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Background: Metastatic castration-resistant prostate cancer (mCRPC) that progresses on androgen receptor pathway inhibitors (ARPIs) may continue to be driven by AR signaling. BMS-986365 is an orally administered ligand-directed degrader targeting the AR via a first-in-class dual mechanism of AR degradation and antagonism. CC-94676-PCA-001 (NCT04428788) is a phase I multicenter study of BMS-986365 in patients with progressive mCRPC., Patients and Methods: Patients who progressed on androgen deprivation therapy, one or more ARPIs, and taxane chemotherapy (unless declined/ineligible) were enrolled. The study included dose escalation (part A) and expansion (part B) of BMS-986365 up to 900 mg twice daily. Primary objectives were safety and tolerability, and to define maximum tolerated dose and/or recommended phase II dose. Key secondary endpoints included decline in prostate-specific antigen ≥50% (PSA50) and radiographic progression-free survival (rPFS)., Results: Parts A and B enrolled 27 and 68 patients, respectively. In part B, the median number of prior therapies was 4 (range 2-11). The most common treatment-related adverse events were asymptomatic prolonged corrected QT interval (47%) and bradycardia (34%). Part A maximum tolerated dose was not reached and recommended phase II dose selection is ongoing. Across part B three highest doses (400-900 mg twice daily, n = 60), PSA50 was 32% (n = 19), including 50% (n = 10/20) at 900 mg; median rPFS (95% confidence interval) was 6.3 months (5.3-12.6 months), including 8.3 months (3.8-16.6 months) at 900 mg; and rPFS was longer in patients without versus with prior chemotherapy: 16.5 months (5.5 months-not evaluable) versus 5.5 months (2.7-8.3 months), respectively. Efficacy was observed in patients with mCRPC with AR ligand binding domain (LBD) WT or with AR LBD mutations., Conclusions: BMS-986365 was well tolerated, with a manageable safety profile, and demonstrated activity in heavily pretreated patients with mCRPC with potentially higher benefit in chemotherapy-naive patients. These data show the potential of BMS-986365 to overcome resistance to current ARPIs, regardless of AR LBD mutation status., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Engagement of programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) can interfere with the CD28 signaling requisite for T-cell activation. While immune checkpoint inhibitors (ICIs) can relieve this suppression, they are unable to drive CD28 costimulation that may mechanistically contribute to ICI resistance. Thus, CD28 costimulation in the context of checkpoint inhibition may activate immunosuppressed T-cells in the tumor microenvironment. Davoceticept (ALPN-202) is an Fc fusion of a CD80 variant immunoglobulin domain (vIgD) designed to mediate PD-L1-dependent CD28 costimulation while inhibiting the PD-L1 and CTLA-4 checkpoints. PD-L1-restriction of davoceticept's CD28 costimulatory activity may minimize systemic T-cell activation and avoid untoward systemic toxicities. At the same time, preclinical studies have suggested that treatment with davoceticept during PD-1 inhibition may enhance antitumor activity by upregulating PD-L1, potentially synergizing with davoceticept's PD-L1-dependent costimulatory mechanism. This report details two cases of fatal cardiac events following treatment with davoceticept in combination with pembrolizumab (anti-PD-1) in the phase 1 study, NEON-2. Both events occurred in females in their 60s; one with choroidal melanoma and prior immunotherapy, the other with ICI-naïve microsatellite stable colorectal cancer. The clinical courses were fulminant with symptom onset at 2 weeks, followed by rapid decline. Cardiac autopsy from one patient confirmed immune-related myocarditis, and immunosequencing revealed expansion of a single T-cell clone that was not present in the pretreatment tumor. These cases highlight the importance of understanding risk factors that may contribute to immune-related myocarditis and other severe immune-related adverse events when CD28 agonism is targeted in the context of checkpoint inhibition.NEON-2 (NCT04920383)., Competing Interests: Competing interests: LC: Consultant: Janssen, AstraZeneca, Pliant Therapeutics, CDR-Life, Actuate TherapeuticsSRC: Research Support (institutional): Alpine Immune SciencesKL: Nothing to disclose. FS: Grants or Contracts: NIH P01 (Deciphering LKB1-associated immunotherapy resistance in lung adenocarcinoma). NL: Support for the present manuscript (institutional): Alpine Immune Sciences; Consulting Fees: SK Life Sciences; Research Funding (institutional): Alexo Therapeutics, Ascentage Pharma, BeiGene, Constellation Pharmaceuticals, Forty Seven, Loxo, Macrogenics, Merck, Pfizer, Regeneron, Apexian Pharmaceuticals, Coordination Therapeutics, Symphogen, CytomX Therapeutics, InhibRx, Incyte, Jounce Therapeutics, Livzon, Northern Biologics, Tesaro, Innovent Biologics, LAM Therapeutics, Ikena, Celgene, Shattuck Labs, Alpine Immune Sciences, Genmab, Odonate, Mersana, Seagen, Alpine Biosciences, Astellas Pharma, Celgene, Helsinn, Therapeutics, Ikena Oncology, Lilly, Sapience Therapeutics, Epizyme, Gilead, Glaxo Smith Kline, Tizona, Servier, Alkermes, KSQ, Repare Therapeutics, Biosplice/Samumed, Sapience Therapeutics, SK Life Sciences, Janssen, Arcus, Artios, BioNTech SE, Alkermes/Mural OncologyAE: Employee of Alpine Immune Sciences; Holds stock options in Alpine Immune Sciences; Support for attending meetings: Alpine Immune Sciences; Patents planned, issued or pending: Tempest Therapeutics, University of CaliforniaHL: Former employee of Alpine Immune Sciences; Holds stock or stock options in Alpine Immune SciencesJS: Employee of Adaptive Biotechnologies; Holds stock in Adaptive Biotechnologies. HT: Support for present manuscript: Biostatistician supporting work on the manuscript; Employee of Alpine Immune Sciences; Holds stock options in Alpine Immune SciencesMJC: Employee of Merck Sharp & Dohme, a subsidiary of Merck & Co., Rahway, New Jersey, USA; Owns stock in Merck & Co. SLP: Employee of Alpine Immune Sciences; Holds stock or stock options in Alpine Immune Sciences. AN: Employee of Alpine Immune Sciences; Holds stock options in Alpine Immune SciencesDD: Support for present manuscript: Alpine Immune Sciences; Grants/Research Support (institutional): Arcus, CellSight Technologies, Immunocore, Merck, Regeneron Pharmaceuticals, Tesaro/GSK. Consulting Fees: ACM Bio, Ascendis Pharma; Clinical Care Options (CCO), Gerson Lehrman Group (GLG), Merck, Medical Learning Group (MLG), Xilio Therapeutics. Payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing or educational events: Castle Biosciences. Patents planned, issued or pending: US Patent 63/124,231, “Compositions and Methods for Treating Cancer”, December 11, 2020 US Patent 63/208,719, “Compositions and Methods For Responsiveness to Immune Checkpoint Inhibitors (ICI), Increasing Effectiveness of ICI and Treating Cancer”, June 9, 2021., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The optimisation of patients in primary care is a prime opportunity to manage patient care within the community and reduce the burden of referrals on secondary care. This paper presents a quality improvement clinical programme taking place within an NHS Primary Care Network as part of the wider Leicester Leicestershire Rutland integrated chronic kidney disease programme., Method: Patients are optimised to guidelines from the National Institute for Health and Care Excellence, by a primary care clinical team who are supported by nephrology consultants and nephrology pharmacists. Multidisciplinary team meetings take place with secondary care specialists and primary care staff. Learning is passed to the community clinicians for better patient treatment locally., Results: A total of 526 patients were reviewed under this project.The total number of referrals to secondary care which were discharged following first outpatient appointment, reduced from 42.9% to 10%. This reduction of 32.9% represents the optimisation of patient cases through this quality improvement project. Patients can be optimised and managed within the community, reducing the number of unnecessary referrals to secondary care., Conclusion: This programme has the potential to offer significant improvement in patient outcomes when expanded to a larger patient base. Medicine management and the use of clinical staff are optimised in both primary and secondary care., (© 2024. The Author(s).)

