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Background and Aims: Engaging healthcare providers (HCPs) is critical for early identification of overweight and obesity. The aim of this study is to describe the trend in clinicians' adherence to clinical recommendations to discuss body weight status with adults with overweight and obesity., Methods and Results: We analyzed the data of adults aged 20 and older with overweight or obesity from the National Health and Nutrition Examination Surveys, 1999 to 2016 with a 2-year data-release cycle. The question of interest was "Has a doctor or other health professionals ever told you that you were overweight?" Adjusted biennial percentage ratio (abPR) of being notified was estimated. We observed a significant increasing trend of notification in adults with overweight [abPR = 1.04 (95% confidence interval: 1.03, 1.06), about 4% increase for every two-years] and obesity [1.01 (1.00, 1.02)]. The highest increase occurred in adults with overweight aged 20-34 [1.12 (1.08, 1.16)], however, young adults with overweight remained the group with the lowest percentage (24%, 2015-2016 survey) of notification compared to others in recent survey. Notification in adults with obesity demonstrated similar trends. In 2015-2016, among adults with obesity who visited HCPs last year, 80% of these aged 50-64 and 78% of these aged 65 and older were notified. More than 80% of adults with overweight or obesity visited HCPs at least once last year., Conclusions: There was an improvement in informing patients of overweight/obesity status. However, less than a quarter of young adults with overweight were notified in recent surveys, compromising the opportunities of preventing overweight from becoming obesity in early adulthood., (Copyright © 2020 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Objective: To compare a simultaneous vs sequential approach to residual post chemotherapy mass resections in metastatic testis cancer., Methods: A retrospective review was performed of patients who underwent retroperitoneal and thoracic/cervical resection of post chemotherapy residual masses between 2002 and 2018. Group 1: "Simultaneous" (Combined Retroperitoneal and Thoracic/Cervical resections on the same date); Group 2: "Sequential" (Retroperitoneal and Thoracic/Cervical resections at separate dates)., Results: During the study period, 35 simultaneous and 17 sequential resections were performed. The median age at surgery was 28 years (Range 16-61). The median follow-up from last surgical procedure was 62.7 months (Range 0.4-194). Histology revealed teratoma in 38 (73.1%) patients, necrosis in 8 (15.4%) and viable tumor in 6 (11.5%). Discordant pathology findings between thoracic/cervical and abdominal resections were noted in 16 (30.8%) patients. No differences were observed between the simultaneous vs sequential groups in median operating time (585 minutes vs 545 minutes, P = .64), blood loss (1300 vs 1300 mls, P = .42), or length of stay (9 vs 11 days, P = .14). There was no difference between the 5-year (65.7% vs 68.6%) relapse-free survival between the 2 groups (P = .84) or the 5-year (88.6% vs 100%) overall and disease-specific survival (P = .25)., Conclusion: Simultaneous resection of retroperitoneal and thoracic/cervical post chemotherapy metastases is a feasible in some patients. It requires multidisciplinary collaboration and a longer primary procedure., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Patients with cancer who are treated with immune checkpoint modulators (ICMs) have their health-related quality of life (HRQOL) measured using general patient-reported outcome (PRO) tools. To the authors' knowledge, no instrument has been developed to date specifically for patients treated with ICMs. The objective of the current study was to develop a toxicity subscale PRO instrument for patients treated with ICMs to assess HRQOL., Methods: Input was collected from a systematic review as well as patients and physicians experienced with ICM treatment. Descriptive thematic analysis was used to evaluate the qualitative data obtained from patient focus groups and interviews, which informed an initial list of items that described ICM side effects and their impact on HRQOL. These inputs informed item generation and/or reduction to develop a toxicity subscale., Results: Focus groups and individual interviews with 37 ICM-treated patients generated an initial list of 176 items. After a first round of item reduction that produced a shortened list of 76 items, 16 physicians who care for patients who are treated with ICMs were surveyed with a list of 49 patient-reported side effects and 11 physicians participated in follow-up interviews. A second round of item reduction was informed by the physician responses to produce a list of 25 items., Conclusions: To the authors' knowledge, this 25-item list is the first HRQOL-focused toxicity subscale for patients treated with ICMs and was developed in accordance with US Food and Drug Administration guidelines, which prioritize patient input in developing PRO tools. The subscale will be combined with the Functional Assessment of Cancer Therapy-General (FACT-G) to form the FACT-ICM. Prior to recommending the formal use of this PRO instrument, the authors will evaluate its validity and reliability in longitudinal studies involving substantially more patients., (© 2019 American Cancer Society.)

Background: There is no mechanism to predict health utility (HU) values from the University of Washington Quality of Life Questionnaire (UWQoL) scores. We sought to develop a mapping algorithm capable of using UWQoL data to approximate HU scores., Methods: Outpatients with head and neck cancer completed the UWQoL, EQ-5D, and the Health Utilities Index-Mark 3 (HUI-3). Results of the UWQoL were mapped onto both EQ-5D and HUI-3 scores using ordinary least-squares regression models. Two-part models were explored. The predictive power of the model was assessed using 10-fold cross-validation., Results: A total of 209 patients were recruited. The reduced model converting UWQoL data into EQ-5D scores performed best (adjusted R 2 = 0.628, root mean square error = 0.076). Both models demonstrated construct validity by discriminating between clinical indices of disease severity., Conclusions: The abovementioned algorithms enable researchers to perform health economic evaluations with existing UWQoL data in cases where prospectively collected HU values are not available., (© 2019 Wiley Periodicals, Inc.)

Background: The current study was conducted to determine whether the incidence of late-stage head and neck cancer (HNC) is decreasing and to estimate the risk of late-stage HNC diagnosis based on race and sex., Methods: Age-adjusted incidence rates for patients aged ≥18 years with stage IV HNC were abstracted from the Surveillance, Epidemiology, and End Results database (2004-2015). Rates were stratified by race, sex, and age. Joinpoint regression estimated annual percent changes (APCs) in rates over time, and logistic regression estimated adjusted odds ratios (aORs)., Results: There were 57,118 patients with stage IV HNC in the current study cohort, with an average age of 61.9 years. From 2004 to 2015, the age-adjusted incidence rates for stage IV HNC significantly increased by 26.1% (6.11 per 100,000 person-years in 2004 to 7.70 per 100,000 person-years in 2015). White and Asian/Pacific Islander/American Indian/Alaska Native patients had significant increases in incidence (APC for white patients, 3.03 [P < .01] and APC for other races, 1.95 [P < .01]), whereas rates among black patients remained stable but were highest across racial groups. Incidence was higher among males compared with females. When restricted only to patients with stage IVC (metastatic) HNC, there remained a significant increase in incidence, especially for oropharyngeal cancer, which showed a 22.9% increase (0.21 per 100,000 person-years in 2004 vs 0.25 per 100,000 person-years in 2015). Despite a decreasing overall incidence of stage IV HNC in black patients (aOR, 1.28; 95% CI, 1.22-1.34) they, along with males (aOR, 3.95; 95% CI, 3.80-4.11), had significantly increased risks of being diagnosed with late-stage HNC., Conclusions: There is an increasing incidence of late-stage HNC in the United States, with male patients and black individuals faring the worst., (© 2019 American Cancer Society.)

Porous starch is attractive by providing high surface area for many applications. In this study amyloglucosidase (AMG) and maltogenic α-amylase (MA) were investigated in direct comparison to elucidate potential effects in producing porous starch using high amylose rice starch as a substrate. Both enzymes generated pores at the surface as illustrated by Scanning Electron Microscopy (SEM). The enzyme-treated granules had higher relative crystallinity as deduced from Wide Angle X-ray Scattering (WAXS). MA treatment increased the number of short amylopectin chains and decreased the molecular weight with extended incubation time. The MA-treated starch had higher solubility whereas swelling capacity, amylose content, peak viscosity, final viscosity, breakdown and setback of both treatments were decreased compared to the control. Enzymatic treatments produced starch with delayed gelatinization temperature and increased the enthalpy. The results demonstrate that porous rice starch can provide different functionalities depending on the enzyme mechanisms, extending the range of applications., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The effects of multicycle ultrasound-assisted ice recrystallization (US+IR) combined with amyloglucosidase (AMG) or maltogenic α-amylase (MA) catalyzed hydrolysis on structure were investigated. Scanning electron microscopy (SEM) showed that the US+IR produced shallow indentations and grooves on the exterior of granules while the combination US+IR and enzyme hydrolysis created additional pores on starch granules. MA displayed a higher number of pores than AMG. The highest values of specific surface area (S BET ) and the total pore volume were obtained for US+IR→MA (1.96 m 2  g - 1 and 7.26 × 10 - 3  cm 3  g - 1 , respectively). The US+IR treatment significantly decreased the relative crystallinity, amylose content and swelling capacity. Those parameters were further efficiently decreased following enzymatic hydrolysis. The combined treatments generated products with higher initial gelatinization temperature (Ti) compared to the corresponding controls. The US+IR increased the digestion rate constant (k-value) compared to native starch. However, the combined treatment, US+IR→AMG, significantly decreased the k-value from 2.97 × 10 - 3 to 2.50 × 10 - 3  min - 1 compared to its control. Our study demonstrates that US+IR treatment in combination with enzyme hydrolysis is a useful method to produce specifically functionalized porous rice starch that can be used as e.g. absorbents and for further chemical modifications., (Copyright © 2019. Published by Elsevier B.V.)

