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After an initial decline, tuberculosis cases involving severe illness increased., A mandated shelter-in-place and other restrictions associated with the coronavirus disease pandemic precipitated a decline in tuberculosis diagnoses in San Francisco, California, USA. Several months into the pandemic, severe illness resulting in hospitalization or death increased compared with prepandemic levels, warranting heightened vigilance for tuberculosis in at-risk populations.

Case investigation (CI) and contact tracing (CT) are key to containing the COVID-19 pandemic. Widespread community transmission necessitates a large, diverse workforce with specialized knowledge and skills. The University of California, San Francisco and Los Angeles partnered with the California Department of Public Health to rapidly mobilize and train a CI/CT workforce. In April through August 2020, a team of public health practitioners and health educators constructed a training program to enable learners from diverse backgrounds to quickly acquire the competencies necessary to function effectively as CIs and CTs. Between April 27 and May 5, the team undertook a curriculum design sprint by performing a needs assessment, determining relevant goals and objectives, and developing content. The initial four-day curriculum consisted of 13 hours of synchronous live web meetings and 7 hours of asynchronous, self-directed study. Educational content emphasized the principles of COVID-19 exposure, infectious period, isolation and quarantine guidelines and the importance of prevention and control interventions. A priority was equipping learners with skills in rapport building and health coaching through facilitated web-based small group skill development sessions. The training was piloted among 31 learners and subsequently expanded to an average weekly audience of 520 persons statewide starting May 7, reaching 7,499 unique enrollees by August 31. Capacity to scale and sustain the training program was afforded by the UCLA Extension Canvas learning management system. Repeated iteration of content and format was undertaken based on feedback from learners, facilitators, and public health and community-based partners. It is feasible to rapidly train and deploy a large workforce to perform CI and CT. Interactive skills-based training with opportunity for practice and feedback are essential to develop independent, high-performing CIs and CTs. Rigorous evaluation will continue to monitor quality measures to improve the training experience and outcomes.

Background: The American Thoracic Society, U.S. Centers for Disease Control and Prevention, European Respiratory Society, and Infectious Diseases Society of America jointly sponsored this new practice guideline on the treatment of drug-resistant tuberculosis (DR-TB). The document includes recommendations on the treatment of multidrug-resistant TB (MDR-TB) as well as isoniazid-resistant but rifampin-susceptible TB. Methods: Published systematic reviews, meta-analyses, and a new individual patient data meta-analysis from 12,030 patients, in 50 studies, across 25 countries with confirmed pulmonary rifampin-resistant TB were used for this guideline. Meta-analytic approaches included propensity score matching to reduce confounding. Each recommendation was discussed by an expert committee, screened for conflicts of interest, according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Results: Twenty-one Population, Intervention, Comparator, and Outcomes questions were addressed, generating 25 GRADE-based recommendations. Certainty in the evidence was judged to be very low, because the data came from observational studies with significant loss to follow-up and imbalance in background regimens between comparator groups. Good practices in the management of MDR-TB are described. On the basis of the evidence review, a clinical strategy tool for building a treatment regimen for MDR-TB is also provided. Conclusions: New recommendations are made for the choice and number of drugs in a regimen, the duration of intensive and continuation phases, and the role of injectable drugs for MDR-TB. On the basis of these recommendations, an effective all-oral regimen for MDR-TB can be assembled. Recommendations are also provided on the role of surgery in treatment of MDR-TB and for treatment of contacts exposed to MDR-TB and treatment of isoniazid-resistant TB.

Talimogene laherparepvec (T-VEC) has demonstrated efficacy for unresectable melanoma. We explored response patterns from a phase 2 study evaluating patients with unresectable stage IIIB–IVM1c malignant melanoma who received T-VEC plus ipilimumab or ipilimumab alone. Patients with objective response per modified irRC were evaluated for pseudo-progression (single ≥25% increase in tumour burden before response). Patients without pseudo-progression were classified by whether they responded within or after 6 months of treatment start; those with pseudo-progression were classified by whether pseudo-progression was due to increase in existing lesions or development of new lesions. Overall, 39% (n = 38/98) in the combination arm and 18% (n = 18/100) in the ipilimumab arm had an objective response. Eight responders (combination, n = 7 [18.4%]; ipilimumab, n = 1 [5.6%]) had pseudo-progression; most occurred by week 12 and were caused by an increase in existing lesions. These data reinforce use of T-VEC through initial progression when combined with checkpoint inhibitors. Trial Registration {"type":"clinical-trial","attrs":{"text":"NCT01740297","term_id":"NCT01740297"}}NCT01740297 (ClinicalTrials.gov; date of registration, December 4, 2012); 2012-000307-32 (ClinicalTrialsRegister.eu; date of registration, May 13, 2014).

Identifying and treating individuals with latent TB infection (LTBI) represents a critical and challenging component of national TB elimination. Medical consultations by the Centers for Disease Control and Prevention (CDC) funded TB Centers of Excellence (COEs) are an important resource for healthcare professionals (HCPs) caring for individuals with LTBI. This study aimed to identify the most common clinical concerns regarding LTBI care and to describe epidemiologic and clinical features of patients discussed in these consultations.This mixed-methods study randomly sampled 125 consultation inquiries related to LTBI from the COEs' medical consultation database in 2018. Text from consultation records were reviewed and coded to identify reasons for the inquiries and common epidemiologic and clinical patient characteristics.The most common topics of inquiry for consultation included accurate LTBI diagnosis (36%), management of LTBI treatment-related issues (22%), and choice of appropriate LTBI treatment regimen (17%). Patients for whom consultations were requested commonly had another medical condition (34%), were non-U.S. born (31%), were children (25%), and had a history of travel to TB-endemic areas (18%).Our findings emphasize the challenge of managing patients with either suspected or confirmed LTBI, highlighting the need for ongoing medical consultation support for nuanced clinical and epidemiologic scenarios.L’identification et le traitement des personnes atteintes d’infection tuberculeuse latente (LTBI) sont des composantes essentielles et difficiles de la stratégie nationale d’élimination de la TB. Les consultations médicales des TB Centers of Excellence (COE), financés par les Centres pour le contrôle et la prévention des maladies (CDC), sont d’importantes ressources pour les professionnels de santé qui prennent en charge les personnes atteintes de LTBI. Cette étude avait pour objectif d’identifier les problèmes cliniques les plus fréquents en matière de prise en charge de la LTBI, et de décrire les caractéristiques épidémiologiques et cliniques des patients évoquées lors de ces consultations.Cette étude à méthodes mixtes a sélectionné de manière aléatoire 125 demandes de consultations relatives à la LTBI à partir de la base de données des consultations médicales du COE en 2018. Les notes des dossiers de consultation ont été revues et codées pour identifier les raisons des demandes, ainsi que les caractéristiques cliniques et épidémiologiques fréquentes des patients.Les raisons les plus fréquentes de demandes de consultation étaient diagnostic précis de LTBI (36%), prise en charge des problèmes liés au traitement de la LTBI (22%) et choix d’un schéma thérapeutique approprié de la LTBI (17%). Les patients pour lesquels des consultations étaient demandées avaient fréquemment une autre pathologie (34%), n’étaient pas nés aux États-Unis (31%), étaient des enfants (25%) et avaient des antécédents de voyage dans des zones où la TB est endémique (18%).Nos résultats mettent l’accent sur les défis de la prise en charge des patients avec une LTBI présumée ou confirmée, soulignant le besoin d’aide continue aux consultations médicales pour des scénarios épidémiologiques et cliniques nuancés.

