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Introduction: Previous studies have evaluated stereotactic body radiotherapy (SBRT) in oligometastatic patients with NSCLC, including multimodality treatment with anti-programmed cell death protein-1 monotherapy. Questions remain regarding the timing of SBRT and immunotherapy, safety with dual checkpoint blockade, and the utility in widely metastatic patients. This randomized phase 1 trial combined nivolumab and ipilimumab with sequential or concurrent multisite SBRT in patients with stage IV NSCLC to evaluate safety and obtain preliminary activity data., Methods: Treatment-naive patients with metastatic NSCLC were randomized to concurrent (SBRT with immunotherapy) or sequential (SBRT followed by immunotherapy) treatment. A maximum of four treatment fields received SBRT. Nivolumab and ipilimumab were continued until clinical progression, development of toxicity, or after 2 years. Dose-limiting toxicity was defined as greater than or equal to grade 3 toxicity to the relevant organ system attributed to SBRT and immunotherapy occuring within 3 months., Results: A total of 37 patients were assessable. No dose-limiting toxicity occurred in the concurrent cohort (n = 18). The sequential cohort required a dose reduction in the central lung group owing to two grade 4 pneumonitis events (2 of 19). Overall best response was as follows: 5.4% (2 of 37) complete response, 40.5% (15 of 37) partial response, 16.2% (6 of 37) stable disease, and 37.8% (14 of 37) progressive disease. Median progression-free survival was 5.8 months (95% confidence interval: 3.6-11.4 mo), with median follow-up of 17.0 months. Median overall survival was not reached., Conclusions: Concurrent nivolumab, ipilimumab, and SBRT were not more toxic than sequential therapy, and multisite SBRT was well tolerated in widely metastatic patients. Multimodality therapy resulted in durable metastasis control and encouraging early overall survival., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: Combination of antiprogrammed cell death protein-1 (PD-1) plus anti-cytotoxic T-cell lymphocyte-4 (anti-CTLA-4) immunotherapy shows greater response rates (RRs) than anti-PD-1 antibody alone in melanoma, but RR after initial anti-PD-1 and programmed death ligand-1 (PD-L1) antibody progression awaits robust investigation. Anti-CTLA-4 antibody alone after anti-PD-1/L1 antibody progression has a historical RR of 13%. We report the results of the first prospective clinical trial evaluating ipilimumab 1 mg/kg plus pembrolizumab following progression on anti-PD-1 immunotherapy., Methods: Patients with advanced melanoma who had progressed on anti-PD-1/L1 antibody as immediate prior therapy (including non-anti-CTLA-4 antibody combinations) were eligible. Patients received pembrolizumab 200 mg plus ipilimumab 1 mg/kg once every 3 weeks for four doses, followed by pembrolizumab monotherapy. The primary end point was RR by irRECIST. After 35 patients, the trial met the primary end point and was expanded to enroll a total of 70 patients to better estimate the RR., Results: Prior treatments included 60 on anti-PD-1 antibody alone and 10 on anti-PD-1/L1 antibody-based combinations. Thirteen patients had progressed in the adjuvant setting. The median length of prior treatment with anti-PD-1/L1 antibody was 4.8 months. Response assessments included five complete and 15 partial responses, making the irRECIST RR 29% among the entire trial population. The median progression-free survival was 5.0 months, and the median overall survival was 24.7 months. The median duration of response was 16.6 months. There was no difference in median time on prior anti-PD1/L1 or time to PD1 + CTLA4 initiation between responders and nonresponders. Grade 3-4 drug-related adverse events occurred in 27% of patients. Responses occurred in PD-L1-negative, non-T-cell-inflamed, and intermediate tumor phenotypes., Conclusion: To our knowledge, this is the first prospective study in melanoma of pembrolizumab plus low-dose ipilimumab after anti-PD-1/L1 immunotherapy failure, demonstrating significant antitumor activity and tolerability., Competing Interests: Zeynep ErogluConsulting or Advisory Role: Regeneron, Sun Pharma, Genentech/Roche, Novartis, OncoSec, Natera, ElsevierResearch Funding: Novartis, Pfizer Bruce BrocksteinConsulting or Advisory Role: Exelixis/IpsenResearch Funding: AstraZenecaPatents, Royalties, Other Intellectual Property: UpToDate. Author and Editorial duties Andrew S. PoklepovicConsulting or Advisory Role: NovartisSpeakers' Bureau: Bristol Myers Squibb Sunil BabuEmployment: Fort Wayne Medical Oncology & HematologyStock and Other Ownership Interests: Fort Wayne Medical Oncology & Hematology, Lutheran HospitalHonoraria: Bristol Myers Squibb, Alexion Pharmaceuticals, Lilly, Bayer, AstraZenecaConsulting or Advisory Role: Bristol Myers Squibb, Alexion Pharmaceuticals, AstraZeneca, argenx, Boehringer Ingelheim, Bayer, Kite, a Gilead company, Janssen Oncology, AmgenSpeakers' Bureau: Alexion PharmaceuticalsResearch Funding: Bristol Myers Squibb, Novartis, Genentech/Roche, AstraZeneca/MedImmune, Janssen Oncology, Amgen, TG Therapeutics, Abbvie, Lilly, Alexion Pharmaceuticals, Merck, Novartis, Syndax, Nektar, Sanofi, argenxTravel, Accommodations, Expenses: Bristol Myers Squibb, Alexion Pharmaceuticals, Lilly, Janssen Oncology, Genentech/Roche Sigrun HallmeyerLeadership: Association of Community Cancer Centers (ACCC)Honoraria: Cardinal HealthConsulting or Advisory Role: Bristol Myers Squibb, Cardinal Health, Array PharamceuticalSpeakers' Bureau: Bristol Myers SquibbTravel, Accommodations, Expenses: Cardinal Health, Bristol Myers SquibbUncompensated Relationships: Society for Immunotherapy of Cancer Mario VelascoEmployment: Cancer Care Specialists of IL Jose LutzkyConsulting or Advisory Role: Castle Biosciences, Iovance Biotherapeutics, Replimune, RegeneronResearch Funding: Bristol Myers Squibb, Novartis, Iovance Biotherapeutics, Immunocore, Regeneron, Replimune, Vyriad Emily HiggsEmployment: LillyStock and Other Ownership Interests: LillyResearch Funding: LillyPatents, Royalties, Other Intellectual Property: Jeffrey D. Helterbrand, Richard E. Higgs, Phillip W. Iversen, Automatic Contextual Segmentation for Imaging Bones for Osteoporosis Therapies (Granted February 1, 2000, US Patent 6,021,213). Raymond E. Kaiser, Richard E. Higgs, Randall K. Julian Jr, System and Methods for Quantitatively Comparing Complex Mixtures Using Single Ion Chromatograms Derived From Spectroscopic Analysis of Such Admixtures (Granted March 23, 1999, US Patent 5,885,841)Travel, Accommodations, Expenses: Lilly Vernon K. SondakConsulting or Advisory Role: Merck/Schering Plough, Novartis, Bristol Myers Squibb, Regeneron, Replimune, EisaiTravel, Accommodations, Expenses: Polynoma, Merck, Bristol Myers Squibb, Replimune Thomas F. GajewskiStock and Other Ownership Interests: Jounce Therapeutics, Evelo Therapeutics, Five Prime Therapeutics, PyxisConsulting or Advisory Role: Merck, Jounce Therapeutics, Adaptimmune, FOGPharma, Allogene Therapeutics, Pyxis, Trillium Therapeutics, Janssen Oncology, Gilead SciencesResearch Funding: Bristol Myers Squibb, Merck, Roche/Genentech, Incyte, Seattle Genetics, Ono Pharmaceutical, Aduro Biotech, Pyxis, BayerPatents, Royalties, Other Intellectual Property: Licensing to Evelo, Licensing to Aduro, Licensing to BMS, Licensing to Pyxis Nikhil I. KhushalaniStock and Other Ownership Interests: Bellicum Pharmaceuticals, Mazor Robotics, Amarin Corporation, Asensus SurgicalHonoraria: SanofiConsulting or Advisory Role: Bristol Myers Squibb, AstraZeneca, Regeneron, Array BioPharma, Immunocore, Merck, Incyte, Jounce Therapeutics, Iovance Biotherapeutics, NCCN/PfizerResearch Funding: Bristol Myers Squibb, Merck, Novartis, GlaxoSmithKline, HUYA Bioscience International, Amgen, Regeneron, Celgene, Replimune Jason J. LukeStock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical, Pyxis, Alphamab, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch OncologyConsulting or Advisory Role: Array BioPharma, Bristol Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, TTC Oncology, Alphamab, Compugen, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf Therapeutics, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius Therapeutics, Tesaro, Xilio Therapeutics, XencorResearch Funding: Merck, Bristol Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Checkmate Pharmaceuticals, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma, EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring Bank, Trishula TherapeuticsPatents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)Travel, Accommodations, Expenses: Bristol Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio TherapeuticsNo other potential conflicts of interest were reported.

Background: Androgen deprivation therapy (ADT) improves outcomes in unfavorable-risk prostate cancer (PCa) treated with radiation therapy (RT). It was hypothesized that replacing luteinizing hormone-releasing hormone (LHRH) agonists with a 5-α-reductase inhibitor (5-ARI) would improve hormonal health-related quality of life (HRQOL) without differentially suppressing androgen-responsive (AR) gene expression., Methods: Patients with localized unfavorable-risk PCa, aged ≥70 years or Charlson Comorbidity Index score ≥2 were treated with oral ADT (oADT), consisting of 4 months of bicalutamide, a 5-ARI, and RT at 78 Gy. The primary end point was Expanded Prostate Cancer Index Composite HRQOL at 6 months ≤30%, and improvement compared with a synchronous standard of care (SOC) cohort receiving 4 months of bicalutamide and long-term LHRH agonist with RT. RNA sequencing was performed from matched pre-/post-ADT prostate tumor biopsies in a subset of men. Differential gene and pathway expressional changes were examined using gene set enrichment., Results: Between 2011 and 2018, 40 and 30 men were enrolled in the oADT and SOC cohorts, respectively. Median follow-up was 40 months. Those with ≤30% decline in hormonal HRQOL at 6 months was 97% (oADT) and 93% (SOC). The average 6-month hormonal decline was 1% (oADT) versus 12% (SOC; P = .04). The 4-year freedom from biochemical failure was 88% (oADT) versus 81% (SOC; P = .48). RNA sequencing (n = 9) showed similar numbers of downregulated and upregulated genes between the treatment groups (fold-change = 2; false-discovery rate-adjusted P ≤ .05). Both treatments comparably decreased the expression of 20 genes in canonical androgen receptor signaling., Conclusions: For men with PCa undergoing RT, oral versus standard ADT may improve 6-month QOL and appears to have a similar impact on androgen-responsive gene expression., (© 2021 American Cancer Society.)