Objective: To assess the association between gentamicin exposure in the neonatal period and hearing in school age., Methods: This study included children exposed to a high-dose (6 mg/kg) gentamicin regimen as neonates (2004-2012), invited for follow-up at school age, and a healthy age-matched control group. We assessed hearing with pure tone audiometry including the extended high-frequency (EHF) range. Outcomes were average hearing thresholds in the midfrequencies (0.5-4 kHz) and the EHFs (9-16 kHz). The measures of gentamicin exposure were cumulative dose and highest trough plasma concentration. We used linear regression models to assess the impact of gentamicin exposure, and other peri- and postnatal morbidities, on hearing thresholds., Results: A total of 219 gentamicin-exposed and 33 healthy-control children were included in the audiological analysis. In the gentamicin cohort, 39 (17%) had a birth weight <1500 g. Median cumulative doses and trough plasma concentrations were 30 (interquartile range 24-42) mg/kg and 1.0 (interquartile range 0.7-1.2) mg/L, respectively. Median hearing thresholds for the midfrequencies and the EHFs were 2.5 (0 to 6.3) dB hearing level and -1.7 (-5.0 to 5.0) dB hearing level, both of which were within the normal range. In an adjusted analysis, increasing hearing thresholds were associated with lower birth weight and postnatal middle-ear disease but not level of gentamicin exposure. After adjusting for birth weight, there was no difference in hearing threshold between the gentamicin-exposed cohort and healthy controls., Conclusions: Exposure to a high-dose gentamicin regimen in the neonatal period was not associated with an increase in hearing thresholds in schoolchildren being able to complete audiometry., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Purpose: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti‒programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer., Patients and Methods: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review., Results: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events., Conclusion: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.

Aim: To develop a comprehensive item library of patient-reported, immunotherapy-related adverse events (irAEs) that draws from and expands on the Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System., Methods: Literature review and iterative expert input. Based on a literature review of irAEs, we developed a framework of immunotherapy classes and their associated symptoms. Clinical experts then reviewed iterations of symptom summaries and item maps linked to the immunotherapy framework. Experts provided content review and feedback was shared across experts until consensus was reached. The iterative process facilitated creation of a Primary Symptom List associated with immune checkpoint modulators (ICMs), drawn from the larger set of symptoms. Existing FACIT items were mapped to the symptom list, and new items were written as needed to create the item library., Results: The full item library of irAEs is comprised of 239 items, covering 142 unique symptoms across 75 inflammatory reactions/immune conditions. A subset of 66 items comprises a Primary Symptom List considered most common/relevant to ICM treatment. This includes gastrointestinal, skin, pulmonary, neurologic, musculoskeletal, and multiple miscellaneous and constitutional symptoms., Conclusion: The FACIT Immunotherapy Item Library is a compilation of 239 self-report items that capture the wide range of AEs experienced by people receiving immune treatments. A subset of 66 items comprises a Primary Symptom List meant for ICM therapy. Use of items selected from this library is encouraged in clinical research and clinical practice evaluation., Competing Interests: Conflicts of interest Heather S.L. Jim is a consultant for RedHill BioPharma Ltd and Janssen Scientific Affairs; Aaron R. Hansen is a consultant for Merck (compensated) and GSK (compensated), and has received grant/research support from (Clinical Trials for institution) from Genentech/Roche, Merck, GSK, Bristol-Myers Squibb, Novartis, Boston Biomedical, Boehringer-Ingelheim, AstraZeneca, Medimmune, Janssen, Karyopharm, and Macrogenics; David Cella is the President and owner of FACIT.org; Kimberly A. Webster is an owner of FACIT.org; Clifton O. Bingham III is a consultant to Bristol Myers Squibb, Regeneron/Sanofi, and Genentech/Roche, and has received grant support from Bristol Myers Squibb; Adam P. Dicker is an advisor for Roche, EMD Serono, Celldex, Janssen, Cybrexa, Self Care Catalysts, Oncohost, ThirdBridge, and Noxopharm (compensated), and to Google LaunchPad Accelerator, Dreamit Ventures, and Evolution Road (uncompensated). He has also provided expert testimony for Intellectual property (Wilson Soncini); Josephine Feliciano is a consultant to Astra Zeneca, Genentech, Eli Lilly, Pfizer, and Merck. Sheetal Kircher, Monica Janda, Laurie E. Steffen McLouth, N. Lynn Henry, Mary O’Connor and Kari Ala-leppilampi declare no relevant interests, financial or otherwise.

Introduction: Carcinomas of unknown primary site (CUP) of the head and neck have historically been worked up and managed heterogeneously. Failure to identify a primary site may result in large radiotherapy mucosal volumes. Transoral approaches such as Transoral Robotic Surgery (TORS) may improve the yield of identifying hidden primaries. We aim to assess the oncological and functional outcomes of a combined treatment approach with TORS and tailored radiotherapy., Methods and Analysis: Twenty-five patients with metastatic squamous cell carcinoma to the neck without clinical or radiographic evidence of a primary site will be enrolled in a phase II trial. Patients will undergo a diagnostic or therapeutic approach with TORS based on specific algorithms incorporating tailored radiotherapy according to the location and laterality of the primary tumour. The primary outcome is to evaluate the out-of-field failure rate over a 2-year period. Secondary outcomes include identification rates, survival outcomes, patient reported outcomes and functional swallowing outcomes., Ethics and Dissemination: The University Health Network Research Ethics Board approved this study (ID 15-9767). The results will be published in an open access journal., Trial Registration Number: NCT03281499., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

With the advent of checkpoint inhibitor treatment for various cancer types, the optimization of drug selection, pharmacokinetics and biomarker assays is an urgent and as yet unresolved dilemma for clinicians, pharmaceutical companies and researchers. Drugs which inhibit cytotoxic T-lymphocyte associated protein-4 (CTLA-4), such as ipilimumab and tremelimumab, programmed cell death protein-1 (PD-1), such as nivolumab and pembrolizumab, and programmed cell death ligand-1 (PD-L1), such as atezolizumab, durvalumab and avelumab, each appear to have varying pharmacokinetics and clinical activity in different cancer types. Each drug differs in terms of dosing, which becomes an issue when drug comparisons are attempted. Here, we examine the various checkpoint inhibitors currently used and in development. We discuss the antibodies and their protein targets, their pharmacokinetics as measured in various tumor types, and their binding affinities to their respective antigens. We also examine the various dosing regimens for these drugs and how they differ. Finally, we examine new developments and methods to optimize delivery and efficacy in the field of checkpoint inhibitors, including non-fucosylation, prodrug formations, bispecific antibodies, and newer small molecule and peptide checkpoint inhibitors., Competing Interests: The authors declare no conflict of interest

We previously showed that infants born with long-gap esophageal atresia (LGEA) demonstrate clinically significant brain MRI findings following repair with the Foker process. The current pilot study sought to identify any pre-existing (PRE-Foker process) signs of brain injury and to characterize brain and corpus callosum (CC) growth. Preterm and full-term infants ( n = 3/group) underwent non-sedated brain MRI twice: before (PRE-Foker scan) and after (POST-Foker scan) completion of perioperative care. A neuroradiologist reported on qualitative brain findings. The research team quantified intracranial space, brain, cerebrospinal fluid (CSF), and CC volumes. We report novel qualitative brain findings in preterm and full-term infants born with LGEA before undergoing Foker process. Patients had a unique hospital course, as assessed by secondary clinical end-point measures. Despite increased total body weight and absolute intracranial and brain volumes (cm 3 ) between scans, normalized brain volume was decreased in 5/6 patients, implying delayed brain growth. This was accompanied by both an absolute and relative CSF volume increase. In addition to qualitative findings of CC abnormalities in 3/6 infants, normative CC size (% brain volume) was consistently smaller in all infants, suggesting delayed or abnormal CC maturation. A future larger study group is warranted to determine the impact on the neurodevelopmental outcomes of infants born with LGEA.

Background: Staphylococcus aureus is a highly prevalent respiratory pathogen in cystic fibrosis (CF). It is unclear how this organism establishes chronic infections in CF airways. We hypothesized that S. aureus isolates from patients with CF would share common virulence properties that enable chronic infection., Methods: 77 S. aureus isolates were obtained from 45 de-identified patients with CF at the University of Iowa. We assessed isolates phenotypically and used genotyping assays to determine the presence or absence of 18 superantigens (SAgs)., Results: We observed phenotypic diversity among S. aureus isolates from patients with CF. Genotypic analysis for SAgs revealed 79.8% of CF clinical isolates carried all six members of the enterotoxin gene cluster (EGC). MRSA and MSSA isolates had similar prevalence of SAgs. We additionally observed that EGC SAgs were prevalent in S. aureus isolated from two geographically distinct CF centers., Conclusions: S. aureus SAgs belonging to the EGC are highly prevalent in CF clinical isolates. The greater prevalence in these SAgs in CF airway specimens compared to skin isolates suggests that these toxins confer selective advantage in the CF airway.

Background: Treatment options are limited for recurrent nasopharyngeal carcinoma (NPC). We report results from a phase II study of CC-486 (oral azacitidine) in advanced NPC., Patients and Methods: Patients with locally advanced or metastatic NPC and 1-2 prior treatment regimens received CC-486 300 mg daily on days 1-14 of 21-day cycles until disease progression or unacceptable toxicity. The first 6 patients of Asian-Pacific Islander (API) ethnicity received a reduced dose of 200 mg to preserve safety and tolerability; if well tolerated, subsequent API patients received CC-486 300 mg. The study could advance to stage 2 if > 4 patients achieved a response. Co-primary end-points were overall response rate (ORR) and progression-free survival (independent review). Key secondary end-points were overall survival and safety., Results: Owing to faster-than-anticipated enrolment, 36 patients, including 13 of API ethnicity, were enrolled; the median age was 54.0 years. Most patients were male (81%) and had an Eastern Cooperative Oncology Group performance status ≤ 1 (97%). Among 25 efficacy-evaluable patients, the ORR was 12%; the median progression-free and overall survival were 4.7 and 18.0 months, respectively. The most common grade III/IV treatment-emergent adverse events were neutropenia (33%) and febrile neutropenia (11%). Twenty-one posttreatment deaths, primarily due to progressive disease or disease complications, and 1 on-treatment death (epistaxis, unrelated to study drug) occurred. The study did not advance to stage 2., Conclusion: CC-486 did not show sufficient clinical activity to support further development as monotherapy in this patient population. The safety profile of CC-486 in NPC was consistent with that in other solid tumours., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: No validated molecular biomarkers exist to help guide prognosis of renal cell carcinoma (RCC) patients. We seek to evaluate the quality of published prognostic circulating RCC biomarker manuscripts using the Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK) guidelines., Methods: The phrase "(renal cell carcinoma OR renal cancer OR kidney cancer OR kidney carcinoma) AND circulating AND (biomarkers OR cell free DNA OR tumor DNA OR methylated cell free DNA OR methylated tumor DNA)" was searched in Embase, Medline and PubMed March 2018. Relevant manuscripts were scored using 48 REMARK sub-criteria for a maximal score of 20 points., Results: The search identified 535 publications: 33 were manuscripts of primary research and were analyzed. The mean REMARK score was 10.6 (range 6.42-14.2). All manuscripts stated their biomarker, study objectives and method of case selection. The lowest scoring criteria: time lapse between storage of blood/serum and marker assay (n = 2) and lack of flow diagram (n = 2). REMARK scores were significantly higher in publications stating adherence to REMARK guidelines (p = 0.0307) and reporting statistically significant results (p = 0.0318)., Conclusions: Most RCC prognostic biomarker manuscripts poorly adhere to the REMARK guidelines. Better designed studies and appropriate reporting are required to address this urgent unmet need., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Advisory/Consulting/Research for Genentech/Roche, Merck, GSK, Bristol-Myers Squibb, Novartis, Boston Biomedical, Boehringer-Ingelheim, AstraZeneca, Medimmune to Aaron Hansen. The aforementioned conflict of interests does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Immuno-oncology (IO) is rapidly evolving in early drug development. We aimed to develop and prospectively validate a prognostic index for patients treated in IO phase I trials to assist with patient selection., Methods: The development cohort included 192 advanced solid tumor patients treated in 13 IO phase I trials, targeting immune checkpoint and/or co-stimulatory molecules. A prognostic scoring system was developed from multivariate survival analysis of 10 clinical factors, and subsequently validated in two independent validation cohorts (n = 152 and n = 80)., Results: In the development cohort, median age was 57.5 years (range = 20.4-84.8 years). Median progression-free survival and overall survival (OS) were 13.4 and 73.6 weeks, respectively, 90-day mortality was 16%, and overall response rate was 20%. In multivariate analysis, Eastern Cooperative Oncology Group performance status greater than or equal to 1 (hazard ratio [HR] = 3.2, 95% confidence interval [CI] = 1.8 to 5.7; P  < .001), number of metastatic sites greater than 2 (HR = 2.0, 95% CI = 1.3 to 3.1; P  = .003), and albumin less than the lower limit of normal (HR = 1.8, 95% CI = 1.2 to 2.7; P  = .007) were independent prognostic factors; comprising the Princess Margaret Immuno-oncology Prognostic Index (PM-IPI). Patients with a score of 2-3 compared with patients with a score of 0-1 had shorter OS (HR = 3.4, 95% CI = 1.9 to 6.1; P  < .001), progression-free survival (HR = 2.3, 95% CI = 1.7 to 3.2; P  < .001), higher 90-day mortality (odds ratio = 8.1, 95% CI = 3.0 to 35.4; P  < .001), and lower overall response rate (odds ratio = 0.4, 95% CI = 0.2 to 0.8; P = .019). The PM-IPI retained prognostic ability in both validation cohorts and performed better than previously published phase I prognostic scores for predicting OS in all three cohorts., Conclusions: The PM-IPI is a validated prognostic score for patients treated in phase I IO trials and may aid in improving patient selection., (© The Author(s) 2019. Published by Oxford University Press.)

Background: Enhancing the effectiveness of docetaxel for men with metastatic castration-resistant prostate cancer (mCRPC) is an unmet clinical need. Preclinical studies demonstrated that high-dose pantoprazole can prevent or delay resistance to docetaxel via the inhibition of autophagy in several solid tumor xenografts., Materials and Methods: Men with chemotherapy-naive mCRPC with a prostate-specific antigen (PSA) >10 ng/mL were eligible for enrolment. Men received intravenous pantoprazole (240 mg) prior to docetaxel (75 mg/m 2 ) every 21 days, with continuous prednisone 5 mg twice daily. Primary endpoint was a confirmed ≥50% decline of PSA. The trial used a Simon's two-stage design., Results: Between November 2012 and March 2015, 21 men with a median age of 70 years (range, 58-81) were treated (median, 6 cycles; range, 2-11). Men had received prior systemic therapies (median, 1; range, 0-3), and 14 had received abiraterone and/or enzalutamide. PSA response rate was 52% (11/21), which did not meet the prespecified criterion (≥13/21 responders) to proceed to stage 2 of the study. At interim analysis with a median follow-up of 17 months, 18 (86%) men were deceased (15 castration-resistant prostate cancer, 2 unknown, 1 radiation complication). Of the men with RECIST measurable disease, the radiographic partial response rate was 31% (4/13). The estimated median overall survival was 15.7 months (95% confidence interval [CI], 9.3-19.6) and median PFS was 5.3 months (95% CI, 2.6-12.9). There were no toxic deaths, and all adverse events were attributed to docetaxel., Conclusion: The combination of docetaxel and pantoprazole was tolerable, but the resultant clinical activity was not sufficient to meet the ambitious predefined target to warrant further testing., Implications for Practice: To date, no docetaxel combination regimen has reported superior efficacy over docetaxel alone in men with metastatic castration-resistant prostate cancer (mCRPC). The PANDORA trial has demonstrated that the combination of high dose pantoprazole with docetaxel is tolerable, but the clinical activity was not sufficient to warrant further testing. The chemotherapy standard of care for men with mCRPC remains docetaxel with prednisone. Future studies of autophagy inhibitors will need to measure autophagy inhibition accurately and determine the degree of autophagy inhibition required to produce a meaningful clinical response., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

The human microbiome is an emerging target in cancer development and therapeutics. It may be directly oncogenic, through promotion of mucosal inflammation or systemic dysregulation, or may alter anti-cancer immunity/therapy. Microorganisms within, adjacent to and distant from tumors may affect cancer progression, and interactions and differences between these populations can influence the course of disease. Here we review the microbiome as it pertains to cancer for clinicians. The microbiota of cancers including colorectal, pancreas, breast and prostate are discussed. We examine "omics" technologies, microbiota associated with tumor tissue and tumor-site fluids such as feces and urine, as well as indirect effects of the gut microbiome. We describe roles of the microbiome in immunotherapy, and how it can be modulated to improve cancer therapeutics. While research is still at an early stage, there is potential to exploit the microbiome, as modulation may increase efficacy of treatments, reduce toxicities and prevent carcinogenesis., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: To evaluate the impact of cisplatin cumulative dose (CDDP-D) and smoking pack-years (PYs) on cause-specific survival (CSS) and overall survival (OS) in human papillomavirus-positive (HPV+) oropharyngeal carcinoma (OPSCC) using the eighth edition tumour-node-metastasis (TNM) staging classification (TNM8)., Patients and Methods: We reviewed patients with HPV+ OPSCC treated with high-dose CDDP and intensity-modulated radiotherapy between 2005 and 2015 at Princess Margaret Cancer Centre. CSS and OS were compared according to CDDP-D <200/=200/>200 mg/m 2 stratified by TNM8., Results: A total of 482 consecutive patients were evaluated (stage I/II/III: N = 189/174/119; CDDP-D <200/=200/>200 mg/m 2 : N = 112/220/150). Median follow-up duration was 5.1 years (range: 0.6-12.8). Five-year CSS and OS differed by stages I/II/III: 96%/85%/88% (p=0.005) and 93%/84%/78% (p = 0.001), respectively. Five-year CSS by CDDP-D <200/=200/>200 mg/m 2 was similar in stage I (98%/95%/95%, p = 0.74) and stage II (88%/84%/84%, p = 0.86) but different in stage III (76%/98%/84%, p = 0.02). Five-year OS by CDDP-D <200/=200/>200 mg/m 2 did not differ significantly among stages. In the multivariable analysis, CDDP-D <200 mg/m 2 did not influence CSS in the whole cohort versus = 200/>200 mg/m 2 (p=0.53/0.79, respectively) but was associated with reduced CSS in stage III subgroup versus =200 mg/m 2 (=200 mg/m 2 versus < 200 mg/m 2 hazard ratio [HR] = 0.08; 95% confidence interval [CI]: 0.01-0.67; p = 0.02). Higher smoking PYs had no effect on CSS (p = 0.34) but reduced OS in the whole cohort (HR = 1.14 [95% CI: 1.02-1.27], p=0.01)., Conclusion: CDDP-D correlated with neither survival nor disease-specific outcomes in this large and homogeneous HPV+ cohort, although reduced CSS was observed in stageIII HPV+ OPSCC receiving CDDP-D <200 mg/m 2 . Smoking PYs were negatively associated with OS but not with CSS., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The analysis of circulating tumor cells (CTCs) provides a means to collect information about the evolving properties of a tumor during cancer progression and treatment. For patients with metastatic prostate cancer, noninvasive serial measurements of bloodborne cells may provide a means to tailor therapeutic decisions based on an individual patient's response. Here, we used a high-sensitivity profiling approach to monitor CTCs in patients with metastatic castrate-resistant prostate cancer (mCRPC) undergoing treatment with abiraterone and enzalutamide, two drugs used to treat advanced prostate cancer. The capture and profiling approach uses antibody-functionalized magnetic nanoparticles to sort cells according to protein expression levels. CTCs are tagged with magnetic nanoparticles conjugated to an antibody specific for the epithelial cell adhesion molecule (EpCAM) and sorted into four zones of a microfluidic device based on EpCAM expression levels. Our approach was compared to the FDA-cleared CellSearch method, and we demonstrate significantly higher capture efficiency of low-EpCAM cells compared to the commercial method. The nanoparticle-based approach detected CTCs from 86% of patients at baseline, compared to CellSearch which only detected CTCs from 60% of patients. Patients were stratified as prostate specific antigen (PSA) progressive versus responsive based on clinically acceptable definitions, and it was observed that patients with a limited response to therapy had elevated levels of androgen receptor variant 7 (ARV7) and the mesenchymal marker, N-cadherin, expressed on their CTCs. In addition, these CTCs exhibited lower EpCAM expression. The results highlight features of CTCs associated with disease progression on abiraterone or enzalutamide, including mesenchymal phenotypes and increased expression levels of ARV7. The use of a high-sensitivity method to capture and profile CTCs provides more informative data concerning the phenotypic properties of these cells as patients undergo treatment relative to an FDA-cleared method.

Purpose: To identify adverse radiologic nodal features in cN+ TNM-8 stage I human papillomavirus-related (HPV+) oropharyngeal cancer (OPC)., Methods and Materials: All patients with HPV+ cT1-T2cN1 OPC treated with definitive intensity modulated radiation therapy from 2008 to 2015 were included. Radiologically involved lymph node number (LN), radiologic extranodal extension (rENE), retropharyngeal LN (RPLN), and lower neck (level 4 or 5b) LN involvement were assessed on pre-treatment computed tomography/magnetic resonance imaging by a specialized head and neck neuroradiologist. Disease-free survival (DFS), locoregional control, and distant control were compared between those with versus without rENE. Univariable and multivariable analysis with stepwise modal selection were applied to identify prognostic factors for DFS., Results: A total of 45 rENE+ and 234 rENE- were identified. The rENE+ cohort had a higher number of LNs per patient (median: 6 vs 2, P < .001) and was more likely to have necrotic LNs (33 [73%] vs 132 [56%], P = .046). Median follow-up was 4.8 years. Although locoregional control was high in both cohorts (93% vs 97%, P = .34), the rENE+ group had inferior 5-year distant control (78% [59-88] vs 95% [91-97], P < .001) and DFS (58% [43-77] vs 90% [86-94], P < .001). In multivariable analysis, rENE+ (HR [hazard ratio] 4.3 [2.3-8.1], P < .001], T2 (vs T1) category (HR 2.1 [1.0-4.2], P = .039), smoking pack-years (HR 1.02 [1.0-1.03], P = .013), and the addition of systemic agents (HR 0.4 [0.2-0.8], P = .005) were prognostic for DFS. RPLN was prognostic for distant metastasis (HR 3.2, P = .013) but not for DFS after adjusting for rENE., Conclusions: Data from this contemporaneously treated cT1-T2N1 HPV+ OPC cohort suggest that the presence of rENE is an independent prognostic factor within stage I HPV+ OPC. RPLN is also associated with DM risk but not with DFS., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Standard-dose computed tomography (SDCT) scans are associated with radiation exposure during stage I testicular cancer surveillance., Objective: To evaluate low-dose CT (LDCT) for clinical use., Design, Setting, and Participants: In this single-arm prospective study, patients on surveillance for stage I testicular germ cell tumour underwent SDCT and LDCT scans on their first visit after enrolment. The adequacy of LDCT image quality was assessed for subsequent use. Patients were followed with LDCT only and suspected relapse was confirmed by SDCT., Outcome Measures and Statistical Analysis: We assessed whether initial LDCT scans were of sufficient quality for routine clinical use. We compared mean differences in nodal size at relapse between LDCT and SDCT using a one-sample paired t test. The relapse free-rate was calculated using the Kaplan-Meier method., Results and Limitations: Of 257 patients, one was excluded because of inadequate image quality. At median follow-up of 5.25 yr, 35 patients had relapsed, 33 with retroperitoneal lymphadenopathy. The 2- and 5-yr relapse-free rates were 89.5% and 85.3%, respectively. The mean size of retroperitoneal nodal relapse was 17.3 and 17.5mm on the short axis, 23.2 and 22.7mm on the long axis, and 26.1 and 26.7mm on craniocaudal length for LDCT and SDCT, respectively. The mean difference between LDCT and SDCT was 0.14mm (p=0.55) short axis, -0.54mm (p=0.092) long axis, and -0.51mm (p=0.086) length. A limitation was the lack of a control arm., Conclusions: LDCT image quality was adequate for clinical use, and retroperitoneal nodal relapse was detected with minimal differences seen between LD and SDCT. LDCT can be safely adopted and will decrease overall radiation exposure in stage I germ cell tumour surveillance., Patient Summary: We studied the use of low-dose computed tomography scans for detecting testicular cancer recurrence in lymph nodes of the abdomen and pelvis and found that they were safe, effective and would potentially reduce overall X-ray exposure. This trial is registered at ClinicalTrials.gov as NCT03142802., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Enrichment of patients based on molecular biomarkers is increasingly used in early phase clinical trials. Molecular profiling of patients with advanced cancers can identify specific genomic alterations to inform decisions about investigational treatment(s). Our aim was to evaluate the outcomes of new patient referrals to a large academic solid tumor phase I clinical trial program after the implementation of molecular profiling., Materials and Methods: Retrospective chart review of all new referrals to the Princess Margaret Cancer Centre (PM) phase I clinic from May 2012 to December 2014. Molecular profiling using either MALDI-TOF hotspot mutation genotyping or targeted panel DNA sequencing was performed for patients at PM or community hospitals through the institutional IMPACT/COMPACT trials., Results: A total of 971 new patient referrals were included for this analysis. Twenty-seven percent of referrals assessed in clinic were subsequently enrolled in phase I trials. Of all new referrals, 41% had prior molecular profiling, of whom 11% ( n  = 42) were enrolled in genotype-matched trials. Patients with prior molecular profiling were younger, more heavily pretreated, and had more favorable Princess Margaret Hospital Index (PMHI) scores. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 ( p  = .002), internal referrals within PM ( p  = .002), and PMHI ( p  ≤ .001) were independently associated with successful trial enrollment in multivariable analysis., Conclusion: Although nearly half of new patients referred to a phase I clinic had prior molecular profiling, the proportion subsequently enrolled into clinical trials was low. Prior molecular profiling was not an independent predictor of clinical trial enrollment., Implications for Practice: The landscape of oncology drug development is evolving alongside technological advancements. Recently, large academic medical centers have implemented clinical sequencing protocols to identify patients with actionable genomic alterations to enroll in therapeutic clinical trials. This study evaluates patient referral and enrollment patterns in a large academic phase I clinical trials program following the implementation of a molecular profiling program. Performance status and referral from a physician within the institution were associated with successful trial enrollment, whereas prior molecular profiling was not an independent predictor., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: Pheochromocytoma (PCC) and paraganglioma (PGL) are uncommon neoplasms with high morbidity in advanced stages. Effective systemic treatments are limited., Methods: A multisite phase 2 trial evaluated sunitinib in patients with progressive PCC/PGL. Patients received 50 mg orally for 4-6 weeks., Results: Between May 2009 and May 2016, 25 patients were enroled. The median age was 50 years and 56% were male. Three patients (12%) received prior chemotherapy and 16 (64%) prior surgery. The DCR was 83% (95% CI: 61-95%) and median PFS 13.4 (95% CI: 5.3-24.6) months. Of 23 evaluable patients, 3 (13%) with germline mutations (SDHA, SDHB, RET) achieved a PR. The patient with mutated RET and MEN2A remains on treatment after 64 cycles. The median time on treatment was 12.4 (1-88.0) months. Grade 3 or 4 toxicities were as expected and manageable; fatigue (16%) and thrombocytopenia (16%) were most common. One patient with grade 3 hypertension and 2 with grade 3 cardiac events discontinued treatment., Conclusion: Although the primary endpoint of disease control was met, the overall response rate of sunitinib was low in unselected patients with progressive PCC/PGL. Patients with germline variants in RET or in the subunits of SDH may derive greatest benefit.

Purpose: In contrast to the popularity of pets, research on the health effects of living with pets, particularly, on the risk of cancer, is minimal and inconclusive. We longitudinally examined relationships between pet ownership and the risk of dying from lung cancer., Methods: We analyzed nationally representative data of 13,725 adults aged ≥ 19 who answered the question about pet ownership in the Third National Health and Nutrition Examination Survey, 1988-1994, as the baseline survey. Vital status was followed through December 31st, 2010., Results: About 43% of the study population owned pets, with 20.4% having cats and 4.6% having birds. A total of 213 lung cancer deaths were recorded by the end of 183,094 unweighted person-years of follow-up with a lung-cancer specific death rate of 1.00 per 1000 person-years. After adjustment for cigarette smoking, alcohol drinking, physical activity, body mass index, history of atopic conditions, and serum cotinine, owning a pet (any) was associated with a doubled mortality rate among women for lung cancer [hazard ratio (HR)= 2.31 (1.41-3.79)] over non-owners. This association was largely attributed to having a cat or a bird. The HR was 2.85 (1.62-5.01) for cats, and 2.67 (0.68-10.5) for birds. The HR for dogs was 1.01 (0.57-1.77). No significant patterns of association were observed among men either for any pets or for a subtype of pet., Conclusions: Living with a pet, especially, a cat or a bird, was significantly associated with elevated hazard of dying from lung cancer among women. The detrimental effect that pets conferred was not explained by confounding from cigarette smoking or atopic conditions., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: In the present study, we explored the real-world efficacy of the immuno-oncology checkpoint inhibitor nivolumab and the tyrosine kinase inhibitor cabozantinib in the second-line setting., Methods: Using the International Metastatic Renal Cell Carcinoma Database Consortium (imdc) dataset, a retrospective analysis of patients with metastatic renal cell carcinoma (mrcc) treated with nivolumab or cabozantinib in the second line after prior therapy targeted to the vascular endothelial growth factor receptor (vegfr) was performed. Baseline characteristics and imdc risk factors were collected. Overall survival (os) and time to treatment failure (ttf) were calculated using Kaplan-Meier curves. Overall response rates (orrs) were determined for each therapy. Multivariable Cox regression analysis was performed to determine survival differences between cabozantinib and nivolumab treatment., Results: The analysis included 225 patients treated with nivolumab and 53 treated with cabozantinib. No significant difference in median os was observed: 22.10 months [95% confidence interval (ci): 17.18 months to not reached] with nivolumab and 23.70 months (95% ci: 15.52 months to not reached) with cabozantinib ( p = 0.61). The ttf was also similar at 6.90 months (95% ci: 4.60 months to 9.20 months) with nivolumab and 7.39 months (95% ci: 5.52 months to 12.85 months) with cabozantinib ( p = 0.20). The adjusted hazard ratio (hr) for nivolumab compared with cabozantinib was 1.30 (95% ci: 0.73 to 2.3), p = 0.38. When adjusted by imdc criteria and age, the hr was 1.32 (95% ci: 0.74 to 2.38), p = 0.35., Conclusions: Real-world imdc data indicate comparable os and ttf for nivolumab and cabozantinib. Both agents are reasonable therapeutic options for patients progressing after initial first-line vegfr-targeted therapy., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare the following interests: FD declares research funding from Novartis, Pfizer, and Ipsen; TKC declares research funding from AstraZeneca, Bristol–Myers Squibb, Exelixis, Genentech, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, Roche, Tracon Pharmaceuticals, and Eisai, and consulting or advisory fees from AstraZeneca, Bayer, Bristol–Myers Squibb, Cerulean, Eisai, Foundation Medicine, Exelixis Genentech/Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, and Prometheus Labs; BB declares honoraria from Amgen, Pfizer, Janssen, and Bayer, and was also an investigator on the European Clinical Trials Database 2011-006085-40/MetaSun trial supported by Pfizer; NA declares consulting fees from Pfizer, Exelixis, Argos, and Cerulean; RK declares honoraria from Novartis, Pfizer, and Bayer; TY declares remuneration for a lecture from Pfizer Japan and Novartis Pharma Japan; DYCH declares consulting fees from Pfizer, Novartis, Bristol–Myers Squibb, Janssen Pharmaceuticals, and Astellas Pharma; IDD is supported by an Australian National Health and Medical Research Council Practitioner Fellowship (APP1102604), and has received research funding from Astellas and Exelixis. The remaining authors have no conflicts to disclose.

The patient-reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) complements capture of symptomatic adverse events (AEs) by clinicians. Previous trials have typically used a limited subset of relevant symptomatic AEs to reduce patient burden. We aimed to determine the feasibility of administering all 80 AEs included in the PRO-CTCAE library by approaching consecutive patients enrolled in a large academic phase I program at three points in time. Here, we report a preplanned analysis after enrolling the first 20 patients. All items were answered on 51 of 56 potential visits (adherence 91%). Three (5%) additional PRO-CTCAE assessments were partially completed, and two (4%) were missed because of conflicting appointments. No patient withdrew consent or chose not to complete the assessments once enrolled on study. Future trials of experimental drugs that incorporate the PRO-CTCAE should consider using this unselected approach to identify adverse events more completely., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Background: Immune checkpoint inhibitors (ICIs) demonstrate unprecedented efficacy in multiple malignancies; however, the mechanisms of sensitivity and resistance are poorly understood and predictive biomarkers are scarce. INSPIRE is a phase 2 basket study to evaluate the genomic and immune landscapes of peripheral blood and tumors following pembrolizumab treatment., Methods: Patients with incurable, locally advanced or metastatic solid tumors that have progressed on standard therapy, or for whom no standard therapy exists or standard therapy was not deemed appropriate, received 200 mg pembrolizumab intravenously every three weeks. Blood and tissue samples were collected at baseline, during treatment, and at progression. One core biopsy was used for immunohistochemistry and the remaining cores were pooled and divided for genomic and immune analyses. Univariable analysis of clinical, genomic, and immunophenotyping parameters was conducted to evaluate associations with treatment response in this exploratory analysis., Results: Eighty patients were enrolled from March 21, 2016 to June 1, 2017, and 129 tumor and 382 blood samples were collected. Immune biomarkers were significantly different between the blood and tissue. T cell PD-1 was blocked (≥98%) in the blood of all patients by the third week of treatment. In the tumor, 5/11 (45%) and 11/14 (79%) patients had T cell surface PD-1 occupance at weeks six and nine, respectively. The proportion of genome copy number alterations and abundance of intratumoral 4-1BB+ PD-1+ CD8 T cells at baseline (P < 0.05), and fold-expansion of intratumoral CD8 T cells from baseline to cycle 2-3 (P < 0.05) were associated with treatment response., Conclusion: This study provides technical feasibility data for correlative studies. Tissue biopsies provide distinct data from the blood and may predict response to pembrolizumab.

Background: Sunitinib is administered on a rigid schedule that may not be optimal for all patients. We hypothesised that toxicity-driven dose and schedule changes would optimise drug exposure and outcome for each patient., Materials and Methods: In a phase 2 trial, 117 patients with metastatic clear cell renal cell cancer were started on sunitinib 50 mg/day with the aim to treat for 28 days. Treatment breaks were reduced to 7 days. Sunitinib dose and the number of days on therapy were individualised based on toxicity aiming for ≤ grade II toxicity with dose escalation in patients with minimal toxicity. The null hypothesis for the primary end-point was a progression-free survival (PFS) of 8.5 months based on a study with similar eligibility criteria., Results: The null hypothesis was rejected (p < 0.001) with a median PFS of 12.5 months (95% confidence interval [CI]: 9.6-16.5). The median overall survival was 38.5 months (95% CI: 28.3-not reached). The objective response rate (46.1%) and stable disease rate (38.5%) translated into a clinical benefit for 84.6% of patients with no decline in quality of life scores during therapy. Fewer patients were dose reduced (26.5% vs. 50%) or discontinued due to toxicity (7.7 vs. 18-20%) compared to standard sunitinib dosing, and 20 (18.4%) patients were dose escalated to 62.5 mg (12) and 75 mg (8) with a wide individual variation in the optimal dose and treatment duration., Conclusions: Individualised sunitinib therapy is feasible, safe and an effective method to manage toxicity with one of the best efficacy seen for oral vascular endothelial growth factor inhibitors in metastatic renal cell carcinoma. CLINICALTRIALS., Gov Identifier: NCT01499121., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Major depressive disorder (MDD) affects 350 million people worldwide and is a serious socio-economic burden. The most efficient treatment of MDD is electroconvulsive therapy (ECT), which has been shown to influence the oxidative status believed to be part of the pathophysiology of MDD. We investigated the effects of chronic electroconvulsive stimulation (ECS) on mitochondrial respiration and mitochondrial hydrogen peroxide production, RNA oxidation, and the content of mitochondria in the piriform cortex of the rat. We found reductions of mitochondrial respiration in respiratory states 2 and 3 by 33% and 32%, respectively, and a 23% reduction in electron transfer capacity. RNA oxidation, as measured by 8-oxo-7,8-dihydroguanosine, was increased by 58%, while mitochondrial production of H 2 O 2 was unaffected. The increased oxidative stress may thus be ascribed to extra-mitochondrial sources., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Immunotherapy (IO) agents can cause late-onset immune-related adverse events (irAEs). In phase I trials, observation for dose-limiting toxicities (DLTs) is typically limited to the first cycle. The incidence of delayed-onset DLTs and their potential impact on dose determination have not been fully elucidated., Patients and Methods: Consecutive patients enrolled in early phase IO trials at Princess Margaret Cancer Centre between August 2012 and September 2016 were retrospectively reviewed, applying trial-specific definitions for DLTs. A clinically significant AE (csAE) was defined as a treatment-related adverse event requiring corticosteroids, hormone replacement, IO delay or discontinuation., Results: A total of 352 consecutive trial enrolments in 21 early phase clinical trials were included. Two-hundred seventy-eight patients (79%) received monotherapy and 74 (21%) received combination IO. Two hundred sixty (74%) patients experienced irAEs. There were two protocol-defined DLTs. Twenty (5.7%) patients had 24 csAEs qualifying as DLTs except for occurrence after the protocol-specified DLT period. One-hundred and six (10%) of irAEs were csAEs, including endocrine (26%), respiratory (14%), gastrointestinal (11%), general (10%), dermatological (8%), hepatic (8%), musculoskeletal (6%), pancreatic (6%), haematological, metabolic, neurological, cardiac (each 2%), infective and ocular (each 1%) events. The highest risk of first-onset csAE was during the first 4 weeks compared with the period from 4 weeks to end of treatment (odds ratio 3.13, 95% confidence interval 1.95-5.02). The median time to first onset csAE was significantly shorter with combination than monotherapy IO (32 vs. 146 days, P < 0.001)., Conclusions: In our series of early phase IO trials, the risk of csAE was highest during the initial 4 weeks on IO treatment, supporting the use of the conventional DLT period for dose escalation decision. However, there were 24 clinically significant late-onset DLTs in 5.7% of patients. Combination IO was associated with greater risk of and also earlier onset for csAE, which may need to be considered for early phase trial design., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: After chemotherapy, approximately 50% of patients with metastatic testicular germ cell tumors (GCTs) who undergo retroperitoneal lymph node dissections (RPNLDs) for residual masses have fibrosis. Radiomics uses image processing techniques to extract quantitative textures/features from regions of interest (ROIs) to train a classifier that predicts outcomes. We hypothesized that radiomics would identify patients with a high likelihood of fibrosis who may avoid RPLND., Patients and Methods: Patients with GCT who had an RPLND for nodal masses > 1 cm after first-line platinum chemotherapy were included. Preoperative contrast-enhanced axial computed tomography images of retroperitoneal ROIs were manually contoured. Radiomics features (n = 153) were used to train a radial basis function support vector machine classifier to discriminate between viable GCT/mature teratoma versus fibrosis. A nested 10-fold cross-validation protocol was used to determine classifier accuracy. Clinical variables/restricted size criteria were used to optimize the classifier., Results: Seventy-seven patients with 102 ROIs were analyzed (GCT, 21; teratoma, 41; fibrosis, 40). The discriminative accuracy of radiomics to identify GCT/teratoma versus fibrosis was 72 ± 2.2% (area under the curve [AUC], 0.74 ± 0.028); sensitivity was 56.2 ± 15.0%, and specificity was 81.9 ± 9.0% ( P = .001). No major predictive differences were identified when data were restricted by varying maximal axial diameters (AUC range, 0.58 ± 0.05 to 0.74 ± 0.03). The prediction algorithm using clinical variables alone identified an AUC of 0.76. When these variables were added to the radiomics signature, the best performing classifier was identified when axial masses were limited to diameter < 2 cm (accuracy, 88.2 ± 4.4; AUC, 0.80 ± 0.05; P = .02)., Conclusion: A predictive radiomics algorithm had a discriminative accuracy of 72% that improved to 88% when combined with clinical predictors. Additional independent validation is required to assess whether radiomics allows patients with a high predicted likelihood of fibrosis to avoid RPLND.

Objectives: To identify differentially expressed genes between relapsed and non-relapsed clinical stage I testicular germ cell tumours (TGCTs)., Materials and Methods: We reviewed patients with clinical stage I non-seminoma and seminoma from an institutional database (2000-2012) who were managed by active surveillance. Patients with non-relapsed non-seminoma and non-relapsed seminoma were defined as being relapse-free after 2 and 3 years of surveillance, respectively. RNA extraction and gene expression analysis was performed on archival primary tumour samples and gene-set enrichment analysis (GSEA) was conducted in order to identify differentiating biological pathways., Results: A total of 57 patients (relapsed non-seminoma, n = 12; relapsed seminoma, n =15; non-relapsed non-seminoma, n = 15; non-relapsed seminoma, n = 15) were identified, with a median (range) relapse time of 5.6 (2.5-18.1) and 19.3 (4.7-65.3) months in the relapsed non-seminoma and relapsed seminoma cohorts, respectively. A total of 1 039 differentially expressed genes were identified that separated relapsed and non-relapsed groups. In patients with relapse, GSEA revealed enrichment in pathways associated with differentiation, such as skeletal development (i.e. FGFR1, BMP4, GLI2, SPARC, COL2A1), tissue (i.e. BMP4, SPARC, COL13A1) and bone remodelling (i.e. CARTPT, GLI2, MGP). A discriminative gene expression profile between relapsed and non-relapsed cases was discovered when combining non-seminoma and seminoma samples using 10- and 30-probe signatures; however, this profile was not observed in the seminoma and non-seminoma cohorts individually., Conclusion: A discriminating signature for relapsed disease was identified for clinical stage I TGCT that we were not able to identify by histology alone. Further validation is required to determine if this signature provides independent prognostic information to standard pathological risk factors., (© 2018 The Authors BJU International © 2018 BJU International Published by John Wiley & Sons Ltd.)

Objectives: The objectives of this study were to (1) determine the degree of alignment between an existing public health curricula and disease intervention specialist (DIS) workforce training needs, (2) assess the appropriateness of public health education for DISs, and (3) identify existing curriculum gaps to inform future DIS training efforts., Methods: Using the iterative comparison analysis process of crosswalking, we compared DIS job tasks and knowledge competencies across a standard Council on Education for Public Health (CEPH)-accredited bachelor of science in public health (BSPH) and master of public health (MPH) program core curricula offered by the Georgia Southern University Jiann-Ping Hsu College of Public Health. Four researchers independently coded each DIS task and competency as addressed or not in the curriculum and then discussed all matches and non-matches between coders. Researchers consulted course instructors when necessary, and discussion between researchers continued until agreement was reached on coding., Results: The BSPH curriculum aligned with 75% of the DIS job tasks and 42% of the DIS knowledge competencies. The MPH core curriculum aligned with 55% of the job tasks and 40% of the DIS knowledge competencies. Seven job tasks and 9 knowledge competencies were considered unique to a DIS and would require on-the-job training., Conclusions: Findings suggest that an accredited public health academic program, grounded in CEPH competencies, could address multiple components of DIS educational preparation. Similar analyses should be conducted at other CEPH-accredited schools and programs of public health to account for variations in curriculum.

Purpose: Fine-needle biopsy (FNB) and liquid biopsy are minimally invasive methods of tumor sampling that provide feasible means to assess tumor genotypes in real time. However, more data are needed to establish the strength of these methods by benchmarking against the current gold standard methods, core-needle biopsy (CNB) or surgical excision of the tumor., Patients and Methods: Eligible patients with advanced solid tumors were prospectively recruited. We performed mutation profiling using matched tumor DNA obtained by CNB, FNB and liquid biopsy, and matrix-assisted laser desorption/ionization time-of-flight custom mass-spectrometry or targeted next-generation DNA sequencing. The actionability of detected mutations was determined using the OncoKB Web tool. Agreement between mutations detected in CNBs, FNBs, and circulating tumor DNA (ctDNA) was examined., Results: Forty-one patients underwent tumor biopsy. Thirty CNBs (73%) and 34 FNBs (83%) had sufficient tumor and DNA for mutation profiling. Median DNA yield from CNB and FNB were 775 ng (interquartile range, 240 to 347 4ng) and 649 ng (interquartile range, 180 to1350 ng), respectively. Of 29 CNB/FNB pairs available for comparison, actionable mutation results were concordant in 28 (96%). Six of nine actionable mutations (67%) that were found by CNB, FNB, or both were detectable in ctDNA. Two additional actionable mutations were found exclusively in ctDNA., Conclusion: Optimally processed FNB and liquid biopsy can be used routinely for tumor mutation profiling to identify actionable mutations.

Objectives: We examined trends in prevalence rates of smoking and smoking cessation during pregnancy among women in the United States to assess achievement of Healthy People 2020 prevention targets., Methods: We assessed the smoking habits of 30 667 mothers whose children were born between 1985 and 2014 and who were sampled by the National Health and Nutrition Examination Survey, 1999-2014. Sampled participants were children aged 0-15 at the time of interview; however, an adult proxy-usually the biological mother-responded on the child's behalf and reported information about maternal tobacco use during pregnancy. We calculated prevalence rates, adjusted odds ratios (aORs), and predicted annual increase or decrease of smoking and quitting smoking during pregnancy, adjusting for mother's age at delivery and income level and child's race/ethnicity and sex., Results: The average annual prevalence of smoking at any time during pregnancy decreased from 25.7% (95% confidence interval [CI], 15.3%-36.0%) in 1985 to 10.1% (95% CI, 7.1%-13.0%) in 2014 ( P < .001), and quitting smoking at any time during the index pregnancy increased from 36.6% (95% CI, 20.3%-52.9%) in 1985 to 54.9% (95% CI, 44.4%-65.4%) in 2008 ( P = .002). The adjusted annual risk of smoking during pregnancy decreased significantly by 3% (aOR = 0.97; 95% CI, 0.95-0.98; P < .001). The prevalence rate of smoking in the year 2020 extrapolated from the current trend would be 6.1%., Conclusions: Smoking during pregnancy in the United States is declining. However, renewed public health measures are needed to achieve the Healthy People 2020 objectives of preventing smoking among pregnant women in the United States.

Purpose: Previous oncological studies showed that lymph node ratio (LNR) (ratio of number of lymph nodes that tested positive for metastasis to the total number of lymph nodes examined) is a negative indicator of cancer survival. The American Joint Committee on Cancer (AJCC) staging system incorporates tumor size, lymph node involvement, and metastasis in a comprehensive model of cancer progression, but LNR alone has been shown to outperform the AJCC system in prognostic and survival predictions for various types of cancer. The effectiveness of LNR has not been evaluated in breast cancer staging. Evaluating LNR for predicting cancer staging in breast cancer has the potential to improve treatment recommendations., Methods: The Surveillance, Epidemiology, and End Results dataset was used to identify 10,655 breast cancer patients who underwent nodal evaluation from 2010 to 2013, and their LNRs were calculated. Descriptive statistics of lymph node evaluation in the patients are provided. Logistic regression with LNR as the continuous independent variable was conducted to determine whether LNR could predict cancer progression, coded as regional or distant. Analysis was conducted using SPSS version 24., Results: Patient's mean age was 59.43±18.62. Logistic regression analysis revealed that for every 1.3% increase in LNR, the odds of falling into the distant stage of the TNM staging system increased by 13.7% (odds ratio, 14.73; 95% confidence interval, 12.00-18.08)., Conclusion: LNR, while correlated with breast cancer staging, serves as a better predictor of survival. Precision staging can influence treatment modality, and improved treatments can significantly improve quality of life. Additional research and diagnostic examinations using LNR as a potential tool for accurate staging in breast cancer patients are warranted., Competing Interests: CONFLICT OF INTEREST: The authors declare that they have no competing interests.

Obesity has become a serious issue affecting millions of Americans, especially in the southern United States. One avenue for addressing obesity is the workplace setting. This formative research study examined the feasibility of an obesity prevention worksite intervention in the barbershop for African American barbershop owners (employers) and barbers (employees). The study proposes an intervention where the owner of the barbershop would be trained to educate his barbers about obesity prevention. Twenty in-depth interviews were conducted with the owners ( n = 5) and barbers ( n = 15) of five barbershops in Statesboro, Georgia, to determine the feasibility of the intervention. The results of this study indicated that the owners and barbers all felt that the intervention was feasible and could be implemented in the barbershop. The owners and barbers felt that obesity was an important issue in their community. Additional themes identified include program benefits, empowerment of owners and barbers, and motivational components to help produce healthy habits. The owners felt comfortable educating their barbers about obesity prevention, and the barbers were receptive toward the idea of being educated by their employer. In order for this intervention to be implemented and effective, it must be tailored to fit within the barbershop environment. This intervention addresses known health disparities that exist in the African American community and underscores the need for additional worksite health promotion programs in medically underserved communities.

Background: Patients with castration-resistant prostate cancer derive only modest clinical benefit from available therapies. Blockade of the inhibitory programmed death 1 (PD-1) receptor by monoclonal antibodies has been effective in several malignancies. Results from the prostate adenocarcinoma cohort of the nonrandomized phase Ib KEYNOTE-028 trial of pembrolizumab in advanced solid tumors are presented., Materials and Methods: Key eligibility criteria included advanced prostate adenocarcinoma, unsuccessful standard therapy, measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1), and PD-1 ligand (PD-L1) expression in ≥1% of tumor or stromal cells. Patients received pembrolizumab 10 mg/kg every 2 weeks until disease progression or intolerable toxicity for up to 24 months. Primary end point was objective response rate (ORR) per RECIST v1.1 by investigator review., Results: Median patient age in this cohort (n = 23) was 65 years; 73.9% of patients received at least two prior therapies for metastatic disease. There were four confirmed partial responses, for an ORR of 17.4% [95% confidence interval (CI) 5.0%-38.8%]; 8 of 23 (34.8%) patients had stable disease. Median duration of response was 13.5 months. Median progression-free survival (PFS) and overall survival (OS) were 3.5 and 7.9 months, respectively; 6-month PFS and OS rates were 34.8% and 73.4%, respectively. One patient remained on treatment at data cutoff. After a median follow-up of 7.9 months, 14 (60.9%) patients experienced treatment-related adverse events (TRAEs), most commonly nausea (n = 3, 13.0%). Four (17.3%) experienced grade 3/4 TRAEs: grade 3 peripheral neuropathy, grade 3 asthenia, grade 3 fatigue, and grade 4 lipase increase. No pembrolizumab-related deaths or discontinuations occurred., Conclusion: Pembrolizumab resulted in durable objective response in a subset of patients with heavily pretreated, advanced PD-L1-positive prostate cancer, and its side effect profile was favorable., Clinicaltrials.gov Identifier: NCT02054806.

Plant cell walls are highly complex structures composed of diverse classes of polysaccharides, proteoglycans, and polyphenolics, which have numerous roles throughout the life of a plant. Significant research efforts aim to understand the biology of this cellular organelle and to facilitate cell-wall-based industrial applications. To accomplish this, researchers need to be provided with a variety of sensitive and specific detection methods for separate cell wall components, and their various molecular characteristics in vitro as well as in situ . Cell wall component-directed molecular detection probes (in short: cell wall probes, CWPs) are an essential asset to the plant glycobiology toolbox. To date, a relatively large set of CWPs has been produced-mainly consisting of monoclonal antibodies, carbohydrate-binding modules, synthetic antibodies produced by phage display, and small molecular probes. In this review, we summarize the state-of-the-art knowledge about these CWPs; their classification and their advantages and disadvantages in different applications. In particular, we elaborate on the recent advances in non-conventional approaches to the generation of novel CWPs, and identify the remaining gaps in terms of target recognition. This report also highlights the addition of new "compartments" to the probing toolbox, which is filled with novel chemical biology tools, such as metabolic labeling reagents and oligosaccharide conjugates. In the end, we also forecast future developments in this dynamic field.

Objective Current report assessed the trends in smoking prevalence and the percentage of smoking cessation during pregnancy among women from three major races/ethnicities. Methods Data were collected between 1999 and 2014 from the continuous National Health and Nutrition Examination Survey (NHANES). Smoking habits of women while pregnant with the child sampled by NHANES were assessed retrospectively. A total of 28,090 women who gave live birth between 1985 and 2014 were included. The prevalence ratios (PRs) of smoking and quitting smoking during pregnancy were calculated. The adjusted annual prevalence ratio (aaPR: the ratio associated with a 1-year increase in time) was estimated using logistic regression with the year of birth as a predictor. Results With child's race/ethnicity, gender, and mother's age controlled, the aaPR of smoking was 0.95 (95% confidence interval 0.92-0.97) for Hispanics, 0.96 (0.94-0.98) for whites, and 0.98 (0.94-1.00) for blacks. The aaPR of quitting smoking was 1.09 (1.02-1.16) for Hispanics, 1.01 (0.97-1.06) for whites, and 1.03 (0.95-1.12) for blacks. Compared with the counterparts aged 35 years or older, pregnant women younger than 20 years were more likely to smoke among whites [PR 1.56 (1.07-2.29)] but less likely among blacks [PR 0.37 (0.26-0.52)]. Conclusions for Practice Smoking prevalence has been declining continuously for all but at different rates among three major races/ethnicities. The risk profiles of smoking during pregnancy were race/ethnicity specific. Culturally appropriate programs should be developed to further reduce the maternal smoking during pregnancy.

In the USA, African American children residing in rural areas are disproportionately affected by childhood obesity. One strategy for preventing childhood obesity is helping caregivers to recognize their child is overweight or obese. The purpose of this study is to assess African American caregivers' perceived level of their child's obesity status and concordance between caregiver's reported height and weight of their children compared to the objective measure of their child's height and weight. Caregivers completed a paper-based survey about perceptions of their child's weight status including body silhouettes (n = 119) and self-reported their child's body mass index status (n = 68). Children's (n = 71) height and weight were objectively measured. Spearman rho and independent sample t tests were calculated to assess the relationship between caregiver's self-reported and objective BMI status. Caregiver's visually perceived their child's weight status to be underweight; yet, self-reported that their child's body mass index status was obese. The Spearman's rho correlation indicated a significant relationship between caregiver's self-reported and objective body mass index (r = .39, p < .001). The independent sample t test reflected that the mean self-reported body mass index and objective body mass index were statistically significant with calculated body mass index perception. The investigation of three different methods for assessing body mass index perceptions may contribute to the development of tailored programs and interventions that include counseling strategies that increase parental education about their child's body mass index.

Testicular seminoma most commonly affects young men and is associated with favourable prognosis. Various followup schedules and imaging protocols for testicular seminoma have been described without overall consensus. We reviewed the literature together with our experience at the Princess Margaret Cancer Centre and present an evidence-based followup approach for patients with stage I and II seminoma.

Purpose To establish the safety profile and antitumor activity of the anti-programmed death 1 receptor monoclonal antibody, pembrolizumab, in patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) that expressed programmed death-ligand 1 (PD-L1). Patients and Methods KEYNOTE-028 (NCT02054806) is a nonrandomized, multicohort, phase Ib trial of pembrolizumab in patients with PD-L1-positive advanced solid tumors. Key eligibility criteria for the NPC cohort included unresectable or metastatic disease, failure on prior standard therapy, and PD-L1 expression in 1% or more of tumor cells or tumor-infiltrating lymphocytes. Patients received pembrolizumab 10 mg/kg every 2 weeks up to 2 years or until disease progression or unacceptable toxicity. Primary end point was objective response rate (ORR) per investigator review. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) every 8 weeks for the first 6 months and every 12 weeks thereafter. Results Twenty-seven patients received pembrolizumab. Median age was 52.0 years (range, 18 to 68 years); 92.6% received prior therapies for RM-NPC; 70.4% had received three or more therapies. Partial response and stable disease were observed in seven and 14 patients, respectively, for an ORR of 25.9% (95% CI, 11.1 to 46.3) over a median follow-up of 20 months. ORR by central review was similar (26.3%). Drug-related adverse events that occurred in 15% or more of patients included rash (25.9%), pruritus (25.9%), pain (22.2%), hypothyroidism (18.5%), and fatigue (18.5%). Grade ≥ 3 drug-related adverse events occurred in eight patients (29.6%), and there was one drug-related death (sepsis). As of the data cutoff (June 20, 2016), two patients remained on pembrolizumab treatment. Conclusion Pembrolizumab demonstrated antitumor activity and a manageable safety profile in patients with RM-NPC.