Worldwide, Drug-resistant Tuberculosis (DR-TB) remains a big problem; the diagnostic capacity has superseded the clinical management capacity thereby causing ethical challenges. In Sub-Saharan Africa, treatment is either inadequate or lacking and some diagnosed patients are on treatment waiting lists. In Uganda, various health system challenges impeded scale-up of DR-TB care in 2012; only three treatment initiation facilities existed, with only 41 of the estimated 1010 RR-TB/MDR-TB cases enrolled on treatment yet 300 were on the waiting list and there was no DR-TB treatment scale-up plan. To scale up care, the National TB and leprosy Program (NTLP) with partners rolled out a DR-TB mixed model of care. In this paper, we share achievements and outcomes resulting from the implementation of this mixed Model of DR-TB care. Routine NTLP DR-TB program data on treatment initiation site, number of patients enrolled, their demographic characteristics, patient category, disease classification (based on disease site and human immunodeficiency virus (HIV) status), on co-trimoxazole preventive therapy (CPT) and antiretroviral therapy (ART) statuses, culture results, smear results and treatment outcomes (6, 12, and 24 months) from 2012 to 2017 RR-TB/MDR-TB cohorts were collected from all the 15 DR-TB treatment initiation sites and descriptive analysis was done using STATA version 14.2. We presented outcomes as the number of patient backlog cleared, DR-TB initiation sites, RR-TB/DR-TB cumulative patients enrolled, percentage of co-infected patients on the six, twelve interim and 24 months treatment outcomes as per the Uganda NTLP 2016 Programmatic Management of drug-resistant Tuberculosis (PMDT) guidelines (NTLP, 2016). Over the period 2013–2015, the RR-TB/MDR-TB Treatment success rate (TSR) was sustained between 70.1% and 74.1%, a performance that is well above the global TSR average rate of 50%. Additionally, the cure rate increased from 48.8% to 66.8% (P = 0.03). The Uganda DR-TB mixed model of care coupled with early application of continuous improvement approaches, enhanced cohort reviews and use of multi-disciplinary teams allowed for rapid DR-TB program expansion, rapid clearance of patient backlog, attainment of high cumulative enrollment and high treatment success rates. Sustainability of these achievements is needed to further reduce the DR-TB burden in the country. We highly recommend this mixed model of care in settings with similar challenges.

Purpose We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. Methods Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, ≤ 4 mL × 106 plaque-forming units/mL; after 3 weeks, ≤ 4 mL × 108 plaque-forming units/mL every 2 weeks). Ipilimumab (3 mg/kg every 3 weeks; up to four doses) began week 1 in the ipilimumab alone arm and week 6 in the combination arm. The primary end point was objective response rate evaluated by investigators per immune-related response criteria. Results One hundred ninety-eight patients were randomly assigned to talimogene laherparepvec plus ipilimumab (n = 98), or ipilimumab alone (n = 100). Thirty-eight patients (39%) in the combination arm and 18 patients (18%) in the ipilimumab arm had an objective response (odds ratio, 2.9; 95% CI, 1.5 to 5.5; P = .002). Responses were not limited to injected lesions; visceral lesion decreases were observed in 52% of patients in the combination arm and 23% of patients in the ipilimumab arm. Frequently occurring adverse events (AEs) included fatigue (combination, 59%; ipilimumab alone, 42%), chills (combination, 53%; ipilimumab alone, 3%), and diarrhea (combination, 42%; ipilimumab alone, 35%). Incidence of grade ≥ 3 AEs was 45% and 35%, respectively. Three patients in the combination arm had fatal AEs; none were treatment related. Conclusion The study met its primary end point; the objective response rate was significantly higher with talimogene laherparepvec plus ipilimumab versus ipilimumab alone. These data indicate that the combination has greater antitumor activity without additional safety concerns versus ipilimumab.

Background: The U.S. Centers for Disease Control and Prevention (CDC) funds five Regional Tuberculosis Training and Medical Consultation Centers (RTMCCs) that provide training and consultation for tuberculosis (TB) control and management. RTMCC utilization for assistance with diagnosis and management of TB in children has not been described. We analyzed pediatric TB consultations performed across all RTMCCs in terms of question type, provider type, and setting. Methods: The CDC medical consultation database was queried for consultations regarding patients ≤ 18 years provided between 1/1/13–4/22/15 by all RTMCCs (Curry International TB Center, Heartland National TB Center, Mayo Clinic Center for TB, New Jersey Medical School Global TB Institute, Southeastern National TB Center). Each query was categorized into multiple subject areas based on provider type, setting, consultation topic, and patient age. Results: The 5 RTMCCs received 1164 pediatric consultation requests, representing approximately 20% of all consultations performed by the centers during the study period. Providers requesting consults were primarily physicians (46.3%) or nurses (45.0%). The majority of pediatric consult requests were from state and local public health departments (679, 58.3%) followed by hospital providers (199, 17.1%); fewer requests came from clinicians in private practice (84, 7.2%) or academic institutions (40, 3.4%). Consults addressed 14 different topics, most commonly management of children with TB disease (19.1%), latent TB infection (LTBI) (18.2%), diagnosis or laboratory testing (18.7%), and pharmacology (9.2%). Discussion: Pediatric consultations accounted for approximately 20% of all consultations performed by RTMCCs during the study period. RTMCCs were utilized primarily by public health departments regarding management of TB disease, LTBI, and diagnosis or laboratory testing. The relative underutilization of the RTMCCs by clinicians in non-public health settings, who often manage children with TB exposure or infection, warrants further study. As US TB case rates decline and providers become less experienced with childhood TB, medical consultation support may become increasingly important. Keywords: Tuberculosis, Pediatric, Consultation

With only 9105 new US tuberculosis (TB) cases reported in 2017, expert consultation is essential for TB care. Data were captured 2013–2017 from consultations by 5 CDC-funded centers, now the TB Centers of Excellence (COEs). 14 586 consultations were provided to TB providers, most related to TB disease and treatment regimens.

Purpose Combining immunotherapeutic agents with different mechanisms of action may enhance efficacy. We describe the safety and efficacy of talimogene laherparepvec (T-VEC; an oncolytic virus) in combination with ipilimumab (a cytotoxic T-lymphocyte–associated antigen 4 checkpoint inhibitor) in patients with advanced melanoma. Methods In this open-label, multicenter, phase Ib trial of T-VEC in combination with ipilimumab, T-VEC was administered intratumorally in week 1 (106 plaque-forming units/mL), then in week 4 and every 2 weeks thereafter (108 plaque-forming units/mL). Ipilimumab (3 mg/kg) was administered intravenously every 3 weeks for four infusions, beginning in week 6. The primary end point was incidence of dose-limiting toxicities. Secondary end points were objective response rate by immune-related response criteria and safety. Results Median duration of treatment with T-VEC was 13.3 weeks (range, 2.0 to 95.4 weeks). Median follow-up time for survival analysis was 20.0 months (1.0 to 25.4 months). Nineteen patients were included in the safety analysis. No dose-limiting toxicities occurred, and no new safety signals were detected. Grade 3/4 treatment-related adverse events (AEs) were seen in 26.3% of patients; 15.8% had AEs attributed to T-VEC, and 21.1% had AEs attributed to ipilimumab. The objective response rate was 50%, and 44% of patients had a durable response lasting ≥ 6 months. Eighteen-month progression-free survival was 50%; 18-month overall survival was 67%. Conclusion T-VEC with ipilimumab had a tolerable safety profile, and the combination appeared to have greater efficacy than either T-VEC or ipilimumab monotherapy.

