater contacts with the criminal justice system, received more social service benefits, had more lost work hours and greater accrued debt. A cost difference of £590 (95% CI −£1016 to −£163) was evident between veterans with scores indicating problem gambling and those reporting no problems. Costs varied by problem gambling status.ConclusionsOur sample of UK AF veterans has higher healthcare, social service and societal costs than non-veterans. Veterans experiencing problem gambling are more costly but have no reduction in quality of life.

BackgroundClinical guidelines recommend evidence-based treatments for comorbid mental and substance use disorders but these are not reliably translated into practice. We aimed to evaluate the impact of the Pathways to Comorbidity Care (PCC) training program for alcohol and other drug (AOD) clinicians to improve the management of comorbidity and to identify barriers and facilitators of implementation according to the Consolidated Framework for Implementation Research (CFIR).MethodsA controlled before-and-after study using PCC training was conducted across 6 matched sites in Australia including 35 clinicians. Controls received standard workplace training. PCC training included seminar presentations, workshops conducted by local ‘clinical champions’, individual clinical supervision, and access to an online information portal. A mixed methods approach examined i) identification (screening, assessment) and treatment (treatment, referral) of comorbidity in practice (N = 10 clinical files per clinician), ii) self-efficacy, knowledge and attitudes of clinicians, iii) barriers and facilitators of implementation.ResultsSignificant improvements were observed in the PCC group but not the control sites with regards to the rate of clinical files showing identification of comorbidity (+50% v −12% change from baseline respectively; X2 (1, N = 340) = 35.29, p = .01) with only a trend for improvements in the rate of files demonstrating treatment of comorbidity (X2 (1, N = 340) = 10.45, p = .06). There were significant improvements in the PCC relative to the control group for clinician self-efficacy (F (1,33) = 6.40, p = .02) and knowledge and attitudes of comorbidity monitoring (F (1,33) = 8.745, p = .01). Barriers included inner setting (e.g. allocated time for learning) and characteristics of individuals (e.g. resistance). Facilitators included intervention characteristics (e.g. credible sources), inner setting (e.g. leadership) and outer setting domains (e.g. patient needs). Clinical champions were identified as an important component of the implementation process.ConclusionsThe PCC training package effectively improved identification of comorbidity, self-efficacy and attitudes towards screening and monitoring of comorbidity. Specific barriers included provision of allocated time for learning. Specific facilitators included provision of a credible clinical supervisor, strong leadership engagement and an active clinical champion.

Background PD-1/L1 inhibitors are treatment options for patients with HCC who have progressed after first-line sorafenib treatment. Tislelizumab, an anti-PD-1 monoclonal antibody, has demonstrated single-agent antitumor activity in patients with advanced, previously treated HCC in two early phase studies (NCT02407990, NCT04068519). Association of biomarkers, including PD-L1 expression and gene expression profiles (GEP), with response and resistance to tislelizumab were explored. Methods PD-L1 expression was evaluated on tumor cells (TC) using the VENTANA PD-L1 (SP263) assay in baseline tumor samples collected before or after sorafenib treatment. GEP were assessed using the 1392-gene HTG GEP EdgeSeq panel. Signature scores were calculated using the Gene Set Variation Analysis package with publicly available gene signatures (GS). Wilcoxon rank-sum test was used to analyze differential gene signatures (DEG); GS association with PFS and OS was evaluated using Cox proportional hazards models. Results Single-agent tislelizumab demonstrated antitumor activity in advanced, previously treated HCC (ORR=13%; CB [PR+SD >6 months]=31%, median PFS=3.3 months; median OS=13.3 months). PD-L1+ (TC≥1%) prevalence and GEP showed different patterns in samples collected before and after sorafenib exposure (figure 1). While non-exposed samples (n=16) were enriched for immune suppressive signatures, sorafenib-exposed samples (n=41) showed higher PD-L1+ prevalence (53.7% vs 25%; P=0.08) and immune-cell activation signatures along with co-inhibition molecules. In sorafenib-exposed samples, PD-L1 expression was positively correlated with CB (P=0.0027) and a trend of longer PFS (HR=0.56, 95% CI:0.28–1.13). ORR was higher in PD-L1+ than PD-L1− sorafenib-exposed samples (23.8% vs 0%; P=0.049). DEG analysis in sorafenib-exposed samples demonstrated that NK-mediated cytotoxicity GS was positively correlated with CB (P=0.03), as well as a trend of longer PFS (HR=0.43, 95% CI:0.17–1.06). Across the different analyses, no correlation with OS was observed. Patients considered non-responders (NRs) were found clustered into three distinct GEP subgroups (NR1, NR2, NR3). Compared with responders, NR1 had enhanced angiogenesis signatures (P=0.01), including TEK, KDR, HGF, and EGR1. Despite high inflamed tumor signatures, NR2 had increased expression of T-cell inhibition GS scores (P=0.01), including CD274, CTLA4, TIGIT, and CD96. The NR3 subgroup showed higher cell-cycle GS scores compared with responders (P=0.05), including E2F7, FOXA1, and FANCD2. Conclusions Prior sorafenib exposure appears to be associated with increased PD-L1 expression and tumor microenvironment-related GS, as well as response and PFS from tislelizumab in advanced HCC patients. Elevated angiogenesis, immune exhaustion, and cell-cycle GS levels may indicate resistance to single-agent PD-1 inhibitors and is suggestive of potential treatment strategies. Validation is warranted in future clinical trials (NCT03412773). Acknowledgements This study was sponsored by BeiGene, Ltd. Writing and editorial assistance was provided by Regina Switzer, PhD, and Elizabeth Hermans, PhD (OPEN Health Medical Communications, Chicago. IL), and funded by the study sponsor. Trial Registration NCT02407990, NCT04068519

