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Molecular chaperones establish essential protein-protein interaction networks. Modified versions of these assemblies are generally enriched in certain maladies. A study published in Nature Communications used epichaperomics to identify unique changes occurring in chaperone-formed protein networks during mitosis in cancer cells. more...

Background: Data on the safety profiles and clinical outcomes of patients with solid tumors and cardiac metastasis treated with immune checkpoint inhibitors (ICIs) are limited., Methods: This is an international multicenter retrospective study of patients with cancer and cardiac metastasis at baseline. Patients who had received ≥1 dose of ICI were included. Treatment-related adverse events (trAEs) were graded per Common Terminology Criteria for Adverse Event V.5.0. Objective response rates (ORR) were evaluated by Response Evaluation Criteria in Solid Tumors V.1.1 when available. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method., Results: Among 110 pts, median age at ICI initiation was 65 (IQR: 59-75). Median follow-up time since ICI initiation was 36 (95% CI: 26 to 51) months. Melanoma (38%, n=42) and non-small cell lung cancer (24%, n=26) were the most common. 68 (62%) patients received ICIs as first-line, and 29 (26%) patients were treated with combination anti-programmed death-1 and anti-cytotoxic T-lymphocyte antigen 4. The most common location of cardiac metastasis was in the atria (37%, n=41) and ventricles (35%, n=39). 15 patients (13.6%) had bilateral cardiac/pericardial metastasis, 44 (40%) had left-sided, and 43 (39.8%) had right-sided. At ICI initiation, 21% (n=23) had a cardiac thrombus. Cardiology referrals and cardiac MRIs at the time of cancer diagnosis were completed on 58 (53%) and 52 (47%) patients, respectively. Cardiac events occurred in 40 (36%) patients, including arrhythmias (n=14, 13%), arterial/venous emboli (n=4, 3.6%), and cardiac tamponade (n=3, 2.7%). 53 (47%) patients developed trAEs; most common were colitis/diarrhea (n=16, 15%), dermatitis (n=13, 12%), and hepatitis (n=9, 8.2%). ICI-related major cardiac trAEs occurred in 2 (1.8%) patients. 22 patients (20%) developed grade ≥3 trAE. Patients with multiple cardiac metastases had significantly lower responses to ICI-based regimens compared with patients with single cardiac metastasis (11% vs 63%, p=0.02). For melanoma, ORR, median PFS, and median OS were 38%, 9.0 months, and 28.9 months, respectively. 83% of patients with melanoma had concordant responses in overall disease burden and cardiac disease. 91 patients discontinued ICIs, and the main reason was progression or death in 55 (49%) patients., Conclusions: Among patients with pre-existing cardiac metastasis, ICIs demonstrated meaningful clinical efficacy with no increase in safety signals. Most patients had concordant responses in the overall disease burden and cardiac mass. Multidisciplinary teams are crucial for the appropriate management of patients with cardiac metastasis., Competing Interests: Competing interests: AHN receives honoraria from OncLive, TEMPUS, and Korean Society for Medical Oncology. Consulting fees: Guidepoint Global. EHY: Research funding/grants from CSL Behring, Boehringer Ingelheim and Eli and Lilly, Bristol Myers Squibb, and Amgen. Consulting fees from Pfizer, Xencor. RRM: consultant/advisor: AstraZeneca, Ambrx, Aveo, Bayer, Blue Earth Diagnostics, Bristol-Myers Squibb, Calithera, Caris, Dendreon, Exelixis, Eisai, Johnson & Johnson, Lilly, Merck, Myovant, Novartis, Pfizer, Sanofi, Seagen, Sorrento, Telix, Tempus. AD: Ad Board/Consulting for: SeaGen, Astra Zeneca, Merck, EMD Serono, Exelixis, Eli Lilly, Infinity, Roche.DJP: Lecture fees: Bayer Healthcare, Astra Zeneca, EISAI, Bristol Myers-Squibb, Roche, Ipsen; Travel expenses: Bristol Myers-Squibb, Roche, Bayer Healthcare; Consulting fees: Mina Therapeutics, Boehringer Ingelheim, Ewopharma, EISAI, Ipsen, Roche, H3B, Astra Zeneca, DaVolterra, Mursla, Avammune Therapeutics, LiFT