Background: Davoceticept (ALPN-202) is an Fc fusion of a CD80 variant immunoglobulin domain designed to mediate programmed death-ligand 1 (PD-L1)-dependent CD28 co-stimulation while inhibiting the PD-L1 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) checkpoints. The safety and efficacy of davoceticept monotherapy and davoceticept and pembrolizumab combination therapy in adult patients with advanced solid tumors were explored in NEON-1 and NEON-2, respectively., Methods: In NEON-1 (n=58), davoceticept 0.001-10 mg/kg was administered intravenous either once weekly (Q1W) or once every 3 weeks (Q3W). In NEON-2 (n=29), davoceticept was administered intravenously at 2 dose levels (0.1 or 0.3 mg/kg) Q1W or Q3W with pembrolizumab (400 mg once every 6 weeks). In both studies, primary endpoints included incidence of dose-limiting toxicities (DLT); type, incidence, and severity of adverse events (AEs) and laboratory abnormalities; and seriousness of AEs. Secondary endpoints included antitumor efficacy assessed using RECIST v1.1, pharmacokinetics, anti-drug antibodies, and pharmacodynamic biomarkers., Results: The incidence of treatment-related AEs (TRAEs) and immune-related adverse events (irAEs) was 67% (39/58) and 36% (21/58) with davoceticept monotherapy, and 62% (18/29) and 31% (9/29) with davoceticept and pembrolizumab combination, respectively. The incidence of ≥grade (Gr)3 TRAEs and ≥Gr3 irAEs was 12% (7/58) and 5% (3/58) with davoceticept monotherapy, and 24% (7/29) and 10% (3/29) with davoceticept and pembrolizumab combination, respectively. One DLT of Gr3 immune-related gastritis occurred during davoceticept monotherapy 3 mg/kg Q3W. During davoceticept combination with pembrolizumab, two Gr5 cardiac DLTs occurred; one instance each of cardiogenic shock (0.3 mg/kg Q3W, choroidal melanoma metastatic to the liver) and immune-mediated myocarditis (0.1 mg/kg Q3W, microsatellite stable metastatic colorectal adenocarcinoma), prompting early termination of both studies. Across both studies, five patients with renal cell carcinoma (RCC) exhibited evidence of clinical benefit (two partial response, three stable disease)., Conclusions: Davoceticept was generally well tolerated as monotherapy at intravenous doses up to 10 mg/kg. Evidence of clinical activity was observed with davoceticept monotherapy and davoceticept in combination with pembrolizumab, notably in RCC. However, two fatal cardiac events occurred with the combination of low-dose davoceticept and pembrolizumab. Future clinical investigation with davoceticept should not consider combination with programmed death-1-inhibitor anticancer mechanisms, until its safety profile is more fully elucidated., Trial Registration Number: NEON-1 (NCT04186637) and NEON-2 (NCT04920383)., Competing Interests: Competing interests: DD: Support for the present manuscript: Alpine; Grants/Research Support (institutional): Arcus, CellSight Technologies, Immunocore, Merck, Regeneron Pharmaceuticals, Tesaro/GSK. Consultant: ACM Bio, Clinical Care Options (CCO), Gerson Lehrman Group (GLG), Merck, Medical Learning Group (MLG), Xilio Therapeutics. CE Speakers’ Bureau: Castle Biosciences. Stockholder: None. Patents planned, issued or pending: US Patent 63/124,231, “Compositions and Methods for Treating Cancer”, December 11, 2020; US Patent 63/208,719, “Compositions and Methods for Responsiveness to Immune Checkpoint Inhibitors (ICI), Increasing Effectiveness of ICI and Treating Cancer”, June 9, 2021. LC: Honoraria/Consultant: Pliant Therapeutics, Janssen, CDR-Life, Actuate Therapeutics. NL: Support for the present manuscript (institutional): Alpine Immune Sciences; Consulting Fees: SK Life Sciences; Research Funding (institutional): Alexo Therapeutics, Ascentage Pharma, BeiGene, Constellation Pharmaceuticals, Forty Seven, Loxo, Macrogenics, Merck, Pfizer, Regeneron, Apexian Pharmaceuticals, Coordination Therapeutics, Symphogen, CytomX Therapeutics, InhibRx, Incyte, Jounce Therapeutics, Livzon, Northern Biologics, Tesaro, Innovent Biologics, LAM Therapeutics, Ikena, Celgene, Shattuck Labs, Alpine Immune Sciences, Genmab, Odonate, Mersana, Seagen, Alpine Biosciences, Astellas Pharma, Celgene, Helsinn, Therapeutics, Ikena Oncology, Lilly, Sapience Therapeutics, Epizyme, Gilead, Glaxo Smith Kline, Tizona, Servier, Alkermes, KSQ, Repare Therapeutics, Biosplice/Samumed, Sapience Therapeutics, SK Life Sciences, Janssen, Arcus, Artios, BioNTech SE, Alkermes/Mural Oncology. JM: Support for the present manuscript (institutional): Alpine Immune Sciences; Grants or contracts (institutional): NovoCure, Genentech, Alpine Immune Sciences, Amgen, Trishula Therapeutics, BioEclipse Therapeutics, FujiFilm, ImmuneSensor, Simcha, Repertoire Immune Sciences, Nektar Therapeutics, Synthorx, Istari Oncology, Ideaya Biosciences, Rubius, University of Arizona, Senwha, Storm Therapeutics, Werewolf Therapeutics, Fate Therapeutics, Y-Mab, Agenus, T-Scan, Lovance; Consulting Fees: BMS, Amunix, Thirona Bio, Adagene, Imaging Endpoints, Boxer Capitol, Oberland Capital, IQVIA, Genome Insight, Incyte, Novotech, Red Arrow Therapeutics; Payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing or educational events: Caris Life Sciences, Daiichi-Sankyo, TGen; Participation on a data safety monitoring board or advisory board: Topotecan Episcleral Plaque for Treatment of Retinoblastoma; Other: Board member: Caris Molecular Tumor Board, Caris Consultant; Speakers Bureau: Caris Life Sciences, Immunocore, Castle Biosciences. MMi: Support for the present manuscript (institutional): Alpine Immune Sciences; Consulting Fees (Advisory Board): The Limbic, Bristol Myers Squibb Pty Ltd, Guardant Health, Beigene Australia Pty Ltd, Merck Pte Ltd, AstraZeneca Pty Ltd, Pfizer Australia Pty Ltd; Honoraria (meeting chair): Roche Products Pty Ltd, The Limbic; Participation on a Data Safety Monitoring Board: Novartis Pharma AG (Europe); Leadership or fiduciary role on a Scientific Advisory Board: Thoracic Oncology Group Australia, Melanoma and Skin Cancer Trials Australia. MMc: Support for the present manuscript (institutional): Alpine Immune Sciences; Grants or contracts (institutional): Aadi Biosciences, Alpine Immune Sciences, Arcus Biosciences, Arvinas, Ascentage Pharma Group, ASCO, Astellas, Aulos Bioscience, Bayer, Bicycle Therapeutics, BioMed Valley Discoveries, BioNTech, Bristol-Myers Squibb, C4 Therapeutics, Dragonfly Therapeutics, EMD Serono, Epizyme, Erasca, Exelixis, Foghorn Therapeutics, GI Therapeutics, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, IDEAYA Biosciences, Ikena Oncology, ImmVira Pharma, Infinity Pharmaceuticals, Jacobio Pharmaceuticals, Kechow Pharma, Kezar Life Sciences, Kinnate BioPharma, MedImmune, Mereo BioPharma, Metabomed, Moderna, NBE Therrapeutics, Nektar, Novartis, NucMito Pharmaceuticals, OncoC4, Oncorus, OnKure, PACT Pharma, Pfizer, Plexxikon, Poseida, Prelude Therapeutics, Pyramid Biosciences, Regeneron, Sapience Therapeutics, Scholar Rock, Seattle Genetics, Synthrox, Teneobio, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, TopAlliance Biosciences, Xilio; Consulting Fees (institutional): Castle Biosciences, IQVIA, Merck, Moderna, Pfizer. MV: Support for the present manuscript: Alpine Immune Sciences (institutional); Honoraria: MSD; Consulting or Advisory Role: AstraZeneca, MSD; Grants or Contracts (Research Funding, institutional): AstraZeneca/MedImmune, AstraZeneca, MSD, Alpine Immune Sciences, Virocure, Hinova Pharmaceutics, Atridia, Antengene, BeiGene, Hengrui Pharmaceutical. RES: Grants and Contracts: AstraZeneca, Merck; Consulting (steering committee): GlaxoSmithKline, Janssen Oncology, Daiichi, BeiGene; Consulting (advisory board): AstraZeneca, Macrogenics, Sanofi, Gilead, Regeneron, Targeted Oncology, GI Therapeutics, GE Health Care, Lily Oncology; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events (educational presentations: Illumina, GameOn!, OncLive, Binay Foundation, APP Oncology, Masters in Thoracic Oncology Summit; consulting for manuscript: EMD Serono. JSG: Grants or contracts: Novartis; Consulting: Amgen, Arcus Biosciences, AI Proteins, AstraZeneca, Beigene, Blueprint Medicines, Bristol Myers Squibb, Genentech/Roche, EMD Serono, InterVenn Biosciences, Gilead Sciences, iTeos Therapeutics, Jounce Therapeutics, Karyopharm Therapeutics, Lilly, Loxo, Merus, Mirati Therapeutics, Pfizer, Sanofi, Silverback Therapeutics, Merck, Moderna Therapeutics, Mariana Oncology, Takeda; Payment or Honoraria: Merck, Pfizer, Novartis, Pfizer, Takeda; Leadership or fiduciary role: SAB Happy Lungs; Stock or Stock Options: Immediate family member is an employee with equity in Ironwood Pharmaceuticals. AN: Payment for honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Dava Oncology. AP: Honoraria: Texas Society of Clinical Oncology (TxSCO); Consulting or Advisory Role: Bayer, Novartis, Merck, Seattle Genetics, Silverback Therapeutics, Shenzhen IONOVA Life Sciences, Gilead, Daiichi Sankyo, HalioDx, Janssen; Consulting or Advisory Role (immediate family member): Genentech/Roche, Merck, Bristol-Myers Squibb; Research Funding (institutional): Merck, Pfizer, Lilly, Plexxikon, Corvus Pharmaceuticals, Tesaro, AbbVie, Forty Seven, Five Prime Therapeutics, Infinity Pharmaceuticals, Pieris Pharmaceuticals, Surface Oncology, Livzon, Vigeo Therapeutics, Astellas Pharma, Klus Pharma, Symphogen, Syndax, Arcus, Fochon, Upsher-Smith, Exelixis, Seattle Genetics, Bolt, Ionova, Daiichi Sankyo, Sanofi, Gilead Sciences, Seagen, Shenzhen Ionova Life Science, Pionyr Immunotherapeutics, Loxo Oncology, Inc. On behalf of Eli Lilly and company, Nektar Therapeutics, Alpine Immune Sciences, Amgen, Institut de Recherches Internationales Servier (I.R.I.S.), 1200 Pharma, Arcus Biosciences, Genentech, Aadi Bioscience, Prelude, KSQ Therapeutics, Carrick Therapeutics. JFG: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Bristal Myers Squibb, Curio Sciences. MS: Consulting fees: Adagene, Adaptimmune, Alkermes, Alligator, Anaptys, Asher, Biond, Biontech, Boston Pharmaceuticals, Bristol-Myers, Dragonfly, Evaxion, Evolveimmune, Gilead, Glaxo Smith Kline, Ichnos, Immunocore, Incyte, Innate pharma, Iovance, iTEOS, Jazz Pharmaceuticals, Kanaph, Merck, Molecular Partners, Nextcure, Nimbus, Normunity, Numab, Ocellaris-Lilly, Oncohost, Ontario Institute for Cancer Research, Partner Therapeutics, Pfizer, Pierre-Fabre, PIO Therapeutics, Pliant, Regeneron, Rootpath, Sapience, Simcha, Sumitomo, Targovax, Teva, Turnstone, Verastem, Xilio; Leadership or fiduciary role in other board, society, committee or advocacy group: Society for Immunotherapy of Cancer, past President (unpaid); Stock options: Actym, Adaptive Biotechnologies, Amphivena, Asher, Evolveimmune, Intensity, Nextcure, Normunity, Oncohost, Thetis; Stock: Johnson and Johnson, Glaxo-Smith Kline. AE: Employee of Alpine Immune Sciences; Support for attending meetings and/or travel: Alpine Immune Sciences; Patents planned, issued, or pending: Tempest Therapeutics, University of California; Holds stock or stock options in Alpine Immune Sciences. LB: Employee of Alpine Immune Sciences; Holds stock options in Alpine Immune Sciences. HL: All support for the present manuscript: Former employee of Alpine Immune Sciences; Holds stock or stock options in Alpine Immune Sciences. HT: All support for the present manuscript: Alpine Immune Sciences biostatistician supporting work on the manuscript; Employee of Alpine Immune Sciences; Holds stock options in Alpine Immune Sciences. MJC: Merck Sharp & Dohme, a subsidiary of Merck & Co., Rahway, New Jersey, USA; Owns stock in Merck & Co, Rahway, New Jersey, USA. SLP: Employee of Alpine Immune Sciences; Holds stock options in Alpine Immune Sciences. AN: Employee of Alpine Immune Sciences; Holds stock options in Alpine Immune Sciences., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Pamiparib is a potent, selective, poly (ADP-ribose) polymerase 1/2 inhibitor that demonstrates synthetic lethality in cells with breast cancer susceptibility gene mutations or other homologous recombination deficiency. This two-stage phase 1b study (NCT03150810) assessed pamiparib in combination with temozolomide (TMZ) in adult patients with histologically confirmed locally advanced and metastatic solid tumors., Methods: Oral pamiparib 60 mg was administered twice daily. During the dose-escalation stage, increasing doses of TMZ (40-120 mg once daily pulsed or 20-40 mg once daily continuous) were administered to determine the recommended dose to be administered in the dose-expansion stage. The primary objectives were to determine safety and tolerability, maximum tolerated/administered dose, recommended phase 2 dose and schedule, and antitumor activity of pamiparib in combination with TMZ. Pharmacokinetics of pamiparib and TMZ and biomarkers were also assessed., Results: Across stages, 139 patients were treated (dose escalation, n = 66; dose expansion, n = 73). The maximum tolerated dose of TMZ, which was administered during dose expansion, was 7-day pulsed 60 mg once daily. The most common treatment-emergent adverse events (TEAEs) were anemia (dose escalation, 56.1%; dose expansion, 63.0%), nausea (dose escalation, 54.5%; dose expansion, 49.3%), and fatigue (dose escalation, 48.5%; dose expansion, 47.9%). In the dose-escalation stage, four patients experienced dose-limiting toxicities (three neutropenia and one neutrophil count decreased). No TEAEs considered to be related to study drug treatment resulted in death. Antitumor activity was modest, indicated by confirmed overall response rate (dose escalation, 13.8%; dose expansion, 11.6%), median progression-free survival (3.7 and 2.8 months), and median overall survival (10.5 and 9.2 months). Administration of combination therapy did not notably impact pamiparib or TMZ pharmacokinetics., Conclusions: Pamiparib in combination with TMZ had a manageable safety profile. Further investigation of the efficacy of this combination in tumor types with specific DNA damage repair deficiencies is warranted., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Despite research into how to effectively implement evidence-based recommendations into clinical practice, a lack of standardisation in the commissioning and development of clinical practice guidelines can lead to inconsistencies and gaps in implementation. This research aimed to ascertain how topics in kidney care worthy of guideline development within the UK should be chosen, prioritised, designed and implemented., Methods: Following a modified Delphi methodology, a multi-disciplinary panel of experts in kidney healthcare from across the UK developed 35 statements on the issues surrounding the selection, development and implementation of nephrology guidelines. Consensus with these statements was determined by agreement using an online survey; the consensus threshold was defined as 75% agreement., Results: 419 responses were received. Of the 364 healthcare practitioners (HCPs), the majority had over 20 years of experience in their role (n=123) and most respondents were nephrologists (n=95). Of the 55 non-clinical respondents, the majority were people with kidney disease (n=41) and the rest were their carers or family. Participants were from across England, Northern Ireland, Scotland and Wales. Consensus between HCPs was achieved in 32/35 statements, with 28 statements reaching ≥90% agreement. Consensus between patients and patient representatives was achieved across all 20 statements, with 13/20 reaching ≥90% agreement., Conclusions: The current results have provided the basis for six recommendations to improve the selection, design and implementation of guidelines. Actioning these recommendations will help improve the accessibility of, and engagement with, clinical guidelines, contributing to the continuing development of best practice in UK kidney care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Retifanlimab is a humanized, hinge-stabilized immunoglobulin G4κ monoclonal antibody against human programmed cell death protein 1 (PD-1). This first-in-human, phase I study assessed the safety and efficacy of retifanlimab in patients with advanced solid tumors and identified optimal dosing., Patients and Methods: POD1UM-101 was conducted in two parts: (i) dose escalation-evaluated retifanlimab [1 mg/kg every 2 weeks (q2w), 3 or 10 mg/kg q2w or every 4 weeks (q4w)] in patients with relapsed/refractory, unresectable, locally advanced or metastatic solid tumors; (ii) cohort expansion-biomarker-unselected tumor-specific cohorts [endometrial, cervical, sarcoma, non-small-cell lung cancer (NSCLC)] received retifanlimab 3 mg/kg q2w, and tumor-agnostic cohorts received flat dosing [375 mg every 3 weeks (q3w), or 500 and 750 mg q4w]. Primary objectives were safety and tolerability; secondary objective was efficacy in selected tumor types., Results: Thirty-seven patients were enrolled in dose escalation, 134 in PD-1 therapy-naïve tumor-specific cohort expansion (endometrial, n = 29; cervical, NSCLC, soft tissue sarcoma, each n = 35), and 45 in flat dosing (375 mg q3w, 500 and 750 mg q4w, each n = 15). No dose-limiting toxicities occurred during dose escalation; maximum tolerated dose was not reached and 3-mg/kg q2w expansion dose was selected based on safety and pharmacokinetic data. Immune-related adverse events were experienced by 40 patients (30%) in tumor-specific cohorts (most frequently hypothyroidism, hyperthyroidism, colitis, nephritis) and 6 (13%) in flat dosing (most frequently hypothyroidism, hyperthyroidism). Objective response rate (95% confidence interval) was 14% (4.8 to 30.3), 14% (3.9 to 31.7), 20% (8.4 to 36.9), and 3% (0.1 to 14.9) in advanced NSCLC, endometrial, cervical, and sarcoma tumor-specific cohorts that progressed after multiple prior systemic therapies., Conclusions: Retifanlimab demonstrated clinical pharmacology, safety, and antitumor activity consistent with the programmed death (ligand)-1 inhibitor class. POD1UM-101 results support further exploration of retifanlimab as monotherapy and backbone immunotherapy in combination treatments, with recommended doses of 500 mg q4w and 375 mg q3w., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Food insecurity and perinatal depression are significant public health concerns for perinatal services, however descriptive research examining their association is limited. The purpose of this study was to examine the views and perspectives of staff from the Special Supplemental Nutrition Program for Women, Infants and Children (WIC) program on the relationship between food insecurity and perinatal depression among their WIC clients. Four, semi-structured focus groups with WIC staff ( n = 24) were conducted across four diverse nonmetropolitan public health districts in Midwestern counties in the United States. WIC staff included social workers, nurses, nutritionists and ancillary staff. All interviews were audio-recorded, transcribed, and verified, and data were organized using NVivo 11.4.2. Thematic networking analysis was employed as the qualitative analysis to identify organizing themes. Three themes emerged including (1) depression experienced by clients; (2) food insecurity experienced by clients; and (3) barriers preventing clients from accessing services for themselves and their children. Research on food insecurity and perinatal depression is sparse, with fewer studies having included health staff of low-income women. Our findings suggest that the association between food insecurity and mental health needs among WIC clients is a significant public health issue to which policy change and interventions are required.