(250 words)In substance use treatment settings, there is a high prevalence of comorbid mental health problems. Yet an integrated approach for managing comorbidity, implementation of evidence-based intervention in drug and alcohol settings remains problematic. Technology can help the adoption of evidence-based practice and successfully implement effective treatment health care pathways. This study sought to examine aspects of electronic resources utilisation (barriers and facilitators) by clinicians participating in the PCC training. MethodA self-report questionnaire and a semi-structured interview was designed to measure overall satisfaction with the PCC portal and e-resources available throughout the 9-month intervention for participating clinicians. An adapted version of the ‘Non-adoption, Abandonment, Scale-up, Spread and, Sustainability’ (NASSS) framework was used to facilitate discussion in regards to the study findings. ResultsA total of 20 clinicians from drug and alcohol services responded to all the measures. Facilitators of portal use included: i. clinician acceptance of the PCC portal; ii. guidance from the clinical supervisor or clinical champion that encouraged the use of e-resources. Some of the barriers included: i. complexity of the illness (condition), ii. clinicians’ preference (adopter system) for face-to-face resources and training modes (e.g. clinical supervision, clinical champion workshops), and iii. lack of face-to-face training on how to use the portal (technology and organisation).ConclusionBased on the NASSS framework, we were able to identify several barriers and facilitators including such as the complexity of the illness, lack of face-to-face training and clinician preference for training mediums. Recommendations include ongoing consultation of clinicians to assist in the development of tailored e-health resources and offering in-house training on how to operate and effectively utilise these resources.

Background MUC16 is a tumor-specific antigen overexpressed in ovarian (OC) and pancreatic (PC) cancers. The antibody–drug conjugate (ADC), DMUC5754A, contains the humanized anti-MUC16 monoclonal antibody conjugated to the microtubule-disrupting agent, monomethyl auristatin E (MMAE). Patients and methods This phase I study evaluated safety, pharmacokinetics (PK), and pharmacodynamics of DMUC5754A given every 3 weeks (Q3W, 0.3–3.2 mg/kg) or weekly (Q1W, 0.8–1.6 mg/kg) to patients with advanced recurrent platinum-resistant OC or unresectable PC. Biomarker studies were also undertaken. Results Patients (66 OC, 11 PC) were treated with DMUC5754A (54 Q3W, 23 Q1W). Common related adverse events (AEs) in >20% of patients (all grades) over all dose levels were fatigue, peripheral neuropathy, nausea, decreased appetite, vomiting, diarrhea, alopecia, and pyrexia in Q3W patents, and nausea, vomiting, anemia, fatigue, neutropenia, alopecia, decreased appetite, diarrhea, and hypomagnesemia in Q1W patients. Grade ≥3-related AE in ≥5% of patients included neutropenia (9%) and fatigue (7%) in Q3W patients, and neutropenia (17%), diarrhea (9%), and hyponatremia (9%) in Q1W patients. Plasma antibody-conjugated MMAE (acMMAE) and serum total antibody exhibited non-linear PK across tested doses. Minimal accumulation of acMMAE, total antibody, or unconjugated MMAE was observed. Confirmed responses (1 CR, 6 PRs) occurred in OC patients whose tumors were MUC16-positive by IHC (2+ or 3+). Two OC patients had unconfirmed PRs; six OC patients had stable disease lasting >6 months. For CA125, a cut-off of ≥70% reduction was more suitable for monitoring treatment response due to the binding and clearance of serum CA125 by MUC16 ADC. We identified circulating HE4 as a potential novel surrogate biomarker for monitoring treatment response of MUC16 ADC and other anti-MUC16 therapies in OC. Conclusions DMUC5754A has an acceptable safety profile and evidence of anti-tumor activity in patients with MUC16-expressing tumors. Objective responses were only observed in MUC16-high patients, although prospective validation is required. Clinical Trial Number NCT01335958.

