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Objective: To evaluate the impact of celiac artery (CA) compression by median arcuate ligament (MAL) on technical metrics and long-term CA patency in patients with complex aortic aneurysms undergoing fenestrated/branched endograft repairs (F/B-EVARs)., Methods: Single-center, retrospective review of patients undergoing fenestrated/branched endovascular aortic aneurysm repairs and requiring incorporation of the CA between 2013 and 2023. Patients were divided into two groups-those with (MAL+) and without (MAL-) CA compression-based on preoperative computed tomography angiography findings. MAL was classified in three grades (A, B, and C) based on the degree and length of stenosis. Patients with MAL grade A had ≤50% CA stenosis measuring ≤3 mm in length. Those with grade B had 50% to 80% CA stenosis measuring 3 to 8 mm long, whereas those with grade C had >80% stenosis measuring >8 mm in length. End points included device integrity, CA patency and technical success-defined as successful implantation of the fenestrated/branched device with perfusion of CA and no endoleak., Results: One hundred and eighty patients with complex aortic aneurysms (pararenal, 128; thoracoabdominal, 52) required incorporation of the CA during fenestrated/branched endovascular aortic aneurysm repair. Majority (73%) were male, with a median age of 76 years (interquartile range [IQR], 69-81 years) and aneurysm size of 62 mm (IQR, 57-69 mm). Seventy-eight patients (43%) had MAL+ anatomy, including 33 patients with MAL grade A, 32 with grade B, and 13 with grade C compression. The median length of CA stenosis was 7.0 mm (IQR, 5.0-10.0 mm). CA was incorporated using fenestrations in 177 (98%) patients. Increased complexity led to failure in CA bridging stent placement in four MAL+ patients, but completion angiography showed CA perfusion and no endoleak, accounting for a technical success of 100%. MAL+ patients were more likely to require bare metal stenting in addition to covered stents (P = .004). Estimated blood loss, median operating room time, contrast volume, fluoroscopy dose and time were higher (P < .001) in MAL+ group. Thirty-day mortality was 3.3%, higher (5.1%) in MAL+ patients compared with MAL- patients (2.0 %). At a median follow-up of 770 days (IQR, 198-1525 days), endograft integrity was observed in all patients and CA events-kinking (n = 7), thrombosis (n = 1) and endoleak (n = 2) -occurred in 10 patients (5.6%). However, only two patients required reinterventions. MAL+ patients had overall lower long-term survival., Conclusions: CA compression by MAL is a predictor of increased procedural complexity during fenestrated/branched device implantation. However, technical success, long-term device integrity and CA patency are similar to that of patients with MAL- anatomy., Competing Interests: Disclosures J.M. repotrts the use of investigational device in an FDA-approved IDE (G220004) and is a consultant for W. L. Gore & Associates and Medtronic., (Copyright © 2024 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: After a concussion diagnosis, the most important issue for patients and loved ones is how long it will take them to recover. The main objective of this study is to develop a prognostic model of concussion recovery. This model would benefit many patients worldwide, allowing for early treatment intervention., Methods: The Concussion Assessment, Research and Education (CARE) consortium study enrolled collegiate athletes from 30 sites (NCAA athletic departments and US Department of Defense service academies), 4 of which participated in the Advanced Research Core, which included diffusion-weighted MRI (dMRI) data collection. We analyzed the dMRI data of 51 injuries of concussed athletes scanned within 48 h of injury. All athletes were cleared to return-to-play by the local medical staff following a standardized, graduated protocol. The primary outcome measure is days to clearance of unrestricted return-to-play. Injuries were divided into early (return-to-play < 28 days) and late (return-to-play >= 28 days) recovery based on the return-to-play clinical records. The late recovery group meets the standard definition of Persisting Post-Concussion Symptoms (PPCS). Data were processed using automated, state-of-the-art, rigorous methods for reproducible data processing using brainlife.io. All processed data derivatives are made available at https://brainlife.io/project/63b2ecb0daffe2c2407ee3c5/dataset. The microstructural properties of 47 major white matter tracts, 5 callosal, 15 subcortical, and 148 cortical structures were mapped. Fractional Anisotropy (FA) and Mean Diffusivity (MD) were estimated for each tract and structure. Correlation analysis and Receiver Operator Characteristic (ROC) analysis were then performed to assess the association between the microstructural properties and return-to-play. Finally, a Logistic Regression binary classifier (LR-BC) was used to classify the injuries between the two recovery groups., Results: The mean FA across all white matter volume was negatively correlated with return-to-play (r = -0.38, p = 0.00001). No significant association between mean MD and return-to-play was found, neither for FA nor MD for any other structure. The mean FA of 47 white matter tracts was negatively correlated with return-to-play (rμ = -0.27; rσ = 0.08; r min  = -0.1; r max  = -0.43). Across all tracts, a large mean ROC Area Under the Curve (AUC FA ) of 0.71 ± 0.09 SD was found. The top classification performance of the LR-BC was AUC = 0.90 obtained using the 16 statistically significant white matter tracts., Discussion: Utilizing a free, open-source, and automated cloud-based neuroimaging pipeline and app (https://brainlife.io/docs/tutorial/using-clairvoy/), a prognostic model has been developed, which predicts athletes at risk for slow recovery (PPCS) with an AUC=0.90, balanced accuracy = 0.89, sensitivity = 1.0, and specificity = 0.79. The small number of participants in this study (51 injuries) is a significant limitation and supports the need for future large concussion dMRI studies and focused on recovery., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr Broglio has current or past research funding from the National Institutes of Health; Centers for Disease Control and Prevention; Department of Defense – USA Medical Research Acquisition Activity, National Collegiate Athletic Association; National Athletic Trainers’ Association Foundation; National Football League/Under Armour/GE; Simbex; and ElmindA. He has consulted for US Soccer (paid), US Cycling (unpaid), University of Calgary SHRed Concussions external advisory board (unpaid), medico-legal litigation, and received speaker honorarium and travel reimbursements for talks given. He is co-author of “Biomechanics of Injury (3rd edition)” and has a patent on “Brain Metabolism Monitoring Through CCO Measurements Using All-Fiber-Integrated Super-Continuum Source” (U.S. 11,529,091 B2). He is on the and is/was on the editorial boards (all unpaid) for Journal of Athletic Training (2015 to present), Concussion (2014 to present), Athletic Training & Sports Health Care (2008 to present), British Journal of Sports Medicine (2008 to 2019). Thomas McAllister has Concussion Research Grants from NIH; US Dept. of Defense; US Dept. of Energy; and the NCAA. He also has Royalties from American Psychiatric Assoc. Publishing for Textbook of TBI. He is part of the Concussion Scientific Advisory Committee; Australian Football League – uncompensated. Michael McCrea has Research funding to Medical College of Wisconsin from US Dept. of Defense (DoD) and NCAA; Research funding to Medical College of Wisconsin from NIH, VA, DoD, CDC, NFL, NCAA, Abbott Laboratories; Book royalties from Oxford University Press. He is Consultant, Neurotrauma Sciences, Inc.; Consultant, Green Bay Packers; Medical legal consulting. He receives Honoraria and travel support for professional speaking engagements and for professional meetings., (Copyright © 2024. Published by Elsevier Inc.)

