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Supplementary Figure S1. CA125 response to lifastuzumab vedotin in ovarian cancer patients. All patients with radiographic responses also had {greater than or equal to}50 decrease in CA125 from baseline levels.

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.

Supplementary Figure S2. Representative NaPi2b ICH images for PROC and NSCLC patients.

Supplementary Table S1. Adverse events regardless of relationship to study drug occurring in 10 or more patients Supplementary Table S2. Adverse events grades 3-5 regardless of relationship to study drug occurring in 2 or more patients Supplementary Table S3. Pulmonary adverse events by frequency of occurrence in all patients regardless of relationship to study drug Supplementary Table S4. Pulmonary adverse events of NCI-CTCAE grade 3 or higher by frequency of occurrence in all patients regardless of relationship to study drug Supplementary Table S5. Mean (standard deviation) of the pharmacokinetic parameters for antibody-conjugated MMAE in plasma Supplementary Table S6. Mean (standard deviation) of the pharmacokinetic parameters for total antibody in plasma Supplementary Table S7. Mean (standard deviation) of the pharmacokinetic parameters for unconjugated MMAE in plasma Supplementary Table S8. Response outcomes and duration

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.

Comorbid drug and alcohol and mental health disorders are highly prevalent. Significant gaps in service provision make this problem particularly difficult to address in regional Australia. The Pathways to Comorbidity Care (PCC) program was designed to improve management of comorbidity by outpatient drug and alcohol clinicians in New South Wales, Australia. This paper uses the Consolidated Framework for Implementation Research (CFIR) to evaluate variations in implementation outcomes across geographically diverse services.Twenty clinicians across three drug and alcohol services from metropolitan, outer metropolitan and regional geographic locations were engaged at multiple levels of influence (directors, managers, clinicians) during the implementation of the multimodal PCC training package. The CFIR guided the development of self-report measures and semi-structured interviews evaluating implementation of the PCC training, and disparities in implementation barriers and facilitators were determined.Metropolitan clinicians identified less barriers than regional clinicians on several intervention characteristics (adaptability, complexity, design quality and packaging), as well as outer setting (peer pressure), inner setting (implementation climate, staff incentives, leadership engagement, available resources) and process (planning, opinion leaders, executing) domains. Regional clinicians evaluated the networks and communications construct more favourably.Specific barriers identified more strongly by regional clinicians included the importance of communication with local clinicians and leadership about the practicalities of incorporating the approach into routine practice (allocation of time, increased accessibility of implementation team). Metropolitan clinicians provided more favourable evaluations of the package design, implementation climate and specific implementation processes such as a clear and informative implementation plan.

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...

In substance use treatment settings, comorbid mental health problems can occur in up to 70% of people. An integrated approach for managing comorbidity, implementing evidence-based intervention in drug and alcohol settings, remains problematic. Technology can help in adopting evidence-based practice to implement effective treatment healthcare pathways. This study sought to examine aspects of tailored portal utilization (barriers and facilitators) by participants taking part in a program aimed at improving the implementation of evidence-based practice for comorbidity management Pathways to Comorbidity Care (PCC). Method A self-report questionnaire and a semi-structured interview were designed to measure clinician satisfaction with the PCC portal and e-resources throughout a 9-month intervention. An adapted version of the “Non-adoption, Abandonment, Scale-up, Spread and, Sustainability” (NASSS) framework facilitated discussion of the findings. Results Twenty participants from drug and alcohol services responded to all measures. Facilitators included: (i). clinician acceptance of the portal; (ii). guidance from the clinical supervisor or champion to encourage e-resource use. Barriers included: (i). complexity of the illness (condition); (ii). participants’ preference (adopter system) for face-to-face resources and training modes; and, (iii). lack of face-to-face training on how to use the portal ( technology and organization). Conclusion Based on the NASSS framework, we identified several barriers and facilitators of the use of the portal including the complexity of illness, lack of face-to-face training, and clinician preference for training mediums. Recommendations include ongoing organizational support, in-house clinical supervision, and consultation with clinical providers to assist in the development of tailored e-health resources and open training opportunities on how to operate and effectively utilize these resources.