Pamiparib, an investigational, oral PARP 1/2 inhibitor, demonstrated preclinical brain penetration and synergistic cytotoxicity with TMZ. We report updated safety and antitumor data for pamiparib plus RT and/or TMZ in ND-GBM or R/R-GBM (SNO 2019, ACTR-39). This dose-escalation/expansion study includes three arms: A, pamiparib (2, 4, or 6 weeks) plus RT (6–7 weeks) in ND-GBM with unmethylated MGMT promoter (unmethylated-GBM); B, pamiparib (6 weeks) plus RT and increasing TMZ doses in Weeks 1 and 5 of RT in unmethylated ND-GBM; and C, pamiparib plus increasing TMZ doses in methylated/unmethylated R/R-GBM. Most patients in Arms A (expansion) and B received maintenance pamiparib plus TMZ after post-RT rest period at Arm C expansion. As of April 10, 2020, enrollment was complete (N=116; A, n=60; B, n=9; C, n=47). Median study follow-up was 11.3 mo (A/B) and 7.1 mo (C). Common grade ≥3 AEs were anemia (10%) in Arm A; decreased neutrophil and white blood cell count (each 22%) in B; anemia, fatigue, and decreased lymphocyte count (each 11%) in C. Brain edema (A) and pneumonia (C) (n=1 each) were fatal treatment-unrelated AEs. In ND-GBM, modified disease control rate (DCR following post-RT rest period) was 69.8% (95% CI, 55.7–81.7) overall, 68.8% (50.0–83.9) in A, and 80.0% (28.4–99.5) in B. Median duration of response was 5.1 mo (overall), 3.8 mo (A), and NE (B). In Arms A/B, median progression-free survival (PFS) and median overall survival (OS) were 4.4 mo and 12.7 mo, respectively; 12-mo OS rate, 54% (95% CI, 40–66). In R/R-GBM (Arm C), confirmed ORR was 9.1% (95% CI, 2.5–21.7); median PFS and OS were 1.9 mo and 7.3 mo, respectively; 6-mo PFS rate, 19% (95% CI, 9–32). These results showed a manageable safety profile for pamiparib +/- RT +/-TMZ; response and survival results support further evaluation of these combinations in GBM.

Toca 511 (vocimagene amiretrorepvec) is an investigational retroviral replicating vector that selectively infects dividing cancer cells, integrates into the genome and replicates due to immune defects in tumors. Toca 511 spreads through tumors and stably delivers the gene encoding an optimized yeast cytosine deaminase that converts the prodrug Toca FC (an investigational, extended-release formulation of 5-fluorocytosine) into 5-fluorouracil. 5-fluorouracil kills infected cancer cells and surrounding cancer cells, myeloid derived suppressor cells and tumor associated macrophages, thus enabling immune activity against the tumor. In this phase 1 trial (NCT01470794), ascending doses of Toca 511 were injected into the resection bed of patients with rHGG, followed by multiple courses of oral Toca FC. Additional cohorts included combination of the investigational therapy with bevacizumab or lomustine. Objective responses (ORs) are observed in patients with IDH1 wildtype and mutant tumors, including 3 complete responses (CRs) and 2 partial responses with the investigational therapy, and 1 CR with the investigational therapy and bevacizumab. The IDH1-mutant patients treated at 1st recurrence all had CRs and the fact that a CR in rHGG is rare suggests that the investigational treatment may be playing a role. ORs are observed 6–19 months after Toca 511 injection, consistent with an immunologic mechanism. Median time to initial response is 9.2 months; median duration of response (mDoR) is 25.2 months. Excluding combination cohorts, mDoR is 26.7 months. All responders are alive 21.2+ to 42.6+ months, suggesting a correlation of durable responses (ORs lasting > 24 weeks) with overall survival. In a 24-patient subgroup who received the recommended Ph2 Toca 511 dose, a durable response rate of 20.8% was observed. Across the Phase 1 program, the safety profile remains favorable. Updated clinical benefit, safety, immune activity, and molecular profiles will be reported.

Background: The dissemination and adoption of research into clinical practice in health care settings is a complex and challenging process. Clinical champions have been increasingly used in health care to facilitate the implementation and adoption of evidence-based practice and to overcome organizational barriers. In relation to substance use and mental health disorders, translation of new evidence into practice is an ongoing challenge. The utilization of a clinical champion to motivate staff to implement evidence-based practice in these settings may improve treatment quality and reduce the burden of disease. We thus aimed to conduct a systematic review to examine the role and efficacy of clinical champions in the drug and alcohol and mental health settings. Methods: We conducted a systematic literature search (1980-present) using the following databases: PubMed and PsycINFO. Additional studies were identified using reference searches of relevant reviews. Results: Thirteen separate studies were included in the final review. Clinical champions were typically selected rather than emergent, including clinical staff members engaging in a professional clinical role (e.g., physicians, psychologists, social workers). Training provided for these roles was often not stated. Clinical champions assisted with faster initiation and persistence in the application of novel interventions, facilitating overcoming system barriers, and enhanced staff engagement and motivation. Conclusions: In the substance use and mental health field, clinical champions appear to be an important component to facilitating practice changes. Future studies should provide specific details regarding attributes and training and also examine the relevant combination of personal characteristics and training sufficient to facilitate implementation of evidence-based practice in drug and alcohol and mental health settings. Plain language abstract Treatment delivery in drug and alcohol and mental health settings may not always be based on best available evidence. Organizational context and individual factors are important in determining whether new practices will be adopted. Passive approaches such as websites or treatment manuals do not necessarily lead to change in practice. The clinical champion model has been shown to be effective in aiding implementation of evidence-based practice in health care settings. However, there is limited evidence evaluating its use in drug and alcohol and mental health settings. The current review aims to synthesize and evaluate the use of clinical champions in implementation research in drug and alcohol and mental health settings. We found that clinical champions were typically clinical staff members engaging in a professional clinical role. Training provided for these roles was often limited. Clinical champions may assist with faster initiation and persistence in the application of novel interventions, facilitating overcoming system barriers, and enhanced staff engagement and motivation.