Biosciences, Exact Sciences; Research funding (to institution): MSD, BMS, GSK.Alessio Cortellini received grants for consultancies/advisory boards: BMS, MSD, OncoC4, IQVIA, Roche, GSK, AstraZeneca, Access Infinity, Ardelis Health and REGENERON. He also received speaker fees from AstraZeneca, EISAI, MSD, SANOFI/REGENERON and Pierre-Fabre. KN receives honorarium from Pfizer, Eisai, AstraZeneca, Eli Lilly, Takeda, Chugai, Fuji Film Pharma, PDR pharma, MSD, Boehringer Ingelheim, Ono, Daiichi-Sankyo, Bayer, Jansen, and Sanofi. Advisory board: Eisai, AstraZeneca, Sanofi, Genmab, Gliad, OncXerna, Takeda, Novartis, MSD, Henlius. Research support (to institution): MSD, Daiichi-Sankyo, Merck Biopharma, AstraZeneca, Taiho, Pfizer, Novartis, Takeda, Chugai, Ono, Sanofi, Seattle Genetics, Eisai, Eli Lilly, Genmab, Boehringer Ingelheim, Kyowa Hakko Kirin, Nihon Kayaku, Haihe. Principal investigator: MSD, Daiichi-Sankyo, AstraZeneca, Taiho, Merck Biopharma Pfizer, Novartis, Takeda, Chugai, Ono, Sanofi, Seattle Genetics, Eisai, Eli Lilly, Genmab, Boehringer Ingelheim, Kyowa Hakko Kirin, Nihon Kayaku, Haihe. SG received honoraria from BMS, MSD, Sanofi, Novartis, Medison, Merck Serono. JE receives honoraria from Roche, AstraZeneca, and BMS. Consulting: Roche. Expert testimony: Roche. Travel expenses: MSD. SD: consultancy role with AstraZeneca, Gilead Sciences, Pfizer, Novartis, Myocardial Solutions, Eli Lilly none relevant to this manuscript. Funding: None. TKC 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, Neomorph, Nuscan/PrecedeBio, 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; 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; Mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/Foreign Components; The institution (Dana-Farber Cancer Institute) may have received additional independent funding from drug companies or/and royalties potentially involved in research around the subject matter; TKC is supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE (2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, Pan Mass Challenge, Hinda and Arthur Marcus Fund and Loker Pinard Funds for Kidney Cancer Research at DFCI. 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, Exelexis, 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 Funding: None., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.) more...

The incidence of gastroesophageal cancers is rising, driven, in part, by an increasing burden of risk factors of obesity and gastroesophageal reflux. Despite efforts to address these risk factors, and a growing interest in methods of population screening, the bulk of these tumours are unresectable at diagnosis. In this setting, effective systemic treatments are paramount to improve survival and quality of life. Early and accurate identification of oncogenic drivers, such as human epidermal growth factor receptor 2 (HER2), present in 5-30% of gastroesophageal adenocarcinomas (GEAs), is integral to guide choice of therapies due to the clear predictive implications that arise from overexpression of this receptor. After trastuzumab, the first anti-HER2 agent with approved use in HER2-positive GEA, the addition of pembrolizumab to first-line trastuzumab-chemotherapy and trastuzumab deruxtecan in the refractory space have more recently changed practice. Yet, the response to these agents has been vastly different across patients with HER2-positive disease, underpinning the need for reliable biomarkers of response. Emergent data have suggested that levels of HER2 expression on tissue or liquid biopsies may predict response to first-generation HER2 therapies while HER2 heterogeneity, receptor changes, co-occurring molecular alterations and oncogenic genomic and metabolic reprogramming may be implicated in resistance. A robust knowledge of the mechanisms of resistance and response to HER2-directed therapies is necessary to inform novel strategies of HER2-targeting and guide choice combinations with other biomarker-directed therapies, to improve outcomes from a new generation of clinical