Background: Treatment options are limited for participants with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) that progressed after two or more prior therapies. Studies have shown that blockade of both lymphocyte-activation gene 3 (LAG-3) and programmed cell death protein 1 (PD-1) can improve antitumor activity. Here, we evaluate the antitumor activity of the LAG-3 antibody favezelimab alone or in combination with pembrolizumab in participants with MSS mCRC., Patients and Methods: Eligible participants with MSS PD-1/programmed death-ligand 1 (PD-L1) treatment-naive mCRC that progressed on two or more prior therapies received 800 mg favezelimab, 800 mg favezelimab plus 200 mg pembrolizumab, or 800 mg favezelimab/200 mg pembrolizumab co-formulation, every 3 weeks. The primary endpoint was safety, the secondary endpoint was objective response rate (ORR), and exploratory endpoints included duration of response, progression-free survival (PFS), and overall survival (OS)., Results: At the data cut-off date of 23 October 2020, a total of 20 participants received favezelimab alone, 89 received favezelimab plus pembrolizumab (including as favezelimab/pembrolizumab co-formulation); 48 had PD-L1 combined positive score (CPS) ≥1 tumors. At this interim analysis median follow-up was 5.8 months with favezelimab and 6.2 with favezelimab plus pembrolizumab. Treatment-related adverse events (TRAEs) were 65% with favezelimab and 65.2% with favezelimab plus pembrolizumab. Grade ≥3 TRAEs were 15% with favezelimab and 20% with favezelimab plus pembrolizumab. No grade 5 TRAEs occurred. Common TRAEs (≥15%) included fatigue (20.0%), nausea (15.0%) with favezelimab, and fatigue (16.9%) with favezelimab plus pembrolizumab. Confirmed ORR was 6.3% with favezelimab plus pembrolizumab, with median duration of response of 10.6 months (range 5.6-12.7 months), median OS of 8.3 months (95% confidence interval 5.5-12.9 months), and median PFS of 2.1 months (1.9-2.2 months). In an exploratory analysis of PD-L1 CPS ≥1 tumors, the confirmed ORR was 11.1%, median OS was 12.7 months (4.5 to not reached), and median PFS was 2.2 months (1.8-4.2 months) with favezelimab plus pembrolizumab., Conclusions: Favezelimab with or without pembrolizumab had a manageable safety profile, with no treatment-related deaths. Promising antitumor activity was observed with combination therapy, particularly in participants with PD-L1 CPS ≥1 tumors., Competing Interests: Disclosure EG reports research funding to the institution for clinical studies from Merck Sharp & Dohme (MSD), Novartis, AstraZeneca/MedImmune, Roche, Thermo Fisher Scientific, Taiho Oncology, Affimed Gmbh, Amgen SA, Anaveon AG, AstraZeneca AB, Biontech Gmbh, Catalym Gmbh, Cytomx, F. Hoffmann La Roche Ltd, F-Star Beta Limited, Genentech Inc., Genmab B.V., Hutchison, Medipharma Limited, Icon, Imcheck Therapeutics, Immunocore Ltd, Janssen-Cilag SA, MedImmune LLc, Merck Kgga, S.A – Peptomyc, Ribon Therapeutics, Roche Farma SA, Seattle Genetics Inc., Symphogen A/S, fees for consulting and advisory roles from Roche, Ellipses Pharma, NeoMed, Janssen, Boehringer Ingelheim, Seattle Genetics, TFS, Alkermes, Thermo Fisher Scientific, Bristol Myers Squibb (BMS), mAb Discovery, Anaveon, fees for speakers bureau from MSD, Roche, Thermo Fisher Scientific, Lilly, reimbursement for travel from BMS, Menarini, Glycotope GmbH, MSD; AS reports research funding to the institution from MSD, stock in BMS, Merck, fee for speakers bureau from Merck, Eisai; NJL, AP, YYL, TG report research funding to the institution for clinical studies from MSD; SAI reports research funding to the institution for clinical studies from MSD, AstraZeneca, Eisai, Boryung Pharm, Daewon Pharm, Roche, Pfizer, fees for consulting or advisory role from AstraZeneca, Daiichi Sankyo, Eisai, GlaxoSmithKline, Lilly, MSD, Novartis, Pfizer, Roche; RG reports research funding to the institution for clinical studies from MSD, Novartis, honoraria from BMS, Lilly, Medison, Roche, Novartis, Janssen, Takeda, MSD, Pfizer, Merck, fees for consulting or advisory role from Eisai, AstraZeneca, Bayer, MSD, Novartis, Boehringer Ingelheim, BOL Pharma, Roche, reimbursement for travel from Merck, Bayer, BMS, Medison; MDM reports research funding to the institution from MSD, Roche, Sanofi, PharmaMar, AbbVie, Janssen, Faron, Genentech, MacroGenics, Menarini, Nektar, Novartis; MW reports research funding to the institution for clinical studies, fees for consulting or advisory roles from BMS, Novartis, Kite, Heidelberg Pharma, Roche, Boehringer Ingelheim, honoraria from BMS, Merck, Roche, Novartis, Kite, Boehringer Ingelheim, AstraZeneca, reimbursement for travel from Glenmark, BMS, AstraZeneca; JP, SJ, MC, AA, JH are employees of MSD LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD) and hold stock in Merck & Co., Inc., Rahway, NJ, USA; GSF reports research funding to the institution for clinical studies from 3-V Biosciences, Abbisko, AbbVie, ABL Bio ADC Therapeutics, Aileron, American Society of Clinical Oncology, Amgen, ARMO/Eli Lilly, Artios, AstraZeneca, BeiGene, BioAtla, BioInvent, Biothera, Bicycle, Boehringer Ingelheim, Celldex, Celgene, CicloMed, Curegenix, Curis, Cyteir, Daiichi, DelMar, eFFECTOR, Eli Lilly, EMD Serono, Epizyme, Erasca, Exelixis, Freenome, Fujifilm, Genmab, GlaxoSmithKline, Hutchison MediPharma, IGM Biosciences, Ignyta, ImmunoGen/MacroGenics, Incyte, Jacobio, Jounce, Kolltan, Loxo/Bayer, MedImmune, Millennium, Merck, miRNA Therapeutics, National Institutes of Health, Navire, NiKang, Novartis, OncoMed, Oncorus, Oncothyreon, Poseida, Precision Oncology, Prelude, PureTech, Pyramid, RasCal, Regeneron, Rgenix, Ribon, Samumed, Sapience, Silicon, Strategia, Syndax, Synthorx/Sanofi, Taiho, Takeda, Tarveda, Teneobio, Tesaro, Tocagen, Turning Point Therapeutics, U.T. MD Anderson Cancer Center, Vegenics, Xencor, fees for consulting or advisory role from Fujifilm, Silicon, Navire, Turning Point, Predicine, EMD Serono, reimbursement for travel from BMS, EMD Serono, Fujifilm, Millenium, Sarah Cannon Research Institute, speakers honoraria from Total Health Conferencing, Rocky Mountain Oncology Society., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Activation of leukemia inhibitory factor (LIF) is linked to an immunosuppressive tumor microenvironment (TME), with a strong association between LIF expression and tumor-associated macrophages (TAMs). MSC-1 (AZD0171) is a humanized monoclonal antibody that binds with high affinity to LIF, promoting antitumor inflammation through TAM modulation and cancer stem cell inhibition, slowing tumor growth. In this phase I, first-in-human, open-label, dose-escalation study, MSC-1 monotherapy was assessed in patients with advanced, unresectable solid tumors., Materials and Methods: Using accelerated-titration dose escalation followed by a 3 + 3 design, MSC-1 doses of 75-1500 mg were administered intravenously every 3 weeks (Q3W) until progression or unmanageable toxicity. Additional patients were enrolled in selected cohorts to further evaluate safety, pharmacokinetics (PK), and pharmacodynamics after escalation to the next dose had been approved. The primary objective was characterizing safety and determining the recommended phase II dose (RP2D). Evaluating antitumor activity and progression-free survival (PFS) by RECIST v1.1, PK and immunogenicity were secondary objectives. Exploratory objectives included pharmacodynamic effects on circulating LIF and TME immune markers., Results: Forty-one patients received treatment. MSC-1 monotherapy was safe and well tolerated at all doses, with no dose-limiting toxicities. The maximum tolerated dose was not reached and the RP2D was determined to be 1500 mg Q3W. Almost half of the patients had treatment-related adverse events (TRAEs), with no apparent trends across doses; no patients withdrew due to TRAEs. There were no objective responses; 23.7% had stable disease for ≥2 consecutive tumor assessments. Median PFS was 5.9 weeks; 23.7% had PFS >16 weeks. On-treatment changes in circulating LIF and TME signal transducers and activators of transcription 3 signaling, M1:M2 macrophage populations, and CD8+ T-cell infiltration were consistent with the hypothesized mechanism of action., Conclusions: MSC-1 was very well tolerated across doses, with prolonged PFS in some patients. Biomarker and preclinical data suggest potential synergy with checkpoint inhibitors., Competing Interests: Disclosure EB has provided advisory work for BioNTech SE and Imaging Endpoints LLC, and has participated in a speaker’s bureau for Ipsen. AMS has received fees and/or research grants from AstraZeneca, Northern Biologics, Merus, Kura Oncology, Surface Oncology, Lilly Oncology, Pfizer, Black Diamond Therapeutics, BeiGene, and Relay Therapeutics. EG has received personal fees for a consultant/advisory role from Janssen, Seattle Genetics, TFS HealthScience, Alkermes, Thermo Fisher Scientific, Bristol Myers Squibb, and MSD; and research grants from Menarini Diagnostics and Glycotope Biotechnology GmbH. IB has received research funding from Northern Biologics, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, MSD, Novartis, OrionPharma, Regeneron, Seattle Genetics, Shattuck Labs, and VCN Biosciences SL; institutional grants from Cellex Foundation, La Caixa Foundation, and Banco Bilbao Vizcaya Argentaria Foundation (BBVA Foundation); educational grants from Bristol Myers Squibb; consulting fees from Achilles Therapeutics PLC, Bristol Myers Squibb, Cancer Expert Now, Etherna Immunotherapies Nv, Merck Serono, MSD, and Rakuten; payment of honoraria from Bristol Myers Squibb, Merck Serono, and MSD; support from attending meetings and/or travel from Merck Serono and MSD; and has a leadership or fiduciary role in another board, society, committee, or advocacy group, paid or unpaid, with ESMO Head and Neck track, EORTC Head and Neck group, and Cancer Core Europe Clinical Taskforce. MVV has received personal fees from Roche outside the work submitted. AS has received research funding from AstraZeneca, Northern Biologics, Alkermes, Array BioPharma/Pfizer, Bayer, Bristol Myers Squibb, GlaxoSmithKline, Janssen Oncology/Johnson & Johnson, Merck, Novartis, Regeneron Pharmaceuticals, Roche, Surface Oncology, Symphogen, Treadwell Therapeutics, and Oncorus; and personal fees from Bristol Myers Squibb, Merck, and Oncorus. MO has received personal fees from Bristol Myers Squibb, Merck, and MSD; non-financial support from Bristol Myers Squibb and MSD; and research grants from the Spanish Society of Medical Oncology, CRIS Contra el Cancer Foundation, and ASO Conquer Cancer Foundation, all outside of the work submitted. NJL has received honoraria for advisory boards from Innovent Biologics; and research funding from AstraZeneca, Northern Biologics, Alpine Immune Sciences, ALX Oncology, Apexian Pharmaceuticals, Ascentage Pharma, Alexion Pharmaceuticals, Asana, BeiGene, CytomX, Constellation Pharmaceutical, Cerulean Pharma, Formation Biologics (Forbius), Forty Seven, Ikena Oncology, Incyte Corporation, Inhibrx, Innovent Biologics, Jounce Therapeutics, Merck, Mersana Therapeutics, Pfizer, Regeneron Pharmaceuticals, Symphogen, and TaiRx. KH is a former employee and holds shares of Northern Biologics. RMH is a former employee and holds shares of Northern Biologics. DM is a former employee and holds shares of Northern Biologics. FH has received funding from Northern Biologics for the present work as part of Applied BioMath. JH has received funding from Northern Biologics for the present work as part of Applied BioMath; and owns shares of Pfizer. PG is a former employee and holds shares of Northern Biologics. JA is a former employee and holds shares of Northern Biologics. AK was a consultant to Northern Biologics at the time the study was conducted. PJV is a former employee and holds shares of Northern Biologics. RW is a former employee and holds shares of Northern Biologics. JS is a co-founder of Mosaic Biomedicals and has ownership interests from Mosaic Biomedicals and Northern Biologics; and had received grant/research support from Mosaic Biomedicals, Northern Biologics, Roche Glycart AG, and F. Hoffmann-La Roche Ltd. LLS has received financial compensation for consulting/advisory work from Merck, Pfizer, Celgene, AstraZeneca, Morphosys, Roche, GeneSeeq, Loxo Oncology, Oncorus, Symphogen, Seattle Genetics, GlaxoSmithKline, Voronoi, Treadwell Therapeutics, Arvinas, Tessa Therapeutics, Navire Pharma, Relay Therapeutics, and Rubius Therapeutics; and research grants/support from Novartis, Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca, Merck, Celgene, Astellas, AbbVie, Amgen, Symphogen, Intensity Therapeutics, Mirati Therapeutics, Shattuck Labs, and Avid Radiopharmaceuticals. DMH is an employee of Loxo Oncology at Lilly, a wholly owned subsidiary of Eli Lilly (salary and equity). DVH is an employee of McKesson Corporation; he has stock or other ownership interests in Medtronic, CerRx, SynDevRx, UnitedHealthcare, Anthem Inc, Stromatis Pharma, Systems Oncology, StingRay Therapeutics, Forma Therapeutics, and Orpheus Bioscience; he has received financial compensation for consulting/advisory work from DNAtrix, Esperance Pharmaceuticals, Five Prime Therapeutics, Imaging Endpoints, Medical Prognosis Institute, Senhwa Biosciences, Tolero Pharmaceuticals, Alpha Cancer Technologies, Arvinas, Bellicum Pharmaceuticals, CanBas, Horizon Discovery, Lixte Biotechnology, Oncolyze, Translational Drug Development (TD2), Aadi Bioscience, Aptose Biosciences, BiolineRx, CytomX Therapeutics, EMD Serono, Evelo Biosciences, Fujifilm, Kura Oncology, Phosplatin Therapeutics, Sotio, Strategia Therapeutics, Synergene Therapeutics, 7 Hills Pharma, Actinium Pharmaceuticals, Cancer Prevention Pharmaceuticals, Geistlich Pharma, Huya Bioscience International, Immunophotonics, Genzada Pharmaceuticals, L.E.A.F. Pharmaceuticals, Oncology Venture, Turning Point Therapeutics, Verily Life Sciences, Athenex, Samus Therapeutics, Aeglea Biotherapeutics, Novita Pharmaceuticals, NuCana, Vicus Therapeutics, Codiak Biosciences, Agenus, Kelun, Radimmune Therapeutics, Samumed, Sobi, BioXcel therapeutics, Bryologyx, Celgene, BioPharma Services, Sirnaomics, AIMed, Boston Scientific, Corcept Therapeutics, Erimos Pharmaceuticals, Gimbal Bio, Amunix Pharmaceuticals, Pfizer, Apeiron Biologics, GiraFpharma, Axis Therapeutics, DrugCendR, ImmuneOncia, Orphagen Pharmaceuticals, Array BioPharma, MaveriX Oncology, Northern Biologics, Viracta Therapeutics, Varian Biopharma, Xerient Pharma, AlaMab Therapeutics, Avesta76 Therapeutics, Bessor Pharma, NeoTx, Decoy Biosystems, Noxxon Pharma, RefleXion Medical, and Reglagene; and has received research grants/support from Eli Lilly, Genentech, Celgene, Incyte, Merrimack Pharmaceuticals, Plexxikon, Minneamrita Therapeutics, AbbVie, Aduro Biotech, Cleave Biosciences, CytRx Corporation, Daiichi Sankyo, Deciphera Pharmaceuticals, Endocyte, Exelixis, Five Prime Therapeutics, Gilead Sciences, Merck, Pfizer, Pharmacyclics, Phoenix Biotechnology, Samumed, Strategia Therapeutics, and Halozyme. JT reports personal financial interests in the form of scientific consultancy role for Array BioPharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech, Inc., HalioDx SAS, Hutchison MediPharma, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati Therapeutics, Inc., NeoPhore, Novartis, Orion Biotechnology, Peptomyc SL, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho Pharmaceutical, Tessa Therapeutics, and TheraMyc Limited., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: PNT2258 is a liposomal formulation that encapsulates multiple copies of PNT100, a native, chemically unmodified, 24-base DNA oligonucleotide designed to target the regulatory region upstream of the B-cell lymphoma 2 (BCL2) gene., Methods: This phase II, multicenter, single-arm, open-label, 2-stage design study investigated the single-agent activity of PNT2258 in patients with relapsed/refractory DLBCL. Initially, patients had to have a performance status (PS) of ≤2 and prior exposure to CD20-targeted therapy, an alkylating agent, and a steroid with no upper limit. Criteria were modified to PS of 0 or 1 and at least 1 to ≤3 prior therapies (identified as the target population) after observing an initially high frequency of rapid disease progression in patients with extensive prior therapies or poor PS., Results: The study was stopped early following an interim analysis, despite surpassing the protocol predetermined futility boundary, because the ORR was below the expectations of response in an evolving DLBCL treatment landscape. The final analysis included all 45 enrolled patients and demonstrated an ORR of 11%. In the response evaluable subset (n = 26), defined as patients in the target population with exposure to ≥8 doses of PNT2258 within the first 35 days and evaluable baseline/post-baseline scans, the ORR was 19%. The most common adverse events were fatigue (44%), nausea (42%), diarrhea (40%), pyrexia (36%), anemia (32%), and vomiting (27%)., Conclusions: PNT2258 was well-tolerated in a chemotherapy refractory DLBCL population. Despite demonstration of single-agent activity, ORR was lower than acceptable for further new therapy development., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: PROCLAIM-CX-2029 is a phase I first-in-human study of CX-2029, a Probody-drug conjugate targeting CD71 (transferrin receptor 1) in adults with advanced solid tumors. Although the transferrin receptor is highly expressed across multiple tumor types, it has not been considered a target for antibody-drug conjugates (ADCs) due to its broad expression on normal cells. CX-2029 is a masked form of a proprietary anti-CD71 antibody conjugated to monomethyl auristatin E, designed to be unmasked in the tumor microenvironment by tumor-associated proteases, therefore limiting off-tumor toxicity and creating a therapeutic window for this previously undruggable target., Patients and Methods: This was a dose-escalation, multicenter trial to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of CX-2029. The primary endpoint was to determine the maximum tolerated dose (MTD) and cycle 1 dose-limiting toxicity (DLT). CX-2029 was administered i.v. every 3 weeks., Results: Forty-five patients were enrolled in eight dose levels. No DLTs were reported in the dose escalation through 4 mg/kg. At 5 mg/kg, there were two DLTs (febrile neutropenia and pancytopenia). Following expansion of the 4 mg/kg dose to six patients, two additional DLTs were observed (infusion-related reaction and neutropenia/anemia). Both the 4 and 5 mg/kg doses were declared above the maximum tolerated dose. The recommended phase II dose is 3 mg/kg. The most common dose-dependent hematologic toxicities were anemia and neutropenia. Confirmed partial responses were observed in three patients, all with squamous histologies., Conclusions: The Probody therapeutic platform enables targeting CD71, a previously undruggable ADC target, at tolerable doses associated with clinical activity. See related commentary by Oberoi and Garralda, p. 4459 ., (©2021 American Association for Cancer Research.)