DNA damage caused by TMZ or RT sensitizes tumors to PARP inhibitors, especially in highly replicating tumors (eg, GBM). Pamiparib is a selective PARP1/2 inhibitor with potent PARP trapping that can cross the blood-brain barrier and has shown synergistic cytotoxicity with TMZ in nonclinical experiments. At 60mg BID, the human-equivalent dose-to-trough brain concentrations above the nonclinical efficacy threshold, pamiparib was generally well tolerated and showed antitumor activity in early clinical studies ({"type":"clinical-trial","attrs":{"text":"NCT02361723","term_id":"NCT02361723"}}NCT02361723; {"type":"clinical-trial","attrs":{"text":"NCT03333915","term_id":"NCT03333915"}}NCT03333915). This ongoing dose-escalation/expansion study ({"type":"clinical-trial","attrs":{"text":"NCT03150862","term_id":"NCT03150862"}}NCT03150862) will determine the safety/tolerability and antitumor effects of pamiparib (60mg BID)+RT and/or TMZ. The dose-escalation component consists of three arms. Arm A will establish tolerable duration of pamiparib (2, 4, 6 weeks)+RT in newly diagnosed GBM patients with unmethylated MGMT promoter (unmethyl-GBM). In Arm B, newly diagnosed patients with unmethyl-GBM will receive pamiparib+RT with increasing TMZ doses. Enrollment in Arm B will commence once RP2D for pamiparib+RT is established. In Arm C, patients with recurrent/refractory methylated- or unmethyl-GBM receive pamiparib with increasing TMZ doses. As of 28 March 2018, 15 patients were enrolled (A: 2-wk, n=3; 4-wk, n=6; C: TMZ [40mg], n=6). One DLT (grade 3 nausea) was reported in Arm C. Across arms, pamiparib-related AEs occurring in >3 patients were nausea (n=6) and fatigue (n=5). Two patients experienced three pamiparib-related AEs grade 3 (diarrhea [A: 4-wk, n=1]; fatigue and nausea [C: n=1]). All three resolved with concomitant medication and treatment interruption (A) or discontinuation (C). Of the seven patients with 1 tumor assessment, one (A: 4-wk) achieved an unconfirmed PR; four (A: 2-wk, n=2; 4-wk, n=2) had SD, and two (A: 2-wk, n=1; C: n=1) had PD. Preliminary data suggests pamiparib at 60mg BID is generally well tolerated by patients when administered 4 weeks concurrently with RT for newly diagnosed unmethyl-GBM and when combined with 40 mg TMZ for recurrent/refractory GBM.

Methamphetamine use is a serious public health concern in many countries and is second to cannabis as the most widely abused illicit drug in the world. Effective management for methamphetamine dependence remains elusive and the large majority of methamphetamine users relapse following treatment. Areas covered: Progression in the understanding of the pharmacological basis of methamphetamine use has provided us with innovative opportunities to develop agents to treat dependence. The current review summarizes relevant literature on the neurobiological and clinical correlates associated with methamphetamine use. We then outline agents that have been explored for potential treatments in preclinical studies, human laboratory phase I and phase II trials over the last ten years. Expert opinion: No agent has demonstrated a broad and strong effect in achieving MA abstinence in Phase II trials. Agents with novel therapeutic targets appear promising. Advancement in MA treatment, including translation into practice, faces several clinical challenges.

Synthetic cannabinoids (SCs) have rapidly proliferated as recreational drugs, and may present a substantial health risk to vulnerable populations. However, information on possible effects of long-term use is sparse. This study compared acute and residual effects of the popular indazole carboxamide SC compounds AB-PINACA and AB-FUBINACA in adolescent rats with ∆9-tetrahydrocannabinol (THC) and control treatments. Albino Wistar rats were injected (i.p.) with AB-PINACA or AB-FUBINACA every second day (beginning post-natal day (PND) 31), first at a low dose (0.2 mg/kg on 6 days) followed by a higher dose (1 mg/kg on a further 6 days). THC-treated rats received equivalent doses of 6 × 1 mg/kg and 6 × 5 mg/kg. During drug treatment, THC, AB-PINACA, and AB-FUBINACA decreased locomotor activity at high and low doses, increased anxiety-like behaviours and audible vocalisations, and reduced weight gain. Two weeks after dosing was completed, all cannabinoid pre-treated rats exhibited object recognition memory deficits. These were notably more severe in rats pre-treated with AB-FUBINACA. However, social interaction was reduced in the THC pre-treated group only. Six weeks post-dosing, plasma levels of cytokines interleukin (IL)-1α and IL-12 were reduced by AB-FUBINACA pre-treatment, while cerebellar endocannabinoids were reduced by THC and AB-PINACA pre-treatment. The acute effects of AB-PINACA and AB-FUBINACA were broadly similar to those of THC, suggesting that acute SC toxicity in humans may be modulated by dose factors, including inadvertent overdose and product contamination. However, some lasting residual effects of these different cannabinoid receptor agonists were subtly different, hinting at recruitment of different mechanisms of neuroadaptation.