trials in HER2-positive GEA. Understanding and close examination of previous failures in this space form an important part of this assessment, as does correlative biomarker and translational work pertaining to the role of HER2 and dynamic changes that result through treatment exposure. In this review, we aim to provide an overview of strategies for HER2 targeting, summarising both the successes and disappointments in this therapeutic landscape and discuss existing challenges and future perspectives on development in this highly morbid tumour type., Competing Interests: Declarations. Funding: No external funding was used in the preparation of this manuscript. Conflicts of Interest: Elizabeth Catherine Smyth reported grants and personal fees from BMS and AstraZeneca; personal fees from Amgen, Daiichi-Sankyo, Merck, Viracta, Astellas, Novartis, Pfizer, Zymeworks, and BeiGene; personal fees and non-financial support from Mirati; support by the NIHR Biomedical Research Centre at Oxford. Elizabeth Catherine Smyth is an Editorial Board member of Drugs. Elizabeth Catherine Smyth was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Antonella Cammarota and Rachel Woodford declare that they have no conflicts of interest that might be relevant to the contents of this manuscript. Ethics Approval: Ethics approval was not required for the formulation of this review. Consent to Participate: Not applicable. Consent for Publication: Consent for publication was not required for this review. Availability of Data and Material: All data used in this review are available online through the given references. Code Availability: No coding was used in the formulation of this review. Author Contributions: All authors have contributed to the design, data collection and interpretation, drafting and critical review of the manuscript, and have approved its final version., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.) more...

Introduction: Approximately 50 % of resected stage II-IV melanoma patients develop recurrent disease by 5 years despite adjuvant anti-PD-1 therapy. Data to define best management of recurrences is lacking., Methods: This was a multicentre, international, retrospective cohort study. Patients with resected stage II-IV melanoma who commenced adjuvant anti-PD-1-based therapy before January 2022 and later recurred were identified. Data on demographics, disease characteristics, recurrence patterns, management and outcomes were collected., Results: 711 patients from 17 sites were included. Median age was 60 [range 16-92], 64 % were male, 2 % stage II, 91 % were stage III, 7 % stage IV. Median time to recurrence was 6.2 months (0-68.5) and median follow up time from recurrence was 19.8 months (range 0.2-73.1). 63 % recurred on anti-PD-1 therapy, 36 % off therapy [3 % < 6 months, 33 % > 6 months]. Initial recurrences were locoregional (LR) alone in 44 %, distant alone (DR) in 43 %, and 11 % in both sites. LR recurrences were managed with local therapy, alone (62 %) or with "second adjuvant" anti-PD-1 (14 %) or BRAF/MEK therapy (23 %); 12 m RFS2 was 25 %, 29 % and 69 % respectively (p = 0.0045). Definitive systemic therapy at first recurrence was given in 16 % LR and 86 % DR, with best outcomes for anti-CTLA4 + anti-PD-1 and trial combinations (24 m PFS 63 % and 69 %, respectively). The 24 m OS for the entire cohort was 65 %., Conclusion: Most recurrences following adjuvant anti-PD-1 based therapy occur early and while still on drug. Outcomes are poor, regardless of site, timing of recurrence, and subsequent treatment., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AMM has served on advisory boards for BMS, MSD, Novartis, Roche, Pierre-Fabre, and Qbiotics. JK has received research funding from LEO Pharma, honorium from BMS, Amgen, Janssen; and educational funding from MSD, Janssen and Astra Zeneca. RRT has served on advisory boards for BMS, MSD, Amgen, Pierre-Fabre, Astra Zeneca and Roche. CL has received research funding from BMS, Roche, consulting fees from