Purpose: We investigated safety, tolerability, pharmacokinetics, and antitumor activity of the protein tyrosine kinase 7 (PTK7)-targeted, auristatin-based antibody-drug conjugate (ADC) PF-06647020/cofetuzumab pelidotin (NCT02222922)., Patients and Methods: Patients received PF-06647020 intravenously every 3 weeks at 0.2-3.7 mg/kg or every 2 weeks at 2.1-3.2 mg/kg, in sequential dose escalation, following a modified toxicity probability interval method. In dose expansion, pretreated patients with advanced, platinum-resistant ovarian cancer, non-small cell lung cancer (NSCLC), or triple-negative breast cancer (TNBC) received PF-06647020 2.8 mg/kg every 3 weeks., Results: The most common, treatment-related adverse events for PF-06647020 administered every 3 weeks were nausea, alopecia, fatigue, headache, neutropenia, and vomiting (45%-25%); 25% of patients had grade ≥ 3 neutropenia. Two patients experienced dose-limiting toxicities (grade 3 headache and fatigue) at the highest every 3 weeks dose evaluated. The recommended phase II dose was 2.8 mg/kg every 3 weeks. The overall safety profile observed with PF-06647020 administered every 2 weeks was similar to that of the every 3 weeks regimen. Systemic exposure for the ADC and total antibody generally increased in a dose-proportional manner. Antitumor activity was observed in treated patients with overall objective response rates of 27% in ovarian cancer ( n = 63), 19% in NSCLC ( n = 31), and 21% in TNBC ( n = 29). Responders tended to have moderate or high PTK7 tumor expression by IHC., Conclusions: This PTK7-targeted ADC demonstrated therapeutic activity in previously treated patients with ovarian cancer, NSCLC, and TNBC at a dose range of 2.1-3.2 mg/kg, supporting further clinical evaluation to refine dose, schedule, and predictive tissue biomarker testing in patients with advanced malignancies., (©2021 The Authors; Published by the American Association for Cancer Research.)