Purpose Talimogene laherparepvec (T-VEC) is an oncolytic immunotherapy designed to induce tumor regression of injected lesions through direct lytic effects, and of uninjected lesions through induction of systemic antitumor immunity. In this study, we describe the patterns and time course of response to T-VEC from the phase III OPTiM trial of 436 patients with unresected stages IIIB–IV melanoma. Methods Lesion-level response analyses were performed based on the type of lesion (injected or uninjected cutaneous, subcutaneous, or nodal lesions; or visceral lesions [uninjected]), and the best percentage change from baseline of the sum of products of the longest diameters was calculated. Patients randomized to T-VEC (n = 295) who experienced a durable response (continuous partial or complete response for ≥6 months) were evaluated for progression prior to response (PPR), defined as the appearance of a new lesion or >25 % increase in total baseline tumor area. Results T-VEC resulted in a decrease in size by ≥50 % in 64 % of injected lesions (N = 2116), 34 % of uninjected non-visceral lesions (N = 981), and 15 % of visceral lesions (N = 177). Complete resolution of lesions occurred in 47 % of injected lesions, 22 % of uninjected non-visceral lesions, and 9 % of visceral lesions. Of 48 patients with durable responses, 23 (48 %) experienced PPR, including 14 who developed new lesions only. No difference in overall survival was observed, and median duration of response was not reached in patients with PPR versus those without PPR. Conclusions Responses in uninjected lesions provide validation of T-VEC-induced systemic immunotherapeutic effects against melanoma. PPR did not negatively impact the clinical effectiveness of T-VEC. Electronic supplementary material The online version of this article (doi:10.1245/s10434-016-5286-0) contains supplementary material, which is available to authorized users.

Aims Subjects with lipoprotein(a) [Lp(a)] elevation have increased arterial wall inflammation and cardiovascular risk. In patients at increased cardiovascular risk, arterial wall inflammation is reduced following lipid-lowering therapy by statin treatment or lipoprotein apheresis. However, it is unknown whether lipid-lowering treatment in elevated Lp(a) subjects alters arterial wall inflammation. We evaluated whether evolocumab, which lowers both low-density lipoprotein cholesterol (LDL-C) and Lp(a), attenuates arterial wall inflammation in patients with elevated Lp(a). Methods and results In this multicentre, randomized, double-blind, placebo-controlled study, 129 patients {median [interquartile range (IQR)]: age 60.0 [54.0–67.0] years, Lp(a) 200.0 [155.5–301.5] nmol/L [80.0 (62.5–121.0) mg/dL]; mean [standard deviation (SD)] LDL-C 3.7 [1.0] mmol/L [144.0 (39.7) mg/dL]; National Cholesterol Education Program high risk, 25.6%} were randomized to monthly subcutaneous evolocumab 420 mg or placebo. Compared with placebo, evolocumab reduced LDL-C by 60.7% [95% confidence interval (CI) 65.8–55.5] and Lp(a) by 13.9% (95% CI 19.3–8.5). Among evolocumab-treated patients, the Week 16 mean (SD) LDL-C level was 1.6 (0.7) mmol/L [60.1 (28.1) mg/dL], and the median (IQR) Lp(a) level was 188.0 (140.0–268.0) nmol/L [75.2 (56.0–107.2) mg/dL]. Arterial wall inflammation [most diseased segment target-to-background ratio (MDS TBR)] in the index vessel (left carotid, right carotid, or thoracic aorta) was assessed by 18F-fluoro-deoxyglucose positron-emission tomography/computed tomography. Week 16 index vessel MDS TBR was not significantly altered with evolocumab (−8.3%) vs. placebo (−5.3%) [treatment difference −3.0% (95% CI −7.4% to 1.4%); P = 0.18]. Conclusion Evolocumab treatment in patients with median baseline Lp(a) 200.0 nmol/L led to a large reduction in LDL-C and a small reduction in Lp(a), resulting in persistent elevated Lp(a) levels. The latter may have contributed to the unaltered arterial wall inflammation.

Background Increasing diabetes prevalence affects a substantial number of pregnant women in the United States. Our aims were to evaluate health outcomes, medical costs, risks and types of complications associated with diabetes in pregnancy for mothers and newborns. Methods In this retrospective claims analysis, patients were identified from the Truven Health MarketScan® database (2004–2011 inclusive). Participants were aged 18–45 years, with ascertainable diabetes status [Yes/No], date of birth event >2005 and continuous health plan enrolment ≥21 months before and 3 months after the birth. Results In total, 839 792 pregnancies were identified, and 66 041 (7.86%) were associated with diabetes mellitus [type 1 (T1DM), 0.13%; type 2 (T2DM), 1.21%; gestational (GDM), 6.29%; and GDM progressing to T2DM (patients without prior diabetes who had a T2DM diagnosis after the birth event), 0.23%]. Relative risk (RR) of stillbirth (2.51), miscarriage (1.28) and Caesarean section (C-section) (1.77) was significantly greater with T2DM versus non-diabetes. Risk of C-section was also significantly greater for other diabetes types [RR 1.92 (T1DM); 1.37 (GDM); 1.63 (GDM progressing to T2DM)]. Risk of overall major congenital (RR ≥ 1.17), major congenital circulatory (RR ≥ 1.19) or major congenital heart (RR ≥ 1.18) complications was greater in newborns of mothers with diabetes versus without. Mothers with T2DM had significantly higher risk (RR ≥ 1.36) of anaemia, depression, hypertension, infection, migraine, or cardiac, obstetrical or respiratory complications than non-diabetes patients. Mean medical costs were higher with all diabetes types, particularly T1DM ($27 531), than non-diabetes ($14 355). Conclusions Complications and costs of healthcare were greater with diabetes, highlighting the need to optimize diabetes management in pregnancy. © 2015 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons, Ltd.

Portal hypertension is a common clinical syndrome associated with chronic liver diseases, and is characterized by a pathological increase in portal pressure that leads to the formation of portosystemic collaterals resulting in shunting of portal blood into the systemic circulation. The increase in portal pressure is due to an increase in vascular resistance and an elevated portal blood flow. The site of increased resistance is variable, and dependent upon the disease process. The site of relative obstruction may be prehepatic, hepatic, or posthepatic. There are several intrahepatic lesions that lead to increased resistance. Some of these lesions are irreversible, like fibrosis, regenerating nodules, and capillarization of the space of Disse; however, there is a functional component, increased vascular tone, which contributes to increased intrahepatic resistance and is potentially reversible. Another important factor contributing to the increased portal pressure is elevated portal blood flow. Peripheral vasodilatation initiates the classical profile of decreased systemic resistance, expanded plasma volume, elevated splanchnic blood flow, and elevated cardiac index, which characterize the hyperdynamic circulatory state. This hyperdynamic circulation is responsible for various complications of portal hypertension.