BMS, Pierre-Fabre, Sanofi, Novartis, MSD, Amgen, Merck Serono, Roche and Iflax; speaking fees from Amgen, BMS, Pierre-Fabre, Sanofi, Novartis, MSD, Incyte, Pfizer, Roche; and travel funding from BMS, MSD, Novartis, Pierre-Fabre, Roche, Sanofi and served on advisory boards for BMS, Pierre Fabre, Sanofi, Novartis, MSD, Magen, Merck Serono, Roche and Inflax. CA has received travel funding from BMS, Roche and Amgen and speaking fees from Novartis. RJS has served on advisory boards for Merck, Novartis, Pfizer, and Replimune and receives grant funding from Merck. CR has served on advisory boards for Pierre Fabre, Sanofi, BMS, MSD, Novartis, Merck, Roche, Pfizer, Sun Pharma, Ultimovacs, Regeneron, Egle, Philogen, Maat Pharma; involved in steering committees for Novartis, Regeneron, Pfizer and IO Biotech and a consultant IDMC for Ultimovacs; received speaking fees from Pierre Fabre, Sanofi, BMS, MSD and Novartis and travel funding from Pierre Fabre. JM has intermittent project focused consultant or advisory relationships with Merck Sharp & Dohme, Novartis, Bristol Myers Squibb, Johnson & Johnson, and Pierre Fabre and has received travel support from L′ Oreal, Merck Sharp & Dohme, Bristol Myers and Squibb and Pierre Fabre outside of the submitted work. MSC has served on advisory boards or as a consultant for Amgen, BMS, Eisai, Ideaya, MSD, Nektar, Novartis, Oncosec, Pierre Fabre, Qbiotics, Regeneron, Roche, Merck, and Sanofi and received honoraria from BMS, MSD, and Novartis. DBJ has served on advisory boards or as a consultant for AstraZeneca, BMS, The Jackson Laboratory, Mallinckrodt, Merck, Mosaic ImmunoEngineering, Novartis, Pfizer, Targovax, and Teiko, and has received research funding from BMS and Incyte. BN has received financial compensation from Novartis, Roche, BMS, MSD, and Pierre-Fabre for service on advisory boards and speaking engagements; and institutional research funding from Pfizer, Novartis, Roche and Merck-Serono. VR has received honoraria from AstraZeneca and has received travel and education funding from MSD and Novartis. PAA has served as a consultant for BMS, MSD, Roche-Genentech, Ventana, Novartis, Amgen and Array and received research funding from BMS, Roche-Genentech and Ventana. JW has served as a consultant for Merck, Genentech, AstraZeneca, GSK, Novartis, Nektar, Celldex, Incyte, Biond, Moderna, ImCheck, Sellas, Evaxion, Pfizer, Regeneron, EMD Serono, and Bristol Myers Squibb; has had equity roles in Biond, Evaxion, OncoC4, and Instill Bio; received institutional research support from Bristol Myers Squibb, Merck, GSK, Moderna, Pfizer, Novartis, and AstraZeneca; served in scientific advisory roles with CytomX, Incyte, ImCheck, Biond, Sellas, Instill Bio, OncoC4, and NexImmune; and holds patent agreements with Moffitt Cancer Center and Biodesix. PR has received honoraria from BMS, MSD, Novartis, Pierre-Fabre, Merck and Sanofi; and served in an advisory capacity for MSD, BMS, Sanofi, Pierre-Fabre, Blueprint Medicines and Philogen. GAM has received institutional research funding through Roche-Genentech, MSD, Roche, and BMS and other funding through Novartis and BMS. SH has served as a consultant for Amgen, Genmab, Xencor, Astellas Pharma, Regeneron, and Nektar. AA has served as a consultant for BMS, Roche, Novartis, Pierre Fabre, MSD, Merck, Sanofi; received speaking fees from Pierre Fabre, Novartis, MSD, BMS, Roche, Merck, Sanofi; institutional funding from Pierre-Fabre, Novartis, Roche, BMS, MSD, Merck and Sanofi; and travel funding from BMS, MSD, Novartis, Pierre-Fabre. AH has served on an advisory board for BMS, MSD and Novartis. RD has received honoraria from Roche, Novartis, Bristol Myers Squibb, MSD, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, CatalYm, Second Genome, Regeneron, Alligator Bioscience, MaxiVax, touchIME, T3 Pharmaceuticals, Pfizer; served as a consultant for Roche, Bristol Myers Squibb, MSD, Novartis, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, CatalYm, Second Genome, Alligator Bioscience, touchIME, MaxiVax, Regeneron, Pfizer, T3 Pharmaceuticals