Background Endoscopic retrograde cholangiopancreatography (ERCP) can be associated with complications, including precipitation of peri-procedural myocardial ischemia. However, data regarding the trends and impact of previous myocardial infarction (MI) and/or percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) on ERCP outcomes remains unknown. Methods Using the National Inpatient Sample (2007-2014) and relevant ICD-9-CM codes, we identified adults who underwent ERCP with (Group 1) and without (Group 2) prior history of MI/PCI/CABG, and compared their demographics, comorbidities, and inpatient outcomes. Primary endpoints were inpatient mortality and post-ERCP complications. The secondary endpoints were discharge disposition, the mean length of stay, and total hospital charges. Results Of 1,374,773 ERCP procedures performed, 120,418 (8.8%) were performed in adult patients with a prior history of MI/PCI/CABG with an increasing trend from 2007-2014 (7.5% to 9.5%, p trend =0.022). Group 1 consisted of older, white, males compared to Group 2. Group 1 demonstrated a higher prevalence of all-cause mortality (1.7% vs. 1.5%, p<0.001), other cardiovascular comorbidities, post-ERCP cardiopulmonary complications (5.6% vs. 3.8%, p<0.001), sepsis (10.2% vs. 8.2%, p<0.001) and hemorrhage (1.5% vs.1.2%, p<0.001) as compared to Group 2. However, post-ERCP pancreatitis (14.1% vs. 15.4%, p<0.001) was lower in Group 1 without any difference in frequency of cholecystitis (0.4% vs. 0.4%, p=0.180). The mean length of stay was marginally higher in Group 1, without any difference in the hospitalization charges between the groups. Conclusions This nationwide study revealed higher inpatient mortality, sepsis, and hemorrhage in adult patients who underwent ERCP with a prior history of MI/PCI/CABG., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Patel et al.)

Background: Inhibition of programmed cell death receptor protein-1 (PD-1) has proven to be a highly effective strategy for immunotherapy of cancer. Approvals of both PD-1 and PD-L1 inhibitors [PD-(L)1i] in multiple tumor types are evidence of the durable benefits they provide to patients with cancer. In this first-in-human trial, we assessed the safety and tolerability of JTX-4014, a fully human antibody targeting PD-1., Methods: JTX-4014 was administered to 18 patients with multiple solid tumor types who had not previously received a PD-(L)1i. The primary objectives were to evaluate the safety and tolerability of JTX-4014 and determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Secondary objectives included evaluation of the pharmacokinetics (PK) of JTX-4014, anti-drug antibodies (ADA) against JTX-4014, and clinical activity., Results: JTX-4014 was well tolerated and no new safety signals were identified as compared with other PD-1is. The MTD was not reached and the RP2D was selected, based on PK modelling and supportive safety data, to be 500 mg every 3 weeks or 1000 mg every 6 weeks. Clinical activity, based on RECIST v1.1 criteria, demonstrated an overall response rate of 16.7% (n = 3) with one complete and two partial responses and a disease control rate of 44.4% (n = 8). The responses occurred at different doses in patients with PD-L1 positive tumors and in tumor types that are not typically PD-1i responsive., Conclusions: Further development of JTX-4014 is warranted as a monotherapy or in combination with other innovative cancer therapies., Trial Registration Number: NCT03790488, December 31 2018.

Destination memory (the ability to remember who one has told information to) has been studied in adult samples, but not with child participants. The goals of the current research were to describe the development of children's destination memory abilities across early to middle childhood and to compare destination memory with source-monitoring abilities within the same age range. In two studies, children aged 5-10 years had conversations with two puppets and were later asked to recall which puppet they had disclosed specific information to. Study 1 (N = 86) revealed age to be a significant predictor of destination memory accuracy. Study 2 (N = 90) demonstrated that source memory and destination memory were related and shared a similar developmental trajectory but that source accuracy was higher on average than destination accuracy. This research contributes to our theoretical understanding of children's memory development, and directions for future research are highlighted in the Discussion. Implications for investigative interviews in which children are asked about prior disclosures are discussed., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The objective of study was to assess the outcome of feeding six total mixed rations (TMR), differing in NDF and protein content, for their synergistic effect on ameliorating heat load of lactating Murrah buffaloes evident through improved physiological and production performance. Thirty six lactating Murrah buffaloes (587 ± 12.3, MY 9 ± 2.2, Parity 2.5 ± 1.5) were arranged in a 3 × 2 factorial design with three levels of dietary NDF (30, 34.5 and 37% dietary NDF) and two levels of metabolizable protein (MP; 7.0% and 8.4%). Buffaloes were fed either of six dietary treatments: 30%NDF; 7.0% MP (CF1, as recommended), 34.5%NDF; 7.0% MP (MF1), 37%NDF; 7.0% MP (HF1), 30%NDF; 8.4% MP (CF2), 34.5%NDF; 8.4% MP (MF2) and 37%NDF; 8.4% MP (HF2). TMR offered with maize silage and respective concentrate for 90 days feeding trial. Fortnightly feed samples and weekly milk samples collection was done for analyses. Metabolic trial conducted in mid of experiment for estimating nutrient digestibility. Throughout the trial, THI level (79.7-83.8) denoted that buffaloes were exposed to stressful environment. Higher MP in diet reduced pulse rate in buffaloes as compared with lower MP diet. Rectal temperature was lower in Murrah buffaloes fed MF2 diet whereas; minimum breathing rate was recorded for high protein fed group. The MF2 diet increased dry matter intake (kg/d) by 2.7%, milk yield (kg/d) by 8.3% and feed efficiency (milk/DMI) by 7.2% as compared with CF1 group indicating reduced heat load. Increase in protein intake along with improved protein digestibility in MF2 group was recorded. Measured 6%FCM and ECM (kg/d), milk fat (%) and total solid (%) were higher in MF2 treatment group. Results revealed that 34.5% NDF and 8.4% MP have a positive influence on amelioration of heat stress in present experimental conditions., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Toxicity management is a challenge with cancer treatment, including oral anticancer drugs. A review of claims data showed that a majority of publically funded oral anticancer drugs were filled in the community where pharmacists may not necessarily possess the specialized knowledge, skills, and experience required to provide effective patient care. A survey of community pharmacists in Ontario was conducted to identify the behaviours and preferences of community pharmacists specific to the management of treatment-related toxicities in order to standardize cancer care in this area., Methods: An electronic questionnaire was distributed to approximately 5000 community pharmacists. The 21-question survey gathered information on the demographic profile of the pharmacists, basic geographic and socioeconomic variables associated with their practice setting, current toxicity management practices, education and training needs, and preferences for communicating with other providers., Results: Of 349 pharmacists, almost all (94.9%) were interested in managing chemotherapy-related toxicities as part of their work, but the majority (77.1%) did not feel that their current level of pharmacy training has provided them with an oncology education sufficient for the demands of their practice. Approximately 52% of respondents indicated that they have reached out to the health care provider at a cancer centre, and of those, 72.7% reported that their questions were resolved within 48 h. More than half of all survey respondents (53.9%) indicated that they would prefer to receive a response within 12 h from cancer centres., Conclusions: The results of this study support the need to provide community pharmacists with oncology-specific training and timely correspondences from providers at prescribing institutions in order to manage toxicities.