Background: Tuberculosis (TB) Regional Training and Medical Consultation Centers (RTMCCs) were established in 2005 for TB medical consultation, training and education in the United States. A medical consultation database (MCD) captured all consultations provided by RTMCCs; we report on those provided from June 1, 2010 to May 31, 2014. Methods: All MCD consultations during 2010–2014 were categorized into: provider type, setting, consultation topic, and patient age. We analyzed data frequencies and performed subgroup analyses by RTMCC, by TB incidence for the geographical area, and by year of consultation. End-user satisfaction was assessed by a 2016 telephone evaluation of RTMCC services. Results: A total of 11,074 consultations were delivered, with 10,754 (97.1%) in the U.S. and its current or former territories. Of these, 6018 (56%) were for high, 2443 (22.7%) for medium, and 2293 (21.3%) for low TB incidence settings. Most were for adults (81.3%) and answered within 24 h (96.2%). Nearly 2/3 consultations originated from health departments; providers included mostly physicians (44.3%) or nurses (37.6%). Common consult categories included TB disease (47.7%), case management (29.8%), latent TB infection (19.3%), diagnosis (16.1%), pharmacology (14.7%) and adverse side effects (14.3%). Among adverse side effects, hepatotoxicity was most common (39.6%). Volume and nature of consult requests remained relatively stable over the four-year period. Feedback from a 2016 CDC evaluation indicated overall satisfaction with RTMCC medical consultation services. Conclusion: RTMCCS were an important source of TB medical consultation over the time-frame of this assessment and provided quality expert consultation within 24 h. RMTCCs represent a reservoir of TB subject-matter expertise in the United States. Keywords: Tuberculosis, Database, Consultation

On June 13, 2012, a group of key stakeholders, leaders, and national experts on tuberculosis (TB), occupational health, and laboratory science met in Atlanta, Georgia, to focus national discussion on the higher than expected positive results occurring among low-risk, unexposed healthcare workers undergoing serial testing with interferon-γ release assays (IGRAs). The objectives of the meeting were to present the latest clinical and operational research findings on the topic, to discuss evaluation and treatment algorithms that are emerging in the absence of national guidance, and to develop a consensus on the action steps needed to assist programs and physicians in the interpretation of serial testing IGRA results. This report summarizes its proceedings.

Kevin J Harrington,1 Robert HI Andtbacka,2 Frances Collichio,3 Gerald Downey,4 Lisa Chen,5 Zsolt Szabo,6 Howard L Kaufman7 1The Institute of Cancer Research/The Royal Marsden Hospital NIHR Biomedical Research Centre, London, UK; 2Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; 3Division of Hematology and Oncology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 4Amgen Ltd, Cambridge, UK; 5Amgen Inc, Thousand Oaks, CA, USA; 6Amgen GmbH, Zug, Switzerland; 7Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA Objectives: Talimogene laherparepvec is the first oncolytic immunotherapy to receive approval in Europe, the USA and Australia. In the randomized, open-label Phase III OPTiM trial (NCT00769704), talimogene laherparepvec significantly improved durable response rate (DRR) versus granulocyte-macrophage colony-stimulating factor (GM-CSF) in 436 patients with unresectable stage IIIB–IVM1c melanoma. The median overall survival (OS) was longer versus GM-CSF in patients with earlier-stage melanoma (IIIB–IVM1a). Here, we report a detailed subgroup analysis of the OPTiM study in patients with IIIB–IVM1a disease. Patients and methods: The patients were randomized (2:1 ratio) to intralesional talimogene laherparepvec or subcutaneous GM-CSF and were evaluated for DRR, overall response rate (ORR), OS, safety, benefit–risk and numbers needed to treat. Descriptive statistics were used for subgroup comparisons. Results: Among 249 evaluated patients with stage IIIB–IVM1a melanoma, DRR was higher with talimogene laherparepvec compared with GM-CSF (25.2% versus 1.2%; P

Background Cutaneous head and neck melanoma has poor outcomes and limited treatment options. In OPTiM, a phase 3 study in patients with unresectable stage IIIB/IIIC/IV melanoma, intralesional administration of the oncolytic virus talimogene laherparepvec improved durable response rate (DRR; continuous response ≥6 months) compared with subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF). Methods Retrospective review of OPTiM identified patients with cutaneous head and neck melanoma given talimogene laherparepvec (n = 61) or GM-CSF (n = 26). Outcomes were compared between talimogene laherparepvec and GM-CSF treated patients with cutaneous head and neck melanoma. Results DRR was higher for talimogene laherparepvec–treated patients than for GM-CSF treated patients (36.1% vs 3.8%; p = .001). A total of 29.5% of patients had a complete response with talimogene laherparepvec versus 0% with GM-CSF. Among talimogene laherparepvec–treated patients with a response, the probability of still being in response after 12 months was 73%. Median overall survival (OS) was 25.2 months for GM-CSF and had not been reached with talimogene laherparepvec. Conclusion Treatment with talimogene laherparepvec was associated with improved response and survival compared with GM-CSF in patients with cutaneous head and neck melanoma. © 2016 The Authors Head & Neck Published by Wiley Periodicals, Inc. Head Neck, 2016

Background: Using a large cohort of western Canadian sawmill workers (n=28,794), the association between psychosocial work conditions and attempted and completed suicide was investigated. Methods: Records of attempted and completed suicide were accessed through a provincial hospital discharge registry to identify cases that were then matched using a nested case control method. Psychosocial work conditions were estimated by expert raters using the demand—control model. Univariate and multivariate conditional logistic regression was used to estimate the association between work conditions and suicide. Results: In multivariate models, controlling for sociodemographic (marital status, ethnicity) and occupational confounders (job mobility and duration), low psychological demand was associated with increased odds for completed suicide, and low social support was associated with increased odds for attempted suicides. Conclusions: This study indicates that workers with poor psychosocial working conditions may be at increased risk of both attempted and completed suicide.