and received institutional research funding from Roche, BMS, Novartis, MSD and Amgen. CUB has served as a consultant for AstraZeneca, Bristol-Myers Squibb, GenMab, GlaxoSmithKline, Lilly, MSD Oncology, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, and Third Rock Ventures; received institutional research funding from SC, Bristol-Myers Squibb, NanoString Technologies, and Novartis; provided expert testimony for Freshfields Bruckhaus Deringer; received travel funding from BMS; and has ownership interest in Immagene and Signature Oncology. GVL has received honoraria from BMS, Pierre-Fabre and received served as a consultant for Agenus, Amgen, Array BioPharma, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion Biotech, Hexal AG (Sandoz Company), Highlight Therapeutics, Innovent Biologics USA Inc, Merck Sharp & Dohme, Novartis, OncoSec Medical Australia, PHMR Limited, Pierre Fabre, Provectus, QBiotics, Regeneron, and AstraZeneca. The remaining authors have nothing to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.) more...

The superior productivity of C 4 plants is achieved via a metabolic C 4 cycle which acts as a CO 2 pump across mesophyll and bundle sheath (BS) cells and requires an additional input of energy in the form of ATP. The importance of chloroplast NADH dehydrogenase-like complex (NDH) operating cyclic electron flow (CEF) around Photosystem I (PSI) for C 4 photosynthesis has been shown in reverse genetics studies but the contribution of CEF and NDH to cell-level electron fluxes remained unknown. We have created gene-edited Setaria viridis with null ndhO alleles lacking functional NDH and developed methods for quantification of electron flow through NDH in BS and mesophyll cells. We show that CEF accounts for 84% of electrons reducing PSI in BS cells and most of those electrons are delivered through NDH while the contribution of the complex to electron transport in mesophyll cells is minimal. A decreased leaf CO 2 assimilation rate and growth of plants lacking NDH cannot be rescued by supplying additional CO 2 . Our results indicate that NDH-mediated CEF is the primary electron transport route in BS chloroplasts highlighting the essential role of NDH in generating ATP required for CO 2 fixation by the C 3 cycle in BS cells., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.) more...

Background: Anti-PD-1 antibodies and BRAK/MEK inhibitors (BRAF/MEKi) reduce the risk of recurrence for patients with resected stage III melanoma. BRAFV600-mutated (BRAFmut) melanoma patients who recur with isolated disease following adjuvant therapy may be suitable for 'second adjuvant' treatment after local therapy. We sought to examine the efficacy and safety of 'second adjuvant' BRAF/MEKi., Patients and Methods: Patients with BRAFmut melanoma treated with adjuvant PD-1 based immunotherapy who recurred, underwent definitive local therapy and were then treated with adjuvant BRAF/MEKi were identified retrospectively from 13 centres (second adjuvant group). Demographics, disease and treatment characteristics and outcome data were examined. Outcomes were compared to BRAFmut patients who did not receive 'second adjuvant' therapy (no second adjuvant group)., Results: 73 patients were included; 61 who received 'second adjuvant' therapy and 12 who did not. Most initially recurred on PD-1 therapy (66%). There were no differences in characteristics between groups. 92% of second adjuvant group received dabrafenib and trametinib and median duration of therapy was 11.8 months (0.4, 34.5). 