Background: HER2 mutations are targetable alterations in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). In the SUMMIT basket study, patients with HER2-mutant MBC received neratinib monotherapy, neratinib + fulvestrant, or neratinib + fulvestrant + trastuzumab (N + F + T). We report results from 71 patients with HR+, HER2-mutant MBC, including 21 (seven in each arm) from a randomized substudy of fulvestrant versus fulvestrant + trastuzumab (F + T) versus N + F + T., Patients and Methods: Patients with HR+ HER2-negative MBC with activating HER2 mutation(s) and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy received N + F + T (oral neratinib 240 mg/day with loperamide prophylaxis, intramuscular fulvestrant 500 mg on days 1, 15, and 29 of cycle 1 then q4w, intravenous trastuzumab 8 mg/kg then 6 mg/kg q3w) or F + T or fulvestrant alone. Those whose disease progressed on F + T or fulvestrant could cross-over to N + F + T. Efficacy endpoints included investigator-assessed objective response rate (ORR), clinical benefit rate (RECIST v1.1), duration of response, and progression-free survival (PFS). Plasma and/or formalin-fixed paraffin-embedded tissue samples were collected at baseline; plasma was collected during and at end of treatment. Extracted DNA was analyzed by next-generation sequencing., Results: ORR for 57 N + F + T-treated patients was 39% [95% confidence interval (CI) 26% to 52%); median PFS was 8.3 months (95% CI 6.0-15.1 months). No responses occurred in fulvestrant- or F + T-treated patients; responses in patients crossing over to N + F + T supported the requirement for neratinib in the triplet. Responses were observed in patients with ductal and lobular histology, 1 or ≥1 HER2 mutations, and co-occurring HER3 mutations. Longitudinal circulating tumor DNA sequencing revealed acquisition of additional HER2 alterations, and mutations in genes including PIK3CA, enabling further precision targeting and possible re-response., Conclusions: The benefit of N + F + T for HR+ HER2-mutant MBC after progression on CDK4/6is is clinically meaningful and, based on this study, N + F + T has been included in the National Comprehensive Cancer Network treatment guidelines. SUMMIT has improved our understanding of the translational implications of targeting HER2 mutations with neratinib-based therapy., Competing Interests: Disclosure KJ: Consultant/Advisory Board: Novartis, AstraZeneca, Pfizer, BMS, Jounce Therapeutics, Taiho Oncology, Genentech/Roche, Lilly Pharmaceuticals/Loxo Oncology, AbbVie, Eisai, Blueprint Medicines, Seattle Genetics, Daiichi Sankyo, Gilead, Olema Pharmaceuticals, Sun Pharma Advanced Research Company Ltd., Menarini/Stemline, and Scorpion Therapeutics. Research Funding: Novartis, Genentech/Roche, AstraZeneca, Debio Pharmaceuticals, Pfizer, Lilly Pharmaceuticals/Loxo Oncology, Zymeworks, Gilead, Puma Biotechnology, Merck Pharmaceuticals, and Scorpion Therapeutics. HW: His institution received financial compensation on his behalf for advisory boards, lecture fees and/or consultancy fees from Daiichi Sankyo, Gilead, Lilly, Augustine Therapeutics, AstraZeneca, Immutep Pty, MSD, and Roche. He received travel support from Gilead, Daiichi Sankyo, and Pfizer. SAH: Contracted research paid to institution +/- editorial support for authorship: Ambrx, Arvinas, AstraZeneca, Bayer, Celcuity, Cytomx, Daiichi Sankyo, Dantari, Dignitana, Genentech/Roche, G1-Therapeutics, Gilead, Greenwich Life Sciences Inc., GSK, Immunomedics, Eli Lilly, Loxo, Macrogenics, Novartis, OBI Pharma, Orinove, Orum, Pfizer, Phoenix Molecular Designs, Ltd., Pieris, PUMA, Radius, Sanofi, Seattle Genetics/Seagen, and Zymeworks. Speaking: Daiichi Sankyo (2021). AG-Z: Advisory/Consultancy: AstraZeneca, Novartis, MSD, Pierre-Fabre, and Exact Science. Speaker Bureau/Expert testimony: Roche, AstraZeneca, Novartis, MSD, Pfizer, Lilly, and Pierre-Fabre. Research grant/Funding (institution): Pfizer. Travel/Accommodation/Expenses: Roche, Novartis, and Pfizer. NU: Consultant/Advisory Board: Novartis, Eli Lilly, BioTheranostics, Gilead. AB: Consultant: AstraZeneca, Pfizer, Novartis, Lilly, Genentech/Roche, Seagen, Daiichi Sankyo, Merck, Agendia, Sanofi, Puma, Myriad, and Gilead; research support: Agendia and AstraZeneca. HP: Research grants to institution: Adlai Nortye USA, Ambrx, Aprea Therapeutics AB, Array BioPharma, AstraZeneca, BJ Bioscience, Bristol-Myers Squibb, Daiichi Pharmaceutical, Elicio Therapeutics, Exelixis, Fate Therapeutics, Genentech, GlaxoSmithKline, Gossamer Bio, Hutchison MediPharma, ImmuneOncia Therapeutics, ImmunoGen, Mabspace Biosciences, MacroGenics, Merck, Mirati Therapeutics, Novartis Pharmaceuticals, Oncologie, PsiOxus Therapeutics, RePare Therapeutics, Seattle Genetics, Synermore Biologics, TopAlliance Biosciences, Turning Point Therapeutics, Vedanta Biosciences, Xencor. ESY: Research funding: Puma Biotechnology; Advisory boards: Bayer, Clovis; Consultant: AstraZeneca. IS: Institutional Research Funding: Roche/Genentech, Puma Biotechnology, MSD, Merck, AstraZeneca, Incyte, Orion, Genmab, Bristol-Myers Squibb, Bayer/Loxo Oncology, Lilly Pharmaceuticals/Loxo Oncology, Novartis, Pfizer, Amgen, Repare Therapeutics. Honoraria: AstraZeneca. Support for travel and meeting attendance: Roche, Novartis, Merck/Pfizer, Incyte, and AstraZeneca. SR: Consultant/Advisory board: Novartis, AstraZeneca, Gilead, and Daiichi Sankyo. MBh: Consulting/Advisory Board: Daiichi Sankyo, Merck, Pfizer, and AstraZeneca. SV: Funding from Pfizer directly to institution for conducting clinical trial. MA: Consulting or advisory role: Pfizer, AstraZeneca, Menarini, Novartis, Daiichi Sankyo, and Gilead. Speaker’s bureau: Pfizer, Novartis, and Gilead. Research funding: AstraZeneca. F-CB: Consulting or advisory role: Pfizer; AstraZeneca; Lilly; Novartis; Menarini; Sanofi; GSK; Rain Oncology; Caris Life Sciences; GE Healthcare; Exact Sciences; Gilead. Speaker's bureau: Pfizer; Novartis; AstraZeneca; Roche; Lilly; Rain Oncology; Daiichi Sankyo; and Menarini-Stemline. Research Funding: Novartis; Pfizer; Menarini Silicon Biosystems; Prolynx; Merck KGaA; and GE Healthcare. SL: Receives research funding to her institution from Novartis, Bristol Myers Squibb, Merck, Puma Biotechnology, Eli Lilly, Nektar Therapeutics, AstraZeneca, and Seattle Genetics. She has acted as consultant (not compensated) to Seattle Genetics, Novartis, Bristol Myers Squibb, Merck, AstraZeneca, Eli Lilly, Pfizer, Gilead Therapeutics, and Roche-Genentech. She has acted as consultant (paid to her institution) to Aduro Biotech, Novartis, GlaxoSmithKline, Roche-Genentech, AstraZeneca, Silverback Therapeutics, G1 Therapeutics, Puma Biotechnology, Inc., Pfizer, Gilead Therapeutics, Seattle Genetics, Daiichi Sankyo, Merck, Amunix, Tallac Therapeutics, Eli Lilly, and Bristol Myers Squibb. JC: Has taken part in advisory boards for Puma Biotechnology. His unit is the recipient of a peer-reviewed grant from Science Foundation Ireland (an Irish government organization) which is part-funded by Puma Biotechnology Inc. Neither he nor his spouse own Puma Biotechnology stock. MEB: Medical advisory board of Strata Oncology; Research funding from AbbVie, Arcus, Apollomics, Elevation Oncology, Endeavor, Genetech, Puma, Loxo Oncology, and Seagen. SAP-P: Clinical trial research support/grant funding through the institution from AbbVie, Inc., ABM Therapeutics, Inc., Acepodia, Inc., Alkermes, Aminex Therapeutics, Amphivena Therapeutics, Inc., BioMarin Pharmaceutical, Inc., Boehringer Ingelheim, Bristol-Myers Squibb, Cerulean Pharma, Inc., Chugai Pharmaceutical Co., Ltd., Curis, Inc., Cyclacel Pharmaceuticals, Daiichi Sankyo, Eli Lilly, ENB Therapeutics, Epigenetix Inc., Five Prime Therapeutics, F-Star Beta Limited, F-Star Therapeutics, Gene Quantum, Genmab A/S, Gilead Sciences, Inc., GlaxoSmithKline, Helix BioPharma Corp., Hengrui Pharmaceuticals, Co., Ltd., HiberCell, Inc., Immorna Biotherapeutics, Inc., Immunomedics, Inc., Incyte Corp., Jacobio Pharmaceuticals Co., Ltd., Jiangsu Simcere Pharmaceutical Co., Ltd., Lytix Biopharma AS, Medimmune, LLC., Medivation, Inc., Merck Sharp and Dohme Corp., Nectin Therapeutics, Ltd., Novartis Pharmaceuticals, Pieris Pharmaceuticals, Inc., Pfizer, Phanes Therapeutics, Principia Biopharma, Inc., Puma Biotechnology, Inc., Purinomia Biotech, Inc., Rapt Therapeutics, Inc., Replimune, Seattle Genetics, Silverback Therapeutics, Synlogic Therapeutics, Taiho Oncology, Tesaro, Inc., TransThera Bio, ZielBio, Inc., NCI/NIH, P30CA016672—Core Grant (CCSG Shared Resources); and consulting fees from CRC Oncology. JMS: Research grant support: AstraZeneca and Strata Oncology. SC: Advisory/Consultancy: Novartis, F. Hoffmann-La Roche, Pfizer, Eli Lilly, AstraZeneca, Amgen, Gilead, Merck, and Exact Sciences. Research funding to the institution: Novartis, F. Hoffmann-La Roche, Pfizer, Genomic Health/Exact Sciences, AstraZeneca, Genentech, Celgene, Amgen, BMS, Merck, Sanofi, Puma, and Gilead. CS: Consulting, advisory role or travel grants from: AstraZeneca, AX'Consulting, Byondis B.V, Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann-La Roche Ltd., Lilly, MediTech, Merck Sharp & Dohme, Novartis, Pfizer, Philips, Pierre-Fabre, PintPharma, Puma Biotechnology, Seagen, and Zymeworks. JAG-S: Consulting or advisory role: Novartis Pharmaceuticals Corporation, AstraZeneca, Lilly, Seagen, Daiichi Sankyo, Gilead Sciences, Exact Sciences, and Stemline Menarini; speakers bureau: Novartis Pharmaceuticals Corporation, Lilly, AstraZeneca, and Stemline Menarini; travel, accommodations, expenses: Daiichi Sankyo, Gilead Sciences, and Exact Sciences. VG: Advisory Board: Boehringer. Research Funding: Bayer, Boehringer, Roche. Institutional Funding: Genentech, Merck Serono, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astellas, Fibrogen, Amcure, Natera, Sierra Oncology, AstraZeneca, Medimmune, BMS, and MSD. ENG-Y: Honoraria from Novartis, Pfizer, Eli Lilly, MSD, and AstraZeneca. CM: Has received research grants from Puma Biotechnology and Pfizer. She received consulting fees from AstraZeneca, Olaris, Novartis, and Sanofi. ABH: Reports stock and other ownership interests in Pfizer (immediate family member) and research funding from Takeda. JWG: has received institutional research funding from Puma Biotechnology Inc. RB: Receives research grant from Puma; has performed consulting for Genentech. JSKB: Employee (and stockholder) of Tempus Labs. LDE, DD, AF, and AW: Employees and stockholders of Puma Biotechnology. CLA: Has received research grants from Pfizer, Lilly, and Takeda. He serves or has served as scientific advisor to Novartis, Lilly, AstraZeneca, Daiichi Sankyo, Merck, Immunomedics, OrigiMed, Sanofi, TAIHO Oncology, and Puma Biotechnology. DBS: Has served as a consultant for/received honorarium from Pfizer, Vividion Therapeutics, Scorpion Therapeutics, FORE Therapeutics, Fog Pharma, Elsie Biotechnologies, Fog Pharma, Rain Oncology, Function Oncology, and BridgeBio. All other authors have declared no conflicts of interest. Data Sharing The authors declare that the data supporting the findings of this study are available within the article. Qualified researchers and study participants may submit requests for other study documentation and clinical trial data to clinicaltrials@pumabiotechnology.com for consideration., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Regenerative therapeutics for treating peripheral arterial disease are an appealing strategy for creating more durable solutions for limb ischemia. In this work, we performed preclinical testing of an injectable formulation of syndecan-4 proteoliposomes combined with growth factors as treatment for peripheral ischemia delivered in an alginate hydrogel. We tested this therapy in an advanced model of hindlimb ischemia in rabbits with diabetes and hyperlipidemia. Our studies demonstrate enhancement in vascularity and new blood vessel growth with treatment with syndecan-4 proteoliposomes in combination with FGF-2 or FGF-2/PDGF-BB. The effects of the treatments were particularly effective in enhancing vascularity in the lower limb with a 2-4 increase in blood vessels in the treatment group in comparison to the control group. In addition, we demonstrate that the syndecan-4 proteoliposomes have stability for at least 28 days when stored at 4°C to allow transport and use in the hospital environment. In addition, we performed toxicity studies in the mice and found no toxic effects even when injected at high concentration. Overall, our studies support that syndecan-4 proteoliposomes markedly enhance the therapeutic potential of growth factors in the context of disease and may be promising therapeutics for inducing vascular regeneration in peripheral ischemia. STATEMENT OF SIGNIFICANCE: Peripheral ischemia is a common condition in which there is a lack of blood flow to the lower limbs. This condition can lead to pain while walking and, in severe cases, critical limb ischemia and limb loss. In this study, we demonstrate the safety and efficacy of a novel injectable therapy for enhancing revascularization in peripheral ischemia using an advanced large animal model of peripheral vascular disease using rabbits with hyperlipidemia and diabetes., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The senior author (ABB) has a US patent on the technology in this manuscript., (Copyright © 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: First-line nivolumab plus ipilimumab prolongs survival versus chemotherapy in advanced non-small-cell lung cancer (NSCLC). We further characterized clinical benefit with this regimen in a large pooled patient population and assessed the effect of response on survival., Patients and Methods: Data were pooled from four studies of first-line nivolumab plus ipilimumab in advanced NSCLC (CheckMate 227 Part 1, 817 cohort A, 568 Part 1, and 012). Overall survival (OS), progression-free survival (PFS), objective response rate, duration of response, and safety were assessed. Landmark analyses of OS by response status at 6 months and by tumor burden reduction in responders to nivolumab plus ipilimumab were also assessed., Results: In the pooled population (N = 1332) with a minimum follow-up of 29.1-58.9 months, median OS was 18.6 months, with a 3-year OS rate of 35%; median PFS was 5.4 months (3-year PFS rate, 17%). Objective response rate was 36%; median duration of response was 23.7 months, with 38% of responders having an ongoing response at 3 years. In patients with tumor programmed death-ligand 1 (PD-L1) <1%, ≥1%, 1%-49%, or ≥50%, 3-year OS rates were 30%, 38%, 30%, and 48%. Three-year OS rates were 30% and 38% in patients with squamous or non-squamous histology. Efficacy outcomes in patients aged ≥75 years were similar to the overall pooled population (median OS, 20.1 months; 3-year OS rate, 34%). In the pooled population, responders to nivolumab plus ipilimumab at 6 months had longer post-landmark OS than those with stable or progressive disease; 3-year OS rates were 66%, 22%, and 14%, respectively. Greater depth of response was associated with prolonged survival; in patients with tumor burden reduction ≥80%, 50% to <80%, or 30% to <50%, 3-year OS rates were 85%, 72%, and 44%, respectively. No new safety signals were identified in the pooled population., Conclusion: Long-term survival benefit and durable response with nivolumab plus ipilimumab in this large patient population further support this first-line treatment option for advanced NSCLC., Competing Interests: Disclosure HB reports advisory/consulting fees, travel, accommodation, and expenses from Amgen, Bristol Myers Squibb, Genentech, Lilly, Merck, and Novartis; advisory/consulting fees from AbbVie, AstraZeneca, BioNTech AG, Boehringer Ingelheim, Cantargia AB, EMD Serono, Genmab, HUYA Bioscience International, Nuclaei, Pfizer, PharmaMar, Regeneron, Rgenix, Sonnet, Takeda, and Trovagene; honoraria from Amgen, Axiom Biotechnologies, Bristol Myers Squibb, Celgene, and Pfizer; research funding from Bristol Myers Squibb, Celgene, Lilly, Merck, and Millennium; stock interest with Nuclaei, Rgenix, and Sonnet; travel, accommodation, and expenses from Clovis Oncology; data safety monitoring board with Incyte and University of Pennsylvania; and ad boards with Guardant, Natera, and OncoCyte. TEC reports advisory/consulting fees, travel, accommodation, and expenses from Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Ipsen, Janssen, Merck Sharp & Dohme (MSD), Novartis/GlaxoSmithKline, Pfizer, Roche, Sanofi, and Servier. J-SL reports advisory/consulting fees from AstraZeneca and Ono Pharmaceutical. AP reports speaker fees, expert testimony, travel, accommodation, and expenses from Boehringer Ingelheim, Bristol Myers Squibb, and MSD; speaker fees and expert testimony from Roche, speaker fees from Pfizer; and speaker fees, travel, accommodation, and expenses from AstraZeneca. RBC reports advisory/consulting fees from AstraZeneca, Bristol Myers Squibb, MSD, Roche, and Takeda. MG reports advisory fees from Celularity and Guardant 360; and speaker fees from Guardant 360. YO reports advisory/consulting fees, honoraria, and research funding from AstraZeneca and Ono Pharmaceutical; and honoraria and research funding from Bristol Myers Squibb Japan. MN reports advisory/consulting fees, honoraria, and research funding from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Lilly, MSD, Ono Pharmaceuticals, Taiho Pharmaceutical, and Takeda; advisory/consulting fees from AbbVie and Teijin Pharma; honoraria and research funding from Janssen, Merck, Novartis, and Pfizer; and honoraria from Boehringer Ingelheim and Nippon Kayaku. JG reports grant support from Advaxis, AstraZeneca, Bristol Myers Squibb, Genentech, Merck, and Pfizer; consulting and writing fees from Bristol Myers Squibb; and consulting fees from AstraZeneca, Genentech, and Pfizer. NR reports consulting fees and honoraria from AstraZeneca, Bristol Myers Squibb, G1 Therapeutics, Genentech, Merck, and Roche; research funding from Merck; honoraria from Novartis and Celgene; expert testimony fees from Bristol Myers Squibb and Celgene; speaker’s bureau fees from Bristol Myers Squibb; personal fees from AbbVie, Amgen, Jazz, Regeneron, and Sanofi; other fees from AbbVie; and a grant from Amgen. DRS reports grant support from Aeglea BioTherapeutics, Agios, Apollomics, Arcus, Arrys Therapeutics, Astellas Pharma, Bayer, BeiGene, BIND Therapeutics, BioNTech, Blueprint Medicine, Calithera, Celgene, Celldex, Clovis Oncology, Cyteir Therapeutics, Daiichi Sankyo, Denovo Biopharma, Eisai, Elevation Oncology, Eli Lilly, EMD Serono, Evelo, G1 Therapeutics, GlaxoSmithKline, GRAIL, Hutchinson MediPharma, ImClone Systems, ImmunoGen, Incyte, Ipsen, Janssen, Kronos Bio, Loxo Oncology, MacroGenics, MedImmune, Merck, Molecular Partners, Molecular Templates, Nektar, Neon Therapeutics, Novocure, Oncologie, PTC Therapeutics, PureTech Health, Razor Genomics, Repare Therapeutics, Rgenix, Takeda, Tesaro, Tizona Therapeutics, Transgene, University of Texas-Southwestern, and Verastem; and consulting support from Amgen, BeiGene, Curio Science, Eli Lilly, EMD Serono, Evidera, Exelixis, GlaxoSmithKline, Intellisphere, Janssen, Jazz Pharmaceuticals, Mirati Therapeutics, Molecular Templates, Novocure, Puma Biotechnology, Regeneron, and Sanofi-Aventis. SSR reports advisory/consulting fees from Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sanyo, Eisai, Genentech/Roche, GlaxoSmithKline, Lilly, Merck, Sanofi, Takeda; and research funding from Advaxis, AstraZeneca, Bristol Myers Squibb, EMD Serono, Genmab, GlaxoSmithKline, Merck, Takeda, Tesaro. LGPA reports travel, accommodation, and expenses from AstraZeneca, Bristol Myers Squibb, MSD, Pfizer, Roche, and Takeda; honoraria from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Lilly, Merck Serono, Mirati, MSD, Novartis, Pfizer, PharmaMar, Roche/Genetech, Sanofi, Servier, and Takeda; speaker fees from Bristol Myers Squibb, Lilly, Merck Serono, MSD Oncology, Pfizer, and Roche/Genentech; research funding from AstraZeneca, Bristol Myers Squibb, MSD, PharmaMar; and personal fees from Altum Sequencing and Genomica. JFG reports consulting fees and honoraria from AstraZeneca, Blueprint, Bristol Myers Squibb, EMD Serono, Gilead, Glyde Bio, iTeos, Karyopharm, Loxo/Lilly, Merck, Moderna, Novartis, Oncorus, Pfizer, Regeneron, Silverback Therapeutics, and Takeda; grant support from Adaptimmune, Alexo, Array Biopharma, Blueprint, Bristol Myers Squibb, Jounce, Merck, Moderna, Novartis, and Tesaro; and an immediate family member who is an employee with equity at Ironwood Pharmaceuticals. MR reports advisory/consulting fees, travel, accommodation, and expenses from AbbVie and Amgen; advisory/consulting fees, speaker fees, expert testimony, travel, accommodation, and expenses from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Merck, MSD, Novartis, Pfizer, and Roche; and advisory/consulting fees from Samsung. MM reports advisory/consulting fees Alfasigma, Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Incyte, iOnctura, Merck, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, and SciClone. KJO reports advisory/consulting fees, speaker fees, expert testimony, honoraria, travel, accommodation, and expenses from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Lilly Oncology, MSD, Pfizer, and Roche; advisory/consulting fees, speaker fees, expert testimony and honoraria from Novartis; advisory/consulting fees, speaker fees, and honoraria from Teva; advisory/consulting fees and honoraria from Natera, Takeda, Tristar, and Yuhan; and being a shareholder at Carpe Vitae Pharmaceuticals, DGC diagnostics, Foundation Medicine, and RepLuca Pharmaceuticals. AM reports employment and stock interest with Bristol Myers Squibb. FN reports employment at Bristol Myers Squibb; and ownership/stock interest with AstraZeneca, Johnson & Johnson, and Eli Lilly. PT reports employment and stock interest with Bristol Myers Squibb. MDH reports advisory/consulting fees from Achilles, Adagene, Adicet, AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, Da Volaterra, Eli Lilly, Genentech, Genzyme/Sanofi, Immunai, Instill Bio, Janssen, Mana Therapeutics, Merk, Mirati, Pact Pharma, Regeneron, Roche, and Shattuck Labs; research funding from Bristol Myers Squibb; stock interest with Arcus, Factorial, Immunai, and Shattuck Labs; a patent filed by Memorial Sloan Kettering related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from Personal Genome Diagnostics (PGDx); after the completion of this work, MDH began as an employee (and equity holder) at AstraZeneca. JRB reports advisory/consultancy fees and research funding from Bristol Myers Squibb; advisory/consultancy fees from Amgen, AstraZeneca, Genentech, GlaxoSmithKline, Merck, Regeneron, and Sanofi; consultancy fees and honoraria from Janssen; and advisory/consultancy fees and other from Roche/Genentech. SA has declared no conflicts of interest., (Copyright © 2022. Published by Elsevier Ltd.)