Background: To determine the safety and efficacy of the anti-colony-stimulating factor 1 receptor (anti-CSF1R) monoclonal antibody AMG 820 in combination with pembrolizumab in patients with select solid tumors., Patients and Methods: Patients had advanced, refractory mismatch repair-proficient colorectal cancer, pancreatic cancer, or non-small cell lung cancer (NSCLC) with low (<50%) programmed cell death-ligand 1 (PD-L1) expression and were naïve to anti-programmed cell death-1 (PD-1)/PD-L1 or had relapsed/refractory NSCLC after anti-PD-1/PD-L1 treatment with low or high (≥50%) PD-L1 expression; all were anti-CSF1/CSF1R naïve. Patients received 1100 mg or 1400 mg AMG 820 plus 200 mg pembrolizumab intravenously every 3 weeks. The primary endpoints were incidence of dose-limiting toxicities (DLTs) and adverse events (AEs) and objective response rate per immune-related Response Evaluation Criteria in Solid Tumours at the recommended combination dose., Results: Overall, 116 patients received ≥1 dose of AMG 820 plus pembrolizumab (18 at 1400 mg AMG 820; 98 at 1100 mg AMG 820). Most patients (64%) were male; the median age was 64 (range 30-86) years. Seven patients had DLTs (1 at 1400 mg AMG 820; 6 at 1100 mg AMG 820). Almost all patients (99.1%) had AEs, 87.9% with grade ≥3 AEs. The most common AEs were increased aspartate aminotransferase (59.5%), fatigue (48.3%), periorbital/face edema (48.3%), and rash/maculopapular rash (37.1%). The best response was immune-related partial response in 3 patients (3%; duration of response 9.2, 10.0, 12.5 months) and immune-related stable disease in 39 patients (34%). None of the completed phase II cohorts met the predefined threshold for efficacy. Post-treatment there was accumulation of serum colony-stimulating factor 1 (CSF1) and interleukin-34, reduction in CSF1-dependent CD16-expressing monocytes, and increased PD-L1 expression and CD4 and CD8 cell numbers in tumor biopsies., Conclusions: The recommended combination dose of 1100 mg AMG 820 plus 200 mg pembrolizumab had an acceptable safety profile. Although pharmacodynamic effects were observed, antitumor activity was insufficient for further evaluation of this combination in selected patient populations., Trial Registration Number: NCT02713529., Competing Interests: Competing interests: ARAR reports research support from Amgen and Merck, during the conduct of the study. JMC reports grants from AstraZeneca, Merck, and Tesaro, outside the submitted work; personal fees from Bristol Myers Squibb, outside the submitted work; and other from Roche, outside the submitted work. VM reports personal fees from Bayer, Bristol Myers Squibb, Janssen, and Pieris, outside the submitted work. MB reports grants from Amgen, during the conduct of the study; grants from Ascentage Pharma, AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Oncomed, and Pfizer, outside the submitted work; personal fees from AstraZeneca, outside the submitted work; and non-financial support from AstraZeneca and Merck Sharp & Dohme, outside the submitted work. ECA reports grants from AbbVie, Amcure, Amgen, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Boehringer Ingelheim, CytomX, Eli Lilly, H3, Incyte, Janssen, Kura, Loxo, Macrogenics, Menarini, Merck Serono, Merck, Merus, Millennium, Nanobiotix, Nektar, Novartis, Pfizer, PharmaMar, Principia, PsiOxus, Puma, Rigontec, Roche/Genentech, Sanofi, START, Taiho, and Tesaro, outside the submitted work; and other from AbbVie, Amcure, AstraZeneca, Celgene, Cerulean Pharma, EUSA, GLG, Guidepoint Global, HM Hospitals Group, International Cancer Consultants, Janssen-Cilag, Nanobiotix, Novartis, NPO Foundation Intheos (Investigational Therapeutics in Oncological Sciences), Oncoart Associated, Pfizer, Pierre Fabre, PsiOxus Therapeutics, Roche/Genentech, Seattle Genetics, Servier, and START, outside the submitted work. WE has nothing to disclose. JT reports other funding from Amgen, during the conduct of the study. RDH reports grants from Amgen and Merck, during the conduct of the study. AR reports honoraria for public speaking and advisory board meetings for Roche, Bristol Myers Squibb, Novartis, Pierre Fabre, and Sanofi. MAS reports grants from Merck, during the conduct of the study. AJO reports personal fees from Merck, during the conduct of the study; and personal fees from Array, Bristol Myers Squibb, Novartis, and Pfizer, outside the submitted work. DJ has nothing to disclose. NL reports other from Amgen, during the conduct of the study; personal fees from Innovent Biologics, outside the submitted work; and other from Alexion, ALX Therapeutics, Apexian, Asana BioSciences, Ascentage, BeiGene, Cerulean Pharma, Constellation, CytomX, Formation Biologics, Forty Seven, Ikena, Incyte, InhibRx, Innovent Biologics, Jounce Therapeutics, Livzon, Loxo, MacroGenics, Merck, Northern Biologics, Odonate Therapeutics, Pfizer, Regeneron, Symphogen, and TaiRx, outside the submitted work. DPR reports equity in Acworth Pharmaceuticals and MPM Capital and is an advisor for 28/7 Therapeutics, Gritstone Oncology, Maverick Therapeutics, MPM Capital, and Oncorus, outside the submitted work. ER is an employee and stockholder of Amgen. GJ is an employee and stockholder of Amgen. HW is an employee and stockholder of Amgen. NS is an employee and stockholder of Amgen. M-ADS is an employee of Amgen. DN is an employee and stockholder of Amgen. KPP reports funding to START for conduct of this clinical trial from Amgen; funding to START for conduct of clinical trials from 3D Medicines, AbbVie, ADC Therapeutics, ArQule, Calithera Biosciences, Curegenix, Daiichi Sankyo, EMD Serono, Formation Biologics, Incyte, Jounce Therapeutics, MabSpace Biosciences, MedImmune, Merck, Mersana, OncoMed, Peloton Therapeutics, Regeneron, Sanofi, and Syros Pharmaceuticals, outside the submitted work; and advisory board fees from ArQule, Basilea, and Bayer, outside the submitted work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: RET mutations occur in 70% of medullary thyroid cancers, and RET fusions occur rarely in other thyroid cancers. In patients with RET -altered thyroid cancers, the efficacy and safety of selective RET inhibition are unknown., Methods: We enrolled patients with RET -mutant medullary thyroid cancer with or without previous vandetanib or cabozantinib treatment, as well as those with previously treated RET fusion-positive thyroid cancer, in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response), as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety., Results: In the first 55 consecutively enrolled patients with RET -mutant medullary thyroid cancer who had previously received vandetanib, cabozantinib, or both, the percentage who had a response was 69% (95% confidence interval [CI], 55 to 81), and 1-year progression-free survival was 82% (95% CI, 69 to 90). In 88 patients with RET -mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib, the percentage who had a response was 73% (95% CI, 62 to 82), and 1-year progression-free survival was 92% (95% CI, 82 to 97). In 19 patients with previously treated RET fusion-positive thyroid cancer, the percentage who had a response was 79% (95% CI, 54 to 94), and 1-year progression-free survival was 64% (95% CI, 37 to 82). The most common adverse events of grade 3 or higher were hypertension (in 21% of the patients), increased alanine aminotransferase level (in 11%), increased aspartate aminotransferase level (in 9%), hyponatremia (in 8%), and diarrhea (in 6%). Of all 531 patients treated, 12 (2%) discontinued selpercatinib owing to drug-related adverse events., Conclusions: In this phase 1-2 trial, selpercatinib showed durable efficacy with mainly low-grade toxic effects in patients with medullary thyroid cancer with and without previous vandetanib or cabozantinib treatment. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.)., (Copyright © 2020 Massachusetts Medical Society.)

Purpose: ANG1005, a novel taxane derivative, consists of three paclitaxel molecules covalently linked to Angiopep-2, designed to cross the blood-brain and blood-cerebrospinal barriers and to penetrate malignant cells via LRP1 transport system. Preclinical and clinical evidence of efficacy with ANG1005 has been previously shown., Patients and Methods: A multicenter, open-label phase II study in adult patients with measurable recurrent brain metastases from breast cancer (BCBM), with or without leptomeningeal carcinomatosis was conducted ( n = 72 BCBM; n = 28 leptomeningeal carcinomatosis subset). ANG1005 was administered intravenously at 600 mg/m 2 every 3 weeks. Tumor assessment was based on central nervous system (CNS) RECIST 1.1 for intracranial, and RECIST 1.1 for extracranial response. The primary endpoint was determination of intracranial objective response rate (iORR)., Results: Median age was 47.5 years. Safety profile was similar to that of paclitaxel with myelosuppression as the predominating toxicity. Average number of prior CNS-directed therapies was 2.8 and 94% of the patients had prior taxane treatment. Patient benefit (stable disease or better) was seen in 77% (intracranial) and 86% (extracranial) of the evaluable patients, with iORR of 15% (investigator) or 8% (independent radiology facility [IRF] review). In the leptomeningeal carcinomatosis subset, 79% of the patients had intracranial disease control and estimated median overall survival of 8.0 months (95% CI, 5.4-9.4)., Conclusions: Even though the study preset rule for iORR per IRF was not met in this heavily pretreated population, a notable CNS and systemic treatment effect was seen in all patients including symptom improvement and prolonged overall survival compared to historical control for the subset of patients with leptomeningeal carcinomatosis ( n = 28)., (©2020 American Association for Cancer Research.)

Heat stress hampers nutrient utilisation and production of animals, and dietary betaine supplementation can mitigate the adverse effects of heat stress on animals and improve their productivity. The present study was conducted to explore the effects of betaine supplementation on the growth performance of eighteen growing Karan Fries (KF) heifers having similar age and body conditions. The experiment was carried out on three groups (n = 6) of KF heifers viz. control, treatment I (betaine supplemented at 25  g/d/animal), and treatment II (betaine supplemented at 50  g/d/animal). The experiment lasted for eight months covering the three major seasons of Indian tropical conditions viz. hot-dry (temperature humidity index, THI = 83), hot-humid (THI = 85) and thermoneutral season (THI = 73). Blood samples were collected at fortnightly intervals and analysed for plasma growth hormone (GH; competitive ELISA) and total insulin-like growth factor 1 (IGF-1; Sandwich ELISA), as well as expression of IGF-I in peripheral blood mononuclear cells (PBMC) using real-time polymerase chain reaction. Betaine supplementation resulted in significant (p < 0.05) increase in dry matter intake, feed conversion efficiency, body weight gain, plasma GH and IGF-1 levels during all seasons. The concentrations of plasma IGF-1 and the mRNA expression of IGF-1 were higher (p < 0.01) in treatment I as compared to other groups during all seasons. Betaine supplementation at 25  g/d/animal was more cost-effective in improving growth performance of heat-stressed heifers as compared to 50  g/d/animal. The study suggests that the betaine protects intestinal integrity, enhances nutrient utilisation during heat stress and improves growth performance of growing heifers., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the safety, pharmacokinetics, and pharmacodynamics of Hu5F9-G4 (5F9), a humanized IgG4 antibody that targets CD47 to enable phagocytosis., Patients and Methods: Adult patients with solid tumors were treated in four cohorts: part A, to determine a priming dose; part B, to determine a weekly maintenance dose; part C, to study a loading dose in week 2; and a tumor biopsy cohort., Results: Sixty-two patients were treated: 11 in part A, 14 in B, 22 in C, and 15 in the biopsy cohort. Part A used doses that ranged from 0.1 to 3 mg/kg. On the basis of tolerability and receptor occupancy studies that showed 100% CD47 saturation on RBCs, 1 mg/kg was selected as the priming dose. In subsequent groups, patients were treated with maintenance doses that ranged from 3 to 45 mg/kg, and most toxicities were mild to moderate. These included transient anemia (57% of patients), hemagglutination on peripheral blood smear (36%), fatigue (64%), headaches (50%), fever (45%), chills (45%), hyperbilirubinemia (34%), lymphopenia (34%), infusion-related reactions (34%), and arthralgias (18%). No maximum tolerated dose was reached with maintenance doses up to 45 mg/kg. At doses of 10 mg/kg or more, the CD47 antigen sink was saturated by 5F9, and a 5F9 half-life of approximately 13 days was observed. Strong antibody staining of tumor tissue was observed in a patient at 30 mg/kg. Two patients with ovarian/fallopian tube cancers had partial remissions for 5.2 and 9.2 months., Conclusion: 5F9 is well tolerated using a priming dose at 1 mg/kg on day 1 followed by maintenance doses of up to 45 mg/kg weekly.

The present study was performed to ascertain the synergistic effects of phytogenic feed additives (PFA-7) supplementation on immune status and haemato-biochemical profile of buffalo calves. The PFA-7 is a mixture of neem seed cake (Azadirachta indica), mahua seed cake (Madhuca longifolia), fennel seed (Foeniculum vulgare), harad (Terminalia chebula), fruit pulp of bahera (Terminalia bellirica), fruit pulp of amla (Phyllanthus emblica) and ajwain seed (Trachyspermum ammi) mixed in 2:2:2:1:1:1:1 proportion. Male buffalo calves (n = 21) having similar age and body weight were allotted to three groups in a completely randomised design. The dietary treatments were viz. T1: control (without PFA-7) and T2 and T3: provided with PFA-7 at 2 and 4% of dry matter intake (DMI), respectively, plus sodium sulphate at 0.06% of DMI. The feeding trial was carried out for 4 months, and serum isolation was done on days 0, 60 and 120 post-feeding. The concentrations of total protein, albumin, globulin, aspartate transaminase and alanine transaminase increased, whereas cortisol and glucose decreased in the supplemented groups as compared to the control. The levels of triglycerides, urea, albumin/globulin ratio, calcium, phosphorus and alkaline phosphatase were not affected by the supplementation of PFA-7. Both cell-mediated and humoral immune response increased in the supplemented groups. The results revealed that PFA-7 positively impacted haemato-biochemical profile and both cellular and humoral immunity of the growing calves. The PFA-7 can be used as an alternative for chemical feed additives in the diet of growing calves.