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

In 1890, in the midst of an extended public debate on the right of women to work and the conditions of those who did, a small arms ammunition factory was built on the banks of the Maribyrnong River...

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.

(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.

PURPOSE:Theoretical research on the psychological underpinnings of weight management is limited. Recently, the clinical obesity maintenance model (COMM) proposed a theoretical conceptualisation of salient psychological and neuropsychological mechanisms maintaining weight management issues. The current study aimed to empirically test the COMM and elucidate the results in the context of recent empirical findings. METHODS:Participants (N = 165) were recruited from university and community settings in Australia. The sample consisted of adults with normal weight (n = 41), overweight (n = 40), and obesity (n = 84). Participants completed self-report questionnaires and a brief neuropsychological test. Structural equation modelling was used to estimate the associations between the hypothesised variables of the COMM and evaluate the model fit. RESULTS:Findings suggested acceptable to good model fit. Furthermore, several direct effects were found. First, cognitive flexibility directly affected eating habit strength. Second, eating habit strength directly affected eating beliefs. Third, eating beliefs directly affected emotion dysregulation. Fourth, emotion dysregulation directly affected depression and binge eating with depression partially mediating this relationship. Finally, depression directly affected binge eating. CONCLUSION:This was the first study to empirically test the COMM. Overall, findings provide preliminary support for the COMM as a psychological model of weight management and highlight the underlying psychological and neuropsychological mechanisms that may contribute to weight management issues. As this study examined a simplified version of the COMM, future research should continue evaluating this model and consider incorporating these components into more holistic weight management models to improve long-term treatment outcomes. LEVEL OF EVIDENCE:V, cross-sectional descriptive study.

This reflection explores the challenges encountered at the beginnings of a PhD thesis looking at the history of women in the metal trades in Australia. As workers in a traditionally male-dominated ...

Background Glioblastoma (GBM) is a highly aggressive brain tumor with rapid subclonal diversification, harboring molecular abnormalities that vary temporospatially, a contributor to therapy resistance. Fluorescence-guided neurosurgical resection utilizes the administration of 5-aminolevulinic acid (5-ALA) generating individually fluorescent tumor cells within a background population of non-neoplastic cells in the invasive tumor region. The aim of the study was to specifically isolate and interrogate the invasive GBM cell population using a novel 5-ALA-based method. Methods We have isolated the critical invasive GBM cell population by developing 5-ALA-based metabolic fluorescence-activated cell sorting. This allows purification and study of invasive cells from GBM without an overwhelming background “normal brain” signal to confound data. The population was studied using RNAseq, real-time PCR, and immunohistochemistry, with gene targets functionally interrogated on proliferation and migration assays using siRNA knockdown and known drug inhibitors. Results RNAseq analysis identifies specific genes such as SERPINE1 which is highly expressed in invasive GBM cells but at low levels in the surrounding normal brain parenchyma. siRNA knockdown and pharmacological inhibition with specific inhibitors of SERPINE1 reduced the capacity of GBM cells to invade in an in vitro assay. Rodent xenografts of 5-ALA-positive cells were established and serially transplanted, confirming tumorigenicity of the fluorescent patient-derived cells but not the 5-ALA-negative cells. Conclusions Identification of unique molecular features in the invasive GBM population offers hope for developing more efficacious targeted therapies compared to targeting the tumor core and for isolating tumor subpopulations based upon intrinsic metabolic properties.

“Archivist by day and labour historian by night” Jared Davidson combines his complementary occupations to bring us Dead Letters: Censorship and Surveillance in New Zealand 1914–1920, an engaging book that uses the intimacy of surveillance records to explore broader historical themes of wartime state control and resistance. Davidson places his work in the tradition of “history from below,” and this book achieves some of the best qualities of that tradition; the detailed personal histories bring to life characters that may otherwise have been forgotten, but who are in fact connected to transnational webs of communication and migration of people, political ideas, organisations, and bureaucracies of surveillance and control.

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.