The metallurgical engineering of bioresorbable zinc (Zn)-based medical alloys would greatly benefit from clarification of the relationships between material properties and biological responses. Here we investigate the biocompatibility of three Zn-based silver (Ag)-containing alloys, ranging from binary to quinary alloy systems. Selected binary and quinary Zn-Ag-based alloys underwent solution treatment (ST) to increase the solubility of Ag-rich phases within the Zn bulk matrix, yielding two different microstructures (one without ST and a different one with ST) with the same elemental composition. This experimental design was intended to clarify the relationship between elemental profile/microstructure and biocompatibility for the Zn-Ag system. We found that the quinary alloy system (Zn-4Ag-0.8Cu-0.6Mn-0.15Zr) performed significantly better, in terms of histomorphometry, than any alloy system we have evaluated to date. Furthermore, when solution treated to increase strength and ductility and reduce the fraction of Ag-rich phases, the quinary alloy's biocompatibility further improved. In vitro corrosion testing and metallographic analysis of in vivo implants demonstrated a more uniform mode of corrosion for the solution treated alloy. We conclude that Zn-Ag alloys can be engineered through alloying to substantially reduce neointimal growth. The positive effect on neointimal growth can be further enhanced by dissolving the AgZn 3 precipitates in the Zn matrix to improve the corrosion uniformity. These findings demonstrate that neointimal-forming cells can be regulated by elemental additions and microstructural changes in degradable Zn-based implant materials. STATEMENT OF SIGNIFICANCE: The metallurgical engineering of bioresorbable zinc (Zn)-based medical alloys would greatly benefit from clarification of the relationships between material properties and biological responses. Here, selected binary and quinary Zn-Ag-based alloys underwent solution treatment (ST) to increase the solubility of Ag-rich phases within the Zn bulk matrix, yielding two different microstructures (one without ST and a different one with ST) with the same elemental composition. We found that applying a thermal treatment restores mechanical strength and mitigates the strain rate sensitivity of Zn-Ag alloys by dissolving AgZn 3  precipitates. Ag-rich nano-precipitates in Zn decrease biocompatibility, a phenomenon that can be counteracted by dissolving the AgZn 3 precipitates in the bulk Zn matrix., Competing Interests: Declaration of Competing Interest The authors have no interests to declare, (Copyright © 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