Background: Low birthweight, intrauterine growth restriction (IUGR) and perinatal mortality have been associated with air pollution. However, intervention studies that use ultrasound measurements to assess the effects of household air pollution (HAP) on fetal biometric parameters (FBP) are rare. We investigated the effect of a cookstove intervention on FBP and IUGR in a randomized controlled trial (RCT) cohort of HAP-exposed pregnant Nigerian women., Methods: We recruited 324 women early in the second trimester of pregnancy. Between 16 and 18 weeks, we randomized them to either continue cooking with firewood/kerosene (control group) or receive a CleanCook stove and ethanol fuel (intervention group). We measured fetal biparietal diameter (BPD), head circumference (HC), femur length (FL), abdominal circumference (AC) and ultrasound-estimated fetal weight (U-EFW) in the second and third trimesters. The women were clinically followed up at six regular time points during their pregnancies. Once during the women's second trimester and once during the third, we made 72-h continuous measurements of their personal exposures to particulate matter having aerodynamic diameter < 2.5 μm (PM 2.5 ). We adopted a modified intent-to-treat approach for the analysis. Differences between the intervention and control groups on impact of HAP on fetal growth trajectories were analyzed using mixed effects regression models., Results: There were no significant differences in fetal growth trajectories between the intervention and control groups., Conclusions: Larger studies in a setting of low ambient air pollution are required to further investigate the effect of transitioning to a cleaner fuel such as ethanol on intrauterine growth., Trial Registration: ClinicalTrials.gov NCT02394574 ; September 2012.

Penetrating brain injury (PBI) is the most devastating type of traumatic brain injury. Development of coagulopathy in the acute setting of PBI, though common, remains of unclear significance as does its reversal. The aim of this study is to investigate the relationship between coagulopathy and clinical presentation, radiographical features, and outcome in civilian patients with PBI. Eighty-nine adult patients with PBI at a Level I trauma center in Chicago, Illinois who survived acute resuscitation and with available coagulation profile were analyzed. Coagulopathy was defined as international normalized ratio [INR] >1.3, platelet count <100,000 /μL, or partial thromboplastin time >37 sec. Median age (interquartile range; IQR) of our cohort was 27 (21-35) years, and 74 (83%) were male. The intent was assault in 74 cases (83%). The mechanism of PBI was gunshot wound in all patients. Forty patients (45%) were coagulopathic at presentation. In a multiple regression model, coagulopathy was associated with lower Glasgow Coma Scale (GCS)-Motor score (odds ratio [OR], 0.67; confidence interval [CI], 0.48-0.94; p  = 0.02) and transfusion of blood products (OR, 3.91; CI, 1.2-12.5; p  = 0.02). Effacement of basal cisterns was the only significant radiographical features associated with coagulopathy (OR, 3.34; CI, 1.08-10.37; p  = 0.04). Mortality was found to be significantly more common in coagulopathic patients (73% vs. 25%; p  < 0.001). However, in our limited sample, reversal of coagulopathy at 24 h was not associated with a statistically significant improvement in outcome. The triad of coagulopathy, low post-resuscitation GCS, and radiographical effacement of basal cisterns identify a particularly ominous phenotype of PBI. The role, and potential reversal of, coagulopathy in this group warrants further investigation.

The one-year and median overall survival (mOS) rates of advanced gastroesophageal adenocarcinomas (GEA) are ∼50% and <12 months, respectively. Baseline spatial and temporal molecular heterogeneity of targetable alterations may be a cause of failure of targeted/immunooncologic therapies. This heterogeneity, coupled with infrequent incidence of some biomarkers, has resulted in stalled therapeutic progress. We hypothesized that a personalized treatment strategy, applied at first diagnosis then serially over up to three treatment lines using monoclonal antibodies combined with optimally sequenced chemotherapy, could contend with these hurdles. This was tested using a novel clinical expansion-platform type II design with a survival primary endpoint. Of 68 patients by intention-to-treat, the one-year survival rate was 66% and mOS was 15.7 months, meeting the primary efficacy endpoint (one-sided P = 0.0024). First-line response rate (74%), disease control rate (99%), and median progression-free survival (8.2 months) were superior to historical controls. The PANGEA strategy led to improved outcomes warranting a larger randomized study. SIGNIFICANCE: This study highlights excellent outcomes achieved by individually optimizing chemotherapy, biomarker profiling, and matching of targeted therapies at baseline and over time for GEA. Testing a predefined treatment strategy resulted in improved outcomes versus historical controls. Therapeutic resistance observed in correlative analyses suggests that dual targeted inhibition may be beneficial. This article is highlighted in the In This Issue feature, p. 211 ., (©2020 American Association for Cancer Research.)

Purpose: Multisite stereotactic body radiotherapy followed by pembrolizumab (SBRT+P) has demonstrated safety in advanced solid tumors (ASTs). However, no studies have examined the relationships between irradiated tumor response, SBRT-induced tumor gene expression, and overall survival (OS)., Patients and Methods: Patients with AST received SBRT (30-50 Gy in 3-5 fractions) to two to four metastases followed by pembrolizumab (200 mg i.v. every 3 weeks). SBRT was prescribed to a maximum tumor volume of 65 mL. Small metastases received the complete prescribed coverage (complete-Rx), while larger metastases received partial coverage (partial-Rx). Treated metastasis control (TMC) was defined as a lack of progression for an irradiated metastasis. Landmark analysis was used to assess the relationship between TMC and OS. Thirty-five biopsies were obtained from 24 patients: 19 pre-SBRT and 16 post-SBRT (11 matched) prior to pembrolizumab and were analyzed via RNA microarray., Results: Sixty-eight patients (139 metastases) were enrolled with a median follow-up of 10.4 months. One-year TMC was 89.5% with no difference between complete-Rx or partial-Rx. On multivariable analysis, TMC was independently associated with a reduced risk for death (HR, 0.36; 95% confidence interval, 0.17-0.75; P = 0.006). SBRT increased expression of innate and adaptive immune genes and concomitantly decreased expression of cell cycle and DNA repair genes in the irradiated tumors. Elevated post-SBRT expression of DNASE1 correlated with increased expression of cytolytic T-cell genes and irradiated tumor response., Conclusions: In the context of SBRT+P, TMC independently correlates with OS. SBRT impacts intratumoral immune gene expression associated with TMC. Randomized trials are needed to validate these findings., (©2020 American Association for Cancer Research.)

Human papillomavirus (HPV) infection is necessary but insufficient for progression of epithelial cells from dysplasia to carcinoma-in situ (CIS) to invasive cancer. The combination of mutant cellular and viral oncogenes that regulate progression of cervical cancer (CC) remains unclear. Using combinations of HPV16 E6/E7 (E+), mutant Kras (mKras) (K+) and/or loss of Pten (P-/-), we generated autochthonous models of CC without exogenous estrogen, carcinogen or promoters. Furthermore, intravaginal instillation of adenoCre virus enabled focal activation of the oncogenes/inactivation of the tumor suppressor gene. In P+/+ mice, E6/E7 alone (P+/+E+K-) failed to cause premalignant changes, while mKras alone (P+/+E-K+) caused persistent mucosal abnormalities in about one-third of mice, but no cancers. To develop cancer, P+/+ mice needed both E6/E7 and mKras expression. Longitudinal endoscopies of P+/+E+K+ mice predicted carcinoma development by detection of mucosal lesions, found on an average of 23 weeks prior to death, unlike longitudinal quantitative PCRs of vaginal lavage samples from the same mice. Endoscopy revealed that individual mice differed widely in the time required for mucosal lesions to appear after adenoCre and in the time required for these lesions to progress to cancer. These cancers developed in the transition zone that extends, unlike in women, from the murine cervix to the distal vagina. The P-/-E+K+ genotype led to precipitous cancer development within a few weeks and E6/E7-independent cancer development occurred in the P-/-E-K+ genotype. In the P-/-E+K- genotype, mice only developed CIS. Thus, distinct combinations of viral and cellular oncogenes are involved in distinct steps in cervical carcinogenesis., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Patients with cetuximab-resistant, recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) have poor outcomes. This study hypothesized that dual blockade of mammalian target of rapamycin and epidermal growth factor receptor (EGFR) would overcome cetuximab resistance on the basis of the role of phosphoinositide 3-kinase signaling in preclinical models of EGFR resistance., Methods: In this multicenter, randomized clinical study, patients with recurrent/metastatic HNSCC with documented progression on cetuximab (in any line in the recurrent/metastatic setting) received 25 mg of temsirolimus weekly plus cetuximab at 400/250 mg/m 2 weekly (TC) or single-agent temsirolimus (T). The primary outcome was progression-free survival (PFS) in the TC arm versus the T arm. Response rates, overall survival, and toxicity were secondary outcomes., Results: Eighty patients were randomized to therapy with TC or T alone. There was no difference for the primary outcome of median PFS (TC arm, 3.5 months; T arm, 3.5 months). The response rate was 12.5% in the TC arm (5 responses, including 1 complete response [2.5%]) and 2.5% in the T arm (1 partial response; P = .10). Responses were clinically meaningful in the TC arm (range, 3.6-9.1 months) but not in the T-alone arm (1.9 months). Fatigue, electrolyte abnormalities, and leukopenia were the most common grade 3 or higher adverse events and occurred in less than 20% of patients in both arms., Conclusions: The study did not meet its primary endpoint of improvement in PFS. However, TC induced responses in cetuximab-refractory patients with good tolerability. The post hoc observation of activity in patients with acquired resistance (after prior benefit from cetuximab monotherapy) may warrant further investigation., (© 2020 American Cancer Society.)