Fluorine-18-fluorodeoxyglucose-positron emission tomography ((18)F-FDG-PET)-guided focal dose escalation in oropharyngeal cancer may potentially improve local control. We evaluated the feasibility of this approach using volumetric-modulated arc therapy (RapidArc) and compared these plans with fixed-field intensity-modulated radiotherapy (IMRT) focal dose escalation plans. Materials and methods: An initial study of 20 patients compared RapidArc with fixed-field IMRT using standard dose prescriptions. From this cohort, 10 were included in a dose escalation planning study. Dose escalation was applied to (18)F-FDG-PET-positive regions in the primary tumor at dose levels of 5% (DL1), 10% (DL2), and 15% (DL3) above standard radical dose (65 Gy in 30 fractions). Fixed-field IMRT and double-arc RapidArc plans were generated for each dataset. Dose-volume histograms were used for plan evaluation and comparison. The Paddick conformity index (CI(Paddick)) and monitor units (MU) for each plan were recorded and compared. Both IMRT and RapidArc produced clinically acceptable plans and achieved planning objectives for target volumes. Dose conformity was significantly better in the RapidArc plans, with lower CI(Paddick) scores in both primary (PTV1) and elective (PTV2) planning target volumes (largest difference in PTV1 at DL3; 0.81 ± 0.03 [RapidArc] vs. 0.77 ± 0.07 [IMRT], p = 0.04). Maximum dose constraints for spinal cord and brainstem were not exceeded in both RapidArc and IMRT plans, but mean doses were higher with RapidArc (by 2.7 ± 1 Gy for spinal cord and 1.9 ± 1 Gy for brainstem). Contralateral parotid mean dose was lower with RapidArc, which was statistically significant at DL1 (29.0 vs. 29.9 Gy, p = 0.01) and DL2 (29.3 vs. 30.3 Gy, p = 0.03). MU were reduced by 39.8-49.2% with RapidArc (largest difference at DL3, 641 ± 94 vs. 1261 ± 118, p < 0.01). (18)F-FDG-PET-guided focal dose escalation in oropharyngeal cancer is feasible with RapidArc. Compared with conventional fixed-field IMRT, RapidArc can achieve better dose conformity, improve contralateral parotid sparing, and uses fewer MU.