The dual agent antibiotic, trimethoprim/sulfamethoxazole (TMP-SMX), has been prescribed to treat or prevent infections for over 50 years. However, there are no published validated analytical methods for the measurement of TMP metabolites in humans. We developed methodology enabling reliable quantification of TMP and 5 metabolites in human plasma. Chromatographic separation was achieved in less than 8 min using a biphenyl column. Analytes were detected in positive electrospray mode using a tandem Waters Xevo-TQ-XS mass spectrometer. Precision and accuracy values for all analytes were within 15% of nominal values during assay validation., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: The COVID-19 pandemic has greatly exacerbated the United States' overdose crisis. However, the overlapping impacts of COVID-19 and the overdose crisis have not been experienced equally, with unstably housed people who use drugs (PWUD) disproportionately impacted. Amid these changes, there is a need to understand how risk is experienced and managed among unstably housed PWUD to address health and social needs more effectively., Methods: This project draws on ethnographic research conducted from June 2020 to April 2021 in Rhode Island. Data include 39 in-depth interviews with unstably housed PWUD and approximately 50 h of ethnographic fieldwork conducted alongside street-based outreach workers., Results: COVID-19 risks were primarily contextualized in relation to participants' prior experiences of overdose events and adverse health outcomes. However, participants had varying levels of risk tolerance that were managed in ways that allowed them to reassert control and agency within the uncertainty of overlapping public health crises. Given participants' level of structural vulnerabilities, COVID-19 risk was managed alongside meeting their basic needs to survive., Conclusions: Findings demonstrate how COVID-related public health measures (e.g., stay-at-home orders, service closures) reinforced participants' structural vulnerabilities in ways that increased their risk of health and social harms. Implementing and scaling up programs that meet the basic needs of individuals, including permanent housing, social supports, and overdose prevention interventions (e.g., supervised consumption sites) is critically needed to address intersecting risks faced by unstably housed PWUD., Competing Interests: Declarations of Interest No conflicts to declare., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: In the phase III CASPIAN study, first-line durvalumab in combination with etoposide plus either cisplatin or carboplatin (EP) significantly improved overall survival (OS) versus EP alone in extensive-stage small-cell lung cancer (ES-SCLC). Durvalumab plus tremelimumab plus EP numerically improved OS versus EP, but did not reach statistical significance. Here we report updated OS in censored patients after median follow-up of >3 years., Patients and Methods: 805 patients with treatment-naïve ES-SCLC were randomized 1 : 1 : 1 to durvalumab plus EP, durvalumab plus tremelimumab plus EP, or EP. The two primary endpoints were OS for durvalumab plus EP versus EP and for durvalumab plus tremelimumab plus EP versus EP., Results: As of 22 March 2021 (median follow-up 39.4 months, 86% maturity), durvalumab plus EP continued to demonstrate improved OS versus EP: hazard ratio (HR) 0.71 [95% confidence interval (CI) 0.60-0.86; nominal P = 0.0003]; median OS was 12.9 versus 10.5 months, and 36-month OS rate was 17.6% versus 5.8%. Durvalumab plus tremelimumab plus EP continued to numerically improve OS versus EP: HR 0.81 (95% CI: 0.67-0.97; nominal P = 0.0200); median OS was 10.4 months, and 36-month OS rate was 15.3%. Twenty-seven and nineteen patients in the durvalumab plus EP and durvalumab plus tremelimumab plus EP arms, respectively, remained on durvalumab treatment at data cut-off., Conclusions: Three times more patients were estimated to be alive at 3 years when treated with durvalumab plus EP versus EP, with the majority still receiving durvalumab at data cut-off, further establishing durvalumab plus EP as first-line standard of care for ES-SCLC., Competing Interests: Disclosure LPA reports receiving grants from AstraZeneca, Bristol-Myers Squibb, MSD, and Pfizer; consulting fees from Amgen, AstraZeneca, Bayer, Blueprint Medicines, Bristol-Myers Squibb, Ipsen, Lilly, Merck, Mirati, MSD, Novartis, Pfizer, PharmaMar, Roche, Sanofi, and Servier; and honoraria from AstraZeneca, Janssen, Merck, Mirati, and Sanofi, and reports a leadership role with Genomica and Altum Sequencing, all outside the submitted work. YC reports receiving honoraria from Amgen, AstraZeneca, Bristol-Myers Squibb, Guardant Health, Jazz Pharmaceutical, Merck, Pfizer, and Takeda; and a research contract and support for meeting attendance/travel from Ipsen, all outside the submitted work. NR reports receiving honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Hoffmann-La Roche, Lilly, Merck, MSD, Pfizer, and Takeda; and consulting fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Hoffmann-La Roche, Merck, MSD, Pfizer, and Takeda, all outside the submitted work. KH reports receiving grants and personal fees from AstraZeneca during the conduct of the study; grants from Bristol-Myers Squibb, Chugai, Lilly, and MSD outside the submitted work; and honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Lilly, MSD, Nippon Kayaku, Ono, Pfizer, Taiho, and Takeda outside the submitted work. MJH reports receiving speakers’ honoraria from AstraZeneca, Boehringer Ingelheim, MSD, Pfizer, Roche, and Takeda outside the submitted work. MCG reports receiving grants from AstraZeneca and Merck, and personal fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, GlaxoSmithKline, Merck, Novartis, Pfizer, Roche, and Takeda, all outside the submitted work. EM reports receiving grants from AstraZeneca during the conduct of the study and grants from Roche outside the submitted work. HM and TD report full-time employment and stock ownership with AstraZeneca. HJ reports full-time employment and stock ownership with AstraZeneca, and a patent pending for the CASPIAN study trial design. JWG reports receiving research grants from AbbVie, AstraZeneca, Bristol-Myers Squibb, Genentech, and Merck; consulting fees from AbbVie, AstraZeneca, Bristol-Myers Squibb, and Genentech; and support for travel from AstraZeneca all outside the submitted work. All other authors have declared no conflicts of interest. Data sharing Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data-sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We have developed a novel bioactive hybrid metallic implant that integrates the beneficial characteristics of a permanent matrix and a biodegradable substance. Such a combination may generate a material system that evolves into a porous structure within weeks to months following implantation and can be used to form strong interfacial bonding and osseointegration for orthopedic and dental applications. Presently, traditional technologies such as casting, powder metallurgy and plastic forming have limited ability to produce the complex bioactive implant structures that are required in practical applications. The present study aimed to develop an innovative bioactive TiMg (BTiMg) hybrid system using a Ti-lattice (Ti-6Al-4 V) produced by an additive manufacturing (AM) process, in combination with a new Mg-based alloy (Mg-2.4%Nd -0.6%Y -0.3%Zr) as a biodegradable filling material. We evaluated the in-vitro behavior of the BTiMg system in a simulated physiological environment, along with cytotoxicity assessment. The microstructure was evaluated by scanning electron microscopy and X-ray diffraction, mechanical properties were examined in terms of compressive strength, environmental performance analysis was conducted by electrochemical testing using potentiodynamic polarization and impedance spectroscopy (EIS), and cytotoxicity characteristics were assessed by indirect cell viability analysis. The results demonstrated the feasibility to produce geometrically complex implants by AM technology, as well as the strength and non-cytotoxic effects of the BTiMg system. Benefits included a relatively high ultimate compressive strength (UCS) and a high yield point (YP), along with an adequate cell viability response in the range between 70 and 120%., (Published by Elsevier B.V.)