Human epidermal growth factor receptor 2 (HER2) subtype of breast cancer is aggressive, leading to a poor outcome. Targeted therapy with trastuzumab has been shown to be effective in the treatment of HER2-positive breast cancer. Cardiotoxicity is a specific adverse effect associated with trastuzumab. The initial formulation of trastuzumab was intravenous, but presently, a subcutaneous formulation (Herceptin SC) is available. Insufficient data on the response rate and cardiotoxic effects of trastuzumab among indigenous Black populations exist. In all studies evaluating the efficacy and toxicity of trastuzumab alone or in combination with chemotherapy, indigenous Black populations in Africa were not included, yet they are the ones most likely to benefit from highly effective cancer medicines. This is partly due to poor oncology clinical trial infrastructure in sub-Saharan Africa. The ARETTA study protocol (ClinicalTrials.gov identifier: NCT03879577) is a phase II multicenter feasibility study to evaluate the efficacy and toxicity of docetaxel given every 3 weeks for 4 cycles plus trastuzumab in 60 previously untreated women with nonmetastatic breast cancer. The primary endpoint is to assess the proportion of patients with complete pathologic response. Secondary endpoints include the number of patients who require dose delays in docetaxel and trastuzumab attributed to hematologic, GI, and cardiac toxicity. Pharmacokinetic profiles of subcutaneous trastuzumab will also be determined. The ARETTA study will provide important information on the clinical response and cardiac safety of subcutaneous trastuzumab in combination with docetaxel among indigenous African women with nonmetastatic breast cancer. It can also be used as a blueprint for conducting biomarker-driven oncology clinical trials in low-resource settings such as sub-Saharan Africa.

Importance: Patients with locally advanced gastroesophageal adenocarcinoma (ie, stage ≥T3 and/or node positive) have high rates of recurrence despite surgery and adjunctive perioperative therapies, which also have high toxicity profiles. Evaluation of pharmacogenomically dosed perioperative gFOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and UGT1A1 genotype-directed irinotecan) to optimize efficacy while limiting toxic effects may have value., Objective: To evaluate the coprimary end points of margin-negative (R0) resection rates and pathologic response grades (PRGs) of gFOLFIRINOX therapy among patients with locally advanced gastroesophageal adenocarcinoma., Design, Setting, and Participants: This single-group phase 2 trial, conducted at 2 academic medical centers from February 2014 to March 2019, enrolled 36 evaluable patients with locally advanced adenocarcinoma of the esophagus, gastroesophageal junction, and gastric body. Data analysis was conducted in May 2019., Interventions: Patients received biweekly gFOLFIRINOX (fluorouracil, 2400 mg/m2 over 46 hours; oxaliplatin, 85 mg/m2; irinotecan, 180 mg/m2 for UGT1A1 genotype 6/6, 135 mg/m2 for UGT1A1 genotype 6/7, or 90 mg/m2 for UGT1A1 genotype 7/7; and prophylactic peg-filgastrim, 6 mg) for 4 cycles before and after surgery. Patients with tumors positive for ERBB2 also received trastuzumab (6-mg/kg loading dose, then 4 mg/kg)., Main Outcomes and Measures: Margin-negative resection rate and PRG., Results: A total of 36 evaluable patients (27 [78%] men; median [range] age, 66 [27-85] years; 10 [28%] with gastric body cancer; 24 [67%] with intestinal-type tumors; 6 [17%] with ERBB2-positive tumors; 19 [53%] with UGT1A1 genotype 6/6; 16 [44%] with genotype 6/7; and 1 [3%] with genotype 7/7) were enrolled. Of these, 35 (97%) underwent surgery; 1 patient (3%) died after completing neoadjuvant chemotherapy while awaiting surgery. Overall, R0 resection was achieved in 33 of 36 patients (92%); 2 patients (6%) with linitis plastica achieved R1 resection. Pathologic response grades 1, 2, and 3 occurred in 13 patients (36%), 9 patients (25%), and 14 patients (39%), respectively, and PRG 1 was observed in 11 of 24 intestinal-type tumors (46%). Median disease-free survival was 30.1 months (95% CI, 15.0 months to not reached), and median overall survival was not reached (95% CI, 8.3 months to not reached). There were no differences in outcomes by UGT1A1 genotype group. A total of 38 patients, including 2 (5%) with antral tumors, were evaluable for toxic effects. Grade 3 or higher adverse events occurring in 5% or more of patients during the perioperative cycles included diarrhea (7 patients [18%]; 3 of 19 patients [16%] with genotype 6/6; 2 of 16 patients [13%] with genotype 6/7; 2 of 3 patients [67%] with genotype 7/7), anemia (2 patients [5%]), vomiting (2 patients [5%]), and nausea (2 patients [5%])., Conclusions and Relevance: In this study, perioperative pharmacogenomically dosed gFOLFIRINOX was feasible, providing downstaging with PRG 1 in more than one-third of patients and an R0 resection rate in 92% of patients., Trial Registration: ClinicalTrials.gov Identifier: NCT02366819.

Objective: Hydrocephalus occurs in children with congenital toxoplasmosis and can lead to severe disability. In these cases, the decision to intervene is often influenced by the expectation of neurological recovery. In this study, clinical responses to neurosurgical intervention in children with hydrocephalus secondary to congenital toxoplasmosis are characterized., Methods: Sixty-five participants with hydrocephalus due to congenital Toxoplasma gondii infection were evaluated as part of the National Collaborative Chicago-based Congenital Toxoplasmosis Study, and their neuroradiographic findings were reviewed. Clinical outcomes were scored on the basis of cognition and motor skills through the use of IQ scores and Gross Motor Function Classification System (GMFCS) level. Outcomes were then analyzed in relation to approach to management, anatomy of hydrocephalus, and time from diagnosis of hydrocephalus to surgical intervention., Results: There was considerable variation in the outcomes of patients whose hydrocephalus was treated in early life, ranging from normal cognitive and motor function to profound developmental delay and functional limitation. Of the 65 participants included in the study, IQ and GMFCS level were available for 46 (70.8%). IQ and motor score were highly correlated (r = -0.82, p < 0.001). There were people with differing patterns of hydrocephalus or thickness of cortical mantle on initial presentation who had favorable outcomes. Time to neurosurgical intervention data were available for 31 patients who underwent ventriculoperitoneal (VP) shunt placement. Delayed shunt placement beyond 25 days after diagnosis of hydrocephalus was associated with greater cognitive impairment (p = 0.02). Motor impairment also appeared to be associated with shunt placement beyond 25 days but the difference did not achieve statistical significance (p = 0.13). Among those with shunt placement within 25 days after diagnosis (n = 19), the mean GMFCS level was 1.9 ± 1.6 (range 1-5). Five (29.4%) of 17 of these patients were too disabled to participate in formal cognitive testing, after excluding 2 patients with visual difficulties or language barriers that precluded IQ testing. Of the patients who had VP shunt placement 25 or more days after diagnosis (n = 12), the mean GMFCS level was 2.7 ± 1.4 (range 1-4). Of these, 1 could not participate in IQ testing due to severe visual difficulties and 8 (72.7%) of the remaining 11 due to cognitive disability., Conclusions: VP shunt placement in patients with hydrocephalus caused by congenital toxoplasmosis can contribute to favorable clinical outcomes, even in cases with severe hydrocephalus on neuroimaging. Shunt placement within 25 days of diagnosis was statistically associated with more favorable cognitive outcomes. Motor function appeared to follow the same pattern although it did not achieve statistical significance.