Application of distinct positron emission tomography (PET) scan reconstruction algorithms can lead to statistically significant differences in measuring lesion functional properties. We looked at the influence of two-dimensional filtered back projection (2D FBP), two-dimensional ordered subset expectation maximization (2D OSEM), three-dimensional ordered subset expectation maximization (3D OSEM) without 3D maximum a posteriori and with (3D OSEM MAP) on lesion hypoxia tracer uptake using a pre-clinical PET scanner.Reconstructed images of a rodent tumor model bearing P22 carcinosarcoma injected with hypoxia tracer Copper-64-Diacetyl-bis (N4-methylthiosemicarbazone) (i.e. Cu-64 ATSM) were analyzed at 10 minute intervals till 60 minute post injection. Lesion maximum standardized uptake values (SUVmax) and SUVmax/background SUVmean (T/B) were recorded and investigated after application of multiple algorithm and reconstruction parameters to assess their influence on Cu-64 ATSM measurements and associated trends over time.SUVmax exhibited convergence for OSEM reconstructions while ANOVA results showed a significant difference in SUVmax or T/B between 2D FBP, 2D OSEM, 3D OSEM and 3D OSEM MAP reconstructions across all time frames. SUVmax and T/B were greatest in magnitude for 2D OSEM followed by 3D OSEM MAP, 3D OSEM and then 2D FBP at all time frames respectively. Similarly SUVmax and T/B standard deviations (SD) were lowest for 2D OSEM in comparison with other algorithms.Significantly higher magnitude lesion SUVmax and T/B combined with lower SD were observed using 2D OSEM reconstruction in comparison with 2D FBP, 3D OSEM and 3D OSEM MAP algorithms at all time frames. Results are consistent with other published studies however more specimens are required for full validation.Amaç: Farklı pozitron emisyon tomografisi (PET) rekonstrüksiyon algoritmalarının uygulanması lezyonun fonksiyonel özelliklerinde istatistiksel olarak anlamlı farklılıklara neden olabilir. Bu çalışmada iki-boyutlu filtreli geri projeksiyon (2D FBP), iki-boyutlu düzenli subset expectation maksimizasyonu (2D OSEM), 3D maksimum a posteriori olmaksızın (3D OSEM) ve 3D maksimum a posteriori ile (3D OSEM MAP) üç-boyutlu düzenli subset expectation maksimizasyonu kullanımının pre-klinik bir PET tarayıcısı ile lezyon hipoksisini izleyen maddenin (tracer) tutulumu üzerine etkisi incelenmiştir. Yöntem: P22 karsinosarkomlu bir kemirgen tümör modelinde hipoksi izleyen maddenin Copper-64-Diacetyl-bis (N4- methylthiosemicarbazone) (Cu-64 ATSM) enjeksiyonu ile 60. dakikaya kadar her 10 dakikada bir elde edilen rekonstrükte görüntüler incelendi. Lezyonun maksimum standardize tutulum değeri (SUV max ) ve SUV max /taban SUV ortalama (T/B) değerleri kaydedildi, ve multipl algoritma ve rekonstrüksiyon parametresi uygulanmasından sonra bunların Cu-64 ATSM ölçümleri üzerindeki etkisi ve farklı zaman dilimlerindeki seyri araştırıldı. Bulgular: SUV max OSEM rekonstrüksiyonları için konverjans gösterirken ANOVA sonuçları tüm zaman dilimlerinde 2D FBP, 2D OSEM, 3D OSEM ve 3D OSEM MAP rekonstrüksiyonları arasında SUV max veya T/B de anlamlı farklılık tespit etti. En yüksek SUV max ve T/B değerleri tüm zaman dilimlerinde 2D OSEM’de saptandı, bunu sırasıyla 3D OSEM MAP, 3D OSEM ve 2D FBP takip etti. Benzer şekilde SUV max ve T/B standart deviasyonları (SD) diğer algoritmalara kıyasla 2D OSEM’de en düşüktü. Sonuç: 2D OSEM rekonstrüksiyonu ile 2D FBP, 3D OSEM ve 3D OSEM MAP algoritmalarına kıyasla tüm zaman dilimlerinde anlamlı olarak daha yüksek lezyon SUV max ve T/B ile birlikte daha düşük SD gözlemlendi. Sonuçlar daha önce yayınlanmış çalışmalarla uyumlu olmakla birlikte tam onaylama için daha fazla veri gerekmektedir.

Cloud Computing Techno-economic Engineering (CCTE) Workshop aimed to serve as a melting pot for researchers and practitioners both in the areas of cloud computing and business management, in order to discuss and combine best practices in these fields into novel ideas and frameworks to accommodate new business models to harvest the potential of cloud computing taking into account both technological limitations and challenges, as well as market demands.

The purpose of this paper is to explore key concepts and ideas surrounding the security challenges of cloud computing, with particular reference to configuration having considerable impact on securing cloud services. It is critical that the concepts of exploitation and vulnerability, which evidence shows exist in Cloud use, are discussed and understood in order to enhance security protection and user awareness. There are considerable benefits of cloud computing systems, however this paper will primarily focus on the limitations that have emerged through inaccurate configuration setups of both the platforms and applications, and how these might be addressed. It also will highlight some research work in the area that offers possible solutions to the identified issues in Cloud security.

Background: Olfactory Neuroblastoma is a rare, locally aggressive malignant neoplasm arising from the olfactory epithelium, which causes metastasis by lymphatic and haematogenous routes, with most common site being the cervical lymph nodes. Materials and Methods: Clinical history was retrieved from discussion in the Head and Neck multidisciplinary team meeting and medical records. Routine macroscopic and microscopic histological examination along with appropriate immunohistochemistry was performed. In addition, we include the review of literature of olfactory neuroblastoma metastatic to different sites. Results: A 75 year old female presented with a left submandibular mass which on biopsy was diagnosed as high grade neuroendocrine carcinoma requiring further investigation for characterising it as primary or metastatic. The histological diagnosis proved difficult and doubtful, till after five months when on follow up investigation a skull base lesion was identified, this on biopsy was confirmed to be an olfactory neuroblastoma. Conclusion: It is important to think laterally and consider metastatic tumours when evaluating neuroendocrine lesions in the submandibular region as this can be the first manifestation.

Author Summary Background. Combination blockade of human epidermal growth factor receptor (HER) family signaling may confer enhanced antitumor activity than single-agent blockade. We performed a single-arm study of pertuzumab, a monoclonal antibody that inhibits HER2 dimerization, and erlotinib in relapsed non-small cell lung cancer (NSCLC). Methods. Patients received pertuzumab (840-mg loading dose and 420-mg maintenance intravenously every 3 weeks) and erlotinib (150-mg or 100-mg dose orally, daily). The primary endpoint was response rate (RR) by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) at day 56 in all patients and those with EGFR wild-type tumors. Results. Of 41 patients, 28 (68.3%) experienced treatment-related grade ≥3 adverse events, including pneumatosis intestinalis (3 patients), resulting in early cessation of enrollment. Tissue samples from 32 patients showed mutated EGFR status in 9 of 41 (22%) and wild-type EGFR in 23 of 41 (56%). The FDG-PET RR for patients with assessments at day 56 was 19.5% in all patients (n = 41) and 8.7% in patients with wild-type EGFR NSCLC (n = 23). Investigator-assessed computed tomography RR at day 56 was 12.2%. Conclusion. FDG-PET suggests that pertuzumab plus erlotinib is an active combination, but combination therapy was poorly tolerated, which limits its clinical applicability. More research is warranted to identify drug combinations that disrupt HER receptor signaling but that exhibit improved tolerability profiles.