The VEGF pathway has been recognized as a key mediator of angiogenesis to support tumorigenesis. Multiple therapeutic agents targeting VEGF and VEGF receptors have been developed and approved for use in NSCLCs. Preclinical studies have found that the VEGF and EGFR pathways share common downstream signaling, and these pathways can function exclusively of one another during oncogenesis. In EGFR-mutant NSCLCs, up-regulated EGFR signaling increases VEGF through hypoxia-independent mechanisms, and elevated VEGF, in turn, contributes to the emergence of resistance to EGFR tyrosine kinase inhibitors (TKIs). In clinical trials, the addition of anti-VEGF therapy to EGFR TKIs considerably improved clinical outcomes. In recently reported large randomized studies, the addition of bevacizumab or ramucirumab to EGFR TKIs substantially improved progression-free survival in patients with TKI-naive EGFR-mutant NSCLC. This article reviews the preclinical and clinical data supporting dual inhibition of EGFR and VEGF in EGFR-mutant NSCLC as a way to improve patient outcomes., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Biodegradable arterial implants based on zinc have been found to suppress neointimal hyperplasia, suggesting that biodegradable materials containing zinc may be used to construct vascular implants with a reduced rate of restenosis. However, the molecular mechanism has remained unclear. In this report, we show that zinc-containing materials can be used to prevent neointimal formation when implanted into the rat aorta. Indeed, neointimal cells were significantly more TUNEL positive and alpha-actin negative at the interface of biodegradable zinc vs. biostable platinum implants, in association with greater caspase-3 activity. Although zinc stimulated extensive neointimal smooth muscle cell (SMC) death, macrophage and proinflammatory markers CD68 and iNOS were not increased in neointimal tissue relative to biostable platinum control implants. Using arterial explants, ionic zinc was confirmed to promote SMC apoptosis by activating the caspase apoptotic signaling pathway. These observations suggest that zinc-containing materials can be used to construct vascular implants such as stents with reduced neointimal hyperplasia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Zn-based alloys are recognized as promising bioabsorbable materials for cardiovascular stents, due to their biocompatibility and favorable degradability as compared to Mg. However, both low strength and intrinsic mechanical instability arising from a strong strain rate sensitivity and strain softening behavior make development of Zn alloys challenging for stent applications. In this study, we developed binary Zn-4.0Ag and ternary Zn-4.0Ag-xMn (where x = 0.2-0.6wt%) alloys. An experimental methodology was designed by cold working followed by a thermal treatment on extruded alloys, through which the effects of the grain size and precipitates could be thoroughly investigated. Microstructural observations revealed a significant grain refinement during wire drawing, leading to an ultrafine-grained (UFG) structure with a size of 700 nm and 200 nm for the Zn-4.0Ag and Zn-4.0Ag-0.6Mn, respectively. Mn showed a powerful grain refining effect, as it promoted the dynamic recrystallization. Furthermore, cold working resulted in dynamic precipitation of AgZn 3 particles, distributing throughout the Zn matrix. Such precipitates triggered mechanical degradation through an activation of Zn/AgZn 3 boundary sliding, reducing the tensile strength by 74% and 57% for Zn-4.0Ag and Zn-4.0Ag-0.6Mn, respectively. The observed precipitation softening caused a strong strain rate sensitivity in cold drawn alloys. Short-time annealing significantly mitigated the mechanical instability by reducing the AgZn 3 fraction. The ternary alloy wire showed superior microstructural stability relative to its Mn-free counterpart due to the pinning effect of Mn-rich particles on the grain boundaries. Eventually, a shift of the corrosion regime from localized to more uniform was observed after the heat treatment, mainly due to the dissolution of AgZn 3 precipitates. STATEMENT OF SIGNIFICANCE: Owing to its promising biodegradability, zinc has been recognized as a potential biodegradable material for stenting applications. However, Zn's poor strength alongside intrinsic mechanical instability have propelled researchers to search for Zn alloys with improved mechanical properties. Although extensive researches have been conducted to satisfy the mentioned concerns, no Zn-based alloys with stabilized mechanical properties have yet been reported. In this work, the mechanical properties and stability of the Zn-Ag-based alloys were systematically evaluated as a function of microstructural features. We found that the microstructure design in Zn alloys can be used to find an effective strategy to not only improve the strength and suppress the mechanical instability but also to minimize any damage by augmenting the corrosion uniformity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Ltd.)

Our aim was to investigate the patterns and trajectories of white matter (WM) diffusion abnormalities in microtubule-associated protein tau (MAPT) mutations carriers. We studied 22 MAPT mutation carriers (12 asymptomatic, 10 symptomatic) and 20 noncarriers from 8 families, who underwent diffusion tensor imaging (DTI) and a subset (10 asymptomatic, 6 symptomatic MAPT mutation carriers, and 10 noncarriers) were followed annually (median = 4 years). Cross-sectional and longitudinal changes in mean diffusivity (MD) and fractional anisotropy were analyzed. Asymptomatic MAPT mutation carriers had higher MD in entorhinal WM, which propagated to the limbic tracts and frontotemporal projections in the symptomatic stage compared with noncarriers. Reduced fractional anisotropy and increased MD in the entorhinal WM were associated with the proximity to estimated and actual age of symptom onset. The annualized change of entorhinal MD on serial DTI was accelerated in MAPT mutation carriers compared with noncarriers. Entorhinal WM diffusion abnormalities precede the symptom onset and track with disease progression in MAPT mutation carriers. Our cross-sectional and longitudinal data showed a potential clinical utility for DTI to track neurodegenerative disease progression for MAPT mutation carriers in clinical trials., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Recruitment of participants from diverse backgrounds is crucial to the generalizability of genetic research, but has proven challenging. We retrospectively evaluated recruitment methods used for a study on return of genetic results., Methods: The costs of study design, development, and participant enrollment were calculated, and the characteristics of the participants enrolled through the seven recruitment methods were examined., Results: A total of 1118 participants provided consent, a blood sample, and questionnaire data. The estimated cost across recruitment methods ranged from $579 to $1666 per participant and required a large recruitment team. Recruitment methods using flyers and staff networks were the most cost-efficient and resulted in the highest completion rate. Targeted sampling that emphasized the importance of Latino/a participation, utilization of translated materials, and in-person recruitments contributed to enrolling a demographically diverse sample., Conclusions: Although all methods were deployed in the same hospital or neighborhood and shared the same staff, each recruitment method was different in terms of cost and characteristics of the enrolled participants, suggesting the importance of carefully choosing the recruitment methods based on the desired composition of the final study sample. This analysis provides information about the effectiveness and cost of different methods to recruit adults for genetic research.