Background and Aims: It is standard of care to perform ileocolonoscopy within a year of ileocolonic resection for Crohn's disease (CD) and to guide management decisions based on the Rutgeert score (RS). The modified RS subdivides i2 into lesions confined to the anastomosis (i2a) or >5 aphthous lesions in the neoterminal ileum (i2b). There is uncertainty, however, if i2a lesions incur an increased risk of disease recurrence. The primary aim of this study was to compare the rates of endoscopic progression between i2a and i2b when compared with i0-i1., Methods: This was a retrospective, single-center study including patients with CD who had an ileocolonoscopy ≤12 months after ileocolonic resection with primary anastomosis and who had >1 year of documented clinical follow-up after the index endoscopic evaluation. All consecutive eligible patients between 2004 and 2014 were included in the study. Demographic, disease, and treatment data were collected. Patients with i3 or i4 at index colonoscopy were excluded from further analyses. Outcomes included endoscopic progression and recurrent surgery. For patients with RS of i0 to i2, endoscopic progression was predefined as progression of the RS in subsequent colonoscopies to i3 or i4. Recurrent surgical interventions were defined as re-resection or stricturoplasty of the previous ileocolonic anastomosis., Results: Two hundred seven CD patients (median age, 36 years [interquartile range, 26-48]) had an ileocolonoscopy ≤12 months after ileocolonic resection. At index colonoscopy, 95 patients (45.9%) had an RS of i0, 31 (14.9%) i1, 40 (19.3%) i2a, 25 (12.1%) i2b, 10 (4.8%) i3, and 6 (2.9%) i4. One hundred ninety-one patients had an RS of i0 to i2 and were included in the analyses for recurrent surgery. One hundred forty-nine patients had a second endoscopic evaluation and were included in the analysis for the primary outcome of endoscopic disease progression. Kaplan-Meier analyses were performed and found the hazard ratio (HR) of endoscopic progression to be significantly higher with i2b lesions when compared with i0 or i1 (HR, 6.22; 95% confidence interval [CI], 2.38-16.2; P = .0008). Patients with i2a did not have significantly higher rates of endoscopic progression when compared with i0 or i1 (HR, 2.30; 95% CI, .80-6.66; P = .12). Likewise, patients with i2b lesions had higher risk of needing recurrent surgery when compared with i0 or i1 (HR, 3.64; 95% CI, 1.10-12.1; P = .034), whereas patients with i2a lesions were not found to have a significantly elevated risk of recurrent surgery (HR, 1.43; 95% CI, .35-5.77; P = .62)., Conclusion: Endoscopic lesions limited to the ileocolonic anastomosis (RS i2a) in patients with CD undergoing colonoscopy within 1 year of their resection were not associated with a significantly higher rate of progression to more severe disease, whereas those in the neoileum (RS i2b) were. Prospective studies are needed to confirm these findings., (Copyright © 2019 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Selinexor, an oral Selective Inhibitor of Nuclear Export, targets Exportin 1 (XPO1, also termed CRM1). Non-clinical studies support combining selinexor with proteasome inhibitors (PIs) and corticosteroids to overcome resistance in relapsed/refractory multiple myeloma (RRMM). We conducted a phase I dose-escalation trial of twice-weekly selinexor in combination with carfilzomib and dexamethasone (SKd) to determine maximum tolerated dose in patients with RRMM (N = 21), with an expansion cohort to assess activity in carfilzomib-refractory disease and identify a recommended phase II dose (RP2D). During dose escalation, there was one dose-limiting toxicity (cardiac failure). The RP2D of twice-weekly SKd was selinexor 60 mg, carfilzomib 20/27 mg/m 2 and dexamethasone 20 mg. The most common grade 3/4 treatment-emergent adverse events included thrombocytopenia (71%), anaemia (33%), lymphopenia (33%), neutropenia (33%) and infections (24%). Rates of ≥minimal response, ≥partial response and very good partial response were 71%, 48% and 14%, respectively; similar response outcomes were observed for dual-class refractory (PI and immunomodulatory drug)/quad-exposed (carfilzomib, bortezomib, lenalidomide and pomalidomide) patients (n = 17), and patients refractory to carfilzomib in last line of therapy (n = 13). Median progression-free survival was 3·7 months, and overall survival was 22·4 months in the overall population. SKd was tolerable and re-established disease control in RRMM patients, including carfilzomib-refractory patients. Registered at ClinicalTrials.gov (NCT02199665)., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Dual translocation of MYC and BCL2 or the dual overexpression of these proteins in patients with aggressive B-cell lymphomas (termed double-hit lymphoma [DHL] and double-expressor lymphoma [DEL], respectively) have poor outcomes after chemoimmunotherapy with the combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Retrospective reports have suggested improved outcomes with dose-intensified regimens. In the current study, the authors conducted a phase 1 study to evaluate the feasibility, toxicity, and preliminary efficacy of adding lenalidomide to dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin with rituximab (DA-EPOCH-R) in patients with DHL and DEL., Methods: The primary objective of the current study was to determine the maximum tolerated dose of lenalidomide in combination with DA-EPOCH-R. A standard 3+3 design was used with lenalidomide administered on days 1 to 14 of each 21-day cycle (dose levels of 10 mg, 15 mg, and 20 mg). Patients attaining a complete response after 6 cycles of induction therapy proceeded to maintenance lenalidomide (10 mg daily for 14 days every 21 days) for 12 additional cycles., Results: A total of 15 patients were enrolled, 10 of whom had DEL and 5 of whom had DHL. Two patients experienced dose-limiting toxicities at a lenalidomide dose of 20 mg, consisting of grade 4 sepsis. The maximum tolerated dose of lenalidomide was determined to be 15 mg. The most common nonhematologic grade ≥3 adverse events included thromboembolism (4 patients; 27%) and hypokalemia (2 patients; 13%) (toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). The preliminary efficacy of the regimen was encouraging, especially in the DEL cohort, in which all 10 patients achieved durable and complete metabolic responses with a median follow-up of 24 months., Conclusions: The combination of lenalidomide with DA-EPOCH-R appears to be safe and feasible in patients with DHL and DEL. These encouraging results have prompted an ongoing phase 2 multicenter study., (© 2019 American Cancer Society.)

Background: We compared the rates of intraoperative parathyroid hormone (PTH) decline using the Siemens Immulite ® Turbo PTH and Roche Elecsys ® short turnaround time PTH assays in 95 consecutive surgical patients to investigate analytical and turnaround time (TAT) differences between the tests performed in the operating room (OR) vs the central clinical chemistry laboratory (CCL)., Methods: Serial blood samples from 95 patients undergoing parathyroidectomy were collected and measured using the 2 immunoassays. Specimens from the first 15 patients were measured simultaneously in the OR and CCL and used for the TAT study. In addition to 2 baseline samples, specimens were collected at 5, 10, and 15 min (for some patients, >15 min) after parathyroidectomy., Results: In the TAT study, a significant difference was observed (OR median 20 min vs CCL median 27 min; P < 0.05). Of the 95 patient series, slower rates of parathyroid hormone decrease were observed in approximately 20% of the patients when comparing the Roche with the Immulite immunoassay., Conclusions: There was a slightly longer TAT in the CCL compared with running the assay directly within the OR (median difference of approximately 7 min). For a majority of the patients, both methods showed equivalent rates of PTH decline; however, for approximately 20% of the patients, there was a slower rate of PTH decline using the Roche assay., (© 2018 American Association for Clinical Chemistry.)

Background: Cardiac events after electroconvulsive therapy have been reported sporadically, but a systematic assessment of the risk is missing. The goal of this study was to obtain a robust estimate of the incidence of major adverse cardiac events in adult patients undergoing electroconvulsive therapy., Methods: Systematic review and meta-analysis of studies that investigated electroconvulsive therapy and reported major adverse cardiac events and/or mortality. Endpoints were incidence rates of major adverse cardiac events, including myocardial infarction, arrhythmia, pulmonary edema, pulmonary embolism, acute heart failure, and cardiac arrest. Additional endpoints were all-cause and cardiac mortality. The pooled estimated incidence rates and 95% CIs of individual major adverse cardiac events and mortality per 1,000 patients and per 1,000 electroconvulsive therapy treatments were calculated., Results: After screening of 2,641 publications and full-text assessment of 284 studies, the data of 82 studies were extracted (total n = 106,569 patients; n = 786,995 electroconvulsive therapy treatments). The most commonly reported major adverse cardiac events were acute heart failure, arrhythmia, and acute pulmonary edema with an incidence (95% CI) of 24 (12.48 to 46.13), 25.83 (14.83 to 45.00), and 4.92 (0.85 to 28.60) per 1,000 patients or 2.44 (1.27 to 4.69), 4.66 (2.15 to 10.09), and 1.50 (0.71 to 3.14) per 1,000 electroconvulsive therapy treatments. All-cause mortality was 0.42 (0.11 to 1.52) deaths per 1,000 patients and 0.06 (0.02 to 0.23) deaths per 1,000 electroconvulsive therapy treatments. Cardiac death accounted for 29% (23 of 79) of deaths., Conclusions: Major adverse cardiac events and death after electroconvulsive therapy are infrequent and occur in about 1 of 50 patients and after about 1 of 200 to 500 electroconvulsive therapy treatments.

Background: Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor. Metformin may potentiate mTOR inhibition by sirolimus while mitigating its adverse effects. We conducted a pilot study to test this hypothesis., Methods: Patients with advanced solid tumor were treated with sirolimus for 7 days followed by randomization to either sirolimus with metformin (Arm A) or sirolimus (Arm B) until day 21. From day 22 onwards, all patients received sirolimus and metformin. The primary aim was to compare the change in phospho-p70S6K (pp70S6K) in peripheral blood mononuclear cells (PBMC) from day 8 to day 22 using a two-sample t test. Secondary aims were objective response rate, toxicity, and other serum pharmacodynamic biomarkers (e.g., fasting glucose, triglycerides, insulin, C-peptide, IGF-1, IGF-1R, IGF-BP, and leptin)., Results: 24 patients were enrolled, with 18 evaluable for the primary endpoint. There was no significant difference in mean change in pp70S6K in arm A vs. arm B (- 0.12 vs. - 0.16; P = 0.64). Similarly, there were no significant differences in other serum pharmacodynamic biomarkers. There were no partial responses. There were no dose-limiting or unexpected toxicities., Conclusions: Adding metformin to sirolimus, although well tolerated, was not associated with significant changes in pp70S6K in PBMC or other serum pharmacodynamic biomarkers., Impact: Combining metformin with sirolimus did not improve mTOR inhibition.

Purpose Abiraterone acetate (AA) is a standard of care for metastatic castration-resistant prostate cancer (CRPC). Despite a large food effect, AA was administered under fasting conditions in its pivotal trials. We sought to test the hypothesis that low-dose AA (LOW; 250 mg with a low-fat meal) would have comparable activity to standard AA (STD; 1,000 mg fasting) in patients with CRPC. Patients and Methods Patients (n = 72) with progressive CRPC from seven institutions in the United States and Singapore were randomly assigned to STD or LOW. Both arms received prednisone 5 mg twice daily. Prostate-specific antigen (PSA) was assessed monthly, and testosterone/dehydroepiandrosterone sulfate were assessed every 12 weeks with disease burden radiographic assessments. Plasma was collected for drug concentrations. Log change in PSA, as a pharmacodynamic biomarker for efficacy, was the primary end point, using a noninferiority design. Progression-free survival (PFS), PSA response (≥ 50% reduction), change in androgen levels, and pharmacokinetics were secondary end points. Results Thirty-six patients were accrued to both arms. At 12 weeks, there was a greater effect on PSA in the LOW arm (mean log change, -1.59) compared with STD (-1.19), and noninferiority of LOW was established according to predefined criteria. The PSA response rate was 58% in LOW and 50% in STD, and the median PFS was approximately 9 months in both groups. Androgen levels decreased similarly in both arms. Although there was no difference in PSA response or PFS, abiraterone concentrations were higher in STD. Conclusion Low-dose AA (with low-fat breakfast) is noninferior to standard dosing with respect to PSA metrics. Given the pharmacoeconomic implications, these data warrant consideration by prescribers, payers, and patients. Additional studies are indicated to assess the long-term efficacy of this approach.

Background: Restricted mean survival time is a measure of average survival time up to a specified time point. There has been an increased interest in using restricted mean survival time to compare treatment arms in randomized clinical trials because such comparisons do not rely on proportional hazards or other assumptions about the nature of the relationship between survival curves., Methods: This article addresses the question of whether covariate adjustment in randomized clinical trials that compare restricted mean survival times improves precision of the estimated treatment effect (difference in restricted mean survival times between treatment arms). Although precision generally increases in linear models when prognostic covariates are added, this is not necessarily the case in non-linear models. For example, in logistic and Cox regression, the standard error of the estimated treatment effect does not decrease when prognostic covariates are added, although the situation is complicated in those settings because the estimand changes as well. Because estimation of restricted mean survival time in the manner described in this article is also based on a model that is non-linear in the covariates, we investigate whether the comparison of restricted mean survival times with adjustment for covariates leads to a reduction in the standard error of the estimated treatment effect relative to the unadjusted estimator or whether covariate adjustment provides no improvement in precision. Chen and Tsiatis suggest that precision will increase if covariates are chosen judiciously. We present results of simulation studies that compare unadjusted versus adjusted comparisons of restricted mean survival time between treatment arms in randomized clinical trials., Results: We find that for comparison of restricted means in a randomized clinical trial, adjusting for covariates that are associated with survival increases precision and therefore statistical power, relative to the unadjusted estimator. Omitting important covariates results in less precision but estimates remain unbiased., Conclusion: When comparing restricted means in a randomized clinical trial, adjusting for prognostic covariates can improve precision and increase power.