2529 Background: MSLN is a tumor antigen over-expressed in PC and OC. The ADC DMOT4039A is a humanized IgG1 anti-MSLN monoclonal antibody and anti-mitotic agent, MMAE, that shows anti-proliferative...

The purpose of this paper is to explore the challenges and complexity of multi-tenancy issues that have emerged though the development and adoption of cloud computing. The paper will focus specifically around cloud deployment and data storage, in particular relation to privacy concerns due to multi-tenancy. The reason for this lies with the identification of Software as a Service (SaaS) as the most likely adopted service model, particularly for those who are teleworking, as this relies on the service provider adopting a multi-tenancy environment within the data centre. The paper takes the perspective that, for both legal reasons and as part of shared obligation, it is necessary for users to recognise the need for common standards of policy and procedure. For example, this may be in levels of protection to prevent data protection and privacy laws being compromised. Both cloud service providers and legislative bodies need to acknowledge the impact that multi-tenancy can have on user privacy and act accordingly in regulatory steps and in encouraging a culture of adhering to common user standards. Such matters must be addressed at the earliest levels of growth in user demand to be optimally effective, especially when scalability is a fundamental driver for the adoption of cloud computing.

2504 Background: NaPi2b (SLC34A2) is a multi-transmembrane, sodium-dependent phosphate transporter expressed in ~70% non-squamous NSCLC and ~90% OC. DNIB0600A is an ADC consisting of a humanized Ig...

5020 Background: Six-transmembrane epithelial antigen of the prostate-1 (STEAP1) protein is a cell-surface antigen overexpressed in human epithelial prostate cancers. The ADC DSTP3086S contains the humanized IgG1 anti-STEAP1 monoclonal antibody linked to the potent anti-mitotic agent MMAE. Methods: This study evaluated safety, pharmacokinetics, and pharmacodynamic activity of intravenous DSTP3086S (0.3-2.8 mg/kg) given every 3 weeks (q3w) to pts with CRPC. A traditional 3+3 design was used to determine maximum-tolerated dose, followed by cohort expansion at the recommended Phase II dose (RP2D). Clinical activity was evaluated per PCWG criteria. Dose escalation results are presented. Results: Twenty-eight pts were enrolled with a median age of 67 (43-76), all ECOG PS 0-1, and with a median of 7 prior systemic regimens (including a median of 4 hormonal and 3 non-hormonal regimens). Pts received a median of 3 doses (range 1-10) of DSTP3086S. Reversible Grade 3 transaminitis DLTs occurred in one pt each in the 2.25 mg/kg and 2.8 mg/kg cohorts. Serious AEs (SAE) related to study drug (3 total) included one DVT (Grade 3) in the 1.5 mg/kg cohort, as well as one GI hemorrhage (Grade 3) and one sepsis event (Grade 5) in the 2.25 mg/kg cohort. The most common related AEs across all doses were fatigue (36%), nausea (32%), constipation (25%), decreased appetite and diarrhea (each 21%), and musculoskeletal pain and vomiting (each 18%). Exposure for total antibody, free MMAE, and conjugated MMAE was dose proportional. Approximately 60% of the tumor samples assessed showed high STEAP1 expression. CTC reductions were most robust at 2.8 mg/kg; 4/4 patients with unfavorable CTCs at baseline (median of 99, range: 21-205) exhibited CTC conversions from unfavorable to favorable (