Background: Despite the significant antitumor activity of pembrolizumab in NSCLC, clinical benefit has been less frequently observed in patients whose tumors harbor EGFR mutations compared to EGFR wild-type patients. Our single-center experience on the KEYNOTE-001 trial suggested that pembrolizumab-treated EGFR-mutant patients, who were tyrosine kinase inhibitor (TKI) naïve, had superior clinical outcomes to those previously treated with a TKI. As TKI naïve EGFR-mutants have generally been excluded from pembrolizumab studies, data to guide treatment decisions in this patient population is lacking, particularly in patients with programmed death ligand 1 (PD-L1) expression ≥50%., Methods: We conducted a phase II trial (NCT02879994) of pembrolizumab in TKI naive patients with EGFR mutation-positive, advanced NSCLC and PD-L1-positive (≥1%, 22C3 antibody) tumors. Pembrolizumab was administered 200 mg every 3 weeks. The primary endpoint was objective response rate. Secondary endpoints included safety of pembrolizumab, additional pembrolizumab efficacy endpoints, and efficacy and safety of an EGFR TKI after pembrolizumab., Results: Enrollment was ceased due to lack of efficacy after 11 of 25 planned patients were treated. Eighty-two percent of trial patients were treatment naïve, 64% had sensitizing EGFR mutations, and 73% had PD-L1 expression ≥50%. Only 1 patient had an objective response (9%), but repeat analysis of this patient's tumor definitively showed the original report of an EGFR mutation to be erroneous. Observed treatment-related adverse events were similar to prior experience with pembrolizumab, but two deaths within 6 months of enrollment, including one attributed to pneumonitis, were of concern., Conclusions: Pembrolizumab's lack of efficacy in TKI naïve, PD-L1+, EGFR-mutant patients with advanced NSCLC, including those with PD-L1 expression ≥50%, suggests that it is not an appropriate therapeutic choice in this setting., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

It is still an open challenge to find a biodegradable metallic material exhibiting sufficient mechanical properties and degradation behavior to serve as an arterial stent. In this study, Zn-Mg alloys of 0.002 (Zn-002Mg), 0.005 (Zn-005Mg) and 0.08wt% Mg (Zn-08Mg) content were cast, extruded and drawn to 0.25mm diameter, and evaluated as potential biodegradable stent materials. Structural analysis confirmed formation of Mg 2 Zn 11 intermetallic in all three alloys with the average grain size decreasing with increasing Mg content. Tensile testing, fractography analysis and micro hardness measurements showed the best integration of strength, ductility and hardness for the Zn-08Mg alloy. Yield strength, tensile strength, and elongation to failure values of >200-300MPa, >300-400MPa, and >30% respectively, were recorded for Zn-08Mg. This metal appears to be the first formulated biodegradable material that satisfies benchmark values desirable for endovascular stenting. Unfortunately, the alloy reveals signs of age hardening and strain rate sensitivity, which need to be addressed before using this metal for stenting. The explants of Zn-08Mg alloy residing in the abdominal aorta of adult male Sprague-Dawley rats for 1.5, 3, 4.5, 6 and 11months demonstrated similar, yet slightly elevated inflammation and neointimal activation for the alloy relative to what was recently reported for pure zinc., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Molecular profiling has changed the treatment landscape in advanced non-small-cell lung cancer. Accurately identifying the tumours that harbour sensitizing EGFR mutations, the most common targetable molecular alteration, as well as those with acquired resistance mutations (e.g. T790M) on treatment is a high clinical priority. The current clinical gold standard is genotyping of tumour specimens. However, the practical utility of this approach is limited by the lack of available tissue and the potential complications associated with biopsies. With the advent of newer sequencing assays, it has become feasible to assess tumour genomics via a blood sample, termed a 'liquid biopsy'. In this review, we summarize the available techniques for liquid biopsies and their applicability for detecting sensitizing and resistance EGFR mutations and how these results may be used for making treatment decisions.

Metallic zinc implanted into the abdominal aorta of rats out to 6months has been demonstrated to degrade while avoiding responses commonly associated with the restenosis of vascular implants. However, major questions remain regarding whether a zinc implant would ultimately passivate through the production of stable corrosion products or via a cell mediated fibrous encapsulation process that prevents the diffusion of critical reactants and products at the metal surface. Here, we have conducted clinically relevant long term in vivo studies in order to characterize late stage zinc implant biocorrosion behavior and products to address these critical questions. We found that zinc wires implanted in the murine artery exhibit steady corrosion without local toxicity for up to at least 20months post-implantation, despite a steady buildup of passivating corrosion products and intense fibrous encapsulation of the wire. Although fibrous encapsulation was not able to prevent continued implant corrosion, it may be related to the reduced chronic inflammation observed between 10 and 20months post-implantation. X-ray elemental and infrared spectroscopy analyses confirmed zinc oxide, zinc carbonate, and zinc phosphate as the main components of corrosion products surrounding the Zn implant. These products coincide with stable phases concluded from Pourbaix diagrams of a physiological solution and in vitro electrochemical impedance tests. The results support earlier predictions that zinc stents could become successfully bio-integrated into the arterial environment and safely degrade within a time frame of approximately 1-2years., Staement of Significance: Previous studies have shown zinc to be a promising candidate material for bioresorbable endovascular stenting applications. An outstanding question, however, is whether a zinc implant would ultimately passivate through the production of stable corrosion products or via a cell mediated tissue encapsulation process that prevented the diffusion of critical reactants and products at the metal surface. We found that zinc wires implanted in the murine artery exhibit steady corrosion for up to at least 20months post-implantation. The results confirm earlier predictions that zinc stents could safely degrade within a time frame of approximately 1-2years., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Zinc shows great promise as a bio-degradable metal. Our early in vivo investigations implanting pure zinc wires into the abdominal aorta of Sprague-Dawley rats revealed that metallic zinc does not promote restenotic responses and may suppress the activities of inflammatory and smooth muscle cells. However, the low tensile strength of zinc remains a major concern. A cast billet of the Zn-Li alloy was produced in a vacuum induction caster under argon atmosphere, followed by a wire drawing process. Two phases of the binary alloy identified by x-ray diffraction include the zinc phase and intermetallic LiZn 4 phase. Mechanical testing proved that incorporating 0.1wt% of Li into Zn increased its ultimate tensile strength from 116±13MPa (pure Zn) to 274±61MPa while the ductility was held at 17±7%. Implantation of 10mm Zn-Li wire segments into abdominal aorta of rats revealed an excellent biocompatibility of this material in the arterial environment. The biodegradation rate for Zn-Li was found to be about 0.008mm/yr and 0.045mm/yr at 2 and 12months, respectively., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: To determine whether team based learning (TBL) is superior to traditional lecture -based learning in confidence and knowledge retention one year later., Design: A survey was administered 17 months after a completion of a required over-the-counter /self-care (OTC) course to two different cohorts of students. The survey assessed confidence and knowledge related to OTC topics. The lecture group had a traditional lecture based classroom experience; the intervention group experienced a TBL format throughout the entire course., Assessment: One hundred forty-seven students of 283 enrolled (51.9%) in the lecture group and 222 of 305 (72.8%) students in the TBL group participated in the knowledge assessment and survey. Demographic data including student grade point averages (GPA) and confidence were similar in both groups. Mean assessment scores (±SD) on OTC knowledge was significantly higher in the traditional lecture based group versus the TBL group; 62.9±19.3 vs. 54.9±15.7 (p=0.001)., Conclusion: Although TBL is thought to improve student engagement and mastery of material, after an initial implementation of TBL, knowledge retention in the long term appears to be lower than lecture based learning., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Pembrolizumab improved survival as first- and second-line therapy compared with chemotherapy in patients with highly programmed death ligand 1 (PD-L1) expressing advanced non-small cell lung cancer (NSCLC). We report the long-term safety and clinical activity of pembrolizumab as first-line therapy for patients with advanced NSCLC and the correlation between PD-L1 expression and efficacy., Patients and Methods: In the open-label phase 1b KEYNOTE-001 trial, treatment-naive patients with advanced NSCLC whose tumors expressed PD-L1 (≥1% staining, assessed using a prototype assay) were randomly assigned to intravenous pembrolizumab 2 or 10 mg/kg every 3 (Q3W) or 2 (Q2W) weeks. Response was assessed per central RECIST v1.1 every 9 weeks in all patients who received ≥1 pembrolizumab dose. Using pre-treatment tumor tissue, a clinical assay quantified the percentage of tumor cells expressing PD-L1 as tumor proportion score (TPS)., Results: Between 1 March 2013 and 18 September 2015, 101 patients received pembrolizumab 2 mg/kg Q3W (n = 6), 10 mg/kg Q3W (n = 49), or 10 mg/kg Q2W (n = 46). Of these, 27 (26.7%) had TPS ≥50%, 52 (51.5%) had TPS 1%-49%, and 12 (11.9%) had TPS <1%. The objective response rate (ORR) was 27% (27/101, 95% CI 18-37) and median overall survival was 22.1 months (95% CI 17.1-27.2). In patients with PD-L1 TPS ≥50%, ORR, 12-month PFS, and 12-month OS were higher [14/27 (51.9%; 95% CI 32%-71%), 54%, and 85%, respectively] than the overall population [27/101 (26.7%; 95% CI 18.4%-36.5%), 35%, 71%]. Pembrolizumab was well tolerated, with only 12 (11.9%) patients experiencing grade 3/4 treatment-related adverse events and no treatment-related deaths., Conclusions: Pembrolizumab provides promising long-term OS benefit with a manageable safety profile for PD-L1-expressing treatment-naive advanced NSCLC, with greatest efficacy observed in patients with TPS ≥50%., Clinical Trial Name and Number: KEYNOTE-001 (ClinicalTrials.gov, NCT01295827)., (© The Author 2017. 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.)

Background: The hepatocyte growth factor receptor gene (MET) exon 14 skipping (METex14) has recently been described a potential driver alteration in lung cancer targetable by mesenchymal-to-epithelial transition factor (MET) tyrosine kinase inhibitors (TKIs)., Methods: Well-validated hybrid capture-based comprehensive genomic profiling was performed at the request of individual treating physicians., Results: Of 11,205 lung cancers profiled by comprehensive genomic profiling, 298 (2.7%) carcinomas harbored alterations predicted to cause METex14, including adenosquamous (8.2%), sarcomatoid (7.7%), histologic subtype not otherwise specified (3.0%), adenocarcinoma (2.9%), squamous cell (2.1%), large cell (0.8%), and SCLC (0.2%). Acinar features were present in 24% of the METex14 samples. Six cases (2%) harbored MET Y1003X mutations affecting binding of the MET-negative regulator, E3 ubiquitin protein ligase. The median age of all patients with METex14 was 73 years (range 43-95) and 60% were female. Concurrent, murine double minute gene (MDM2) amplification, cyclin-dependent kinase 4 gene (CDK4) amplification, and EGFR amplification were observed in 35%, 21%, and 6.4% of patients with METex14, respectively. KRAS mutation was observed in 3% of cases. Concurrent MET amplification (METamp) (median copy number 10) was identified in 15% of METex14 samples. Significant differences in tumor mutational burden and type of the METex14 alterations were observed between the METamp and non-METamp samples. Response to MET TKI was observed in both in patients with METamp and in patients without METamp METex14., Conclusion: Diverse targetable METex14 alterations were identified in patients with NSCLC across age groups, including elderly patients, and in all major NSCLC histologic subtypes with an overall frequency of 2.7%. These findings support the use of hybrid capture-based molecular profiling across NSCLC subtypes to identify patients who will potentially benefit from MET TKIs., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Porous Mg scaffolds are considered as potential bone growth promoting materials. Unfortunately, the high rate of biocorrosion inherent to Mg alloys may cause a premature loss of mechanical strength, excessive evolution of hydrogen gas, and a rapidly shifting surface topography, all of which may hinder the ability of native cells to attach and grow on the implant surface. Here we investigated the cell cytotoxicity effects during corrosion of a novel magnesium alloy, EW10X04 (Mg-1.2%Nd-0.5%Y-0.5%Zr-0.4%Ca), following diffusion coating (DC) and heat treatment to reduce the corrosion rate. Cells were exposed either to corrosion products or to the corroding scaffold surface, in vitro. The microstructure characterization of the scaffold surface was carried out by scanning electron microscopy (SEM) equipped with a Noran energy dispersive spectrometer (EDS). Phase analyses were obtained by X-ray diffraction (XRD). We found that cell viability, growth, and adhesion were all improved when cultured on the EW10X04+DC surface or under corrosion product extracts due to lower corrosion rates relative to the EW10X04 control samples. It is therefore believed that the tested alloy after Nd coating and heat treatment may introduce a good balance between its biodegradation characteristics and cytotoxic effects towards cells., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Magnesium alloys have been widely investigated for biodegradable medical applications. However, the shielding of harmful cells (eg. bacteria or tumorous cells) from immune surveillance may be compounded by the increased porosity of biodegradable materials. We previously demonstrated the improved corrosion resistance and mechanical properties of a novel EW62 (Mg-6%Nd-2%Y-0.5%Zr)) magnesium alloy by rapid solidification followed by extrusion (RS) compared to its conventional counterpart (CC). The present in vitro study evaluated the influence of rapid solidification on cytotoxicity to murine osteosarcoma cells. We found that CC and RS corrosion extracts significantly reduced cell viability over a 24-h exposure period. Cell density was reduced over 48 h following direct contact on both CC and RS surfaces, but was further reduced on the CC surface. The direct presence of cells accelerated corrosion for both materials. The corroded RS material exhibited superior mechanical properties relative to the CC material. The data show that the improved corrosion resistance of the rapidly solidified EW62 alloy (RS) resulted in a relatively reduced cytotoxic effect on tumorous cells. Hence, the tested alloy in the form of a rapidly solidified substance may introduce a good balance between its biodegradation characteristics and cytotoxic effect towards cancerous and normal cells., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Although corrosion resistant bare metal stents are considered generally effective, their permanent presence in a diseased artery is an increasingly recognized limitation due to the potential for long-term complications. We previously reported that metallic zinc exhibited an ideal biocorrosion rate within murine aortas, thus raising the possibility of zinc as a candidate base material for endovascular stenting applications. This study was undertaken to further assess the arterial biocompatibility of metallic zinc. Metallic zinc wires were punctured and advanced into the rat abdominal aorta lumen for up to 6.5months. This study demonstrated that metallic zinc did not provoke responses that often contribute to restenosis. Low cell densities and neointimal tissue thickness, along with tissue regeneration within the corroding implant, point to optimal biocompatibility of corroding zinc. Furthermore, the lack of progression in neointimal tissue thickness over 6.5months or the presence of smooth muscle cells near the zinc implant suggest that the products of zinc corrosion may suppress the activities of inflammatory and smooth muscle cells., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The high corrosion rate of magnesium (Mg) and Mg-alloys precludes their widespread acceptance as implantable biomaterials. Here, we investigated the potential for rapid solidification (RS) to increase the stress corrosion cracking (SCC) resistance of a novel Mg alloy, Mg-6%Nd-2%Y-0.5%Zr (EW62), in comparison to its conventionally cast (CC) counterpart. RS ribbons were extrusion consolidated in order to generate bioimplant-relevant geometries for testing and practical use. Microstructural characteristics were examined by SEM. Corrosion rates were calculated based upon hydrogen evolution during immersion testing. The surface layer of the tested alloys was analyzed by X-ray photoelectron spectroscopy (XPS). Stress corrosion resistance was assessed by slow strain rate testing and fractography. The results indicate that the corrosion resistance of the RS alloy is significantly improved relative to the CC alloy due to a supersaturated Nd enrichment that increases the Nd2O3 content in the external oxide layer, as well as a more homogeneous structure and reduced grain size. These improvements contributed to the reduced formation of hydrogen gas and hydrogen embrittlement, which reduced the SCC sensitivity relative to the CC alloy. Therefore, EW62 in the form of a rapidly solidified extruded structure may serve as a biodegradable implant for biomedical applications., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: It is hypothesized that outward remodeling in systemic arteries is a compensatory mechanism for lumen area preservation in the face of increasing arterial stenosis. Large brain arteries have also been studied, but it remains unproven if all assumptions about arterial remodeling can be replicated in the cerebral circulation., Methods: The sample included 196 autopsied subjects with a mean age of 55 years; 63 % were men, and 74 % non-Hispanic whites. From each of 1396 dissected cadaveric large arteries of the circle of Willis, the areas of the lumen, intima, media, and adventitia were measured. Internal elastic lamina (IEL) area was defined as the area encircled by this layer. Stenosis was calculated by dividing the plaque area by the IEL area and multiplying by 100., Results: Plotting stenosis against lumen area or stratified by arterial size showed no preservation of the lumen in the setting of growing stenosis. We could not find an association between greater IEL proportion and stenosis (B = 0.44, P = 0.86). Stratifying arteries by their size, we found that smaller arteries have greater lumen reduction at any degree of stenosis (B = -23.65, P ≤ 0.0001), and although larger arteries show a positive association between IEL proportion and stenosis, this was no longer significant after adjusting for covariates (B = 6.0, P = 0.13)., Conclusions: We cannot confirm the hypothesis that large brain arteries undergo outward remodeling as an adaptive response to increasing degrees of stenosis. We found that the lumen decreases proportionally to the degree of stenosis., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Many publications are available on the physiological and pseudophysiological corrosion of magnesium and its alloys for bioabsorbable implant application, yet few focus on the characterization of explanted materials. In this work, commercially pure magnesium wires were corroded in the arteries of rats for up to 1 month, removed, and both bulk and surface products characterized. Surface characterization using infrared spectroscopy revealed a duplex structure comprising heavily magnesium-substituted hydroxyapatite that later transformed into an A-type (carbonate-substituted) hydroxyapatite. To explain this transformation, an ion-exchange mechanism is suggested. Elemental mapping of the bulk products of biocorrosion revealed the elemental distribution of Ca, P, Mg and O in the outer and Mg, O and P in the inner layers. Carbon was not observed in any significant quantity from the inner corrosion layer, suggesting that carbonates are not a prevalent product of corrosion. Backscatter electron imaging of cross-sections showed that thinning or absence of the hydroxyapatite in the later stages of degradation is related to local thickening of the inner corrosion layer. Based on these experimental observations, mechanisms describing corrosion in the quasi-steady state and during terminal breakdown of the magnesium specimens are proposed., (Copyright © 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

During two centuries, advances in medicine and medical research have helped to understand the pathophysiology of chronic myelogenous leukemia (CML). This hematologic malignancy is a unique model of oncogenesis where a single molecular hit, causing cell proliferation and survival, was identified. The chromosomal abnormality first highlighted by P. Nowell and D. Hungerford in 1960, and characterized as the reciprocal translocation t(9;22)(q34;q11), the Philadelphia chromosome, discovered in leukemic cells, by J. Rowley in 1973. At the end of the 20th century, the contribution of molecular biology techniques was crucial by the discovery of the BCR-ABL1 hybrid oncogene derived from the t(9;22), responsible for the translation of an aberrant protein tyrosine kinase. This BCR-ABL1 kinase deregulates signaling pathways that control normal cell cycle and survival in primitive hematopoietic cells and is thus responsible for malignant cell accumulation observed in CML. It was then only necessary to develop a targeted treatment adapted to this molecular hit. Recently, tyrosine kinase inhibitors, by their specific inhibitory activity of BCR-ABL, have revolutionized the treatment of CML, allowing rates of haematological, cytogenetic and molecular responses never seen to date, and has significantly improved the overall survival and the quality of life of patients.

Correlating the in vitro and in vivo degradation of candidate materials for bioabsorbable implants is a subject of interest in the development of next-generation metallic stents. In this study, pure magnesium wire samples were corroded both in the murine artery (in vivo) and in static cell culture media (in vitro), after which they were subjected to mechanical analysis by tensile testing. Wires corroded in vivo showed reductions in strength, elongation, and the work of fracture, with additional qualitative changes between tensile profiles. The in vivo degradation was 2.2±0.5, 3.1±0.8, and 2.3±0.3 times slower than corrosion in vitro in terms of effective tensile strength, strain to failure, and sample lifetime, respectively. Also, a combined metric, defined as strength multiplied by elongation, was 3.1±0.7 times faster in vitro than in vivo. Consideration of the utility and restrictions of each metric indicates that the lifetime-based multiplier is the best suited to general use for magnesium, though other metrics could be used to deduce the mechanical properties of degradable implants in service., (© 2013.)

Tyrosine kinase inhibitors (TKIs) have significant off-target multikinase inhibitory effects. We aimed to study the impact of TKIs on the in vivo B-cell response to vaccination. Cellular and humoral responses to influenza and pneumococcal vaccines were evaluated in 51 chronic phase chronic myeloid leukemia (CML) patients on imatinib, or second-line dasatinib and nilotinib, and 24 controls. Following vaccination, CML patients on TKI had significant impairment of IgM humoral response to pneumococcus compared with controls (IgM titer 79.0 vs 200 U/mL, P = .0006), associated with significantly lower frequencies of peripheral blood IgM memory B cells. To elucidate whether CML itself or treatment with TKI was responsible for the impaired humoral response, we assessed memory B-cell subsets in paired samples collected before and after imatinib therapy. Treatment with imatinib was associated with significant reductions in IgM memory B cells. In vitro coincubation of B cells with plasma from CML patients on TKI or with imatinib, dasatinib, or nilotinib induced significant and dose-dependent inhibition of Bruton's tyrosine kinase and indirectly its downstream substrate, phospholipase-C-γ2, both important in B-cell signaling and survival. These data indicate that TKIs, through off-target inhibition of kinases important in B-cell signaling, reduce memory B-cell frequencies and induce significant impairment of B-cell responses in CML.