A recently described nuclear grading system predicted survival in patients with epithelioid malignant pleural mesothelioma. The current study was undertaken to validate the grading system and to identify additional prognostic factors. We analyzed cases of epithelioid malignant pleural mesothelioma from 17 institutions across the globe from 1998 to 2014. Nuclear grade was computed combining nuclear atypia and mitotic count into a grade of I-III using the published system. Nuclear grade was assessed by one pathologist for three institutions, the remaining were scored independently. The presence or absence of necrosis and predominant growth pattern were also evaluated. Two additional scoring systems were evaluated, one combining nuclear grade and necrosis and the other mitotic count and necrosis. Median overall survival was the primary endpoint. A total of 776 cases were identified including 301 (39%) nuclear grade I tumors, 354 (45%) grade II tumors and 121 (16%) grade III tumors. The overall survival was 16 months, and correlated independently with age (P=0.006), sex (0.015), necrosis (0.030), mitotic count (0.001), nuclear atypia (0.009), nuclear grade (<0.0001), and mitosis and necrosis score (<0.0001). The addition of necrosis to nuclear grade further stratified overall survival, allowing classification of epithelioid malignant pleural mesothelioma into four distinct prognostic groups: nuclear grade I tumors without necrosis (29 months), nuclear grade I tumors with necrosis and grade II tumors without necrosis (16 months), nuclear grade II tumors with necrosis (10 months) and nuclear grade III tumors (8 months). The mitosis-necrosis score stratified patients by survival, but not as well as the combination of necrosis and nuclear grade. This study confirms that nuclear grade predicts survival in epithelioid malignant pleural mesothelioma, identifies necrosis as factor that further stratifies overall survival, and validates the grading system across multiple institutions and among both biopsy and resection specimens. An alternative scoring system, the mitosis-necrosis score is also proposed.

Background: Household air pollution (HAP) exposure has been linked to adverse pregnancy outcomes., Objectives: A randomized controlled trial was undertaken in Ibadan, Nigeria to determine the impact of cooking with ethanol on pregnancy outcomes., Methods: Three-hundred-twenty-four pregnant women were randomized to either the control (continued cooking using kerosene/firewood stove, n=162) or intervention group (received ethanol stove, n=162). Primary outcome variables were birthweight, preterm delivery, intrauterine growth restriction (IUGR), and occurrence of miscarriage/stillbirth., Results: Mean birthweights for ethanol and controls were 3076 and 2988g, respectively; the difference, 88g, (95% confidence interval: -18g to 194g), was not statistically significant (p=0.10). After adjusting for covariates, the difference reached significance (p=0.020). Rates of preterm delivery were 6.7% (ethanol) and 11.0% (control), (p=0.22). Number of miscarriages was 1(ethanol) vs. 4 (control) and stillbirths was 3 (ethanol) vs. 7 (control) (both non-significant). Average gestational age at delivery was significantly (p=0.015) higher in ethanol-users (39.2weeks) compared to controls (38.2weeks). Perinatal mortality (stillbirths and neonatal deaths) was twice as high in controls compared to ethanol-users (7.9% vs. 3.9%; p=0.045, after adjustment for covariates). We did not detect significant differences in exposure levels between the two treatment arms, perhaps due to large seasonal effects and high ambient air pollution levels., Conclusions: Transition from traditional biomass/kerosene fuel to ethanol reduced adverse pregnancy outcomes. However, the difference in birthweight was statistically significant only after covariate adjustment and the other significant differences were in tertiary endpoints. Our results are suggestive of a beneficial effect of ethanol use. Larger trials are required to validate these findings., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Hypothesis: The majority of non-small cell lung cancer (NSCLC) patients treated with anti-PD-1/PD-L1 therapy develop either innate or acquired resistance. Across tumor types, the "T cell-inflamed" tumor microenvironment correlates with clinical response to immunotherapy. We hypothesize that clinical characteristics may be predictive of resistance and that "T cell-inflamed" NSCLC tumors can be identified by gene expression profiling., Results: Of 93 patients, 36 (38.7%) had innate resistance and 57 (61.3%) had initial benefit to immunotherapy. Innate resistance was associated with non-smokers ( p = 0.013), more involved disease sites ( p = 0.011), more prior therapy ( p = 0.001), and a lower albumin level ( p = 0.014). Among patients with initial benefit, factors associated with subsequent progression-free survival included higher Karnofsky Performance Status (KPS) ( p = 0.004) and lower depth of response to anti-PD-1 therapy ( p = 0.003). A "T cell-inflamed" microenvironment was identified in 42% of TCGA adenocarcinoma samples versus 21.0% of squamous cell., Discussion: Specific clinical characteristics appear to be predictive of either innate or acquired resistance to anti-PD-1/PD-L1 therapy. A "T cell-inflamed" tumor was more common in adenocarcinoma than squamous histology., Methods: A retrospective review of NSCLC patients treated with anti-PD-1/PD-L1 monotherapy. Patients with innate resistance to anti-PD-1/PD-L1 therapy (defined as progression at first CT evaluation) were compared to patients with initial clinical benefit. Among those with initial clinical benefit, we identified prognostic factors for time to progression (acquired resistance) or death. To further corroborate our findings on limited numbers, immune gene expression profiling of all NSCLC samples from the TCGA database was also pursued., Competing Interests: CONFLICTS OF INTEREST Authors declare no conflicts of interest.

Rationale: Hypertension during pregnancy is a leading cause of maternal mortality. Exposure to household air pollution elevates blood pressure (BP)., Objectives: To investigate the ability of a clean cookstove intervention to lower BP during pregnancy., Methods: We conducted a randomized controlled trial in Nigeria. Pregnant women cooking with kerosene or firewood were randomly assigned to an ethanol arm (n = 162) or a control arm (n = 162). BP measurements were taken during six antenatal visits. In the primary analysis, we compared ethanol users with control subjects. In subgroup analyses, we compared baseline kerosene users assigned to the intervention with kerosene control subjects and compared baseline firewood users assigned to ethanol with firewood control subjects., Measurements and Main Results: The change in diastolic blood pressure (DBP) over time was significantly different between ethanol users and control subjects (P = 0.040); systolic blood pressure (SBP) did not differ (P = 0.86). In subgroup analyses, there was no significant intervention effect for SBP; a significant difference for DBP (P = 0.031) existed among preintervention kerosene users. At the last visit, mean DBP was 2.8 mm Hg higher in control subjects than in ethanol users (3.6 mm Hg greater in control subjects than in ethanol users among preintervention kerosene users), and 6.4% of control subjects were hypertensive (SBP ≥140 and/or DBP ≥90 mm Hg) versus 1.9% of ethanol users (P = 0.051). Among preintervention kerosene users, 8.8% of control subjects were hypertensive compared with 1.8% of ethanol users (P = 0.029)., Conclusions: To our knowledge, this is the first cookstove randomized controlled trial examining prenatal BP. Ethanol cookstoves have potential to reduce DBP and hypertension during pregnancy. Accordingly, clean cooking fuels may reduce adverse health impacts associated with household air pollution. Clinical trial registered with www.clinicaltrials.gov (NCT02394574).

Introduction/background: Traditional imaging assessment criteria might not correlate well with clinical benefit from vascular endothelial growth factor pathway-directed therapy in metastatic renal cancer. Preclinical data suggest tumor growth is preceded by a rise in K trans level, a parameter derived from dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) that reflects vascular permeability. We thus hypothesized that K trans might be a predictive biomarker for pazopanib., Patients and Methods: Patients with metastatic renal cancer were treated with pazopanib at 800 mg oral daily until disease progression. MRI of the abdomen and pelvis with a DCE-MRI sequence was obtained at baseline and every 8 weeks., Results: Seventy-three DCE-MRI scans were completed and 66 were technically assessable. Of the 17 patients with at least 1 DCE-MRI scan after the baseline scan, 16 (94%) had a decline in K trans level. Changes in K trans compared with baseline after 1, 8, 16, and 24 weeks were -49%, -65%, -63%, and -53%, respectively (P = .0052, repeated measures analysis of variance). The median K trans nadir occurred at 8 weeks. The median progression-free survival (PFS) was 32.1 weeks. PFS was longer in patients with higher baseline K trans values (P = .036, log rank). Baseline K trans did not reach significance in a Cox proportional hazard model including clinical prognostic index and previous treatments (P = .083)., Conclusion: We show that K trans is a pharmacodynamic biomarker for pazopanib therapy in metastatic renal cancer. Because of the small sample size, the predictive capacity of K trans recovery could not be assessed, but baseline K trans correlated with PFS., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Adoptively transferred CD8 + T cells can stabilize the size of solid tumors over long periods of time by exclusively recognizing antigen cross-presented on tumor stroma. However, these tumors eventually escape T-cell-mediated growth control. The aim of this study was to eradicate such persistent cancers. In our model, the SIYRYYGL antigen is expressed by cancer cells that lack the MHC-I molecule K b needed for direct presentation, but the antigen is picked up and cross-presented by tumor stroma. A single injection of antigen-specific 2C CD8 + T cells caused long-term inhibition of tumor growth, but without further intervention, tumors started to progress after approximately 3 months. Escape was associated with reduced numbers of circulating 2C cells. Tumor-infiltrating 2C cells produced significantly less TNFα and expressed more of the "exhaustion" markers PD-1 and Tim-3 than T cells from lymphoid organs. High-dose local ionizing radiation, depletion of myeloid-derived suppressor cells, infusions of additional 2C cells, and antibodies blocking PD-L1 did not prevent tumor escape. In contrast, adoptive transfer of allogeneic CD4 + T cells restored the numbers of circulating Ag-specific CD8 + T cells and their intratumoral function, resulting in tumor eradication. These CD4 + T cells had no antitumor effects in the absence of CD8 + T cells and recognized the alloantigen cross-presented on tumor stroma. CD4 + T cells might also be effective in cancer patients when PD-1/PD-L1 blockade does not rescue intratumoral CD8 + T-cell function and tumors persist. Cancer Immunol Res; 5(2); 127-36. ©2017 AACR., (©2017 American Association for Cancer Research.)