Meeting abstracts T-VEC is a herpes simplex virus-1-based oncolytic immunotherapy designed to selectively replicate in tumors, produce GM-CSF, and stimulate antitumor immune responses. OPTiM, a Phase III trial of T-VEC vs GM-CSF in unresectable stage IIIB-IV melanoma, improved the primary endpoint

Objective: To develop and implement MEDLINE search strategies that access the dental literature in each of seven dental disciplines; to estimate the availability of randomised controlled trials (RCT) in these disciplines that might be used to make clinical decisions; and to examine publication trends. Study design: Search strategies based on Medical Subject Headings (MeSH) for endodontics, implant dentistry, oral surgery, oral medicine/radiology, orthodontics, periodontics and restorative dentistry were developed to examine MEDLINE. Publications were limited to studies in humans, the years 1990 to 2000, and multiple methods of ascertainment employed to identify RCT. Ascertainment methods included maximally sensitive, sensitive, MEDLINE publication type and specific search strategies. Publication trends were examined using one search methodology. Results: In the period 1990–2000, the MEDLINE searches identified a substantial number of RCT that differed significantly from one another, in ascending order by search strategy: specific (1260)

9509 Background: T is a HSV-1-based oncolytic virus designed to selectively replicate in tumors and produce GM-CSF to stimulate antitumor immune responses. I is an anti-CTLA-4 Ab that blocks inhibition of activated T cells. This is the first randomized study to evaluate the addition of an oncolytic virus to a checkpoint inhibitor. Methods: The 1o endpoint was ORR by immune-related response criteria. Key 2o endpoints: duration of response, disease control rate (DCR), PFS, OS, and safety. Prior treatment was allowed but not required. Pts had unresected stage IIIB-IV melanoma with measurable/injectable tumor(s) and no evidence of immunosuppression. T was given at approved dosing until no injectable tumors, disease progression (PD), or intolerance. I was started at w6 in T+I and at w1 in I at 3 mg/kg IV q3w x 4. Primary analysis occurred 6 m after last pt enrolled. Results: 198 pts were randomized: 98 T+I; 100 I. Characteristics were similar: 54% stage IIIB-IVM1a, 46% IVM1b/c. Median follow up time was 68 w (T+I) and 58 w (I). ORR was 38.8% (T+I) and 18.0% I, P = 0.002, Odds ratio (OR) 2.9. 89% T+I and 83% I pts remain in response. Unconfirmed visceral lesion response was 35.5% T+I vs 13.6% I. OS is immature. Of 190 pts (safety set: 95 T+I, 95 I), most common adverse events (AEs) for T+I, I (%) were fatigue (59, 42), chills (53, 3), and diarrhea (42, 35). 28% T+I and 18% I pts had gr ≥3 tx-related AE. There were 3 deaths (all unrelated) in T+I: 1 myocardial infarction and 2 PD. Conclusions: The study met the 1o endpoint. ORR was significantly higher for T+I vs I; responses were not limited to injected lesions. Toxicity of T+I combination was tolerable with no unexpected AEs. Clinical trial information: NCT01740297. [Table: see text]

This study assessed the safety, efficacy, and pharmacokinetics of motesanib, a multitargeted small molecule angiogenesis inhibitor, with and without panitumumab, in combination with FOLFIRI or FOLFOX in patients with metastatic colorectal cancer (mCRC). This open-label, phase 1b, two-part, multicenter study in patients with mCRC and ≤1 prior treatment evaluated escalating doses (50, 75, 100, or 125 mg QD, 75 mg BID) of motesanib with panitumumab and chemotherapy (Part 1) and the target dose of motesanib with chemotherapy (Part 2). At 17 sites in the USA and Australia, 119 patients were enrolled between December 2004 and February 2010. In Part 1 [motesanib plus panitumumab/FOLFIRI (n = 36) or plus panitumumab/FOLFOX (n = 17)], all motesanib doses tested were tolerated and 125 mg QD was deemed the target dose. Following toxicity results for combination therapy in other trials, panitumumab was withdrawn from the study. Part 2 evaluated motesanib 125 mg with chemotherapy [FOLFIRI (n = 37); FOLFOX (n = 29)]. The primary endpoint, objective response rate in patients with measurable disease by RECIST, was 20 % overall and was higher among patients receiving first-line (27 % overall; FOLFOX, 24 %; FOLFIRI, 27 %) compared with second-line therapy (14 % overall; FOLFOX, 0 %; FOLFIRI, 20 %). The most common adverse events were diarrhea, nausea, fatigue, and hypertension. We observed a low rate of cholecystitis [3 of 119 (2.5 %)], a known adverse event of motesanib and other small molecule VEGF inhibitors. Motesanib 125 mg QD in combination with FOLFIRI or FOLFOX chemotherapy was tolerated and demonstrated modest efficacy in first-/second-line mCRC.

Purpose: Panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody (mAb), has demonstrated efficacy in patients with wild-type KRAS metastatic colorectal cancer (mCRC). Rilotumumab and ganitumab are investigational, fully human mAbs against hepatocyte growth factor (HGF)/scatter factor and IGF1R, respectively. Here we evaluate combining rilotumumab or ganitumab with panitumumab in previously treated patients with wild-type KRAS mCRC. Experimental Design: Part 1 was a phase Ib dose-finding study of panitumumab plus rilotumumab. The primary endpoint was the incidence of dose-limiting toxicities (DLT). Part 2 was a randomized phase II trial of panitumumab in combination with rilotumumab, ganitumab, or placebo. The primary endpoint was objective response rate (ORR); safety, progression-free survival (PFS), and overall survival (OS) were secondary endpoints. Archival tissue specimens were collected for exploratory correlative work. Results: In part 1, no DLTs were reported. A recommended phase II dose of 10 mg/kg rilotumumab was selected. In part 2, for the panitumumab plus rilotumumab (n = 48), panitumumab plus ganitumab (n = 46), and panitumumab plus placebo arms (n = 48), the ORRs were 31%, 22%, and 21%, respectively. The median PFS was 5.2, 5.3, and 3.7 months and median OS 13.8, 10.6, and 11.6 months, respectively. Adverse events were tolerable. Exploratory biomarker analyses, including MET and IGF-related protein expression, failed to indicate conclusive predictive evidence on efficacy endpoints. Conclusions: Panitumumab plus rilotumumab met the prespecified criterion for improvement in ORR whereas ganitumab did not. This is the first study to suggest a benefit for combining an HGF inhibitor (rilotumumab) with panitumumab in previously treated patients with wild-type KRAS mCRC. Clin Cancer Res; 20(16); 4240–50. ©2014 AACR.

The authors investigated the relationship between attention-deficit/hyperactivity disorder (ADHD) and cigarette smoking in siblings of ADHD and non-ADHD probands. They conducted a 4-year follow-up of siblings from ADHD and control-group families. In the siblings of ADHD probands, ADHD was associated with higher rates and earlier onset of cigarette smoking. There was also a significant positive association between cigarette smoking and conduct disorder, major depression, and drug abuse in the siblings, even after adjusting for confounding variables. Moreover, smoking was found to be familial among ADHD families but not control-group families. Our findings indicate that ADHD is a risk factor for early initiation of cigarette smoking in the high-risk siblings of ADHD probands.

Objective To determine the predictability and stability of desipramine (DMI) concentrations in a clinically treated sample of children, estimating the risk of developing potentially toxic DMI levels at a higher dose after a most recent level in a clinically acceptable range. Method Subjects were 90 consecutive psychiatrically referred children and adolescents treated with DMI with at least two assays of serum DMI concentrations (462 pairs). Assay data were analyzed after log transformation and linear regression. Results Despite wide between-patient variability in serum DMI levels at the same dose, future within-subject DMI blood levels were highly predictable from knowledge of current levels, current dose, and the future dose. When the DMI serum level was 200 to 300 ng/mL, there was a 7.0% risk for subsequent levels at the same dose to exceed 300 ng/mL, but potentially toxic levels above 500 ng/mL were very infrequent (1.7%). Conclusions Although the results of this naturalistic clinical study may not generalize to other situations, the results indicate a reasonable stability, predictability, and safety of DMI levels in individual psychiatrically treated children that result from clinically chosen dose changes.