Several groups have shown that that the BCR-ABL1 transcript level measured at 3 or 6 months after starting treatment with tyrosine kinase inhibitors strongly predicts clinical outcomes for patients with chronic myeloid leukemia. In this work, we asked whether the prognostic value of the 3-month transcript level could be improved by combining the 3- and 6-month results. We classified patients treated with imatinib and patients treated with dasatinib according to their transcript levels at 3 months and 6 months. The patients who met the 3-month landmark but failed the 6-month one had outcomes identical to those of patients who met both landmarks, whereas the patients who failed the first landmark but met the second one had prognoses similar to those who failed both landmarks. In summary, early intervention strategies can be based robustly just on the transcript level at 3 months. This trial was registered at www.clinicaltrials.gov as # NCT01460693.

A hexanucleotide repeat expansion in C9ORF72 was recently found to cause some cases of frontotemporal lobar degeneration, frontotemporal dementia (FTD)-amyotrophic lateral sclerosis, and amyotrophic lateral sclerosis. Patients with frontotemporal lobar degeneration with the C9ORF72 repeat expansion are more likely than those without to present with psychosis. In this study, we screened DNA samples from 192 unrelated subjects with schizophrenia for the C9ORF72 repeat expansion. None of the subjects with schizophrenia had the pathogenic expansion. C9ORF72 repeat expansions either do not cause schizophrenia, or do so rarely (less than 1% of cases)., (Copyright © 2013 Elsevier Inc. All rights reserved.)

In the present study we aimed to determine the prevalence of C9ORF72 GGGGCC hexanucleotide expansion in our cohort of 53 frontotemporal lobar degeneration (FTLD) patients and 174 neurologically normal controls. We identified the hexanucleotide repeat, in the pathogenic range, in 4 (2 bv-frontotemporal dementia (FTD) and 2 FTD-amyotrophic lateral sclerosis [ALS]) out of 53 patients and 1 neurologically normal control. Interestingly, 2 of the C9ORF72 expansion carriers also carried 2 novel missense mutations in GRN (Y294C) and in PSEN-2(I146V). Further, 1 of the C9ORF72 expansion carriers, for whom pathology was available, showed amyloid plaques and tangles in addition to TAR (trans-activation response) DNA-binding protein (TDP)-43 pathology. In summary, our findings suggest that the hexanucleotide expansion is probably associated with ALS, FTD, or FTD-ALS and occasional comorbid conditions such as Alzheimer's disease. These findings are novel and need to be cautiously interpreted and most importantly replicated in larger numbers of samples., (Published by Elsevier Inc.)

Invariant natural killer T (iNKT) cells are powerful immunomodulatory cells that in mice regulate a variety of immune responses, including acute GVHD (aGVHD). However, their clinical relevance and in particular their role in clinical aGVHD are not known. We studied whether peripheral blood stem cell (PBSC) graft iNKT-cell dose affects on the occurrence of clinically significant grade II-IV aGVHD in patients (n = 57) undergoing sibling, HLA-identical allogeneic HSCT. In multivariate analysis, CD4(-) iNKT-cell dose was the only graft parameter to predict clinically significant aGVHD. The cumulative incidence of grade II-IV aGVHD in patients receiving CD4(-) iNKT-cell doses above and below the median were 24.2% and 71.4%, respectively (P = .0008); low CD4(-) iNKT-cell dose was associated with a relative risk of grade II-IV aGVHD of 4.27 (P = .0023; 95% CI, 1.68-10.85). Consistent with a role of iNKT cells in regulating aGVHD, in mixed lymphocyte reaction assays, CD4(-) iNKT cells effectively suppressed T-cell proliferation and IFN-γ secretion in a contact-dependent manner. In conclusion, higher doses of CD4(-) iNKT cells in PBSC grafts are associated with protection from aGVHD. This effect could be harnessed for prevention of aGVHD.

Second-generation tyrosine kinase inhibitors (2G-TKIs) are effective at inducing complete cytogenetic responses (CCyRs) in approximately half of chronic myeloid leukemia patients treated while still in the chronic phase and after failing imatinib. It is less clear whether these responses are durable. In the present study, we report the clinical outcome of 119 patients who received a 2G-TKI as second-line treatment while still in the chronic phase. In an intention-to-treat analysis, the 4-year probabilities of overall and event-free survival were 81.9% and 35.3%, respectively. Sixty-two patients discontinued the initial 2G-TKI because of resistance or intolerance. To further explore the durability of cytogenetic responses, irrespective of the need for a third-line TKI, we used the concept of "current CCyR-survival" (c-CCyRS). The c-CCyRS at 4 years was 54.4%. After introduction of a 2G-TKI, 77 patients had a 3-month BCR-ABL1/ABL1 transcript ratio of ≤ 10% and had significantly superior overall survival (91.3% vs 72.1%, P = .02), event-free survival (49.3% vs 13.0%, P < .001), and c-CCyRS (67.2% vs 11.2%, P = .0001) compared with the 33 patients with ratios > 10%. The 3-month molecular response was the only independent predictor for overall survival. Using an intention-to-treat analysis, we have shown that the responses to second-line therapies are durable. Patients destined to fare poorly can be identified early during therapy.

We studied the relation between adherence to imatinib measured with microelectronic monitoring systems and the probabilities of losing a complete cytogenetic response (CCyR) and of imatinib failure in 87 CCyR chronic myeloid leukemia patients receiving long-term therapy. We included in our analysis the most relevant prognostic factors described to date. On multivariate analysis, the adherence rate and having failed to achieve a major molecular response were the only independent predictors for loss of CCyR and discontinuation of imatinib therapy. The 23 patients with an adherence rate less than or equal to 85% had a higher probability of losing their CCyR at 2 years (26.8% vs 1.5%, P = .0002) and a lower probability of remaining on imatinib (64.5% vs 90.6%, P = .006) than the 64 patients with an adherence rate more than 85%. In summary, we have shown that poor adherence is the principal factor contributing to the loss of cytogenetic responses and treatment failure in patients on long-term therapy.

Axillary dissection during breast cancer surgery produces extensive lymphatic vessel damage that often leads to lifelong secondary lymphedema of the arm. We have developed a biodegradable material conduit for lymphatic vessel reconstruction where fibers electrospun along the conduit lumen promote endothelial cell alignment and migration in vitro. The diameter and density of the electrospun fibers were optimized for cell migration and direction on two-dimensional substrates by seeding human lymphatic endothelial cells (LECs) onto aligned fibers of varying diameters and densities, randomly oriented fibers, and film substrates with no fibers. We found that LECs became aligned in the fiber direction, with cells seeded on the randomly oriented fibers becoming oriented in random directions, whereas cells seeded on the highly aligned fibers became highly aligned. Cell migration was dependent upon fiber alignment and density, with optimal migration found on 1300 nm diameter aligned fibers of low density. Blood endothelial cells seeded on the fibers exhibited similar behavior as the LECs. Fiber alignment was preserved upon rolling the two-dimensional substrate into the tubular geometry of a lymphatic vessel. The data suggest that aligned electrospun fibers may promote endothelial migration across the conduit in a manner that is independent of lymphatic growth factors., (Copyright © 2010 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: : To determine if diabetes mellitus is a risk factor for venous thromboembolism (VTE)., Research Design and Methods: : Data from the National Hospital Discharge Survey were analyzed from 1979 to 2005. International Classification of Diseases, Ninth Revision, Clinical Modification codes were used to identify diseases., Results: : Among 92,240,000 patients with diabetes mellitus discharged between 1979 and 2005, 1,267,000 (1.4%) had VTE. The relative risk for VTE was elevated only in patients younger than 50 to 59 years and was highest in patients aged 20 to 29 years (relative risk = 1.73). Relative risks of VTE with uncomplicated type 1 diabetes mellitus and uncomplicated type 2 diabetes mellitus were similar and also age dependent. In patients with uncomplicated diabetes mellitus who did not have obesity, stroke, heart failure, or cancer, compared with those who did not have diabetes mellitus and did not have any of these comorbid conditions, the relative risk for VTE was 1.52 in patients aged 20 to 29 years and 1.19 in patients aged 30 to 39 years. In older patients, the relative risk of VTE in patients with diabetes mellitus was not increased., Conclusions: : Diabetes mellitus carries an increased risk for VTE, which is apparent only in younger patients in whom comorbid conditions that also increase the risk of VTE are unlikely to be present.

Objective: The purpose of this study was to evaluate the Down syndrome detection rate at a 5% screen positive rate in first-trimester screening for twins., Study Design: This was a retrospective study from August 2005 to July 2007 of twins who underwent first-trimester screening with nuchal translucency, nasal bone, pregnancy-associated plasma protein-A, and free beta-hCG. Risks were calculated on the basis of the Fetal Medicine Foundation twin algorithm. The model simulated distributions of unaffected and affected cases at 12 weeks of gestation., Results: Two thousand ninety-four twin pregnancies (4188 fetuses) met the inclusion criteria. The addition of nasal bone to nuchal translucency, pregnancy-associated plasma protein-A, and free beta-hCG increased the Down syndrome detection rate from 79-89% at a 5% screen-positive rate., Conclusion: In twins, first-trimester screening with nasal bone is valuable. The improved Down syndrome detection rate can help these high-risk patients with the decision-making process of whether to pursue invasive testing with its associated pregnancy loss risk.