Background: Exposure to household air pollution (HAP) has been linked to systemic inflammation. We determined the impact of transition from traditional firewood/kerosene stove to bioethanol-burning stove on inflammatory biomarkers in pregnant Nigerian women., Methods: Women (n=324), cooking with kerosene/firewood, were recruited during their first trimester of pregnancy from June 2013-October 2015 and were randomly allocated to either control (n=162) or intervention (n=162) group using web-based randomization. Controls continued to use their own firewood/kerosene stove, while intervention participants received bioethanol CleanCook stoves. Serum concentrations of retinol-binding protein (RBP), malondialdehyde (MDA), tumor necrosis factor alpha (TNF)-α, interleukin (IL)-6, and IL-8 were measured by ELISA., Results: After excluding 53 women (loss of follow-up, untimely biomarker assessments, incorrect dates of enrollment), data from 271 women were included in analysis. Mean (SD) change in RBP, MDA, TNF-α, IL-6, and IL-8 between baseline and third trimester was -2.16 (4.47), -19.6 (46.4), 3.72 (37.2), 0.51 (14.4), and 13.2 (197), respectively, in intervention and -2.25 (4.30), -24.6 (43.6), 7.17 (32.6), -1.79, (11.4), and 31.3 (296) in control groups. None of these changes differed significantly between the two treatment arms. However, changes from baseline in TNF-α levels were significantly different between intervention and control groups in subset of women (n=99) using firewood before trial (-7.03 [32.9] vs. +12.4 [33.6]; 95% CI for group difference: -35.4 to -3.4, p=0.018)., Conclusions: Decrease in TNF-α concentration from baseline to third trimesters in intervention group women could indicate reduced cardiovascular stress and prothrombotic effects from decreased HAP. Our findings suggest that ethanol-burning stoves may mitigate cardiovascular health risks., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Wolf-Hisrchhorn Syndrome Candidate 1-Like 1 (WHSC1L1) is a protein lysine methyltransferase that is recurrently amplified (8p11.23) in patients with squamous cell carcinoma of the head and neck (SCCHN). In this study, we investigated the oncogenic role of WHSC1L1 in SCCHN. Using immunohistochemistry on tissue microarrays of patients with locoregionally advanced SCCHN, we found that WHSC1L1 is significantly overexpressed in patients with SCCHN, and is associated with poor grade and heavy smoking history. Knockdown of WHSC1L1 expression resulted in significant growth suppression and reduction of H3K36 dimethylation (H3K36me2) in SCCHN cells. Chromatin immunoprecipitation analysis showed that WHSC1L1 and H3K36me2 are enriched in the gene bodies of the cell cycle-related genes CDC6 and CDK2, implying that WHSC1L1 directly regulates the transcription of these genes. According to the importance of CDC6 and CDK2 for G1 to S transition, WHSC1L1 knockdown induced strong G0/G1 arrest which was rescued by introduction of wild-type WHSC1L1 but not by that of enzyme-inactive WHSC1L1. Our results imply that WHSC1L1 and its product H3K36me2 are essential for the transition from G1 to S phase in SCCHN cells and that WHSC1L1 could serve as a rational target for anticancer drug development for patients with head and neck cancer., Competing Interests: Y. Nakamura is a stock holder and a scientific advisor of OncoTherapy Science and also has research grants from OncoTherapy Science. J. Park is a scientific advisor of OncoTherapy Science. No potential conflicts of interest were disclosed by the other authors.

Purpose: We compared rates of positive surgical margins, use of postoperative radiation therapy, and perioperative outcomes between robotic assisted laparoscopic and open radical prostatectomy in a contemporary population based cohort., Materials and Methods: In the National Cancer Data Base from 2010 through 2011 patients who underwent robotic assisted laparoscopic prostatectomy (73,131) and open radical prostatectomy (23,804) for nonmetastatic prostate adenocarcinoma were identified. Covariates included age, race, Charlson comorbidity index, prostate specific antigen, biopsy Gleason score, clinical stage, final Gleason score, pathological T stage, lymph node dissection, nodal status, facility type, hospital volume and year of surgery. Multivariable logistic regression was used to identify factors associated with positive surgical margins, use of adjuvant/salvage radiation therapy, prolonged length of stay, readmission and 30-day mortality. Outcomes were also compared in 1:1 propensity matched cohorts., Results: Analysis of propensity matched cohorts showed robotic assisted laparoscopic prostatectomy reduced the risk of positive surgical margins (OR 0.88, 95% CI 0.83-0.93, p <0.01), the use of radiation therapy (OR 0.71, 95% CI 0.63-0.80, p <0.01) and 30-day mortality (OR 0.28, 95% CI 0.13-0.60, p <0.01). The protective effect of robotic assisted laparoscopic prostatectomy for positive surgical margins was found in patients with pT2 disease only (pT2-OR 0.85, 95% CI 0.79-0.91, p <0.01; pT3-OR 0.94, 95% CI 0.86-1.04, p=0.2). Similar results were obtained using multivariable regression., Conclusions: In a contemporary large national cohort, robotic assisted laparoscopic prostatectomy was independently associated with clinically meaningful reductions in positive surgical margins, postoperative radiation therapy and 30-day mortality compared to open radical prostatectomy. The oncologic benefit was primarily in patients with organ confined disease. Limitations were those associated with any observational study, namely the potential for bias due to unmeasured confounders., (Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Somatic mutations and copy number variation in the ERBB family are frequent in urothelial carcinoma (UC) and may represent viable therapeutic targets. We studied whether afatinib (an oral, irreversible inhibitor of the ErbB family) has activity in UC and if specific ERBB molecular alterations are associated with clinical response., Patients and Methods: In this phase II trial, patients with metastatic platinum-refractory UC received afatinib 40 mg/day continuously until progression or intolerance. The primary end point was 3-month progression-free survival (PFS3). Prespecified tumor analysis for alterations in EGFR, HER2, ERBB3, and ERBB4 was conducted., Results: The first-stage enrollment goal of 23 patients was met. Patient demographic data included: 78% male, median age 67 years (range, 36 to 82 years), hemoglobin < 10 g/dL in 17%, liver metastases in 30%, median time from prior chemotherapy of 3.6 months, and Eastern Cooperative Oncology Group performance status ≤ 1 in 100%. No unexpected toxicities were observed; two patients required dose reduction for grade 3 fatigue and rash. Overall, five of 23 patients (21.7%) met PFS3 (two partial response, three stable disease). Notably, among the 21 tumors analyzed, five of six patients (83.3%) with HER2 and/or ERBB3 alterations achieved PFS3 (PFS = 10.3, 7.0, 6.9, 6.3, and 5.0 months, respectively) versus none of 15 patients without alterations (P < .001). Three of four patients with HER2 amplification and three of three patients with ERBB3 somatic mutations (G284R, V104M, and R103G) met PFS3. One patient with both HER2 amplification and ERBB3 mutation never progressed on therapy, but treatment was discontinued after 10.3 months as a result of depressed ejection fraction. The median time to progression/discontinuation was 6.6 months in patients with HER2/ERBB3 alterations versus 1.4 months in patients without alterations (P < .001)., Conclusion: Afatinib demonstrated significant activity in patients with platinum-refractory UC with HER2 or ERBB3 alterations. The potential contribution of ERBB3 to afatinib sensitivity is novel. Afatinib deserves further investigation in molecularly selected UC., (© 2016 by American Society of Clinical Oncology.)

Background: Fyn is a kinase that is upregulated in a subset of metastatic castration-resistant prostate cancer. Saracatinib potently inhibits Fyn activation. We have noted a relationship between Fyn expression and directional motility, a cellular process related to metastasis. As such we hypothesized that treatment with saracatinib would increase the time required to develop new metastatic lesions., Methods: Patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel were eligible for enrollment. This study was executed as a randomized discontinuation trial. During a lead-in phase of two 28-Day cycles, all patients received saracatinib. Afterward, patients with radiographically stable disease were randomized to either saracatinib or placebo. Patients continued treatment until evidence of new metastasis., Results: Thirty-one patients were treated. Only 26% of patients had stable disease after 8 weeks and thus proceeded to randomization. This required early termination of the study for futility. The 70% of patients who progressed after the lead-in phase exhibited expansion of existing lesions or decompensation due to clinical progression without new metastatic lesions. Fatigue was reported in more than 25% of patients (all grades) with only two patients experiencing grade 3 toxicity. Other grade 3 adverse events included dehydration, thrombocytopenia, and weakness., Conclusions: This study was unable to determine if saracatinib had potential as metastasis inhibitor. Metastasis inhibition by saracatinib may still be viable in an earlier time in the disease history., (© 2015 Wiley Periodicals, Inc.)

Purpose: Sonic hedgehog (SHH), an activating ligand of smoothened (SMO), is overexpressed in > 70% of pancreatic cancers (PCs). We investigated the impact of vismodegib, an SHH antagonist, plus gemcitabine (GV) or gemcitabine plus placebo (GP) in a multicenter phase Ib/randomized phase II trial and preclinical PC models., Patients and Methods: Patients with PC not amenable to curative therapy who had received no prior therapy for metastatic disease and had Karnofsky performance score ≥ 80 were enrolled. Patients were randomly assigned in a one-to-one ratio to GV or GP. The primary end point was progression-free-survival (PFS). Exploratory correlative studies included serial SHH serum levels and contrast perfusion computed tomography imaging. To further investigate putative biologic mechanisms of SMO inhibition, two autochthonous pancreatic cancer models (Kras(G12D); p16/p19(fl/fl); Pdx1-Cre and Kras(G12D); p53(R270H/wt); Pdx1-Cre) were studied., Results: No safety issues were identified in the phase Ib portion (n = 7), and the phase II study enrolled 106 evaluable patients (n = 53 in each arm). Median PFS was 4.0 and 2.5 months for GV and GP arms, respectively (95% CI, 2.5 to 5.3 and 1.9 to 3.8, respectively; adjusted hazard ratio, 0.81; 95% CI, 0.54 to 1.21; P = .30). Median overall survival (OS) was 6.9 and 6.1 months for GV and GP arms, respectively (95% CI, 5.8 to 8.0 and 5.0 to 8.0, respectively; adjusted hazard ratio, 1.04; 95% CI, 0.69 to 1.58; P = .84). Response rates were not significantly different. There were no significant associations between correlative markers and overall response rate, PFS, or OS. Preclinical trials revealed no significant differences with vismodegib in drug delivery, tumor growth rate, or OS in either model., Conclusion: The addition of vismodegib to gemcitabine in an unselected cohort did not improve overall response rate, PFS, or OS in patients with metastatic PC. Our preclinical and clinical results revealed no statistically significant differences with respect to drug delivery or treatment efficacy using vismodegib., (© 2015 by American Society of Clinical Oncology.)