72% required dose adjustments, 23% had grade 3 + toxicity and 38% permanently discontinued drug due to toxicity. After median 26.1 months (1.9, 56.3) follow-up, recurrence-free survival (RFS) was improved in second adjuvant group versus no second adjuvant group (median 30.8 vs 4 months, HR 0.35; p = 0.014), largely driven by a delay in early recurrence, with no difference in overall survival (p = 0.59)., Conclusion: This is the first study examining outcomes of 'second adjuvant' targeted therapy for melanoma, after failure of adjuvant PD-1 based immunotherapy. Data suggest a short-term improvement in RFS, but at the cost of toxicity. Alternative strategies and more data on sequencing adjuvant therapies are required to improve outcomes., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Disclosures: AMM has served on advisory boards for BMS, MSD, Novartis, Roche, Pierre-Fabre. DBJ has served on advisory boards or as a consultant for BMS, Catalyst Biopharma, Iovance, Mallinckrodt, Merck, Mosaic ImmunoEngineering, Novartis, Oncosec, Pfizer, Targovax, and Teiko, and has received research funding from BMS and Incyte. LZ declares speakers and advisory board honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, Sunpharma, research support from Novartis and travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sanofi, Sunpharma and Novartis; outside the submitted work. CH reports speaker and advisory board honoraria from Almirall, BMS, MSD, Novartis, Pierre Fabre Regeneron, Roche, Sanofi Aventis. GVL is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, OncoSec, PHMR Ltd, Pierre Fabre, Provectus, Qbiotics, Regeneron. PAA has/had a consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, AstraZeneca, Sun Pharma, Sanofi, Sandoz, Immunocore, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTeos, Medicenna, Bio-Al Health, ValoTX, Replimmune, Bayer, Erasca. He also received research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer, Sanofi. Travel support by Pfizer, Bio-Al Health, Replimmune. JP received travel support from Pierre Fabre, MSD, BMS, Novartis outside the scope of this study. JMR received speaker honoraria from Bristol-Myers Squibb, Roche, Amgen and Novartis and travel support by Sanofi, Roche, and Bristol-Myers Squibb through institution. MSC is a consultant advisor for Amgen, BMS, Eisai, Ideaya, MSD, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche, Merck and Sanofi, and received honoraria from BMS, MSD, Sanofi and Novartis. AH declares speakers and advisory board honoraria from Almirall, Bristol-Myers Squibb, Dermagnostix, Eisai, Highlight Therapeutics, Immunocore, Incyte, IO Biotech, KyowaKirin, MerckPfizer, Merck Sharp & Dohme, Neracare, Novartis, Philogen, Pierre Fabre, Regeneron, Replimune, Sanofi-Genzyme, Seagen, SunPharma, Xenthera; outside the submitted work. The remaining authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.) more...

Purpose: In sentinel node-positive (SN+ve) melanoma patients, active surveillance with regular ultrasound examination of the node field has become standard, rather than completion lymph node dissection (CLND). A proportion of these patients now receive adjuvant systemic therapy and have routine cross-sectional imaging (computed tomography [CT] or positron emission tomography [PET]/CT). The role of concurrent ultrasound (US) surveillance in these patients is unclear. The purpose of our study was to describe the modality of detection of nodal recurrence in SN+ve node fields., Methods: SN+ve melanoma patients who did not undergo CLND treated at a single institution from January 1, 2016 to December 31, 2020 were included., Results: A total of 225 SN+ve patients with a median follow-up of 23 months were included. Of these, 119 (53%) received adjuvant systemic therapy. Eighty (36%) developed a recurrence at any site; 24 (11%) recurred first in the SN+ve field, of which 12 (5%) were confirmed node field recurrence only at 2 months follow-up. The nodal recurrences were first detected by ultrasound in seven (3%), CT in seven (3%), and PET/CT in seven (3%) patients. All nodal recurrences evident on US were also evident on PET/CT and vice versa., Conclusions: The high rate of recurrences outside the node field and the identification of all US-detected nodal recurrences on concurrent cross-sectional imaging modalities suggest that routine concurrent ultrasound surveillance of the node-positive field may be unnecessary for SN+ve melanoma patients having routine cross-sectional imaging., (© 2023. The Author(s).) more...