2507 Background: NaPi2b (SLC34A2) is a multi-transmembrane, sodium-dependent phosphate transporter expressed in non-squamous NSCLC and non-mucinous OC. DNIB0600A is an ADC consisting of a humanized IgG1 anti-NaPi2b monoclonal antibody and anti-mitotic agent, MMAE, that shows anti-proliferative activity in xenograft models. Methods: This study evaluated safety, pharmacokinetics, and pharmacodynamics of DNIB0600A (0.2-2.8 mg/kg) given every 3 weeks (q3w) to pts with NSCLC or OC. A traditional 3+3 design was used for dose escalation followed by expansion by disease at the recommended Phase 2 dose (RP2D). Tumor NaPi2b expression was evaluated in archival tissue. Anti-tumor activity was evaluated per RECIST 1.1. Results: As of 10 Dec 2012, 30 dose escalation pts have enrolled (16 NSCLC; 14 OC), median age 61 (range 45-78), PS 0-1, median number of prior regimens 5 (1-12), received a median of 3 (1-17) doses of DNIB0600A. No DLTs occurred at the maximum assessed dose of 2.8 mg/kg; enrollment in the expansion cohort at 2.4 mg/kg is ongoing. The most common related AEs regardless of Grade were fatigue (43%), decreased appetite (37%), nausea (30%), constipation, dysgeusia, vomiting, and peripheral neuropathy (each 17%), and diarrhea (13%). One pt at 1.8 mg/kg experienced a DLT (Grade 3 dyspnea), however, no additional DLTs occurred through the maximally administered dose of 2.8 mg/kg. Expansion at 2.4 mg/kg was selected based on totality of safety data. No accumulation of total antibody, free MMAE, or conjugated MMAE was observed. Exposure of each analyte was dose proportional. Approximately 70% of NSCLCs and 85% of OC expressed high levels (IHC 2+/3+) of NaPi2b. Of the 18 pts treated at dose levels 1.8-2.8 mg/kg (10 NSCLC; 8 OC) 3 pts had a confirmed partial response (PR) with response durations of 8.8+ (OC), 4.4+ (NSCLC), and 1.4+ (OC) months, censored at data cutoff, and 1 additional pt had an unconfirmed PR (OC). Dose expansion data will be presented. Conclusions: DNIB0600A administered q3w has an encouraging safety profile and evidence of anti-tumor activity in both NSCLC and OC. Further studies are planned. Clinical trial information: NCT01375842.

Background: MUC16 is a large transmembrane protein overexpressed by the majority of ovarian cancers (OC), compared with normal tissues. The role of MUC16 in the pathogenesis of ovarian cancer is unknown; however, MUC16 may facilitate the binding of ovarian tumor cells to mesothelial cells lining the peritoneal cavity, and may inhibit natural killer cell-mediated anti-tumor cytotoxic responses. Conjugation of a highly potent cytotoxic drug to a MUC16-specific monoclonal antibody represents a novel approach to treatment of MUC16-expressing tumors. DMUC5754A is an ADC containing the humanized IgG1 anti-MUC16 monoclonal antibody linked to the potent anti-mitotic agent MMAE and demonstrates anti-tumor activity in MUC16-expressing tumor xenograft models. Methods: This phase I study evaluated safety, pharmacokinetics (PK), and pharmacodynamic (PD) activity of DMUC5754A (0.3-3.2 mg/kg) given every 3 weeks (q3w) to patients with advanced recurrent platinum-resistant OC. A standard 3+3 design was used to determine the maximum-tolerated dose, followed by cohort expansion. Tumor tissue was assessed for expression of MUC16 and other relevant markers. Clinical activity was evaluated per RECIST. Results: Forty-four patients (22 escalation, 22 expansion at 2.4 mg/kg), median age 62 (44-79), ECOG PS 0-1, received a median of 4 doses (range 1-20) of DMUC5754A. Two DLTs, 1 Grade 4 neutropenia and 1 Grade 4 uric acid increase, occurred at the maximally administered dose of 3.2 mg/kg. Grade ≥ 3 related adverse events (AE) occurring in ≥ 5% of patients included fatigue (4 at 2.4 mg/kg; 9% total) and neutropenia (1 at 3.2 mg/kg, 3 at 2.4 mg/kg; 9% total). The most common related AEs over all dose levels were fatigue (57%), nausea (34%), vomiting (27%), decreased appetite (25%), peripheral neuropathy (25%), and diarrhea (23%). Serious drug-related AEs (SAE) were small intestine obstruction (2 patients), hypocalcemia (1 patient), and neutropenia (1 patient). Total antibody and conjugated MMAE were not impacted by circulating CA125 and displayed dose-dependent PK with clearance decreasing as dose increased. Accumulation of total antibody, conjugated MMAE and free MMAE was not observed due to their short half-lives (≤5 days). Tumor MUC16 expression was evaluable in 42 patients, showing 20% IHC 0, 16% IHC 2+, and 64% IHC 3+. All confirmed responses (1 CR and 4 PRs) occurred in patients treated at 2.4 mg/kg and whose tumors were MUC16 IHC 2+ or 3+. Six additional patients had minor responses (3 at 2.4 mg/kg). Sixteen of the twenty-nine patients at 2.4 mg/kg were on study ≥ 105 days. Human epididymis protein 4 was a potential surrogate marker for serologic response measures in the presence of anti-MUC16/CA125-binding therapy. Conclusions: DMUC5754A at 2.4 mg/kg q3w has an encouraging safety profile and evidence of anti-tumor activity in MUC16-expressing OC. Further studies are planned. Citation Format: Joyce Liu, Kathleen Moore, Michael Birrer, Suzanne Berlin, Ursula Matulonis, Jeffrey Infante, Jian Xi, Robert Kahn, Yulei Wang, Katie Wood, Daniel Coleman, Daniel Maslyar, Eric Humke, Howard Burris. Targeting MUC16 with the antibody-drug conjugate (ADC) DMUC5754A in patients with platinum-resistant ovarian cancer: A phase I study of safety and pharmacokinetics. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-290. doi:10.1158/1538-7445.AM2013-LB-290