The authors investigated the relationship between attention-deficit/hyperactivity disorder (ADHD) and cigarette smoking in siblings of ADHD and non-ADHD probands. They conducted a 4-year follow-up of siblings from ADHD and control-group families. In the siblings of ADHD probands, ADHD was associated with higher rates and earlier onset of cigarette smoking. There was also a significant positive association between cigarette smoking and conduct disorder, major depression, and drug abuse in the siblings, even after adjusting for confounding variables. Moreover, smoking was found to be familial among ADHD families but not control-group families. Our findings indicate that ADHD is a risk factor for early initiation of cigarette smoking in the high-risk siblings of ADHD probands.

Objective To evaluate the overlap between attention-deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD), addressing whether ODD is a subsyndromal form of conduct disorder (CD) and, if so, whether it is a precursor or prodrome syndrome of CD. Method Assessments from multiple domains were used to examine 140 children with ADHD and 120 normal controls at baseline and 4 years later. Results Of children who had ADHD at baseline, 65% had comorbid ODD and 22% had CD. Among those with ODD, 32% had comorbid CD. All but one child with CD also had ODD that preceded the onset of CD by several years. ODD+CD children had more severe symptoms of ODD, more comorbid psychiatric disorders, lower Global Assessment of Functioning Scale scores, more bipolar disorder, and more abnormal Child Behavior Checklist clinical scale scores compared with ADHD children with nonCD ODD and those without ODD or CD. In addition, ODD without CD at baseline assessment in childhood did not increase the risk for CD at the 4-year follow-up, by midadolescence. Conclusions Conclusions: Two subtypes of ODD associated with ADHD were identified: one that is prodromal to CD and another that is subsyndromal to CD but not likely to progress into CD in later years. These ODD subtypes have different correlates, course, and outcome.

In order to test the hypothesis that ozone (O3)-induced changes in lung function and respiratory tract injury/inflammation are greater in subjects with asthma than in normal subjects, we exposed 18 asthmatic subjects, on separate days, to O3 (0.2 ppm) and filtered air for 4 h during exercise. Symptom questionnaires were administered before and after exposure, and pulmonary function tests (FEV1, FVC, and specific airway resistance [SRaw]) were performed before, during, and immediately after each exposure. Fiberoptic bronchoscopy, with proximal airway lavage (PAL) of the isolated left main bronchus and bronchoalveolar lavage (BAL; bronchial fraction, the first 10 ml of fluid recovered) of the right middle lobe, was performed 18 h after each exposure. The PAL, bronchial fraction, and BAL fluids were analyzed for the following endpoints: total and differential cell counts; total protein, lactate dehydrogenase (LDH), fibronectin, interleukin-8 (IL-8), granulocyte-macrophage colony-stimulating factor (GM-CSF), myeloperoxidase (MPO), and transforming growth factor-beta (TGF beta 2) concentrations. We found a significant O3 effect on FEV1, FVC, SRaw (p < 0.04) and lower respiratory symptoms (p < 0.001) for the asthmatic subjects. Ozone exposure also significantly increased the percent neutrophils in PAL (p < 0.01); percent neutrophils, total protein, and IL-8 in the bronchial fraction (p < 0.001, p < 0.05, and p < 0.01, respectively); and the percent neutrophils, total protein, LDH, fibronectin, IL-8, GM-CSF, and MPO in BAL (p < 0.001, p < 0.01, p < 0.01, p < 0.001, p < 0.05, p < 0.01, and p < 0.001, respectively) for the asthmatic subjects. There were no significant differences in the lung function responses of the asthmatic subjects in comparison with a group of normal subjects (n = 81) previously studied using an identical protocol, although there was a trend toward a greater O3-induced increase in SRaw in the asthmatic subjects (p < 0.13). In contrast, the asthmatic subjects showed significantly greater (p < 0.05) O3-induced increases in several inflammatory endpoints (percent neutrophils and total protein concentration) in BAL as compared with normal subjects who underwent bronchoscopy (n = 20). Our results indicate that asthmatic persons may be at risk of developing more severe O3-induced respiratory tract injury/inflammation than normal persons, and may help explain the increased asthma morbidity associated with O3 pollution episodes observed in epidemiologic studies.

To determine the pulmonary complications in HIV-1-infected patients in Dar es Salaam, Tanzania, and to evaluate the diagnostic utility of bronchoscopy and bronchoalveolar lavage, we carried out a prospective study of 237 patients with acute respiratory disease who were hospitalized at Muhimbili Medical Center (MMC). Diagnoses were made using well-defined criteria. Of the total, 127 (54%) were HIV-1-seropositive and 110 (46%) were seronegative. Tuberculosis was the most common diagnosis occurring in 95 (75%) HIV-1-seropositive and 87 (79%) seronegative patients. Bacterial pneumonia was the next most common diagnosis occurring in 18 (14%) HIV-1-seropositive and 17 (15%) seronegative patients. Pneumocystis carinii pneumonia was diagnosed in one and Kaposi's sarcoma was seen in only two HIV-1-seropositive patients. Bronchoscopy with bronchoalveolar lavage was the sole source of a diagnosis in nine (8%) seropositive and six (5%) seronegative patients. We conclude that the HIV seroprevalence rate among patients hospitalized for acute respiratory disease at MMC is extremely high. Tuberculosis was the most common cause of pulmonary disease, regardless of HIV serostatus, and other HIV-associated opportunistic pulmonary infections were unusual. Bronchoscopy with bronchoalveolar lavage added little to the diagnosis and thus should not be high-priority procedures for the routine workup in resource-poor areas where tuberculosis is endemic.

Success of cervical cancer control programs depends upon the prompt and appropriate treatment of neoplastic lesions. This study assessed whether a woman received full, partial, or no care ...

9568Background: T-VEC is a herpes simplex virus (HSV)-1 -based oncolytic immunotherapy designed to selectively replicate in tumors, produce GM-CSF and stimulate antitumor immune responses in melanoma. T-VEC significantly improved durable response rate vs GM-CSF in stage IIIB-IV melanoma patients (pts) with injectable tumors. Pembro inhibits programmed cell death protein 1 and improves survival in advanced melanoma. The combination may further improve clinical benefit. Here we report phase 1b efficacy, safety and biomarker data from a phase 1b/3 study of T-VEC+pembro in unresectable stage IIIB-IV melanoma (NCT02263508) with all pts having started on T-VEC+pembro ≥ 6 mo prior. Methods: Key inclusion criteria: unresectable stage IIIB-IV melanoma, injectable lesions; no prior systemic tx; and ECOG PS 0-1. T-VEC: ≤ 4 mL in (sub)cutaneous/nodal lesions, 106 PFU/mL d1, 108PFU/mL d22 then Q2W; pembro: IV, 200 mg d36 then Q2W. Tx until first occurrence of: complete response (CR); no injectable tumors (for T-VEC); ...