Theories of ageing have suggested that many older adults adopt different strategies to enhance the experience of ageing. The current study was designed to explore the perceived role of religion and spirituality as a person ages. Eight older adults, four men and four women, aged from 67 to 80 years, participated in semi-structured interviews. The results from a thematic analysis revealed three manifest themes (defining religion and spirituality, the spiritual journey and being older but not feeling older) and one latent theme (faith). Religion and spirituality can play an important role in guiding the lives of older adults as well as helping them establish meaning in their lives and to cope with adverse situations. The results show that the participants see older adulthood as a period of spiritual growth and development which provides a means of compensating for losses that can result from physical decline.

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.

It was a little over a year ago that I first wrote about my quest for employment as a D Grade Staff Nurse; and it was three months later when I wrote of my success in obtaining a post on an infectious diseases unit.

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.

Shiga toxin 1 (Stx1) and Stx2 produced byEscherichia coliO157 are known to be cytotoxic to Vero and HeLa cells by inhibiting protein synthesis and by inducing apoptosis. In the present study, we have demonstrated that 10 ng/ml Stx2 induced DNA fragmentation in human brain microvascular endothelial cells (HBMEC), with cleavage activation of caspase-3, -6, -8, and -9. A microarray approach used to search for apoptotic potential signals in response to Stx2 revealed that Stx2 treatment induced a marked upregulation of C/EBP homologous protein (CHOP)/growth arrest and DNA damage-inducible protein 153 (GADD153). Increased CHOP expression was dependent on enzymatically active Stx1. Knockdown of CHOP mRNA reduced the activation of caspase-3 and prevented apoptotic cell death. These results suggest that Stx2-induced apoptosis is mediated by CHOP in HBMEC and involves activation of both the intrinsic and extrinsic pathways of apoptosis.

Synthetic cannabinoid (SC) designer drugs based on indole and indazole scaffolds and featuring l-valinamide or l-tert-leucinamide side chains are encountered with increasing frequency by forensic researchers and law enforcement agencies and are associated with serious adverse health effects. However, many of these novel SCs are unprecedented in the scientific literature at the time of their discovery, and little is known of their pharmacology. Here, we report the synthesis and pharmacological characterization of AB-FUBINACA, ADB-FUBINACA, AB-PINACA, ADB-PINACA, 5F-AB-PINACA, 5F-ADB-PINACA, ADBICA, 5F-ADBICA, and several analogues. All synthesized SCs acted as high potency agonists of CB1 (EC50 = 0.24-21 nM) and CB2 (EC50 = 0.88-15 nM) receptors in a fluorometric assay of membrane potential, with 5F-ADB-PINACA showing the greatest potency at CB1 receptors. The cannabimimetic activities of AB-FUBINACA and AB-PINACA in vivo were evaluated in rats using biotelemetry. AB-FUBINACA and AB-PINACA dose-dependently induced hypothermia and bradycardia at doses of 0.3-3 mg/kg, and hypothermia was reversed by pretreatment with a CB1 (but not CB2) antagonist, indicating that these SCs are cannabimimetic in vivo, consistent with anecdotal reports of psychoactivity in humans.

Nationally, less than 50 percent of children reenroll in the State Children's Health Insurance Program (SCHIP), a program for children from families with incomes too high to qualify for Medicaid, but too low to afford private health insurance. To identify why, we surveyed parents who disenrolled children from a North Carolina program in 2004. Seventy-two percent of the respondents knew that their children were disenrolled and 28 percent did not know. The most common reasons parents reported for not reenrolling their children were that they never received the reenrollment forms, or they submitted their forms late. Most said they would pay out of pocket now to purchase health care services for their children. Most respondents took their children to see a provider while enrolled in SCHIP in the last year, and most were satisfied with the care received. We conclude that the goal of increasing children's reenrollment in public health insurance programs requires an improvement in health insurance information, an increase in trust in our social and health institutions, and a reorganization of the reenrollment process.