Background: Kawasaki disease is a common childhood vasculitis which may result in cardiovascular morbidity if not adequately treated. Its epidemiology in the African region is not well described. Its features may mimic other childhood infections and hemoglobinopathies and it is rarely diagnosed in the East African region. These are the first reports of this disease from Tanzania., Case Presentation: We present two cases of complete Kawasaki disease seen over a 2 year period and diagnosed as per the criteria defined by the American Heart Association. One child was and infant and the other a 3 year old. Both of them presented with a prolonged fever and mucocutaneous findings. None of the children developed coronary artery aneurysms. One was treated with aspirin alone and the other with both aspirin and intravenous immunoglobulin. Both children had complete recovery and did not have any cardiovascular sequelae., Conclusion: Kawasaki disease may be more common in the East African region than previously thought. It should be considered as a differential diagnosis in children who present with a prolonged fever of greater than 5 days and mucocutaneous findings. More awareness about this condition, its epidemiology, diagnosis and management are required in order to prevent the cardiovascular morbidity associated with it.

Introduction: Interferon alpha 2B (IFN-α) therapy in malignant melanoma has improved relapse free survival and overall survival but is considerably toxic and lowers the overall quality of life (QoL) substantially. A significant number of patients do not complete the full duration (one year) of therapy., Objective: The aim of this study was to evaluate patients' ability to tolerate IFN-α therapy and to compare our results to reported data in the literature., Methods: We conducted a retrospective review of patients diagnosed with cutaneous malignant melanoma who received IFN therapy after surgical resection. Patients were divided into two groups: patient who completed therapy (CIT) and those who did not (incomplete therapy, IIT). Duration of therapy was calculated. Reason for discontinuation and experienced side effects were reported. Statistical significance was determined at p &#60; 0.05., Results: A total of 64 patients were included in the review. There were 16 (25%) patients were able to complete therapy. The most common reasons for discontinuing IFN-α therapy was fatigue (81.3%), fever (40.6%), depression (28.1%) and nausea (18.8%). Patients in the CIT group were younger than those in the IIT group (47.4 ± 14.2 vs 57.8 ± 11.9 years, mean ± SD; p = 0.011). There also seemed to be an association that those with the presence of advanced disease may have been more likely to complete therapy (node positive disease at the time of diagnosis, p = 0.07)., Limitations: It is a retrospective study and has to rely on physician notes for the subjective data. For the survival analyses, the median follow-up times for both of the groups were less than 3.5 years., Conclusions: Younger patients were more likely to complete therapy. There was a trend towards an association between more advanced disease and the completion of therapy. Most common causes of discontinuation of therapy were fatigue, fever, depression, and nausea.

Background: Prescribing errors remain a continuing patient safety concern. Eradicating error in prescribing requires closer working between doctors and pharmacists. We report on interprofessional learning for medical and pharmacy students on complex polypharmacy in older people. This short course enables final-year students to work with in-patients to meticulously assess the completeness and accuracy of their prescriptions. The learning theory applied is experiential learning and reflection., Methods: A mixed-method evaluation study was used to examine students' learning, using a questionnaire, case presentations and ward feedback forms. The quantitative questionnaire data were analysed using spss and qualitative data were analysed using thematic analysis; case presentations and feedback forms were analysed using content analysis., Results: A total of 525 students (294 medical students and 231 pharmacy students) participated in the course. The students' self-ratings suggested significant advances in their knowledge (p < 0.001). The main emerging themes related to the value of collaborative learning, new insights into the management of polypharmacy in older people and how to achieve effective communication to ensure medication safety. In-depth analysis of 58 in-patient cases identified drug errors concerning STOPP/START guidelines, unclear prescriptions and drug interactions. Eradicating error in prescribing requires closer working between doctors and pharmacists, Discussion: Medical and pharmacy students seemed to value collaborative practise to jointly analyse the complexity of polypharmacy in older people. This evaluation highlights the potential benefits of real-life experiential training followed by reflection and analyses to propel student learning and to help practice teams., (© 2016 John Wiley & Sons Ltd.)

Background: Tens of thousands of cardiac and vascular surgeries (CaVS) are performed on seniors in Canada and the United Kingdom each year to improve survival, relieve disease symptoms, and improve health-related quality of life (HRQL). However, chronic postsurgical pain (CPSP), undetected or delayed detection of hemodynamic compromise, complications, and related poor functional status are major problems for substantial numbers of patients during the recovery process. To tackle this problem, we aim to refine and test the effectiveness of an eHealth-enabled service delivery intervention, TecHnology-Enabled remote monitoring and Self-MAnagemenT-VIsion for patient EmpoWerment following Cardiac and VasculaR surgery (THE SMArTVIEW, CoVeRed), which combines remote monitoring, education, and self-management training to optimize recovery outcomes and experience of seniors undergoing CaVS in Canada and the United Kingdom., Objective: Our objectives are to (1) refine SMArTVIEW via high-fidelity user testing and (2) examine the effectiveness of SMArTVIEW via a randomized controlled trial (RCT)., Methods: CaVS patients and clinicians will engage in two cycles of focus groups and usability testing at each site; feedback will be elicited about expectations and experience of SMArTVIEW, in context. The data will be used to refine the SMArTVIEW eHealth delivery program. Upon transfer to the surgical ward (ie, post-intensive care unit [ICU]), 256 CaVS patients will be reassessed postoperatively and randomly allocated via an interactive Web randomization system to the intervention group or usual care. The SMArTVIEW intervention will run from surgical ward day 2 until 8 weeks following surgery. Outcome assessments will occur on postoperative day 30; at week 8; and at 3, 6, 9, and 12 months. The primary outcome is worst postop pain intensity upon movement in the previous 24 hours (Brief Pain Inventory-Short Form), averaged across the previous 14 days. Secondary outcomes include a composite of postoperative complications related to hemodynamic compromise-death, myocardial infarction, and nonfatal stroke- all-cause mortality and surgical site infections, functional status (Medical Outcomes Study Short Form-12), depressive symptoms (Geriatric Depression Scale), health service utilization-related costs (health service utilization data from the Institute for Clinical Evaluative Sciences data repository), and patient-level cost of recovery (Ambulatory Home Care Record). A linear mixed model will be used to assess the effects of the intervention on the primary outcome, with an a priori contrast of weekly average worst pain intensity upon movement to evaluate the primary endpoint of pain at 8 weeks postoperation. We will also examine the incremental cost of the intervention compared to usual care using a regression model to estimate the difference in expected health care costs between groups., Results: Study start-up is underway and usability testing is scheduled to begin in the fall of 2016., Conclusions: Given our experience, dedicated industry partners, and related RCT infrastructure, we are confident we can make a lasting contribution to improving the care of seniors who undergo CaVS., Competing Interests: In-kind industry support is provided by the following industry partners: Philips, QoC Health, XAHIVE, and mPath. The following authors are employed by Philips: Karsten Russell Wood, Michael Weber, Jolene McNeil, and Robyn Alpert. Sarah Sharpe is Co-Founder and shareholder, QoC Health; Sue Bhella is employed by QoC Health. David Mohajer is Co-Founder, Chief Executive Officer, and Vice President, XAHIVE; Sem Ponnambalem is Co-Founder, Chief Operating Officer, and President, XAHIVE. Naeem Lakhani and Rabia Khan are Co-Founders, mPath.

Introduction: One of six priorities of CDC's National Comprehensive Cancer Control Program (NCCCP) is to address the needs of cancer survivors within the local population served by individually funded states, tribes, and territories. This report examines cancer survivorship activities implemented in five NCCCP grantees, which have initiated evidence-based activities outlined in A National Action Plan for Cancer Survivorship: Advancing Public Health Strategies (NAP)., Methods: NCCCP action plans, submitted annually to CDC, from 2010 to 2014 were reviewed in February 2015 to assess implementation of cancer survivorship activities and recommended strategies consistent with the NAP. Four state-level and one tribal grantee with specific activities related to one of each of the four NAP strategies were chosen for inclusion. Brief case reports describing the initiation and impact of implemented activities were developed in collaboration with each grantee program director., Results: New Mexico, South Carolina, Vermont, Washington state, and Fond Du Lac Band of Lake Superior Chippewa programs each implemented activities in surveillance and applied research; communication, education, and training; programs, policies, and infrastructure; and access to quality care and services., Conclusions: This report provides examples for incorporating cancer survivorship activities within Comprehensive Cancer Control programs of various sizes, demographic makeup, and resource capacity. New Mexico, South Carolina, Vermont, Washington state, and Fond Du Lac Band developed creative cancer survivorship activities that meet CDC recommendations. NCCCP grantees can follow these examples by implementing evidence-based survivorship interventions that meet the needs of their specific populations., (Published by Elsevier Inc.)

Next-generation sequencing (NGS) capabilities can affect therapeutic decisions in patients with complex, advanced, or refractory cancer. We report the feasibility of a tumor sequencing advisory board at a regional cancer center. Specimens were analyzed for approximately 2800 mutations in 50 genes. Outcomes of interest included tumor sequencing advisory board function and processes, timely discussion of results, and proportion of reports having potentially actionable mutations. NGS results were successfully generated for 15 patients, with median time from tissue processing to reporting of 11.6 days (range, 5 to 21 days), and presented at a biweekly multidisciplinary tumor sequencing advisory board. Attendance averaged 19 participants (range, 12 to 24) at 20 days after patient enrollment (range, 10 to 30 days). Twenty-seven (range, 1 to 4 per patient) potentially actionable mutations were detected in 11 of 15 patients: TP53 (n = 6), KRAS (n = 4), MET (n = 3), APC (n = 3), CDKN2A (n = 2), PTEN (n = 2), PIK3CA, FLT3, NRAS, VHL, BRAF, SMAD4, and ATM. The Hotspot Panel is now offered as a clinically available test at our institution. NGS results can be obtained by in-house high-throughput sequencing and reviewed in a multidisciplinary tumor sequencing advisory board in a clinically relevant manner. The essential components of a center for personalized cancer care can support clinical decisions outside the university., (Copyright © 2015 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Cataract surgery with an intraocular lens implant is one of the most common and thought to be the most effective surgical procedure in any field of medicine. Although aging is the most common cause, other factors are also known to be associated with cataract formation. Although cataracts are the domain of ophthalmology, primary care physicians are frequently the ones to whom patients present with vision complaints. Knowledge of cataract symptoms, how to evaluate them, and a basic understanding of the surgery to correct cataracts make primary care physicians an integral part of treating this leading cause of preventable blindness., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: Centers for Disease Control and Prevention's (CDC) National Comprehensive Cancer Control Program (NCCCP) funds states, the District of Columbia, tribal organizations, territories, and jurisdictions across the USA develop and implement jurisdiction-specific comprehensive cancer control (CCC) plans. The objective of this study was to analyze NCCCP action plan data for incorporation and appropriateness of cancer survivorship-specific goals and objectives., Methods: In August 2013, NCCCP action plans maintained within CDC's Chronic Disease Management Information System (CDMIS) from years 2010 to 2013 were reviewed to assess the inclusion of cancer survivorship objectives. We used the CDMIS search engine to identify "survivorship" within each plan and calculated the proportion of programs that incorporate cancer survivorship-related content during the study period and in each individual year. Cancer survivorship objectives were then categorized by compatibility with nationally accepted, recommended strategies from the report A National Action Plan for Cancer Survivorship: Advancing Public Health Strategies (NAP)., Results: From 2010 to 2013, 94% (n = 65) of NCCCP action plans contained survivorship content in at least 1 year during the time period and 38% (n = 26) of all NCCCP action plans addressed cancer survivorship every year during the study period. Nearly 64% (n = 44) of NCCCP action plans included cancer survivorship objectives recommended in NAP., Conclusion: Nearly all NCCCP action plans addressed cancer survivorship from 2010 to 2013, and most programs implemented recommended cancer survivorship efforts during the time period., Implications for Cancer Survivors: NCCCP grantees can improve cancer survivorship support by incorporating recommended efforts within each year of their plans.

