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Platinum‐based compounds remain a well‐established chemotherapy for cancer treatment despite their adverse effects which substantially restrict the therapeutic windows of the drugs. Both the cell type‐specific toxicity and the clinical responsiveness of tumors have been associated with mechanisms that alter drug entry and export. We sought to identify pharmacological agents that promote cisplatin (CP) efficacy by augmenting the levels of drug‐induced DNA lesions in malignant cells and simultaneously protecting normal tissues from accumulating such damage and from functional loss. Formation and persistence of platination products in the DNA of individual nuclei were measured in drug‐exposed cell lines, in primary human tumor cells and in tissue sections using an immunocytochemical method. Using a mouse model of CP‐induced toxicity, the antihistaminic drug diphenhydramine (DIPH) and two methylated derivatives decreased DNA platination in normal tissues and also ameliorated nephrotoxicity, ototoxicity, and neurotoxicity. In addition, DIPH sensitized multiple cancer cell types, particularly ovarian cancer cells, to CP by increasing intracellular uptake, DNA platination, and/or apoptosis in cell lines and in patient‐derived primary tumor cells. Mechanistically, DIPH diminished transport capacity of CP efflux pumps MRP2, MRP3, and MRP5 particularly in its C2+C6 bimethylated form. Overall, we demonstrate that DIPH reduces side effects of platinum‐based chemotherapy and simultaneously inhibits key mechanisms of platinum resistance. We propose that measuring DNA platination after ex vivo exposure may predict the responsiveness of individual tumors to DIPH‐like modulators. [ABSTRACT FROM AUTHOR]

Introduction Ovarian carcinoma is associated with the highest mortality of all gynecologic malignancies. Even after optimal treatment, prognosis remains poor. There is no established biomarker to predict individual patient outcome. Objective To evaluate the prognostic significance of PD-1 and PD-L1 expression in tumor tissues from patients with ovarian cancer. Methods Tissue micro-arrays were prepared from routinely formalin-fixed, paraffin-embedded tumor tissues and examined immunohistochemically for the expression of programed cell death protein 1 (PD-1) and one of its ligands (PD-L1) on epithelial tumor cells, as well as on tumor- and stroma-infiltrating immune cells. Results The presence of PD-1 positive tumor-infiltrating immune cells was significantly associated with prolonged overall survival. PD-1 and PD-L1 positive tumor-infiltrating immune cells were associated with the presence of lymph node metastases and higher tumor grade. Interestingly, the amount of PD-1/PD-L1 positive tumor- and stroma-infiltrating immune cells independent of PD-1 or PD-L1 expression did not show any significant correlation with prognostic variables. Conclusion Our results highlight the prognostic value of PD-1 and PD-L1 positive tumor-infiltrating immune cells in ovarian carcinoma. Their association with favorable prognosis supports the hypothesis that the expression of PD-1 and PD-L1 on tumor-infiltrating immune cells represents a strong immune response. [ABSTRACT FROM AUTHOR]

Objective: Cancer-field surgery by peritoneal mesometrial resection and targeted compartmental lymphadenectomy (PMMR+TCL) for the treatment of endometrial cancer (EC) aims at optimal locoregional tumor control without the need for adjuvant radiotherapy. In a previous publication we could demonstrate the feasibility of the method and presented encouraging first oncologic data., Methods: Following up our 2021 publication, we present data on the treatment of EC by PMMR+TCL in much larger cohort and with longer follow-up., Results: One hundred and thirty-five patients with EC International Federation of Gynecology and Obstetrics (FIGO) I-IV (75.6% FIGO I) underwent cancer field surgery via PMMR+TCL for EC in the years 2016-2023. Mean follow-up in our cohort was 27.5 months (0, 83; 19.7). The procedure was feasible and safe with favorable intra-and postoperative complication rates. Even though 50.4% of patients had an indication for postoperative radiotherapy following national and international guidelines, the rate of postoperative irradiation administered was 10.4%. The overall recurrence rate was 8.1% and we observed 2 (1.5%) isolated locoregional recurrences., Conclusion: Our results confirm the feasibility and safety of PMMR+TCL in EC patients. Oncologic data are very encouraging and hint at a superior locoregional control without adjuvant irradiation. Larger studies with longer follow-up will be needed to confirm these results., Competing Interests: Rainer Kimmig declares Proctoring and Presentations for Intuitive Surgical Inc., Advisory Board and Presentations for Medtronic; Advisory Board for Medicaroid. The other authors declare no conflict of interest., (© 2024. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Background: The underlying mechanism of high T-cell presence as a favorable prognostic factor in high-grade serous ovarian carcinoma (HGSOC) is not yet understood. In addition to immune cells, various cofactors are essential for immune processes. One of those are metallothioneins (MTs), metal-binding proteins comprising various isoforms. MTs play a role in tumor development and drug resistance. Moreover, MTs influence inflammatory processes by regulating zinc homeostasis. In particular, T-cell function and polarization are particularly susceptible to changes in zinc status. The aim of the present study was to investigate a possible role of MT-mediated immune response and its association with prognostic outcome in ovarian cancer., Methods: A retrospective study was conducted on a clinically well-characterized cohort of 24 patients with HGSOC treated at the University Hospital of Essen. Gene expression patterns for anti-cancer immunogenicity-related targets were performed using the NanoString nCounter platform for digital gene expression analysis with the appurtenant PanCancer Immune Profiling panel, consisting of 770 targets and 30 reference genes. Tumor-associated immunohistochemical MT protein expression was evaluated using a semi-quantitative four-tier Immunohistochemistry (IHC) scoring., Results: MT immunoexpression was detected in 43% (10/23) of all HGSOC samples. MT immunoexpression levels showed a significant association to survival, leading to prolonged progression-free and overall survival in positively stained tumors. Furthermore, T-cell receptor signaling gene signature showed a strong activation in MT-positive tumors. Activated downstream signaling cascades resulting in elevated interferon-gamma expression with a shift in the balance between T helper cells (T H 1 and T H 2) could be observed in the MT-positive subgroup. In addition, a higher expression pattern of perforin and several granzymes could be detected, overall suggestive of acute, targeted anti-cancer immune response in MT-positive samples., Conclusion: This is the first study combining broad, digital mRNA screening of anti-tumor immune response-associated genes and their relation to MT-I/II in ovarian cancer. MT overexpression is associated with molecular characteristics of an anti-cancer immune response and is a strong prognostic marker in ovarian HGSOC. The observed immune cell activation associated with tumor MT expression comprises but is not limited to T cells and natural killer cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mairinger, Wessolly, Buderath, Borchert, Henrich, Mach, Steinborn, Kimming, Jasani, Schmid, Bankfalvi and Mairinger.)