INTRODUCTION: Glioblastoma multiforme (GBM) is the most common and lethal brain cancer in adults and accounts for 65% of all primary brain tumours. In our unit we routinely utilise fluorescence image guided resection with prior administration of 5-aminolevulinic acid (5-ALA) to the patient for potentially macroscopically resectable GBMs. In the GBM cells 5-ALA is metabolised to protoporphyrin IX, which emits fluorescence when it is excited with violet light, allowing the visualisation of the cancer cells for maximal resection of the tumour. This project looks at the specificity and toxicity of 5-ALA in vitro when characterising the cancer cells isolated from the invasive margin of the tumour. METHODS: Tumour cells are isolated from both the core and the invasive margin of GBM tumours and compared to established cell lines previously derived from the core and to differentiated neural stem cells from mouse cerebellum that were used as a “normal brain” control. Cells were cultured as monolayers, labelled with 5-ALA and analysed by fluorescence microscopy and flow cytometry to determine 5-ALA specific fluorescence. Presto blue assays were carried out to investigate potential toxicity of 5-ALA in vitro. RESULTS: All GBM cells exhibited 5-ALA specific fluorescence whilst the ratio of median fluorescence intensity observed was around 2-fold for the 5-ALA positively labelled compared to the unlabelled cells (SD: 0.51) and no significant fluorescence for the non-neoplastic brain cells. Interestingly, the GBM cells isolated from a recurrent tumour showed some autofluorescence under the microscope. 5-ALA had no toxic effect on the cells. DISCUSSION: The results gained from the fluorescence microscopy and flow cytometry analysis were extremely encouraging and showed that 5-ALA labelling of a mixed population of cells, such as samples obtained from the invasive margin of the tumour, could be used to identify the GBM cells with several downstream applications including cell separation or co-staining. In addition, the technique was found to be non-toxic, with little effect on cell proliferation.

Children are assuming larger roles in household consumer decisions and have also emerged as independent consumers, thus forming an increasingly powerful market segment. Children can be seen as forming, first, a primary market; second, as influencers on their parents’ decision making; and third, as potential future adult consumers. The second role is the main focus of this paper, centring on supermarket purchases. Using focus groups and in-depth interviews, this study explores the influence of children on supermarket shopping. Participants included parents and children of families in Midlothian, Scotland. The results showed that children have a significant influence on supermarket product purchases. The factors which influence children's product preferences are analysed, and their ability to relay their choices to their parents is considered.

SYNOPSISHope is something which we all need in order to live, and which we all seek as we go about our daily lives—hope for our future as well as to encourage us through the despairs and difficulties we all contend with from time to time. This piece is a meditation on stories and philosophies of hope and awe which have inspired me, and which I believe might be an inspiration for others. We are all seeking that which can sustain us and bring us into the presence of the meaning we need in our lives—we are all listening for our own metaphorical ‘violins in Auschwitz’.

Nine children meeting DSM-III-R criteria for Attention Deficit Hyperactivity Disorder (ADHD) and eighteen normal children participated in this study. A screening assessment revealed significantly m...

Fluorine-18-fluorodeoxyglucose-positron emission tomography (¹⁸F-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.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 ¹⁸F-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, p0.01). ¹⁸F-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.

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.

In this study, we postulated the beneficial role of oral alanyl-glutamine, a more stable glutamine derivative to decrease 5-fluorouracil (5-FU)-induced mucositis in mice.We measured different morphologic parameters to assess structural changes over time in the small bowel, including crypt depth, villus height, villus area, mitotic and apoptotic indices at the crypt level using terminal deoxyuridine triphosphate nick end labeling, and hematoxylin-eosin staining of ileal tissue. In addition, we analyzed the effect of different alanyl-glutamine concentrations on animal weight curves after 5-FU treatment.Neither glutamine nor alanyl- glutamine prevented the 5-FU intestinal structural damage or apoptosis in crypt enterocytes at 24 h after 5-FU challenge. However, we found that alanyl-glutamine, but not glutamine, speeds intestinal recovery when compared with 5-FU-treated controls (P0.05), predominantly by enhancing mitotic activity and crypt length.Our findings provide important data to support clinical studies of oral alanyl-glutamine in 5-FU-induced mucositis.

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 (