Purpose: Progression-free survival (PFS)-2, defined as the time from randomization to progression on second-line therapy, is potentially a more reliable surrogate than PFS for overall survival (OS), but will require longer follow-up and a larger sample size. We sought to compare the validity and efficiency, defined as proportional increase in follow-up time and sample size, of PFS-2 to PFS., Methods: We performed an electronic search to identify randomized trials of advanced solid tumors reporting PFS, PFS-2, and OS as prespecified end points. Only studies that had protocols that defined measurement of PFS-2 and follow-up for patients after first disease progression were included. We compared correlations in the relative treatment effect for OS with PFS and PFS-2. We reconstructed individual patient data from survival curves to estimate time to statistical significance (TSS) of the relative treatment effect. We further computed the sample size (person-year [PY] follow-up) required to reach statistical significance., Results: Across the 42 analysis units and 21,255 patients, the correlation of the relative treatment effect between OS and PFS-2, r , was 0.70 (95% CI, 0.41 to 0.80) and r = 0.46 (95% CI, 0.26 to 0.74) for OS and PFS. The median differences in TSS between OS with PFS, OS with PFS-2, and PFS with PFS-2 were 16.59 (95% CI, 4.48 to not reached [NR]), 10.0 (95% CI, 2.2 to NR), and 4.31 (95% CI, 2.92 to 13.13) months, respectively. The median difference in PYs required to reach statistical significance for PFS-2 over PFS was 156 (95% CI, 82 to 500) PYs, equivalent to an estimated median 12.7% increase in PYs., Conclusion: PFS-2 offers improved correlation with OS than PFS with a modest increase in follow-up time and sample size. PFS-2 should be considered as a primary end point in future trials of advanced cancers. more...

Background: The combination of nivolumab + relatlimab is superior to nivolumab alone in the treatment of naive patients and has activity in PD-1 refractory melanoma. We had previously observed a reduced expression of LAG3 in melanoma tissue from patients with type 2 diabetes., Method: To evaluate the impact of diabetes on oncological outcomes of patients with advanced melanoma treated with nivolumab plus the LAG3 inhibitor relatlimab we performed a retrospective multicenter study., Results: Overall, 129 patients were included: 88 without diabetes before the treatment, 37 who were diagnosed with type 2 diabetes before the start of treatment, and 4 without diabetes before treatment who developed immune checkpoint inhibitor-induced diabetes (ICI-DM). PFS was 21.71 months (95% CI: 15.61-27.81) in patients without diabetes, 10.23 months (95% CI: 5.81-14.66) in patients with type 2 diabetes, and 50.85 months (95% CI: 23.04-78.65) in patients who developed ICI-DM. OS was 37.94 months (95% CI: 31.02-44.85) in patients without diabetes, 22.12 months (95% CI: 14.41-29.85) in those with type 2 diabetes and 57.64 months (95% CI: 42.29-72.99) in those who developed ICI-DM. Multivariate analysis showed that the presence of diabetes and LDH was correlated with OS and PFS. The mean OS was 64.63 months in subjects with low levels of glucose (< 137 mg/dl) and 36.27 months in those with high levels (hazard ratio 0.16, 95% CI: 0.04-0.58; p = 0.005). The patients whose glucose blood level increased after 3 months of treatment with nivolumab + relatinib compared to baseline (ratio of blood level at baseline/after 3 months > 1.5) had a worse prognosis than those whose glucose level had not increased. This result was observed also in subgroups treated either in first line or further lines. Patients who developed ICI-DM during the study period had better outcomes than the overall population and patients without diabetes., Conclusions: LAG3 inhibition for treating metastatic or unresectable melanoma has a reduced efficacy in patients with type 2 diabetes, possibly due to a low expression of LAG3 in tumor tissue. Higher level evidence should be obtained., (© 2023. BioMed Central Ltd., part of Springer Nature.) more...