This open-label randomized trial compared isoniazid (9 months) to rifampin (4 months) on toxicity and completion in a jailed population with latent tuberculosis infection. Rifampin resulted in fewer elevated liver function tests (risk ratio [RR] 0.39, 95% confidence interval [CI] [0.18, 0.86]) and less toxicity requiring medication withdrawal (RR 0.51, 95% CI [0.13, 2.01]), although one participant receiving rifampin experienced an allergic reaction. Completion was achieved for 33% receiving rifampin compared to 26% receiving isoniazid (p = .10). With careful monitoring rifampin is a safe and less toxic regimen and appears to be a reasonable alternative because of its shorter duration, allowing more people to complete treatment behind bars. Therapy completion in released inmates is unacceptably low and ensuring follow-up after discharge must be part of a decision to treat.

Background The identification of mental health problems early in life can increase the well-being of children and youth. Several studies have reported that youth who experience mental health disorders are also at a greater risk of developing psychopathological conditions later in life, suggesting that the ability of researchers and clinicians to identify mental health problems early in life may help prevent adult psychopathology. Using large-scale administrative data, this study examined whether permanent settlement and within-province migration patterns may be linked to mental health diagnoses among adolescents (15 to 19 years old), young adults (20 to 30 years old), and adults (30 years old and older) who grew up in rural or urban communities or migrated between types of community (N = 8,502). Methods We conducted a nested case-control study of the impact of rural compared to urban residence and rural-urban provincial migration patterns on diagnosis of mental health. Conditional logistic regression models were run with the following International Classification of Diseases, 9th Revision (ICD-9) mental health diagnoses as the outcomes: neurotic disorders, personality disorder, acute reaction to stress, adjustment reaction, depression, alcohol dependence, and nondependent drug abuse. Analyses were conducted controlling for paternal mental health and sociodemographic characteristics. Results Mental health diagnoses were selectively associated with stability and migration patterns. Specifically, adolescents and young adults who were born in and grew up in the same rural community were at lower risk of being diagnosed with acute reaction to stress (OR = 0.740) and depression (OR = 0.881) compared to their matched controls who were not born in and did not grow up in the same rural community. Furthermore, adolescents and young adults migrating between rural communities were at lower risk of being diagnosed with adjustment reaction (OR = 0.571) than those not migrating between rural communities. No differences were found for diagnoses of neurotic disorders, personality disorder, alcohol dependence, and nondependent drug abuse. Conclusions This study provides some compelling evidence of the protective role of rural environments in the development of specific mental health conditions (i.e., depression, adjustment reaction, and acute reaction to stress) among the children of sawmill workers in Western Canada.

Background: The role of social and family environments in the development of mental health problems among children and youth has been widely investigated. However, the degree to which parental working conditions may impact on developmental psychopathology has not been thoroughly studied. Methods: We conducted a case-control study of several mental health outcomes of 19,833 children of sawmill workers and their association with parental work stress, parental socio-demographic characteristics, and paternal mental health. Results: Multivariate analysis conducted with four distinct age groups (children, adolescents, young adults, and adults) revealed that anxiety based and depressive disorders were associated with paternal work stress in all age groups and that work stress was more strongly associated with alcohol and drug related disorders in adulthood than it was in adolescence and young adulthood. Conclusion: This study provides support to the tenet that being exposed to paternal work stress during childhood can have long lasting effects on the mental health of individuals.

TPS9081 Background: T-VEC is a herpes simplex virus-1-based oncolytic immunotherapy designed to preferentially replicate in tumors, produce GM-CSF and stimulate an anti-tumor immune response. OPTiM...

The aims of this study were to examine, in a conscious rat model of portal hypertension, the effect of postprandial splanchnic hyperemia on collateral blood flow and to determine whether octreotide has an effect on postprandial collateral flow changes.In rats with portal vein ligation, pulsed-Doppler flowmeters were implanted chronically around the splenorenal venous shunt (SRS), which is the main spontaneous collateral vessel in the portal hypertensive rat and around the superior mesenteric artery (SMA). Changes in flow after a standard liquid meal gavage and after the administration of octreotide were examined in the rat under unanesthetized and unrestricted conditions.SRS flow increased significantly after gavage with a standard liquid meal (10.6+/-2.9%) compared to orogastric intubation alone (-6.5+/-2.1%) (P0.01). Similar flow changes were observed in the SMA after liquid meal gavage. The subcutaneous administration of octreotide at a dose of 400 g/kg reduces basal SRS flow (-19.5+/-2.3%) and significantly attenuated the change in SRS flow after liquid meal gavage (-8.1+/-2.9%) compared to animals that received placebo (3.6+/-4.1% and 27.8+/-7.6%, respectively) (P0.05).These results demonstrate that, in an experimental model of prehepatic portal hypertension, postprandial splanchnic hyperemia results in an increase in collateral flow that can be ameliorated with the use of octreotide.

Aim: R is an investigational, fully human monoclonal antibody against hepatocyte growth factor, the only known ligand for the MET proto-oncogene. In a phase 2 study in G/GEJ cancer, trends towards improved overall survival (OS) and progression-free survival (PFS) were seen with R + epirubicin, cisplatin, and capecitabine (ECX) vs placebo + ECX, with benefit due to the MET-positive patients (pts). We describe a methodology to select a cutoff for defining MET positivity. Methods: Eligible pts had unresectable locally advanced or metastatic G/GEJ adenocarcinoma, ECOG performance status ≤ 1, and no prior systemic therapy for this disease. Pts were randomized 1:1:1 to R 15 mg/kg, R 7.5 mg/kg, or placebo IV day 1 Q3W plus ECX (50 mg/m2 IV day 1, 60 mg/m2 IV day 1, 625 mg/m2 BID orally days 1–21, respectively). Formalin-fixed paraffin-embedded archival tumor tissues were stained with the Dako MET IHC pharmDx™ kit, which uses the MET4 antibody. Membrane, cytoplasmic, and total (cytoplasmic and membrane) tumor cell staining were evaluated separately. Percent staining at different intensities (0, 1 + , 2 + , 3+) and combinations of intensities were scored directly, whereas overall percent positive, H-score, and predominant staining intensity were derived scores. OS and PFS for subgroups defined by potential cutoff values (5–95%) at 5% increments were analyzed by Cox proportional hazards regression, Kaplan-Meier, and the log rank test, yielding hazard ratios (HRs), median OS and PFS, and p values. Results: 121 pts were randomized; 91 had tumor samples evaluable for MET IHC. Pts whose tumors showed ≥ 25% membranous staining were classified as MET-positive. A strong treatment benefit (R vs placebo) was seen in MET-positive pts (n = 58; OS: HR = 0.46, 95% CI, 0.24–0.87; PFS: HR = 0.46, 95% CI, 0.25–0.85); median OS: 10.6 vs 5.7 mo; median PFS: 6.8 vs 4.4 mo. No benefit or detriment was seen with R in MET-negative pts (n = 33; OS: HR = 1.23; 95% CI, 0.56–2.70; PFS: HR = 1.00; 95% CI, 0.46–2.16). Cutoff values 25–50% showed a similar benefit of R in MET-positive pts. Conclusions: The subgroup defined by a cutoff of 25% MET-positive membranous staining using the Dako MET IHC pharmDx™ kit showed benefit from R + ECX; no negative impact of R was seen in MET-negative pts. This cutoff is being used to select pts in an ongoing phase 3 study of R + ECX in MET-positive G/GEJ cancer (NCT01697072). Disclosure: M.D. Hale, K.S. Oliner, R. Tang, L. Chen, E. Loh and S.D. Patterson have declared:is an employee of and owns stock in Amgen Inc.; S. Webster: Scott Webster is an employee of Dako North America, an Agilent Technologies Company. All other authors have declared no conflicts of interest.