Four anatomical patterns of hydrocephalus secondary to congenital Toxoplasma gondii infection were identified and characterized for infants enrolled in the National Collaborative Chicago-based Congenital Toxoplasmosis Study. Analysis of parasite serotype revealed that different anatomical patterns associate with Type-II vs Not-Exclusively Type-II strains (NE-II) (P = .035)., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Family clusters and epidemics of toxoplasmosis in North, Central, and South America led us to determine whether fathers of congenitally infected infants in the National Collaborative Chicago-Based Congenital Toxoplasmosis Study (NCCCTS) have a high incidence of Toxoplasma gondii infection., Methods: We analyzed serum samples collected from NCCCTS families between 1981 and 2013. Paternal serum samples were tested for T. gondii antibodies with immunoglobulin (Ig) G dye test and IgM enzyme-linked immunosorbent assay. Additional testing of paternal serum samples was performed with differential-agglutination and IgG avidity tests when T. gondii IgG and IgM results were positive and serum samples were collected by the 1-year visit of the congenitally infected child. Prevalence of paternal seropositivity and incidence of recent infection were calculated. We analyzed whether certain demographics, maternal parasite serotype, risk factors, or maternal/infant clinical manifestations were associated with paternal T. gondii infection status., Results: Serologic testing revealed a high prevalence (29 of 81; 36%) of T. gondii infection in fathers, relative to the average seropositivity rate of 9.8% for boys and men aged 12-49 years in the United States between 1994 and 2004 (P < .001). Moreover, there was a higher-than-expected incidence of recent infections among fathers with serum samples collected by the 1-year visit of their child (6 of 45; 13%; P < .001). No demographic patterns or clinical manifestations in mothers or infants were associated with paternal infections, except for sandbox exposure., Conclusions: The high prevalence of chronic and incidence of recent T. gondii infections in fathers of congenitally infected children indicates that T. gondii infections cluster within families in North America. When a recently infected person is identified, family clustering and community risk factors should be investigated for appropriate clinical management., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background and Objectives: There have been few recent studies that have examined the use of postmastectomy radiotherapy (PMRT) for patients with 1-3 positive nodes., Methods: We utilized the National Cancer Data Base to examine trends in PMRT for 346,218 patients with Stage I-III breast cancer from 2003 to 2011. Neoadjuvant therapy cases were excluded. Log linear models examined trends in PMRT and logistic regressions were used to examine factors related to PMRT., Results: The proportion of pT1-2N1 patients receiving PMRT increased from 23.9% in 2003 to 36.4% in 2011 with an annual percent change (APC) of 6.2% (P < 0.001). There were significant increases in the use of PMRT amongst patients with one (APC = 7.7%), two (APC = 6.7%), and three (APC = 4.2%) positive nodes. In 2011, 27.8%, 43.8%, and 57.8% of patients with one, two or three positive nodes underwent PMRT, respectively. The number of positive nodes and tumor size were the strongest independent predictors of PMRT in the 1-3 node group; lymphovascular invasion, invasive lobular histology, and triple negative phenotypes were also associated with PMRT use., Conclusion: PMRT for patients with pT1-2N1 disease has increased with the greatest increase seen in those with one tumor positive node. Tumor factors remain strong independent predictors of PMRT., (© 2015 Wiley Periodicals, Inc.)

Background We hypothesized that targeting two mechanisms of epigenetic silencing would be additive or synergistic with regard to expression of specific target genes. The primary objective of the study was to establish the maximum tolerated dose (MTD) of belinostat in combination with a fixed dose of azacitidine (AZA). Methods In Part A of the study, patients received a fixed dose of AZA, with escalating doses of belinostat given on the same days 1-5, in a 28 day cycle. Part B was designed to evaluate the relative contribution of belinostat to the combination based on analysis of pharmacodynamic markers, and incorporated a design in which patients were randomized during cycle 1 to AZA alone, or the combination, at the maximally tolerated dose of belinostat. Results 56 patients with myeloid neoplasia were enrolled. Dose escalation was feasible in part A, up to 1000 mg/m(2) dose level of belinostat. In Part B, 18 patients were assessable for quantitative analysis of specific target genes. At day 5 of therapy, MDR1 was significantly up-regulated in the belinostat/AZA arm compared with AZA alone arm (p = 0.0023). There were 18 responses among the 56 patients. Conclusions The combination of belinostat and AZA is feasible and associated with clinical activity. The recommended phase II dose is 1000 mg/m(2) of belinostat plus 75 mg/m(2) of AZA on days 1-5, every 28 days. Upregulation in MDR1 was observed in the combination arm at day 5 compared with the AZA alone arm, suggesting a relative biologic contribution of belinostat to the combination.

Background: Human papillomavirus (HPV) has emerged as a causative agent and positive prognostic factor for oropharyngeal (OP) head and neck squamous cell cancer (HNSCC). This prompts inquiry into whether therapy improvements or increasing incidence of HPV drives the apparent improvements in HNSCC outcomes observed in non-randomized clinical trials., Patients and Methods: We reviewed all locoregionally advanced HNSCC patients treated with chemotherapy and radiation in prospective institutional trials at a single institution. Patients were divided into three groups (1, 2, 3) according to treatment time period (1993-1998, 1999-2003, 2004-2010, respectively). We reasoned that if a favorable trend was observed over time in OP but not non-OP patients, HPV status may be confounding treatment effects, whereas this would be unlikely if both subgroups improved over time., Results: Four hundred and twenty-two patients were identified with OP (55.7%) and non-OP (44.3%) HNSCC. Five-year OP overall survival (OS) improved from 42.3% (group 1) to 72.5% (group 2), and 78.4% (group 3), adjusted P = 0.0084. Non-OP 5-year OS was 51.0% (group 1), 58.8% (group 2), and 66.3% (group 3), adjusted P = 0.51. Five-year recurrence-free survival (RFS) improved for OP groups from 42.3% to 68.4% to 75.8% (adjusted P = 0.017). Non-OP 5-year RFS was 42.9%, 53.6%, and 61.7% for sequential groups (adjusted P = 0.30). Five-year OP distant failure-free survival (DFFS) improved from 42.3% to 71.1% to 77.8% (adjusted P = 0.011). Five-year non-OP DFFS was 46.9%, 57.1%, and 66.0% for sequential groups (adjusted P = 0.38)., Conclusions: Over the past two decades, OP HNSCC outcomes improved significantly, while non-OP outcomes only trended toward improvement. Although our patients are not stratified by HPV status, improving OP outcomes are likely at least partly due to the increasing HPV incidence. These data further justify trial stratification by HPV status, investigations of novel approaches for carcinogen-related HNSCC, and current de-intensification for HPV-related HNSCC., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: The risk of severe neutropenia from treatment with irinotecan is related in part to UGT1A1*28, a variant that reduces the elimination of SN-38, the active metabolite of irinotecan. We aimed to identify the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of irinotecan in patients with advanced solid tumors stratified by the *1/*1, *1/*28, and *28/*28 genotypes., Patients and Methods: Sixty-eight patients received an intravenous flat dose of irinotecan every 3 weeks. Forty-six percent of the patients had the *1/*1 genotype, 41% had the *1/*28 genotype, and 13% had the *28/*28 genotype. The starting dose of irinotecan was 700 mg in patients with the *1/*1 and *1/*28 genotypes and 500 mg in patients with the *28/*28 genotype. Pharmacokinetic evaluation was performed at cycle 1., Results: In patients with the *1/*1 genotype, the MTD was 850 mg (four DLTs per 16 patients), and 1,000 mg was not tolerated (two DLTs per six patients). In patients with the *1/*28 genotype, the MTD was 700 mg (five DLTs per 22 patients), and 850 mg was not tolerated (four DLTs per six patients). In patients with the *28/*28 genotype, the MTD was 400 mg (one DLT per six patients), and 500 mg was not tolerated (three DLTs per three patients). The DLTs were mainly myelosuppression and diarrhea. Irinotecan clearance followed linear kinetics. At the MTD for each genotype, dosing by genotype resulted in similar SN-38 areas under the curve (AUCs; r(2) = 0.0003; P = .97), but the irinotecan AUC was correlated with the actual dose (r(2) = 0.39; P < .001). Four of 48 patients with disease known to be responsive to irinotecan achieved partial response., Conclusion: The UGT1A1*28 genotype can be used to individualize dosing of irinotecan. Additional studies should evaluate the effect of genotype-guided dosing on efficacy in patients receiving irinotecan., (© 2014 by American Society of Clinical Oncology.)