Background: In the PAOLA-1/ENGOT-ov25 primary analysis, maintenance olaparib plus bevacizumab demonstrated a significant progression-free survival (PFS) benefit in newly diagnosed advanced ovarian cancer patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab, irrespective of surgical status. Prespecified, exploratory analyses by molecular biomarker status showed substantial benefit in patients with a BRCA1/BRCA2 mutation (BRCAm) or homologous recombination deficiency (HRD; BRCAm and/or genomic instability). We report the prespecified final overall survival (OS) analysis, including analyses by HRD status., Patients and Methods: Patients were randomized 2 : 1 to olaparib (300 mg twice daily; up to 24 months) plus bevacizumab (15 mg/kg every 3 weeks; 15 months total) or placebo plus bevacizumab. Analysis of OS, a key secondary endpoint in hierarchical testing, was planned for ∼60% maturity or 3 years after the primary analysis., Results: After median follow-up of 61.7 and 61.9 months in the olaparib and placebo arms, respectively, median OS was 56.5 versus 51.6 months in the intention-to-treat population [hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.76-1.12; P = 0.4118]. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 105 (19.6%) olaparib patients versus 123 (45.7%) placebo patients. In the HRD-positive population, OS was longer with olaparib plus bevacizumab (HR 0.62, 95% CI 0.45-0.85; 5-year OS rate, 65.5% versus 48.4%); at 5 years, updated PFS also showed a higher proportion of olaparib plus bevacizumab patients without relapse (HR 0.41, 95% CI 0.32-0.54; 5-year PFS rate, 46.1% versus 19.2%). Myelodysplastic syndrome, acute myeloid leukemia, aplastic anemia, and new primary malignancy incidence remained low and balanced between arms., Conclusions: Olaparib plus bevacizumab provided clinically meaningful OS improvement for first-line patients with HRD-positive ovarian cancer. These prespecified exploratory analyses demonstrated improvement despite a high proportion of patients in the placebo arm receiving poly(ADP-ribose) polymerase inhibitors after progression, confirming the combination as one of the standards of care in this setting with the potential to enhance cure., Competing Interests: Disclosure IRC reports honoraria (personal) from AbbVie, Agenus, Advaxis, Bristol Myers Squibb (BMS), PharmaMar, Genmab, Pfizer, AstraZeneca, Roche, GlaxoSmithKline (GSK), Merck Sharp & Dohme (MSD), Deciphera, Mersana, Merck Sereno, Novartis, Amgen, Tesaro, and Clovis; honoraria (institution) from GSK, MSD, Roche, and BMS; advisory/consulting fees from AbbVie, Agenus, Advaxis, BMS, PharmaMar, Genmab, Pfizer, AstraZeneca, Roche/Genentech, GSK, MSD, Deciphera, Mersana, Merck Sereno, Novartis, Amgen, Tesaro, and Clovis; research grant/funding (self) from MSD, Roche, and BMS; research grant/funding (institution) from MSD, Roche, BMS, Novartis, AstraZeneca, and Merck Sereno; and travel support from Roche, AstraZeneca, and GSK. AL reports grants from AstraZeneca and Sanofi; consulting fees from Seattle Genetics; honoraria/reimbursement and advisory board fees from AstraZeneca; advisory board fees or continuing medical education from Ability Pharma, Biocad, Clovis Oncology, GSK, Medscape, Merck Serono, MSD, TouchCongress, and Zentalis; support for attending meetings and/or travel from AstraZeneca, Clovis Oncology, GSK, and Roche; and participation on a data safety monitoring board or advisory board for ARIEL4 and TROPHIMMUNE. SP reports honoraria from AstraZeneca, Roche, MSD, Pfizer, Tesaro, Clovis Oncology, GSK, and PharmaMar; and research funding (institution) from Roche, MSD, AstraZeneca, and Pfizer. AGM reports advisory/consultancy fees (personal) from Alkermes, Amgen, AstraZeneca, Clovis Oncology, Eisai, Genmab, GSK, Hedera Dx, Illumina, ImmunoGen, MSD, Macrogenics, Mersana, Novartis, Oncoinvent, PharmaMar, Roche, Regeneron, Sotio, and Sutro; speaker bureau fees (personal) from AstraZeneca, Roche, GSK, MSD, Novocure, