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Objective To determine whether 17 alpha-hydroxyprogesterone caproate (17 OHPC) prolongs gestation beyond 37 weeks of gestation (primary outcome) and reduces neonatal morbidity (secondary outcome) in twin pregnancy. Design Randomised controlled double-blind clinical trial. Setting Tertiary-care university medical centre. Population Unselected women with twin pregnancies. Methods Participants received weekly injections of 250 mg 17 OHPC ( n = 194) or placebo ( n = 94), from 16-20 to 36 weeks of gestation. Randomisation was performed using the permuted-block randomisation method. Data were analysed on an intention-to-treat basis. Main outcome measure Preterm birth ( PTB) rate before 37 weeks of gestation. Results There were no significant differences in the average gestational age at delivery, or in the rates of PTB before 37, 32, and 28 weeks of gestation, between the two groups. The proportion of very-low-birthweight neonates (<1500 g) was significantly lower in the 17 OHPC group (7.6%) compared with placebo (14.3%) (relative risk, RR 0.5; 95% confidence interval, 95% CI 0.3-0.9; P = 0.01). Progestogen-treated neonates had a significantly lower composite neonatal morbidity (19.1%) compared with placebo (30.9%) (odds ratio, OR 0.53; 95% CI 0.31-0.90; P = 0.02), with significantly lower odds for respiratory distress syndrome (14.4 versus 23.4%; OR 0.55; 95% CI 0.31-0.98; P = 0.04), retinopathy of prematurity (1.1 versus 4.6%; OR 0.21; 95% CI 0.05-0.96; P = 0.04), and culture-confirmed sepsis (3.4 versus 12.8%; OR 0.24; 95% CI 0.10-0.57; P = 0.00). Conclusions Intramuscular 17 OHPC therapy did not reduce PTB before 37 weeks of gestation in unselected twin pregnancies. Nonetheless, 17 OHPC significantly reduced neonatal morbidity parameters and increased birthweight. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The aim of the study was to assess the rate of acceptance of preimplantation genetic diagnosis (PGD) as an alternative to prenatal diagnosis in Lebanese women with previously affected children with homozygous beta-thalassemia. METHODS: Women with a previously affected child attending a nongovernmentally funded thalassemia care center between 1 June 2005 and 31 May 2007 were offered a genetic counseling session. This was followed by administering a questionnaire through direct interview. RESULTS: All 97 women approached accepted to participate in the study (100% response rate). Sixty eight per cent of women considered PGD a better alternative to prenatal diagnosis. The most important perceived advantage of PGD was the avoidance of termination of an affected pregnancy. CONCLUSIONS: PGD is an acceptable alternative to conventional prenatal diagnosis in women at risk of conceiving a child affected with beta-thalassemia. This is particularly true in countries of the Middle-East where therapeutic abortions for fetal indications are prohibited by the law and religion. Copyright (c) 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine perinatal complications in infants >or = 4500 g according to delivery mode. STUDY DESIGN: Records of 231 mothers and live cephalic infants weighing >or = 4500 g over a 13-year period were retrospectively reviewed. Maternal and perinatal complications were compared in relation to delivery mode. RESULTS: Vaginal delivery (NVD) was achievable in 168/189 (88.9%) of women allowed to labor, of which 36.9% were operative. The cesarean delivery (CS) rate was 27.3%. The NVD group had a lower incidence of diabetes; however, hypoglycemia and transient tachypnea were more common in the CS group. The frequency of low Apgar scores at 1 and 5 minutes was similar in both groups. A total of 13 (7.7%) major fetal injuries were documented in the NVD group (arm weakness 3, hematoma 3, clavicular fracture 2, and brachial plexus injury 5). Shoulder dystocia was documented in only 7/13 (53.8%). CONCLUSION: Vaginal delivery is achievable in 88.9% of pregnancies with infants >or = 4500 g allowed to labor, at the expense of a 7.7% risk of perinatal trauma. [ABSTRACT FROM AUTHOR]

The genome of a cell is continuously battered by a plethora of exogenous and endogenous processes that can lead to damaged DNA. Repair mechanisms correct this damage most of the time, but failure to do so leaves mutations. Mutations do not occur in random manner, but rather typically follow a more or less specific pattern due to known or imputed mutational processes. Mutational signature analysis is the process by which the predominant mutational process can be inferred for a cancer and can be used in several contexts to study both the genesis of cancer and its response to therapy. Recent pan-cancer genomic efforts such as "The Cancer Genome Atlas" have identified numerous mutational signatures that can be categorized into single base substitutions, doublet base substitutions, or small insertions/deletions. Understanding these mutational signatures as they occur in non-small lung cancer could improve efforts at prevention, predict treatment response to personalized treatments, and guide the development of therapies targeting tumor evolution. For non-small cell lung cancer, several mutational signatures have been identified that correlate with exposures such as tobacco smoking and radon and can also reflect endogenous processes such as aging, APOBEC activity, and loss of mismatch repair. Herein, we provide an overview of the current knowledge of mutational signatures in non-small lung cancer., (© The Author(s) 2024. Published by Oxford University Press.)

Introduction: Patients with advanced ALK-positive NSCLC typically have poor response to immunotherapy; the benefit of consolidation durvalumab in patients with unresectable stage III ALK-positive NSCLC remains unclear. Herein, we compare the efficacy and safety of consolidation ALK tyrosine kinase inhibitor (TKI) versus durvalumab or observation after concurrent chemoradiation., Methods: We conducted a retrospective study using a multicenter study of 17 institutions globally. Patients with unresectable stage III ALK-positive NSCLC treated between 2015 and 2022 were included. Patients received ALK TKI, durvalumab, or observation after concurrent chemoradiation. Real-world progression-free survival (rwPFS) and overall survival (OS) were estimated using Kaplan-Meier method. Treatment-related adverse events (trAEs) were classified by Common Terminology Criteria for Adverse Events version 5.0. Outcomes were assessed by multivariable Cox regression analysis., Results: A total of 67 patients were included, of whom 39 (58%) were female. Median age was 57 (interquartile range: 49-67) years. Furthermore, 15 received consolidation ALK TKI, 30 received durvalumab, and 22 underwent observation. Baseline characteristics were similar across the three groups other than differences in race. After adjusting for stage, age, and nodal status, median rwPFS was significantly longer for ALK TKI (rwPFS not reached, 95% confidence interval [CI]: 22.7- not reached) versus durvalumab (11.3 mo, 95% CI: 8.9-18.5, hazard ratio [HR] = 0.12, 95% CI: 0.026-0.5, p-adjusted [p-adj] = 0.006) or observation (7.2 mo, 95% CI: 3.4-10.6, HR = 0.04, 95% CI: 0.009-0.2, p-adj < 0.0001). Durvalumab significantly improved median rwPFS compared with observation (HR = 0.37, 95% CI: 0.19-0.71, p-adj = 0.002). Median OS in the ALK TKI and durvalumab cohorts was significantly improved compared with patients on observation (ALK TKI-observation: p = 0.04; durvalumab-observation: p = 0.03). TrAE of any grade occurred in eight (53%) and 11 (37%) patients treated with ALK TKI and durvalumab, respectively. Grade greater than or equal to three trAEs occurred in 27% (n = 4) of patients treated with ALK TKI and 6.7% of patients treated with durvalumab., Conclusions: Patients with ALK-positive NSCLC experience significantly improved rwPFS when treated with consolidation ALK TKI therapy, surpassing outcomes found with either durvalumab or observation. Although both ALK TKI therapy and durvalumab offer an extension in OS compared with observation alone, it seems that ALK TKI therapy is the superior choice, underscoring its pivotal role in enhancing patient survival., Competing Interests: Disclosure Dr. Nassar receives honoraria from OncLive, TEMPUS, and Korean Society for Medical Oncology and consulting fees from Guidepoint Global and Putnam Associates. Dr. Goldberg receives research funding from AstraZeneca, Boehringer Ingelheim, and Mirati; is an advisory board member for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Amgen, Blueprint Medicine, Sanofi Genzyme, Daiichi Sankyo, Takeda, Janssen, Summit Therapeutics, Merck, Regeneron, and Eli Lilly; and receives honoraria for lectures for Amgen and AstraZeneca. Dr. Naqash receives funding to institution for trials he is PI on Loxo@Lilly, Surface Oncology, ADC Therapeutics, IGM Biosciences, EMD Serono, Aravive, Nikang Therapeutics, Inspirna, Exelexis, Revolution Medicine, Jacobio, Pionyr, Jazz Pharmaceuticals, NGM Biopharmaceuticals, Immunocore, Phanes Therapeutics, Deka, Kymera, IDEAYA, IGM Biosciences, Selexine, and Chipscreen Biosciences; receives consultant editor compensation from JCO Precision Oncology; receives travel compensation from SITC, American Association for Cancer Reasearch, Conquer Cancer Foundation, BinayTara Foundation, Foundation Med, Caris Life Sciences, Sarah Cannon Research Institute, Jazz Pharmaceuticals, ASCO, and ASTRO; serves on the advisory board of Foundation Med and NGM Biosciences; receives current research grant support from Swog Hope Foundation, FDA Broad Agency Award, and OSCTR; and has genomics research agreements from Tempus, Caris, and Foundation One. Dr. Kim receives institutional funding from Loxo@Lilly, AstraZeneca, Boehringer Ingelheim, Genentech, Bristol-Myers Squibb, DynamiCure, Seagen, Genmab, and Nykode Therapeutics. Dr. Reuss reports serving on the advisory board/as consultant of Sanofi/Genzyme, Personalis, Guardant, AstraZeneca, Bristol-Myers Squibb, Arcus, AbbVie, Daiichi Sankyo, Catalym, Seagen, Gilead, Janssen, Novocure, Regeneron, and Summit Therapeutics; receiving research funding (to institution) from Genentech/Roche, Verastem, Nuvalent, and Exelixis; and receiving honoraria from Merck and AstraZeneca. Dr. Cortellini reports receiving grants for consultancies/advisory boards from Merck Sharp & Dohme, Bristol-Myers Squibb, OncoC4, IQVIA, AstraZeneca, Regeneron, Access Infinity, Ardelis Health, Alpha Sight, Guidepoint, and Roche; receiving speaker fees from AstraZeneca, Pierre-Fabre, Merck Sharp & Dohme, and Sanofi/Regeneron; having writing/editorial activity for Bristol-Myers Squibb and Merck Sharp & Dohme; and receiving travel support from Sanofi/Regeneron and Merck Sharp & Dohme. Dr. Marron currently or has previously served on advisory and/or data safety monitoring boards for Rockefeller University, Regeneron, AbbVie, Merck, Bristol-Myers Squibb, Boehringer Ingelheim, Atara, AstraZeneca, Genentech, Celldex, Chimeric, DrenBio, Glenmark, Simcere, Surface, G1 Therapeutics, NGMbio, DBV Technologies, Arcus, Fate, Ono, Larkspur, Avammune, and Astellas; and has received research grants from Regeneron, Genentech, Bristol-Myers Squibb, Merck, and Boehringer Ingelheim. Dr. Fitzgerald receives institutional research funding from Genentech/Roche, PPD, and bioatla and travel funding from IASLC. Dr. Dilling has served on the advisory boards for AstraZeneca and is a member of the NCCN Non–Small Cell Lung Cancer Panel. Dr. Bar is an advisor of AbbVie, Amgen, AstraZeneca, Bayer, Merck Sharp & Dohme, Merck-Serono, Roche, and Takeda; has writing/speaker engagement for Bristol-Myers Squibb, Medison, and Pfizer, and has received research funding from Immunai, OncoHost, Merck Sharp & Dohme, AstraZeneca, Roche, and AbbVie. Dr. Aredo reports receiving consulting fees from AstraZeneca. Dr. Lin has served as a compensated consultant for Genentech, C4 Therapeutics, Blueprint Medicines, Nuvalent, Bayer, Elevation Oncology, Novartis, Mirati Therapeutics, AnHeart Therapeutics, CLaiM Therapeutics, Ellipses, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Yuhan, Merus, Regeneron, Pfizer, and Turning Point Therapeutics; received institutional research funds from Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation Oncology, Roche, Linnaeus Therapeutics, Nuvalent, and Novartis; and has received travel support from Pfizer and Merus. Dr. Kwiatkowski receives research funding from AADI and Genentech; and consults for Genentech, AADI, Expertconnect, Guidepoint, Bridgebio, Slingshot Insights, William Blair, MEDACorp, and Radyus Research. Dr. Yu has done consulting for AstraZeneca, Daiichi, Janssen, Amgen, Black Diamond, Blueprint, Cullinan, Takeda, and Taiho. Dr. Feng reports receiving speaker honoraria from AstraZeneca Canada. Dr. Velazquez reports receiving consulting fees from AstraZeneca, Merus, Novocure, and Regeneron., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Older patients have similar immune checkpoint inhibitor efficacy and rates of adverse events as younger patients, but appear to have decreased tolerability, particularly in the oldest patient cohort (>80 years), often leading to early cessation of therapy. We aimed to determine whether early discontinuation impacts efficacy of anti-PD-1 therapy in patients ≥80 years old. In this retrospective, multicenter, international cohort study, we examined 773 patients with 4 tumor types who were at least 80 years old and treated with anti-PD-1 therapy. We determined response rate, overall survival (OS), and progression-free survival (PFS) in patients who discontinued therapy early (<12 months) for reasons other than progression or death. We used descriptive statistics for demographics, response, and toxicity rates. Survival statistics were described using Kaplan Meier curves. Median (range) age at anti-PD-1 initiation was 83.0 (75.8-97.0) years. The cancer types included were melanoma (n = 286), non-small cell lung cancer (NSCLC) (n = 345), urothelial cell carcinoma (UCC) (n = 108), and renal cell carcinoma (RCC) (n = 34). Of these, 102 met the primary endpoint of <12 months to discontinuation for reasons other than death or progression. Median PFS and OS, respectively, for these patients were 34.4 months and 46.6 months for melanoma, 15.8 months and 23.4 months for NSCLC, and 10.4 months and 15.8 months for UCC. This study suggests geriatric patients who have demonstrated therapeutic benefit and discontinued anti-PD-1 therapy at less than 12 months of duration for reasons other than progression may have durable clinical benefit without additional therapy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alessio Cortellini declares grants for consultancies/advisory boards from MSD, OncoC4, IQVIA, AstraZeneca, Access Infinity, Ardelis-Health, Alpha Sight, Roche, REGENERON; speaker fees from AstraZeneca, Eisai, Pierre-Fabre, MSD, Sanofi/REGENERON; writing/editorial activity from BMS, MSD; travel support from Sanofi, MSD. Anwaar Saaed reports research grants (to institution) from AstraZeneca, Bristol-Myers Squibb, Merck, Clovis, Exelixis, Actuate therapeutics, Incyte Corporation, Daiichi Sankyo, Five prime therapeutics, Amgen, Innovent biologics, Dragonfly therapeutics, Oxford biotherapeutics, KAHR medical, Biontech, and advisory board/consulting fees from AstraZeneca, Bristol-Myers Squibb, Merck, Xilio therapeutics, Arcus therapeutics, Exelixis, Pfizer, and Daiichi Sankyo. Akiva Diamond served on an Advisory Board for Incyte. Christopher Hoimes has served on advisory boards or as a consultant for BMS, Merck, Seagen. Amin H. Nassar receives honoraria from OncLive, TEMPUS, and Korean Society for Medical Oncology and received consulting fees from Guidepoint Global. Dwight Owen discloses research funding (to institution) from BMS, Merck, Genentech, Palobiofarma, and Onc.AI. Toni Choueiri reports institutional and/or personal, paid and/or unpaid support for research, advisory boards, consultancy, and/or honoraria past 5 years, ongoing or not, from: Alkermes, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers-Squibb, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Nuscan, Novartis, Oncohost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, CME events (Peerview, OncLive, MJH, CCO and others), outside the submitted work. TC also reports institutional patents filed on molecular alterations and immunotherapy response/toxicity, and ctDNA; equity: Tempest, Pionyr, Osel, Precede Bio, CureResponse, InnDura Therapeutics, Primium; committees: NCCN, GU Steering Committee, ASCO/ESMO, ACCRU, KidneyCan; medical writing and editorial assistance support may have been funded by Communications companies in part; no speaker's bureau. TC entored several non-US citizens on research projects with potential funding (in part) from non-US sources/Foreign Components. The institution of TC (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter. David J Pinato declares the following competing interests: Lecture fees: Bayer Healthcare, Astra Zeneca, EISAI, Bristol Myers-Squibb, Roche, Ipsen; Travel expenses: Bristol Myers-Squibb, Roche, Bayer Healthcare; Consulting fees: Mina Therapeutics, Boeringer Ingelheim, Ewopharma, EISAI, Ipsen, Roche, H3B, Astra Zeneca, DaVolterra, Mursla, Starpharma, Avammune Therapeutics, LiFT Biosciences, Exact Sciences; Research funding (to institution): MSD, BMS, GSK. Thomas Marron currently or has previously served on Advisory and/or Data Safety Monitoring Boards for Rockefeller University, Regeneron, AbbVie, Merck, Bristol-Meyers Squibb, Boehringer Ingelheim, Atara, AstraZeneca, Genentech, Celldex, Chimeric, DrenBio, Glenmark, Simcere, Surface, G1 Therapeutics, NGMbio, DBV Technologies, Arcus, Fate, Ono, Larkspur, and Astellas. Abdul Rafeh Naqash receives funding for trials he is PI on: Loxo@Lilly, Surface Oncology, ADC Therapeutics, IGM Biosciences, EMD Serono, Aravive, Nikang Therapeutics, Inspirna, Exelexis, Revolution Medicine, Jacobio, Pionyr, Jazz Pharmaceuticals, and NGM Biopharmaceuticals. ARN also received Consultant Editor Compensation from JCO Precision Oncology, Travel Compensation from: SITC/AACR/Conquer Cancer Foundation/BinayTara Foundation and Foundation Med, Caris Life Sciences, and serves on the Advisory Board for Foundation Med. Douglas Johnson has served on advisory boards or as a consultant for BMS, Mallinckrodt, Merck, Mosaic ImmunoEngineering, Novartis, Oncosec, Pfizer, Targovax, and Teiko, and has received research funding from BMS and Incyte., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Small-cell lung cancer (SCLC) has traditionally been considered a recalcitrant cancer with a dismal prognosis, with only modest advances in therapeutic strategies over the past several decades. Comprehensive genomic assessments of SCLC have revealed that most of these tumours harbour deletions of the tumour-suppressor genes TP53 and RB1 but, in contrast to non-small-cell lung cancer, have failed to identify targetable alterations. The expression status of four transcription factors with key roles in SCLC pathogenesis defines distinct molecular subtypes of the disease, potentially enabling specific therapeutic approaches. Overexpression and amplification of MYC paralogues also affect the biology and therapeutic vulnerabilities of SCLC. Several other attractive targets have emerged in the past few years, including inhibitors of DNA-damage-response pathways, epigenetic modifiers, antibody-drug conjugates and chimeric antigen receptor T cells. However, the rapid development of therapeutic resistance and lack of biomarkers for effective selection of patients with SCLC are ongoing challenges. Emerging single-cell RNA sequencing data are providing insights into the plasticity and intratumoural and intertumoural heterogeneity of SCLC that might be associated with therapeutic resistance. In this Review, we provide a comprehensive overview of the latest advances in genomic and transcriptomic characterization of SCLC with a particular focus on opportunities for translation into new therapeutic approaches to improve patient outcomes., (© 2024. Springer Nature Limited.)

Background: Despite a higher risk of classical Hodgkin lymphoma (cHL) in people with HIV and the demonstrated safety and efficacy of PD-1 blockade in cHL, there are limited data on the use of these agents in HIV-associated cHL (HIV-cHL)., Patients/methods: We retrospectively identified patients with HIV-cHL from the "Cancer Therapy using Checkpoint inhibitors in People with HIV-International (CATCH-IT)" database who received nivolumab or pembrolizumab, alone or in combination with other agents, and reviewed records for demographics, disease characteristics, immune-mediated adverse events (imAEs), and treatment outcomes. Changes in CD4 + T-cell counts with treatment were measured via Wilcoxon signed-rank tests. Overall response rate (ORR) was defined as the proportion of patients with partial or complete response (PR/CR) per 2014 Lugano classification., Results: We identified 23 patients with HIV-cHL who received a median of 6 cycles of PD-1 blockade: 1 as 1st-line, 6 as 2nd-line, and 16 as ≥3rd-line therapy. Seventeen (74%) patients received monotherapy, 5 (22%) received nivolumab plus brentuximab vedotin, and 1 received nivolumab plus ifosfamide, carboplatin, and etoposide. The median baseline CD4 + T-cell count was 155 cells/µL, which increased to 310 cells/µL at end-of-treatment (P = .009). Three patients had grade 3 imAEs; none required treatment discontinuation. The ORR was 83% with median duration of response of 19.7 months. The median progression-free survival was 21.2 months and did not differ between patients with <200 versus ≥200 CD4 + cells/µL (P = .95)., Conclusion: Our findings support the use of PD-1 blockade in HIV-cHL for the same indications as the general population with cHL., Competing Interests: Disclosure KL and RR: Bristol Myers Squibb-Celgene, Merck, EMD-Serono, Eli Lilly, Janssen, Lentigen, and CTI BioPharma research support through CRADAs with the NCI. DBJ: BMS, Catalyst Biopharma, Iovance, Mallinckrodt, Merck, Mosaic ImmunoEngineering, Novartis, Oncosec, Pfizer, Targovax, and Teiko—advisory boards or consultancy; BMS and Incyte—research funding. NAW: ChemoCentryx—consultancy and speaker honoraria CK: Ad board/Consulting fee: Novartis, Regeneron, Janssen, Eisai, Daiichi Sankyo, Jazz Pharmaceuticals, Arcus Biosciences, Mirati Therapeutics, Sanofi, Diffuse Pharmaceuticals; Grant Support: Blueprint Medicines, Bristol-Myers Squibb, Daiichi Sankyo, Inc., Debiopharm, Genentech, Inc., Janssen, Karyopharm, Lyell, Novartis Pharmaceuticals, Regeneron, Spectrum TF: ADC therapeutics—speakers bureau; Astrazeneca—Consultancy and Speakers Bureau; Daiichi—Speakers Bureau; Sankyo—Speakers Bureau; Genmab—Consultancy and Speakers Bureau; Karyopharm—Speakers Bureau; Kite/Gilead—Honoraria and Speakers Bureau; MorphoSys—Speakers Bureau; Secura Bio—Speakers Bureau; Juno/Bristol Myers Squibb (BMS)—Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees and Research Funding; Celgene Corporation—Membership on an entity's Board of Directors or advisory committees; Janssen—Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC/Janssen—Honoraria and Membership on an entity's Board of Directors or advisory committees; Seattle Genetics—Membership on an entity's Board of Directors or advisory committees and Research Funding; Takeda—Honoraria, Membership on an entity's Board of Directors or advisory committees and travel expenses; Abbvie—Consultancy and Honoraria; Seagen—Consultancy, Honoraria, travel expenses, and Speakers Bureau; Bayer—honoraria; Portola Pharmaceuticals—research funding; Eisai—research funding; Kyowa Kirin—research funding; Amgen—research funding; Viracta Therapeutics—research funding; Cell Medica—research funding; Roche—research funding; Trillium Therapeutics—research funding; Pfizer—research funding AD: Athos Therapeutics—Current Employment, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees and Patents & Royalties; Attica Sciences—Current Employment, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees and Patents & Royalties; Dyania Health—Consultancy, Current Employment and stocks; Urogen Pharma- Stocks; Alimera Sciences—stocks; Kyn Therapeutics—stocks; Moderna Therapeutics—stocks; Proteas Bioanalystics—stocks and patents and royalties; BMS—consultancy and research funding; AstraZeneca—Consultancy, Other: Travel, accommodations, expenses and Research Funding; Radmetric—consultancy; Seagen—Consultancy and travel, accommodations, expenses; Janssen—consultancy; PACT Pharma—consultancy; Merck—Consultancy and Research Funding; Roche/Genentech—Consultancy and Research Funding; Exelixis—consultancy; Aveo—consultancy; Kite/Gilead—research funding; Jounce Therapeutics—Research funding; Infinity Pharmaceutics—research funding; Seattle Genetics/Astellas—research funding; Immunomedics/Gilead—research funding; Harvard Medical School—patents and royalties to spouse; UCLA—patents and royalties to spouse; Eli Lilly—travel, accommodations, expenses MM: Genentech/Roche—honoraria and speakers bureau, Novartis—honoraria, Sanofi—honoraria, Lexicon—honoraria and Research Funding, Ipsen—Honoraria and Speakers Bureau, Bayer—honoraria, Taiho Pharmaceutical—Honoraria and speakers bureau, Boehringer Ingelheim—honoraria, Eisai—Honoraria, Research Funding and Speakers Bureau, Merck—Honoraria and Research Funding, Exelixis—Honoraria and Speakers Bureau, AstraZeneca/Daiichi Sankyo—Honoraria and Speakers Bureau, Servier—Honoraria and Speakers Bureau, Tersera—Honoraria, QED Therapeutics—Honoraria, Precision Biologics—Research Funding, BMS—research funding, Onyx—research funding, Advanced Accelerator Applciations—research funding, AlphaVax—Research Funding, Duke University—Patents and Royalities DBJ: Advisory boards/consultancy: BMS, Catalyst Biopharma, Iovance, Jansen, Mallinckrodt, Merck, Mosaic ImmunoEngineering, Novartis, Oncosec, Pfizer, Targovax, and Teiko; Research funding: BMS and Incyte AM: Research funding: Nektar, Tracon Pharma, Regeneron, Tempu slabs; Consultancy and research funding: SpringWorks Therapeutics; Honoraria: Targeted Oncology CD: Advisory Board: GenMab; BeiGene; ADC Pharmaceuticals Research funding: Genentech; Seagen; Astrazeneca AL: Advisory Board—Seagen, Kite Pharma; Consultancy—Research to Practice GS: Advisory Board: BMS, Genentech, EMD Serono, Merck, Sanofi, Seattle Genetics/Astellas, Astrazeneca, Exelixis, Janssen, Bicycle Therapeutics, Pfizer, Gilead, Scholar Rock, G1 Therapeutics, Eli Lilly/Loxo Oncology, Infinity Pharmaceuticals, Lucence Health, IMV, Vial, Syapse, Tempus, Ellipses Pharma; Consultant/Scientific Advisory Board (SAB): Suba Therapeutics, Syapse, Servier, Merck Research Support to institution: Sanofi (iaward), Astrazeneca, Gilead, Helsinn, Lucence, BMS, EMD Serono, Jazz Therapeutics; Speaker: BIO—INFORMAÇÃO BRASILEIRA DE ONCOLOGIA Ltda, OLE Forum (Mexico), Seagen, Gilead, Natera, Exelixis, Janssen, Bayer; Data safety monitoring committee honorarium: Mereo; Employment: Spouse employed by Myriad; Writing/Editor fees: Uptodate, Onviv PR: research funding (to institution)—Lilly, Bayer, Telix; speaker's fees—OncLive ARN: Funding to Institution for Trials he is PI on: Loxo@Lilly, Surface Oncology, ADC Therapeutics, IGM Biosciences, EMD Serono, Aravive, Nikang Therapeutics, Inspirna, Exelexis, Revolution Medicine, Jacobio, Pionyr, Jazz Pharmaceuticals, NGM Biopharmaceuticals; Consultant Editor Compensation: JCO Precision Oncology; Travel Compensation from: SITC/ AACR/ Conquer Cancer Foundation/BinayTara Foundation and Foundation Med/Caris Life Sciences; Advisory Board : Foundation Med AFH: Bristol Myers Squibb—research funding, consultancy; Genentech—research funding, consultancy; Merck—research funding, consultancy; Seattle Genetics—research funding, consultancy; KiTE Pharma—research funding; Gilead Sciences—research funding; AstraZeneca—research funding, consultancy; Karyopharm—consultancy; ADC Therapeutics—research funding, consultancy; Takeda—consultancy; Tubulis—consultancy; Regeneron—consultancy; Genmab—consultancy; Pfizer—consultancy; Caribou Biosciences—consultancy; Adicet Bio—consultancy; Abbvie—consultancy; Allogene Therapeutics—consultancy All other authors have nothing to disclose., (Published by Elsevier Inc.)

Renal cell carcinoma with sarcomatoid differentiation (sRCC) is associated with poor survival and a heightened response to immune checkpoint inhibitors (ICIs). Two major barriers to improving outcomes for sRCC are the limited understanding of its gene regulatory programs and the low diagnostic yield of tumor biopsies due to spatial heterogeneity. Herein, we characterized the epigenomic landscape of sRCC by profiling 107 epigenomic libraries from tissue and plasma samples from 50 patients with RCC and healthy volunteers. By profiling histone modifications and DNA methylation, we identified highly recurrent epigenomic reprogramming enriched in sRCC. Furthermore, CRISPRa experiments implicated the transcription factor FOSL1 in activating sRCC-associated gene regulatory programs, and FOSL1 expression was associated with the response to ICIs in RCC in two randomized clinical trials. Finally, we established a blood-based diagnostic approach using detectable sRCC epigenomic signatures in patient plasma, providing a framework for discovering epigenomic correlates of tumor histology via liquid biopsy., Competing Interests: Declaration of interests S.R.V. reports consulting (current or past 3 years) for Jnana Therapeutics, research support from Bayer, and that their spouse is an employee of and holds equity in Kojin Therapeutics. D.A.B. reports honoraria from LM Education/Exchange Services; advisory board fees from Exelixis and AVEO; consulting fees from Merck, Pfizer, and Elephas; equity in Elephas, Fortress Biotech (subsidiary), and CurIOS Therapeutics; personal fees from Schlesinger Associates, Cancer Expert Now, Adnovate Strategies, MDedge, CancerNetwork, Catenion, OncLive, Cello Health BioConsulting, PWW Consulting, Haymarket Medical Network, Aptitude Health, ASCO Post/Harborside, Targeted Oncology, Accolade 2nd.MD, DLA Piper, AbbVie, Compugen, Link Cell Therapies, and Scholar Rock; and research support from Exelixis and AstraZeneca, outside of the submitted work. S.C.B., T.K.C., and M.L.F. are co-founders and shareholders of Precede Biosciences., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Durvalumab improves survival when used as consolidation therapy after chemoradiation (CRT) in patients with stage III NSCLC. The optimal consolidation therapy for patients with EGFR-mutant (EGFRmut) stage III NSCLC remains unknown., Methods: In this multi-institutional, international retrospective analysis across 24 institutions, we evaluated outcomes in patients with stage III EGFRmut NSCLC treated with concurrent CRT followed by consolidation therapy with osimertinib, durvalumab, or observation between 2015 and 2022. Kaplan-Meier method was used to estimate real-world progression-free survival (rwPFS, primary end point) and overall survival (secondary end point). Treatment-related adverse events (trAEs) during consolidation treatment were defined using Common Terminology Criteria for Adverse Events version 5.0. Multivariable Cox regression analysis was used., Results: Of 136 patients with stage III EGFRmut NSCLC treated with definitive concurrent CRT, 56 received consolidation durvalumab, 33 received consolidation osimertinib, and 47 was on observation alone. Baseline characteristics were similar across the three cohorts. With a median follow-up of 46 months for the entire cohort, the median duration of treatment was not reached (NR) for osimertinib (interquartile range: NR-NR) and was 5.5 (interquartile range: 2.4-10.8) months with durvalumab. After adjusting for nodal status, stage III A/B/C, and age, patients treated with consolidation osimertinib had significantly longer 24-month rwPFS compared to those treated with durvalumab or in the observation cohorts (osimertinib: 86%, durvalumab: 30%, observation: 27%, p < 0.001 for both comparisons). There was no difference in rwPFS between the durvalumab and the observation cohorts. No significant difference in overall survival across the three cohorts was detected, likely due to the limited follow-up. Any-grade trAE occurred in 52% (2 [6.1%] grade ≥3) and 48% (10 [18%] grade ≥3) of patients treated with osimertinib and durvalumab, respectively. Of 45 patients who progressed on consolidation durvalumab, 37 (82%) subsequently received EGFR tyrosine kinase inhibitors. Of these, 14 (38%) patients developed trAEs including five patients with pneumonitis (14%; 2 [5.4%] grade ≥3) and five patients with diarrhea (14%; 1 [2.7%] grade ≥3)., Conclusions: This study suggests that among patients with stage III unresectable NSCLC with a sensitizing EGFR mutation, consolidation osimertinib was associated with a significantly longer rwPFS compared to durvalumab or observation. No unanticipated safety signals were observed with consolidation osimertinib., Competing Interests: Disclosure Dr. Nassar receives honoraria from OncLive, TEMPUS, and Korean Society for Medical Oncology and consulting fees from Guidepoint Global. Dr. Kim is on the advisory board for Amgen. Dr. Shepherd reports having stock and other ownership interests from Eli Lilly and AstraZeneca; receiving honoraria from AstraZeneca, Merck Serono, Takeda, and Daiichi Sankyo; having consulting/advisory role at AstraZeneca and Merck Serono; and receiving research funding from Eli Lilly (inst), Pfizer (inst), Bristol-Myers Squibb (inst), AstraZeneca/MedImmune (inst), and Roche Canada (inst). Dr. Gray reports receiving grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, G1 Therapeutics, Ludwig Institute of Cancer Research, Merck & Co., Inc., Novartis, and Pfizer; receiving consulting fees from AbbVie, AstraZeneca, Blueprint Medicines, EMD Serono, Gilead Sciences, Inc., Janssen Scientific Affairs, LLC, Jazz Pharmaceuticals, Loxo Oncology Inc., Merck & Co., Inc., Novartis, OncoCyte Biotechnology, Spectrum ODAC, Takeda Pharmaceuticals, and Triptych Health Partners; and having leadership role as SWOG Lung Committee Chair, IASLC Board of Director member, and ASCO Education Committee Ex-Chair. Dr. Dilling reports receiving consulting fees from AstraZeneca and support for travel from NCCN. Dr. Neal reports receiving grants from Genentech/Roche, Merck, Novartis, Boehringer Ingelheim, Exelixis, Nektar Therapeutics, Takeda Pharmaceuticals, Adaptimmune, GlaxoSmithKline, Janssen, AbbVie, and Novocure; receiving consulting fees from AstraZeneca, Genentech/Roche, Exelixis, Takeda Pharmaceuticals, Eli Lilly and Company, Amgen, Iovance Biotherapeutics, Blueprint Pharmaceuticals, Regeneron Pharmaceuticals, Natera, Sanofi/Regeneron, D2G Oncology, Surface Oncology, Turning Point Therapeutics, Mirati Therapeutics, Gilead Sciences, AbbVie, Summit Therapeutics, Novartis, Novocure, Janssen Oncology, and AnHeart Therapeutics; and receiving honorarium from CME Matters, Clinical Care Options CME, Research to Practice CME, Medscape CME, Biomedical Learning Institute CME, MLI Peerview CME, Prime Oncology CME, Projects in Knowledge CME, Rockpointe CME, MJH Life Sciences CME, Medical Educator Consortium, and HMP Education. Dr. Wakelee reports receiving grants from Arrys Therapeutics Research, AstraZeneca/Medimmune, Bristol-Myers Squibb, Genentech/Roche, Merck, Helsinn, Seagen, and Xcovery; and serving on the advisory board of Mirati (compensated)—ended November 2022, IOBiotech (compensated)—October 2023, Merck (NOT compensated), and Genentech/Roche/Bristol-Myers Squibb/AstraZeneca (NOT compensated). Dr. S.H. Lin reports receiving grants from STCube Pharmaceuticals, Beyond Spring, and Nektar Therapeutics; consulting fees from XRAD Therapeutics; serving on the advisory board of AstraZeneca; having stock/stock options from Apple, Google, Amazon, Tesla, Meta, Rivian, and CreatvMicrotech; and having other support from SEEK Diagnostics (co-founder). Dr. Patil reports receiving grants from Gilead Research Scholars and LUNGevity Foundation Award; consulting fees from AstraZeneca, Boehringer Ingelheim, Bicara, Daiichi, Janssen, Jazz Pharmaceuticals, Mirati Therapeutics, Pfizer, Sanofi, Regeneron, Roche/Genentech, Takeda, Gilead Research Scholars, and LUNGevity Foundation Award; and honorarium from Janssen. Dr. Bar reports receiving grants from Merck Sharp & Dohme, AstraZeneca, Roche, Bristol-Myers Squibb, Takeda, AbbVie, Bayer, Boehringer Ingelheim, and Pfizer; receiving consulting fees from AstraZeneca, Merck Sharp & Dohme, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Takeda, AbbVie, Pfizer, Bayer, and VBL; and having leadership role from Lung Ambition Consortium, Israel Lung Cancer Group, and IASLC committee. Dr. Marron receives grants from Regeneron, Bristol-Myers Squibb, Merck, Boehringer Ingelheim, NCI, and Cancer Research Institute; and serving on the advisory board of AbbVie, Celldex, and Rockefeller University. Dr. Yu receives grants/contracts from AstraZeneca, Pfizer, Daiichi Cullinan Oncology, Janssen, Novartis, Blueprint med, Black Diamond, and Systimmune and consulting fees from AstraZeneca, Daiichi, Taiho, Takeda, Janssen, Amgen, AbbVie, Novocure, and Ipsen. Dr. Owen receives grants/contracts from Bristol-Myers Squibb, Merck, Palobiofarma, Genentech, Onc.AI, and Pfizer; and travel support from Amgen, AstraZeneca, and Genentech. Rocha receives grants/contracts from SEOM, ESMO Fellowship, and AECC; and travel support from Merck Sharp & Dohme, AstraZeneca, and Bristol-Myers Squibb. Dr. Arriola receives grants/contracts from AstraZeneca and Bristol-Myers Squibb; honorarium from Eli Lilly, AstraZeneca, Roche, Takeda, Merck Sharp & Dohme, Pfizer, Janssen, and Bristol-Myers Squibb; and travel support from AstraZeneca, Roche, and Pfizer. Dr. Cheng receives grants/contracts from AstraZeneca and Genentech; and serving on the advisory board of Janssen, G1 Therapeutics, and AstraZeneca. Dr. Parikh receives consulting fees from Jazz Pharmaceuticals, Guardant Health, and AstraZeneca; and honorarium from MJH Life Sciences. Dr. Harris receives grants/contract from NIH P30CA062203, the UC Irvine Comprehensive Cancer Center using UCI Anti-Cancer Challenge Grant, and ACS Seed Grant 129801-IRG-16-187-13-IRG; and serving on the advisory board of UC Irvine as DSMB member. Dr. Nagasaka receives consulting fees from Caris Life Sciences; honorarium/speaker fees from AstraZeneca, Daiichi, Novartis, EMD Serono self, Pfizer, Eli Lilly, Genentech, Regeneron, Takeda, Janssen, Blueprint, and Mirati; travel support from AnHeart Therapeutics; and stock/stock options from Mbrace Therapeutics. Dr. Valazquez receives grants/contracts from ASCO, American Association for Cancer Research (AACR), LUNGevity, NIA P30AG015272, NCI 5U54CA242646-03 Conquer Cancer and Niarchos Foundation, UCSF Clinical Practice Group, and AAMC; consulting fees from AstraZeneca, Merus, Novocure, and Cadence Communications & Research; and having stock/stock options from Corbus Pharmaceuticals. Dr. J.J. Lin receives grants/contracts from Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation Oncology, Roche, Linnaeus Therapeutics, Nuvalent, and Novartis; consulting fees from Genentech, C4 Therapeutics, Blueprint Medicines, Nuvalent, Bayer, Elevation Oncology, Novartis, Mirati Therapeutics, AnHeart Therapeutics, Takeda, CLaiM Therapeutics, Regeneron, Pfizer, Turning Point Therapeutics, Daiichi Sankyo, AstraZeneca, and Merus. Dr. Piotrowska receives grants/contracts from Novartis, Takeda, Spectrum, AstraZeneca, Tesaro/GlaxoSmithKline, Cullinan Oncology, Daiichi Sankyo, AbbVie, Janssen, and Blueprint; consulting fees from Taiho, Janssen, Takeda, AstraZeneca, Cullinan Oncology, C4 Therapeutics, Jazz Pharmaceuticals, and Blueprint; and honorarium from Daiichi Sankyo, Janssen, and Eli Lilly (honoraria for nonpromotional educational events). Dr. Reuss receives grants/contracts from Genentech/Roche, Verastem, Nuvalent, and LUNGevity Foundation; consulting fees from Genentech/Roche, Sanofi/Genzyme, Personalis, Guardant, AstraZeneca, Bristol-Myers Squibb, Arcus, AbbVie, Daiichi Sankyo, Catalym, Seagen, and Gilead; and honorarium from AstraZeneca and Merck. Dr. Baena Espinar receives consulting fees from AstraZeneca, Roche, and Merck Sharp & Dohme; honorarium from AstraZeneca, Roche, and Merck Sharp & Dohme; payment for expert testimony from Roche; and travel support from Roche and Janssen. Leal receives research funding to institution from Pfizer, Advaxis, and Bayer, outside the submitted work. Dr. Mak receives grants/contracts from ViewRay; consulting fees from AstraZeneca, Novartis, and Sio Capital Management; and other support from Founder of HealthAI. Dr. Naqash receives grants/contracts from SWOG Hope Foundation and FDA Broad Agency Contract; serving on the advisory board of JCO Precision Oncology; receiving travel support from SITC/American Association for Cancer Research (AACR)/Conquer Cancer Foundation/BinayTara Foundation and Foundation Med/Caris Life Sciences, and Jazz Pharmaceuticals; and funding to institution for trials from Loxo@Lilly, Surface Oncology, ADC Therapeutics, IGM Biosciences, EMD Serono, Aravive, Nikang Therapeutics, Inspirna, Exelexis, Revolution Medicine, Jacobio, Pionyr, Jazz Pharmaceuticals, NGM Biopharmaceuticals, Immunophotonics, and Selexine. Dr. Goldberg receives grants/contracts from AstraZeneca, Boehringer Ingelheim, and Mirati; and serving on the advisory board of AstraZeneca, Bristol-Myers Squibb, Amgen, Sanofi, Genzyme, Daiichi Sankyo, Regeneron, Takeda, Janssen, Summit, and Merck. The remaining authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Background: The transconjunctival approach paired with lateral canthotomy is a commonly used technique for widened exposure of the orbital floor and infraorbital rim. A major drawback of this approach is the severance of lateral canthal ligament fibers, which predisposes to potential postoperative eyelid malpositioning. To avoid these suboptimal aesthetic outcomes, a modification of this approach has been proposed in which the lower eyelid is mobilized with a paracanthal, trans-tarsal stair-step incision. In this pilot study, we describe our experience with the trans-tarsal stairstep incision for lateral extension of the transconjunctival incision and report its outcomes in a Western population., Methods: All patients who underwent facial fracture operative fixation at a single institution by a single senior surgeon were included. Clinical variables were extracted. Patients were stratified by incision type., Results: Compared with patients who underwent subtarsal incision (n = 20) and transconjunctival incision with lateral canthotomy (n = 4), patients who received the trans-tarsal stair-step incision (n = 10) had no incision-related complications or requirements for revision. The most common complications found in the comparison groups were ectropion and hypertrophic or irregular scarring, and 4 patients required revision., Conclusions: Our initial experience with the transconjunctival approach with the trans-tarsal stair-step incision shows promising outcomes. Further study may promote greater utilization of this technique in Western countries., (© 2024 HMP Global. All Rights Reserved. Any views and opinions expressed are those of the author(s) and/or participants and do not necessarily reflect the views, policy, or position of ePlasty or HMP Global, their employees, and affiliates.)

Purpose: The aim of this study is to analyze obstetrical and reproductive health parameters in Lebanon from 2015 until 2018 in the setting of the Syrian refugee influx in order to evaluate potential risks and provide a management plan to improve outcomes., Description: Data from the Lebanese Ministry of Public Health (LMPH) on all obstetrical deliveries that occurred in Lebanon between 2015 and 2018 was screened and analyzed. Number and mode of delivery as well as maternal and neonatal outcomes were included. Joinpoint regression analysis was used for trends of selected parameters. Independent two-sample t-tests were used for comparisons., Assessment: Women of non-Lebanese nationality residing in Lebanon had a significantly greater number of total deliveries (p-value < 0.001), vaginal deliveries (p-value = 0.002), cesarean sections (p-value = 0.02). When looking at delivery trends from 2015 to 2018, Lebanese women had a significant decrease in total number of deliveries (p-value < 0.001) and vaginal deliveries (p-value < 0.001)., Conclusion: Total number of deliveries and cesarean sections is on the rise in Lebanon. Cesarean section practice should be audited by the LMPH and the Lebanese Order of Physicians (LOP). Local and international agencies should prioritize the implementation and management of family planning facilities in refugee hosting countries., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Patients with paraneoplastic syndromes (PNS) are excluded from clinical trials involving immune checkpoint inhibitors (ICIs) due to safety concerns. Moreover, real-world data on efficacy and safety is scarce., Methods: In this retrospective study, data were collected on patients with PNS and solid tumors receiving ICI between 2015 and 2022 at nine institutions. Patients were classified into: Cohort 1 (pre-existing PNS before ICI initiation), cohort 2 (PNS during ICI treatment), and cohort 3 (PNS after ICI discontinuation). Patients with metastatic non-small cell lung cancer (NSCLC) (mNSCLC) from cohort 1 were matched to patients who were PNS-free at each institution up to a 1:3 ratio for age, sex, type of ICI, use of concurrent chemotherapy, and number of lines of systemic therapy prior to ICI initiation. Kaplan-Meier method was used to assess overall survival (OS) and time-to-next treatment (TTNT)., Results: Among 109 patients with PNS treated with ICIs, median age at ICI initiation was 67 years (IQR: 58-74). The most represented cancer type was NSCLC (n=39, 36%). In cohort 1 (n=55), PNS exacerbations occurred in 16 (29%) patients with median time to exacerbation after ICI of 1.1 months (IQR: 0.7-3.3). Exacerbation or de novo PNS prompted temporary/permanent interruption of ICIs in 14 (13%) patients. For cohort 2 (n=16), median time between ICI initiation and de novo PNS was 1.2 months (IQR: 0.4-3.5). Treatment-related adverse events (trAEs) occurred in 43 (39%) patients. Grade ≥3 trAEs occurred in 18 (17%) patients. PNS-directed immunosuppressive therapy was required in 55 (50%) patients. We matched 18 patients with mNSCLC and PNS (cohort 1) to 40 without PNS, treated with ICIs. There was no significant difference in OS or TTNT between patients with mNSCLC with and without PNS, although a trend was seen towards worse outcomes in patients with PNS. TrAEs occurred in 6/18 (33%) and 14/40 (35%), respectively. Grade ≥3 trAEs occurred in 4 (22%) patients with PNS and 7 (18%) patients without PNS., Conclusions: Exacerbations of pre-existing PNS occurred in 29% of patients treated with ICIs and both exacerbations and de novo PNS occur early in the ICI course. TrAE from ICIs were similar between patients with and without PNS. Our data suggest that pre-existing PNS should not preclude consideration of ICI therapy although patients may not derive the same clinical benefit compared with patients without PNS., Competing Interests: Competing interests: AHN receives honoraria from OncLive, TEMPUS, and Korean Society for Medical Oncology. Consulting fees: Guidepoint Global. RRM: Consulting/Advisory Board – Aveo, AstraZeneca, Bayer, Bristol Myers Squibb, Blue Earth Diagnostics, Calithera, Caris, Denderon, Exelixis, Janssen, Merck, Myovant, Pfizer, Sanofi, SeaGen, Sorrento Therapeutics, Tempus. Institutional Research Funding – AstraZeneca, BMS, Exelixis, Artera, Oncternal, Bayer, Tempus. JAS is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant numbers R01 AR080659, R01 AR077607, P30 AR070253, and P30 AR072577), the R. Bruce and Joan M. Mickey Research Scholar Fund, and the Llura Gund Award funded by the Gordon and Llura Gund Foundation. JAS has received research support from Bristol Myers Squibb and performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, Pfizer, ReCor, and Sobi unrelated to this work. The funders had no role in the decision to publish or preparation of this manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard University, its affiliated academic health care centers, or the National Institutes of Health. AC received grants for consultancies/advisory boards: MSD, OncoC4, IQVIA, AstraZeneca, Access Infinity, Ardelis Health, Alpha Sight. Speaker fees: AstraZeneca, Eisai, Pierre-Fabre, MSD. Writing/Editorial activity: BMS. Travel support: Sanofi and MSD. ARN reports Funding to Institution for Trials he is PI on:Loxo@Lilly, Surface Oncology, ADC Therapeutics, IGM Biosciences, EMD Serono, Aravive, Nikang Therapeutics, Inspirna, Exelixis, Revolution Medicine, Jacobio, Pionyr, Jazz Pharmaceuticals, NGM Biopharmaceuticals. ARN receives Consultant Editor Compensation: JCO Precision Oncology. Consulting/Advisory Board: Foundation Med. ARN reports Travel Compensation from: SITC/ AACR/ Conquer Cancer Foundation, Jazz Pharmaceuticals, Binay Tara Foundation, Foundation Med., (© 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.)

Purpose: Non-small-cell lung cancer (NSCLC) with STK11 mut has inferior outcomes to immune checkpoint inhibitors (ICIs). Using multiomics, we evaluated whether a subtype of STK11 mut NSCLC with a uniquely inflamed tumor immune microenvironment (TIME) harboring TP53 comutations could have favorable outcomes to ICIs., Patients and Methods: NSCLC tumors (N = 16,896) were analyzed by next-generation sequencing (DNA-Seq/592 genes). A subset (n = 5,034) underwent gene expression profiling (RNA-Seq/whole transcriptome). Exome-level neoantigen load for STK11 mut NSCLC was obtained from published pan-immune analysis. Tumor immune cell content was obtained from transcriptome profiles using the microenvironment cell population (MCP) counter. ICI data from POPLAR/OAK (n = 34) and the study by Rizvi et al (n = 49) were used to model progression-free survival (PFS), and a separate ICI-treated cohort (n = 53) from Dana-Farber Cancer Institute (DFCI) was used to assess time to treatment failure (TTF) and tumor RECIST response for STK11 mut TP53 mut versus STK11 mut TP53 wt NSCLC., Results: Overall, 12.6% of NSCLC tumors had a STK11 mut with the proportions of tumor mutational burden (TMB)-high (≥10 mut/Mb), PD-L1 ≥50%, and microsatellite instability-high being 38.3%, 11.8%, and 0.72%, respectively. Unsupervised hierarchical clustering of STK11 mut (n = 463) for stimulator of interferon-gamma (STING) pathway genes identified a STING-high cluster, which was significantly enriched in TP53 mut NSCLC ( P < .01). Compared with STK11 mut TP53 wt , tumors with STK11 mut TP53 mut had higher CD8+T cells and natural killer cells ( P < .01), higher TMB ( P < .001) and neoantigen load ( P < .001), and increased expression of MYC and HIF-1A ( P < .01), along with higher expression ( P < .01) of glycolysis/glutamine metabolism genes. Meta-analysis of data from OAK/POPLAR and the study by Rizvi et al showed a trend toward improved PFS in patients with STK11 mut TP53 mut . In the DFCI cohort, compared with the STK11 mut TP53 wt cohort, the STK11 mut TP53 mut tumors had higher objective response rates (42.9% v 16.7%; P = .04) and also had longer TTF (14.5 v 4.5 months, P adj = .054) with ICI., Conclusion: STK11 mut NSCLC with TP53 comutation is a distinct subgroup with an immunologically active TIME and metabolic reprogramming. These properties should be exploited to guide patient selection for novel ICI-based combination approaches.

Purpose: Recent evidence has shown that higher tumor mutational burden strongly correlates with an increased risk of immune-related adverse events (irAEs). By using an integrated multiomics approach, we further studied the association between relevant tumor immune microenvironment (TIME) features and irAEs., Methods: Leveraging the US Food and Drug Administration Adverse Event Reporting System, we extracted cases of suspected irAEs to calculate the reporting odds ratios (RORs) of irAEs for cancers treated with immune checkpoint inhibitors (ICIs). TIME features for 32 cancer types were calculated on the basis of the cancer genomic atlas cohorts and indirectly correlated with each cancer's ROR for irAEs. A separate ICI-treated cohort of non-small-cell lung cancer (NSCLC) was used to evaluate the correlation between tissue-based immune markers (CD8 + , PD-1/L1+, FOXP3+, tumor-infiltrating lymphocytes [TILs]) and irAE occurrence., Results: The analysis of 32 cancers and 33 TIME features demonstrated a significant association between irAE RORs and the median number of base insertions and deletions (INDEL), neoantigens (r = 0.72), single-nucleotide variant neoantigens (r = 0.67), and CD8 + T-cell fraction (r = 0.51). A bivariate model using the median number of INDEL neoantigens and CD8 T-cell fraction had the highest accuracy in predicting RORs (adjusted r 2 = 0.52, P = .002). Immunoprofile assessment of 156 patients with NSCLC revealed a strong trend for higher baseline median CD8 + T cells within patients' tumors who experienced any grade irAEs. Using machine learning, an expanded ICI-treated NSCLC cohort (n = 378) further showed a treatment duration-independent association of an increased proportion of high TIL (>median) in patients with irAEs (59.7% v 44%, P = .005). This was confirmed by using the Fine-Gray competing risk approach, demonstrating higher baseline TIL density (>median) associated with a higher cumulative incidence of irAEs ( P = .028)., Conclusion: Our findings highlight a potential role for TIME features, specifically INDEL neoantigens and baseline-immune infiltration, in enabling optimal irAE risk stratification of patients.

Background: Primary cardiac soft tissue sarcomas (CSTS) affect young adults, with dismal outcomes., Objectives: The aim of this study was to investigate the clinical outcomes of patients with CSTS receiving immune checkpoint inhibitors (ICIs)., Methods: A retrospective, multi-institutional cohort study was conducted among patients with CSTS between 2015 and 2022. The patients were treated with ICI-based regimens. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Objective response rates were determined according to Response Evaluation Criteria in Solid Tumors version 1.1. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events version 5.0., Results: Among 24 patients with CSTS, 17 (70.8%) were White, and 13 (54.2%) were male. Eight patients (33.3%) had angiosarcoma. At the time of ICI treatment, 18 patients (75.0%) had metastatic CSTS, and 4 (16.7%) had locally advanced disease. ICIs were administered as the first-line therapy in 6 patients (25.0%) and as the second-line therapy or beyond in 18 patients (75.0%). For the 18 patients with available response data, objective response rate was 11.1% (n = 2 of 18). The median PFS and median OS in advanced and metastatic CSTS (n = 22) were 5.7 months (95% CI: 2.8-13.3 months) and 14.9 months (95% CI: 5.7-23.7 months), respectively. The median PFS and OS were significantly shorter in patients with cardiac angiosarcomas than in those with nonangiosarcoma CSTS: median PFS was 1.7 vs 11 months, respectively ( P  < 0.0001), and median OS was 3.0 vs 24.0 months, respectively ( P  = 0.008). Any grade treatment-related adverse events occurred exclusively in the 15 patients with nonangiosarcoma CSTS (n = 7 [46.7%]), of which 6 (40.0%) were grade ≥3., Conclusions: Although ICIs demonstrate modest activity in CSTS, durable benefit was observed in a subset of patients with nonangiosarcoma, albeit with higher toxicity., Competing Interests: Dr Abdel-Wahab is supported by a K01 Mentored Research Scientist Development Award from the National Institute of Allergy and Infectious Diseases (grant K01AI163412) and has received the University of Texas MD Anderson Cancer Center Institutional Research Grant, Division of Internal Medicine Development Award, Survivorship Seed Money Award, Prioritizing Research Innovation and Mentoring Excellence Award, and Melanoma SPORE Career Enhancement Program Award. Dr Nassar has received honoraria from OncLive, TEMPUS, and the Korean Society for Medical Oncology; and has received consulting fees from Guidepoint Global. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: Telomerase reverse transcriptase (TERT) gene promoter mutations have been explored, as biomarkers of improved survival for patients with cancer receiving immune checkpoint inhibitors. We sought to investigate their prevalence by race and sex across different cancer types to inform patient selection in clinical trials., Results: In this observational study, 31 925 patients with cancer underwent next-generation sequencing of their tumors with 88% (27 970) patients self-reported being Whites, 7.1% (2273) Asians, and 5.3% (1682) Blacks. Examining the distribution of TERT promoter mutations by race, White patients with melanoma harbored more TERT promoter mutations than Asian and Black patients (OR = 25.83; 95%CI, 6.84-217.42; P < .001). In contrast, Asian patients with head and neck cancer (HNC) harbored more TERT promoter mutations compared to White patients (OR = 2.47; 95%CI, 1.39-4.37; P = .004). In addition, the distribution of TERT promoter mutations differed by sex. Males were enriched for TERT gene promoter mutations compared to females with melanoma (OR = 1.82; 95%CI, 1.53-2.16; P < .001), cancer of unknown primary (OR = 1.96; 95%CI, 1.43-2.69; P < .001), hepatobiliary (OR = 3.89; 95%CI, 2.65-5.69; P < .001), and thyroid cancers (OR = 1.42; 95%CI, 1.10-1.84; P = .0087), while females were more enriched for TERT promoter mutations compared to males for HNC (OR = 0.56; 95%CI, 0.39-0.81; P = .0021)., Conclusions: The prevalence of TERT gene promoter mutations varies among patients with cancer based on race and sex. These findings inform our understanding of cancer biology and can assist in the design of future clinical trials that leverage drugs targeting TERT promoter dependencies., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Mismatch repair deficiency (dMMR) and microsatellite instability-high (MSI-H) occur in a subset of cancers and have been shown to confer sensitivity to immune checkpoint inhibition (ICI); however, there is a lack of prospective data in urothelial carcinoma (UC)., Methods and Analysis: We performed a systematic review to estimate the prevalence of dMMR and MSI-H in UC, including survival and clinical outcomes. We searched for studies published up to 26 October 2022 in major scientific databases. We screened 1745 studies and included 110. Meta-analyses were performed if the extracted data were suitable., Results: The pooled weighted prevalences of dMMR in bladder cancer (BC) and upper tract UC (UTUC) were 2.30% (95% CI 1.12% to 4.65%) and 8.95% (95% CI 6.81% to 11.67%), respectively. The pooled weighted prevalences of MSI-H in BC and UTUC were 2.11% (95% CI 0.82% to 5.31%) and 8.36% (95% CI 5.50% to 12.53%), respectively. Comparing localised versus metastatic disease, the pooled weighted prevalences for MSI-H in BC were 5.26% (95% CI 0.86% to 26.12%) and 0.86% (95% CI 0.59% to 1.25%), respectively; and in UTUC, they were 18.04% (95% CI 13.36% to 23.91%) and 4.96% (95% CI 2.72% to 8.86%), respectively. Cumulatively, the response rate in dMMR/MSI-H metastatic UC treated with an ICI was 22/34 (64.7%) compared with 1/9 (11.1%) with chemotherapy., Conclusion: Both dMMR and MSI-H occur more frequently in UTUC than in BC. In UC, MSI-H occurs more frequently in localised disease than in metastatic disease. These biomarkers may predict sensitivity to ICI in metastatic UC and resistance to cisplatin-based chemotherapy., Competing Interests: Competing interests None declared.

Background: Incorporating immune checkpoint blockade into perioperative cancer therapy has improved clinical outcomes. However, the safety of immune checkpoint blockade needs better evaluation, given the chances of more prolonged disease-free survival. We aimed to assess how adding immune checkpoint blockade to perioperative therapy affects treatment-related adverse events., Methods: For this systematic review and meta-analysis, we searched PubMed/MEDLINE, Embase, Web of Science, and the Cochrane Library from database inception until Aug 8, 2023, for randomised controlled trials that assessed the addition of immune checkpoint blockade to neoadjuvant or adjuvant therapy for cancer, reported treatment-related deaths, and had a design in which the experimental group assessed immune checkpoint blockade in combination with the therapy used in the control group. Meta-analysis was done to pool odds ratios (ORs) of treatment-related deaths, any grade and grade 3-4 treatment-related adverse events, serious adverse events, and adverse events leading to treatment discontinuation. The protocol is registered with PROSPERO, CRD42022343741., Findings: 28 randomised controlled trials with 16 976 patients were included. The addition of immune checkpoint blockade was not significantly associated with increased treatment-related deaths (OR 1·76, 95% CI 0·95-3·25; p=0·073), consistent across immune checkpoint blockade subtype (I 2 =0%). 40 fatal toxicities were identified across 9864 patients treated with immune checkpoint blockade, with pneumonitis being the most common (six [15·0%]); 13 fatal toxicities occurred among 7112 patients who were not treated with immune checkpoint blockade. The addition of immune checkpoint blockade increased the incidence of grade 3-4 treatment-related adverse events (OR 2·73, 95% CI 1·98-3·76; p<0·0001), adverse events leading to treatment discontinuation (3·67, 2·45-5·51; p<0·0001), and treatment-related adverse events of any grade (2·60 [1·88-3·61], p<0·0001). The immune checkpoint blockade versus placebo design primarily used as adjuvant therapy was associated with increased incidence of treatment-related deaths (4·02, 1·04-15·63; p=0·044) and grade 3-4 adverse events (5·31, 3·08-9·15; p<0·0001), whereas the addition of immune checkpoint blockade in the neoadjuvant setting was not associated with increased incidence of treatment-related death (1·11, 95% CI 0·38-3·29; p=0·84) or grade 3-4 adverse events (1·17, 0·90-1·51; p=0·23)., Interpretation: The addition of immune checkpoint blockade to perioperative therapy was associated with an increase in grade 3-4 treatment-related adverse events and adverse events leading to treatment discontinuation. These findings provide safety insights for further clinical trials assessing neoadjuvant or adjuvant immune checkpoint blockade therapy. Clinicians should closely monitor patients for treatment-related adverse events to prevent treatment discontinuations and morbidity from these therapies in earlier-stage settings., Funding: None., Competing Interests: Declaration of interests EA received travel compensation from the Prostate Cancer Foundation. AHN received funding from the Pain Research, Informatics, Multi-morbidities, and Education (PRIME) Center, US Veterans Health Administration, and honorarium from Tempus. AC received grant consultancies from AstraZeneca, MSD, OncoC4, Roche Access Infinity, AlphaSight, and Ardelis Health; speakers' fees from AstraZeneca, EISAI, and Pierre-Fabre; and travel support from Sanofi and MSD. AC also declares writing engagements with MSD and Bristol Myers Squibb. ARN reports funding to their institution for trials on which they are Principal Investigator: Loxo@Lilly, Surface Oncology, ADC Therapeutics, IGM Biosciences, EMD Serono, Aravive, Nikang Therapeutics, Inspirna, Exelexis, Revolution Medicine, Jacobio, Pionyr, Jazz Pharmaceuticals, and NGM Biopharmaceuticals. ARN receives compensation as a consultant editor of JCO Precision Oncology. ARN also reports travel compensation from the Society for Immunotherapy of Cancer, American Association for Cancer Research, Conquer Cancer Foundation, BinayTara Foundation, and Foundation Med. YF, NH, SZ, and ZA declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Treatment options for penile squamous cell carcinoma are limited. We sought to investigate clinical outcomes and safety profiles of patients with penile squamous cell carcinoma receiving immune checkpoint inhibitors., Methods: This retrospective study included patients with locally advanced or metastatic penile squamous cell carcinoma receiving immune checkpoint inhibitors between 2015 and 2022 across 24 centers in the United States, Europe, and Asia. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. Objective response rates were determined per Response Evaluation Criteria in Solid Tumours 1.1 criteria. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events, version 5.0. Two-sided statistical tests were used for comparisons., Results: Among 92 patients, 8 (8.7%) were Asian, 6 (6.5%) were Black, and 24 (29%) were Hispanic and/or Latinx. Median (interquartile range) age was 62 (53-70) years. In all, 83 (90%) had metastatic penile squamous cell carcinoma, and 74 (80%) had received at least second-line treatment. Most patients received pembrolizumab monotherapy (n = 26 [28%]), combination nivolumab-ipilimumab with or without multitargeted tyrosine kinase inhibitors (n = 23 [25%]), or nivolumab (n = 16 [17%]) or cemiplimab (n = 15 [16%]) monotherapies. Median overall and progression-free survival were 9.8 months (95% confidence interval = 7.7 to 12.8 months) and 3.2 months (95% confidence interval = 2.5 to 4.2 months), respectively. The objective response rate was 13% (n = 11/85) in the overall cohort and 35% (n = 7/20) in patients with lymph node-only metastases. Visceral metastases, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or higher, and a higher neutrophil/lymphocyte ratio were associated with worse overall survival. Treatment-related adverse events occurred in 27 (29%) patients, and 9.8% (n = 9) of the events were grade 3 or higher., Conclusions: Immune checkpoint inhibitors are active in a subset of patients with penile squamous cell carcinoma. Future translational studies are warranted to identify patients more likely to derive clinical benefit from immune checkpoint inhibitors., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)