9026 Background: T-VEC is an intralesional oncolytic immunotherapy comprising a modified HSV-type 1. In the randomized OPTiM phase 3 trial, T-VEC significantly improved DR rate (DRR, continuous par...

Objective The association between attention-deficit hyperactivity disorder (ADHD) and cigarette smoking in children and adolescents was evaluated. Method Subjects were 6− to 17-year-old boys with DSM-III-R ADHD ( n = 128) and non-ADHD comparison boys ( n = 109) followed prospectively for 4 years into mid-adolescence. Information on cigarette smoking was obtained in a standardized manner blind to the proband's clinical status. Cox proportional hazard models were used to predict cigarette smoking at follow-up using baseline characteristics as predictors. Results ADHD was a significant predictor of cigarette smoking at follow-up into mid-adolescence. Our findings also revealed that ADHD was associated with an early initiation of cigarette smoking. This was the case even after controlling for socioeconomic status, IQ, and psychiatric comorbidity. In addition, among children with ADHD, there was a significant positive association between cigarette smoking and conduct, major depressive, and anxiety disorders. Conclusions ADHD, particularly the comorbid subtype, is a significant risk factor for early initiation of cigarette smoking in children and adolescents. Considering the prevalence and early childhood onset of ADHD, these findings highlight the importance of smoking prevention and cessation programs for children and adolescents with ADHD.

In portal-hypertensive humans, portal blood flow and pressure increase after a meal. These hemodynamic changes may increase variceal rupture risk. The aim of this study was to determine whether blood in the stomach lumen increases splanchnic flow and portal pressure (PP) in portal-hypertensive rats.superior mesenteric artery flow and PP were measured in conscious, unrestrained, fasted partial portal vein-ligated rats with chronically implanted Doppler flow probes or portal vein catheters before and after gavage with heparinized, warmed blood from donor rats, air, standard meal, or empty tube.Percentage of changes in flow and pressure from baseline were significantly greater after gavage with blood (an increase of 22.6% +/- 3.5% and an increase of 16.4% +/- 3.1%, respectively) than empty tube (an increase of 3.4% +/- 0.6% and a decrease of 5.4% +/- 3.5%, respectively) (P0.005). Percentage of changes in flow and pressure were slightly but insignificantly greater after gavage with air vs. empty tube (P0.005).In portal-hypertensive rats, blood in the stomach lumen significantly increases splanchnic blood flow and PP. Splanchnic hyperemia from absorption of blood's calories probably contributes to these hemodynamic changes. In patients with variceal hemorrhage, blood in the stomach may increase the risk of persistent variceal bleeding or rebleeding.

4041 Background: GAN and conatumumab (CON) are investigational, fully human, monoclonal antibodies against type 1 insulin-like growth factor receptor (IGF1R) and death receptor 5, respectively. A 3...

OBJECTIVE This study investigated the role of maternal smoking during pregnancy in the etiology of attention deficit hyperactivity disorder (ADHD). METHOD Subjects were 6-17-year-old boys with DSM-III-R ADHD (N = 140) and normal comparison subjects (N = 120) and their first-degree biological relatives. Information on maternal smoking was obtained from mothers in a standardized manner by raters who were blind to the proband's clinical status. RESULTS Twenty-two percent of the ADHD children had a maternal history of smoking during pregnancy, compared with 8% of the normal subjects. This positive association remained significant after adjustment for socioeconomic status, parental IQ, and parental ADHD status. Significant differences in IQ were found between those children whose mothers smoked during pregnancy and those whose mothers did not smoke (mean IQ = 104.9, SD = 12.3, and mean = 115.4, SD = 12.2, respectively). CONCLUSIONS These findings suggest that maternal smoking during pregnancy is a risk factor for ADHD. If confirmed, these findings will stress the importance of programs aimed at smoking prevention in nonsmoking women and smoking cessation in smoking women of childbearing age.

Background: Previous cross-sectional data showed that children and adolescents with attention-deficit hyperactivity disorder (ADHD) are at increased risk of comorbid conduct, mood, and anxiety disorders as well as impairments in cognitive, social, family, and school functioning. However, longitudinal data were needed to confirm these initial impressions. Methods: Using DSM-III-R structured diagnostic interviews and raters blinded as to diagnosis, we reexamined psychiatric diagnoses at 1- and 4-year follow-ups in children with ADHD and controls. In addition, subjects were evaluated for cognitive, achievement, social, school, and family functioning. Results: Analyses of follow-up findings revealed significant differences between children with ADHD and controls in rates of behavioral, mood, and anxiety disorders, with these disorders increasing markedly from baseline to follow-up assessments. In addition, children with ADHD had significantly more impaired cognitive, family, school, and psychosocial functioning than did controls. Baseline diagnosis of conduct disorder predicted conduct disorder and substance use disorders at follow-up, major depression at baseline predicted major depression and bipolar disorder at follow-up, and anxiety disorders at baseline predicted anxiety disorders at follow-up. Conclusions: These results confirm and extend previous retrospective results indicating that children with ADHD are at high risk of developing a wide range of impairments affecting multiple domains of psychopathology such as cognition, interpersonal, school, and family functioning. These findings provide further support for the value of considering psychiatric comorbidity in both clinical assessment and research protocols involving children with ADHD.

Objective To evaluate the psychiatric, cognitive, and functional correlates of attention-deficit hyperactivity disorder (ADHD) children with and without comorbid bipolar disorder (BPD). Method DSM-III-R structured diagnostic interviews and blind raters were used to examine psychiatric diagnoses at baseline and 4-year follow-up in ADHD and control children. In addition, subjects were evaluated for cognitive, academic, social, school, and family functioning. Results BPD was diagnosed in 11% of ADHD children at baseline and in an additional 12% at 4-year follow-up. These rates were significantly higher than those of controls at each assessment. ADHD children with comorbid BPD at either baseline or follow-up assessment had significantly higher rates of additional psychopathology, psychiatric hospitalization, and severely impaired psychosocial functioning than other ADHD children. The clinical picture of bipolarity was mostly irritable and mixed. ADHD children with comorbid BPD also had a very severe symptomatic picture of ADHD as well as prototypical correlates of the disorder. Comorbidity between ADHD and BPD was not due to symptom overlap. ADHD children who developed BPD at the 4-year follow-up had higher initial rates of comorbidity, more symptoms of ADHD, worse scores on the CBCL, and a greater family history of mood disorder compared with non-BPD, ADHD children. Conclusions The results extend previous results documenting that children with ADHD are at increased risk of developing BPD with its associated severe morbidity, dysfunction, and incapacitation.