Background: Overexpression of Met tyrosine kinase receptor is associated with poor prognosis. Overexpression, and particularly MET amplification, are predictive of response to Met-specific therapy in preclinical models. Immunohistochemistry (IHC) of formalin-fixed paraffin-embedded (FFPE) tissues is currently used to select for 'high Met' expressing tumors for Met inhibitor trials. IHC suffers from antibody non-specificity, lack of quantitative resolution, and, when quantifying multiple proteins, inefficient use of scarce tissue., Methods: After describing the development of the Liquid-Tissue-Selected Reaction Monitoring-mass spectrometry (LT-SRM-MS) Met assay, we evaluated the expression level of Met in 130 FFPE gastroesophageal cancer (GEC) tissues. We assessed the correlation of SRM Met expression to IHC and mean MET gene copy number (GCN)/nucleus or MET/CEP7 ratio by fluorescence in situ hybridization (FISH)., Results: Proteomic mapping of recombinant Met identified 418TEFTTALQR426 as the optimal SRM peptide. Limits of detection (LOD) and quantitation (LOQ) for this peptide were 150 and 200 amol/µg tumor protein, respectively. The assay demonstrated excellent precision and temporal stability of measurements in serial sections analyzed one year apart. Expression levels of 130 GEC tissues ranged (<150 amol/µg to 4669.5 amol/µg. High correlation was observed between SRM Met expression and both MET GCN and MET/CEP7 ratio as determined by FISH (n = 30; R2 = 0.898). IHC did not correlate well with SRM (n = 44; R2 = 0.537) nor FISH GCN (n = 31; R2 = 0.509). A Met SRM level of ≥1500 amol/µg was 100% sensitive (95% CI 0.69-1) and 100% specific (95% CI 0.92-1) for MET amplification., Conclusions: The Met SRM assay measured the absolute Met levels in clinical tissues with high precision. Compared to IHC, SRM provided a quantitative and linear measurement of Met expression, reliably distinguishing between non-amplified and amplified MET tumors. These results demonstrate a novel clinical tool for efficient tumor expression profiling, potentially leading to better informed therapeutic decisions for patients with GEC.

Hypertension after treatment with vascular endothelial growth factor (VEGF) receptor inhibitors is associated with superior treatment outcomes for advanced cancer patients. To determine whether increased sorafenib doses cause incremental increases in blood pressure (BP), we measured 12-h ambulatory BP in 41 normotensive advanced solid tumor patients in a randomized dose-escalation study. After 7 days' treatment (400 mg b.i.d.), mean diastolic BP (DBP) increased in both study groups. After dose escalation, group A (400 mg t.i.d.) had marginally significant further increase in 12-h mean DBP (P = 0.053), but group B (600 mg b.i.d.) did not achieve statistically significant increases (P = 0.25). Within groups, individuals varied in BP response to sorafenib dose escalation, but these differences did not correlate with changes in steady-state plasma sorafenib concentrations. These findings in normotensive patients suggest BP is a complex pharmacodynamic biomarker of VEGF inhibition. Patients have intrinsic differences in sensitivity to sorafenib's BP-elevating effects.

Purpose: Retrospective single institution data suggest that postoperative pain after robot-assisted laparoscopic radical prostatectomy is decreased by early removal of the urethral catheter with suprapubic tube drainage. In a randomized patient population we determined whether suprapubic tube drainage with early urethral catheter removal would improve postoperative pain compared with urethral catheter drainage alone., Materials and Methods: Men with a body mass index of less than 40 kg/m(2) who had newly diagnosed prostate cancer and elected robot-assisted laparoscopic radical prostatectomy were included in analysis. Block randomization by surgeon was used and randomization assignment was done after completing the urethrovesical anastomosis. In patients assigned to suprapubic tube drainage the urethral catheter was removed on postoperative day 1 and all catheters were removed on postoperative day 7. Visual analog pain scale and satisfaction questionnaires were administered on postoperative days 0, 1 and 7., Results: A total of 29 patients were randomized to the urethral catheter vs 29 to the suprapubic tube plus early urethral catheter removal at the time of interim futility analysis. Mean visual analog pain scale scores did not differ between the groups at any time point and a similar percent of patients cited the catheter as the greatest bother with nonsignificant differences in treatment related satisfaction. Complications during postoperative week 1 did not vary between the groups. Based on interim results the trial was terminated due to lack of effect., Conclusions: Patients randomized to suprapubic tube vs urethral catheter drainage for the week after prostatectomy had similar pain, catheter related bother and treatment related satisfaction in the perioperative period. We no longer routinely offer suprapubic tube drainage with early urethral catheter removal at our institution., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

An interstitial deletion of chromosome 5, del(5q), is the most common structural abnormality in primary myelodysplastic syndromes (MDS) and therapy-related myeloid neoplasms (t-MNs) after cytotoxic therapy. Loss of TP53 activity, through mutation or deletion, is highly associated with t-MNs with a del(5q). We previously demonstrated that haploinsufficiency of Egr1 and Apc, 2 genes lost in the 5q deletion, are key players in the progression of MDS with a del(5q). Using genetically engineered mice, we now show that reduction or loss of Tp53 expression, in combination with Egr1 haploinsufficiency, increased the rate of development of hematologic neoplasms and influenced the disease spectrum, but did not lead to overt myeloid leukemia, suggesting that altered function of additional gene(s) on 5q are likely required for myeloid leukemia development. Next, we demonstrated that cell intrinsic loss of Tp53 in hematopoietic stem and progenitor cells haploinsufficient for both Egr1 and Apc led to the development of acute myeloid leukemia (AML) in 17% of mice. The long latency (234-299 days) and clonal chromosomal abnormalities in the AMLs suggest that additional genetic changes may be required for full transformation. Thus, loss of Tp53 activity in cooperation with Egr1 and Apc haploinsufficiency creates an environment that is permissive for malignant transformation and the development of AML.

Purpose: The clinical relevance of targeting the RAS/RAF/MEK/ERK pathway, activated in 70% to 80% of patients with acute myelogenous leukemia (AML), is unknown., Experimental Design: Selumetinib is an oral small-molecule inhibitor of MAP-ERK kinase (MEK)-1/2. Forty-seven patients with relapsed/refractory AML or 60 years old or more with untreated AML were enrolled on a phase II study. Patients were stratified by FLT3 ITD mutation status. The primary endpoint was response rate (complete, partial, and minor). Leukemia cells were analyzed for extracellular signal-regulated kinase (ERK) and mTOR phosphorylation., Results: Common drug-related toxicities were grade 1-2 diarrhea, fatigue, nausea, vomiting, and skin rash. In the FLT3 wild-type cohort, six of 36 (17%) patients had a response [one partial response, three minor responses, two unconfirmed minor responses (uMR)]. No patient with FLT3 ITD responded. NRAS and KRAS mutations were detected in 7% and 2% of patients, respectively. The sole patient with KRAS mutation had uMR with hematologic improvement in platelets. Baseline p-ERK activation was observed in 85% of patients analyzed but did not correlate with a response. A single-nucleotide polymorphism (SNP) rs3733542 in exon 18 of the KIT gene was detected in significantly higher number of patients with response/stable disease compared with nonresponders (60% vs. 23%; P = 0.027)., Conclusions: Selumetinib is associated with modest single-agent antileukemic activity in advanced AML. However, given its favorable toxicity profile, combination with drugs that target other signaling pathways in AML should be considered. The potential association of SNP rs3733542 in exon 18 of the KIT gene with antileukemic activity of selumetinib is intriguing, but will require validation in larger trials., (©2013 AACR.)

Therapy-related myeloid neoplasms (t-MN) are a late complication of the successful use of cytotoxic therapy for patients with cancer. A heterozygous deletions of the long arm of chromosome 5 [del(5q)], observed in 40% of patients, is associated with prior exposure to alkylating agents, and a high frequency of TP53 loss or mutation. In previous studies, we demonstrated that haploinsufficiency of 2 del(5q) genes, Egr1, and Apc, individually play a role in the pathogenesis of hematologic disease in mice. We now show that loss of one copy of Egr1 or Tp53 in an Apc haploinsufficient background (Apc (del/+)) accelerated the development of a macrocytic anemia with monocytosis, early features of t-MN. The development of anemia was significantly accelerated by treatment of mice with the alkylating agent, N-ethyl-N-nitrosourea (ENU), regardless of the levels of expression of Egr1 and Tp53. Transplantation of either wild type; Egr1(+/-); Tp53(+/-); Apc(del/+); or Egr1(+/-), Apc(del/+) bone marrow cells into lethally irradiated Apc(del/+) recipients resulted in rapid development of anemia that was further accelerated by administration of ENU to recipients, demonstrating that the Apc(del/+)-induced anemia was cell extrinsic and potentiated by ENU mutagenesis. These data emphasize the synergistic role of cell intrinsic and cell extrinsic (microenvironment) factors in the pathogenesis of t-MN, and raise awareness of the deleterious effects of cytotoxic therapy on the stromal microenvironment.

Immunogenic tumors grow progressively even when heavily infiltrated by CD8(+) T cells. We investigated how to rescue CD8(+) T cell function in long-established immunogenic melanomas that contained a high percentage of endogenous PD-1(+) tumor-specific CD8(+) T cells that were dysfunctional. Treatment with αPD-L1 and αCTLA-4 blocking antibodies did not prevent tumors from progressing rapidly. We then tested exogenous tumor-specific antigen delivery into tumors using Salmonella Typhimurium A1-R to increase antigen levels and generate a proinflammatory tumor microenvironment. Antigen-producing A1-R rescued the endogenous tumor-specific CD8(+) T cell response: proliferation was induced in the lymphoid organs and effector function was recovered in the tumor. Treatment with antigen-producing A1-R led to improved mouse survival and resulted in 32% rejection of long-established immunogenic melanomas. Following treatment with antigen-producing A1-R, the majority of tumor-specific CD8(+) T cells still expressed a high level of PD-1 in the tumor. Combining antigen-producing A1-R with αPD-L1 blocking antibody enhanced the expansion of tumor-specific CD8(+) T cells and resulted in 80% tumor rejection. Collectively, these data demonstrate a powerful new therapeutic approach to rescue dysfunctional endogenous tumor-specific CD8(+) T cells and eradicate advanced immunogenic tumors.

Despite progress in locoregional and systemic therapies, patient survival from lung cancer remains a challenge. Receptor tyrosine kinases are frequently implicated in lung cancer pathogenesis, and some tyrosine kinase inhibition strategies have been effective clinically. The EphB4 receptor tyrosine kinase has recently emerged as a potential target in several other cancers. We sought to systematically study the role of EphB4 in lung cancer. Here, we demonstrate that EphB4 is overexpressed 3-fold in lung tumors compared to paired normal tissues and frequently exhibits gene copy number increases in lung cancer. We also show that overexpression of EphB4 promotes cellular proliferation, colony formation, and motility, while EphB4 inhibition reduces cellular viability in vitro, halts the growth of established tumors in mouse xenograft models when used as a single-target strategy, and causes near-complete regression of established tumors when used in combination with paclitaxel. Taken together, these data suggest an important role for EphB4 as a potential novel therapeutic target in lung cancer. Clinical trials investigating the efficacy of anti-EphB4 therapies as well as combination therapy involving EphB4 inhibition may be warranted.