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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.

Military service, mental health, and gambling activities and motivations as predictors of problem gambling in a sample of UK AF veterans. Age-and-gender matched veterans (n = 1,037) and non-veterans (n = 1,148) completed an online survey of problem gambling, gambling motivation, mental health (depression and anxiety), and posttraumatic stress disorder (PTSD). Past year problem gambling rates were higher in veterans compared to non-veterans. Veteran status predicted increased problem gambling risk. The relationship between problem gambling and gambling to cope with distress was significantly stronger among veterans. Veterans experiencing PTSD and complex PTSD (C-PTSD) were at increased risk of problem gambling. Overall, the present, findings contribute further international evidence that veterans are a population vulnerable to problem gambling. Veterans with PTSD or C-PTSD are most at-risk and may engage in problematic gambling to escape/avoid distress. Routine screening for gambling problems should be undertaken with current and former military personnel, and further research is needed on the interplay between gambling motivation and veterans’ mental health.

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

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.

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.

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.

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.

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.

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.

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...

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