Background: Diffuse large B-cell lymphoma accounts for the large majority of AIDS-related non-Hodgkin lymphoma. Traditionally, this lymphoma has been treated with CHOP-like regimens with the recent addition of rituximab. We report a unique case where an HIV-infected patient with diffuse large B-cell lymphoma had complete regression of the lymphoma with continued antiretroviral therapy (ART) after chemotherapy was stopped., Case Report: A 55-year-old man who presented with fatigue and weight loss had initial CT findings of bilateral renal masses during his workup. Biopsy revealed diffuse large B-cell lymphoma and subsequently he was also diagnosed with HIV. He completed 6 cycles of CHOP-like (4 cycles of EPOCH-R and 2 cycles of R-CHOP) first-line therapy with significant dose delays and dose reductions due to severe adverse effects. Chemotherapy was stopped due to physical deconditioning and intolerable adverse effects. He had a FDG-PET/CT showing progression of his disease 8 weeks after completing chemotherapy. He was maintained only on ART after finishing 6 cycles of chemotherapy. With this therapy alone and with improvement in his immune status, his lymphoma regressed completely., Conclusions: There are very few reported cases in which lymphoma has regressed with treatment of HIV alone, as is regression of diffuse large B-cell lymphoma. This case emphasizes that ART can lead to immune reconstitution of HIV-infected patients and can establish the anti-tumor effect, causing regression of the lymphoma.

Despite evidence that physical activity can reduce the cardiometabolic risk of patients with psoriasis, these patients may engage in less physical activity than those without psoriasis. The aim of this study was to examine the association of the extent of psoriatic skin lesions with the likelihood of participating in leisure-time moderate to vigorous physical activity (MVPA) and metabolic equivalent task (MET)-minutes of MVPA amongst those who participated. The National Health and Nutrition Examination Survey (NHANES) is a population-based survey among U.S. adults. A total of 6549 persons aged 20-59 years responded to the 2003-2006 NHANES dermatology questionnaires, which asked about participation in leisure-time MVPA and MET-minutes of MVPA amongst those who participated. Compared with individuals without psoriasis, those with psoriasis were less likely to have engaged in leisure MVPA in the past 30 days, although this association was not statistically significant. Amongst those who participated in leisure-time MVPA, MET-minutes of leisure-time MVPA were lower on average for patients currently having few to extensive cutaneous lesions (but not for those currently having little or no psoriatic patches), relative to individuals never diagnosed with psoriasis by approximately 30%. Clinicians should encourage patients with psoriasis, especially those with more severe disease, to be more physically active; they should help identify and address possible psychological and physical barriers to their patients' physical activity., (© 2014 Japanese Dermatological Association.)

Gynecologic cancer confers a large burden among women in the United States. Several evidence-based interventions are available to reduce the incidence, morbidity, and mortality from these cancers. The National Comprehensive Cancer Control Program (NCCCP) is uniquely positioned to implement these interventions in the US population. This review discusses progress and future directions for the NCCCP in preventing and controlling gynecologic cancer.

Achieving high and equitable childhood immunisation coverage in Africa will not only protect children from disability and premature death, it will also boost productivity, reduce poverty and support the economic growth of the continent. Thus, Africa needs innovative and sustainable vaccine advocacy initiatives. One such initiative is the African Vaccine-Preventable Diseases Network, formed in 2009. This association of immunisation practitioners, vaccinologists, paediatricians, and infectious disease experts provides a platform to advocate for the introduction of newly available vaccines (e.g. 10-valent and 13-valent pneumococcal conjugate and rotavirus vaccines) into the Expanded Programme on Immunisation (EPI) as well as increased and equitable coverage for established EPI vaccines.

Background and Purpose: PMX464 is a novel benzothiazole substituted cyclohexadienone reportedly targeting the thioredoxin (Trx1)/thioredoxin reductase (TrxR1) system. We have previously shown that PMX464 has enhanced hypoxic anti-proliferative effects in colorectal tumour cells, with some non-tumour cells (quiescent endothelium and fibroblasts) being relatively resistant. The current study aimed to validate the Trx1 system as a molecular target of PMX464 in tumour cells and to investigate the differential sensitivities of normal cells at the molecular level., Experimental Approach: Proliferation, clonogenic survival, protein expression and function, cell cycle and apoptosis assays were conducted using colorectal tumour (HT29), endothelial (HUVEC) and fibroblast (MRCV) cells treated with PMX464 under normoxic and hypoxic (1% O(2)) conditions., Key Results: Protein and enzyme assays showed that PMX464, in HT29, inhibited Trx1 function without altering expression and that inhibition correlated with decreased proliferation and survival, and was more marked under hypoxia. In contrast, although hypoxic HUVEC were sensitive, in terms of proliferation and survival, inhibition of Trx1 function was not observed. Quiescent HUVEC and MRCVs (that have undetectable Trx1 protein) were relatively resistant. The effect on HT29 cells was essentially due to cell cycle inhibition, as apoptosis was modest. Anti-proliferative effects were lost after a lag period, suggesting a reversible phenomenon., Conclusions and Implications: The Trx1 system is an important target in tumour cells and can be inhibited by PMX464. Quiescent HUVEC and fibroblasts are relatively resistant conferring a therapeutic benefit when targeting Trx1.

2-Methoxyestradiol (2ME2) is an endogenously produced metabolite of estradiol currently being tested in phase I and II clinical trials as an anticancer agent. Here, we examined the role of protein binding as a possible determinant of the pharmacokinetic behavior of 2ME2. The distribution of 2ME2 in plasma was studied in vitro using plasma from healthy human volunteers and ex vivo using plasma from patients with cancer receiving the drug orally. The equilibrium dialysis method used to characterize plasma protein binding of 2ME2 utilized a tracer amount of [H]-2-methoxyestradiol on a 96-well microdialysis plate with a 5-kDa cutoff membrane and 250 mul of plasma. The time to equilibrium was approximately 24 h and the mean unbound fraction of 2ME2 (fu) over the observed concentration range in plasma of patients receiving 2ME2 orally was 0.019+/-0.0043. The mean fu was 0.027+/-0.0019 in plasma of healthy human volunteers. The binding was concentration independent, indicating a low-affinity, possibly nonspecific and nonsaturable process. The binding was also unaffected by the presence of 2-methoxyestrone, one of the major metabolites of 2ME2. 2ME2 was found to bind in decreasing order to plasma>albumin>alpha1-acid glycoprotein>sex-hormone-binding globulin. Plasma concentration-time profiles of total 2ME2 and unbound 2ME2 concentrations in a patient with cancer receiving 2ME2 as a single oral dose were parallel to each other. Thus, indicating that plasma protein binding is not an important consideration in pharmacokinetic monitoring of 2ME2.

The changing training needs of the mental health workforce have been increasingly highlighted in recent years with the national development of new services like crisis resolution/home treatment teams. This article presents some key changes made to short training courses in crisis resolution.

Purpose: The use of thalidomide as an antiangiogenic agent has met with only limited success in the treatment of malignant gliomas. On the basis of preclinical data demonstrating synergistic antitumor activity when antiangiogenic agents are combined with cytotoxic agents, we explored the clinical activity of the combination of thalidomide and carmustine (BCNU) in patients with recurrent high-grade gliomas., Patients and Methods: Patients with a histologic diagnosis of high-grade glioma and radiographic evidence of tumor progression after standard surgery, radiation, and chemotherapy were eligible for the study. Patients received BCNU 200 mg/m2 on day 1 of every 6-week cycle, and 800 mg/d of thalidomide that was escalated to a maximal dose of 1,200 mg/d as tolerated., Results: A total of 40 patients (38 with glioblastomas, two with anaplastic gliomas) were accrued to the study. The combination of thalidomide and BCNU was well tolerated; mild myelosuppression and mild to moderate sedation were the most common side effects. The median progression-free survival (100 days) and the objective radiographic response rate (24%) for patients with glioblastoma compared favorably with data from historical controls., Conclusion: This is one of the first clinical trials to evaluate the strategy of combining a putative antiangiogenic agent with a cytotoxic agent in patients with primary brain tumors. Our data demonstrate that thalidomide in combination with BCNU is well tolerated and has antitumor activity in patients with recurrent high-grade gliomas. Although the combination seems to be more active than either agent alone, such conclusions await confirmatory trials.

Study Objective: To evaluate the frequency of venous thromboembolism (VTE) in patients with advanced androgen-independent prostate cancer who were treated with docetaxel alone or in combination with thalidomide., Design: Retrospective analysis of a randomized phase II trial., Setting: National Institutes of Health clinical research center., Patients: Seventy men, aged 50-80 years, with advanced androgen-independent prostate cancer., Intervention: Each patient received either intravenous docetaxel 30 mg/m2/week for 3 consecutive weeks, followed by 1 week off, or the combination of continuous oral thalidomide 200 mg every evening plus the same docetaxel regimen. This 4-week cycle was repeated until there was evidence of excessive toxicity or disease progression., Measurements and Main Results: None of 23 patients who received docetaxel alone developed VTE, whereas 9 of 47 patients (19%) who received docetaxel plus thalidomide developed VTE (p=0.025)., Conclusion: The addition of thalidomide to docetaxel in the treatment of prostate cancer significantly increases the frequency of VTE. Clinicians should be aware of this potential complication when adding thalidomide to chemotherapeutic regimens.

In this phase I/II clinical trial the antitumor activity of high-dose tamoxifen when administered in combination with vinblastine was assessed and the toxicity profile of this combination characterized. All 25 patients enrolled in this study were required to have androgen-independent prostate cancer and to maintain androgen ablation during treatment. Vinblastine was given by continuous infusion over 5 days. Doses were increased from 0.9 mg/m2/day to 1.5 mg/m2/day in successive cohorts of at least 3 patients, with no further escalation even in the absence of dose-limiting toxicity. Intra-patient dose escalation was permitted. Tamoxifen was administered at a dose of 200 mg/kg on day 1, then 120 mg/kg/day on day 2. Standard response criteria were utilized to assess antitumor activity and CTC toxicity criteria were used. Quality of life (QOL) pain assessments were evaluated at each visit to the clinic. Most patients tolerated the highest dose of vinblastine at 1.5 mg/m2/day by continuous infusion over 5 days with 200 mg/kg/day of tamoxifen on day 1 and day 2. One patient had a greater than 50% decline in prostate-specific antigen that lasted for 170 days. Two patients received dose reductions because of toxicity. The most common serious toxicities included neutropenia, and fatigue. Reversible neurosensory, neuromotor, neurocortical and neurocerebellar toxicities were reported. Six of the 25 patients enrolled in the study (24%) experienced reversible neurologic toxicity of at least grade III. No statistically significant differences between precycle assessment of QOL and subsequent cycles were observed. It is concluded that vinblastine at 1.5 mg/m2/day continuous i.v. infusion combined with tamoxifen 200 mg/kg/day on day 1 and day 2 is inactive, and not without toxicity in the treatment of advanced metastatic androgen-independent prostate cancer.

Alcohol use amongst elderly people is an increasingly important area to understand, yet relatively little research has been undertaken and our knowledge remains limited. This paper contains a review of the literature, concentrating on alcohol use in community-dwelling elderly people. Both cross-sectional and longitudinal research papers are reviewed; their findings suggest high abstinence rates amongst the population under consideration, with consumption consistently associated negatively with increasing age and female gender. A summary of the largely non-specific, descriptive literature available is also included. Research concerned with elderly people and alcohol use is problematic and therefore the limitations of the available research are examined in detail. Firm conclusions are difficult to draw from the research to date because, for example, there are varying definitions of terms such as 'alcoholism' and 'heavy drinking' and instruments used for detection have not been validated with older age groups. The need for increased awareness amongst health professionals, especially nurses, about issues surrounding community-dwelling elderly people and alcohol use and misuse is discussed. Finally, the importance of further research, especially amongst largely neglected groups of the elderly population, such as ethnic minority groups and elderly homeless people, is suggested.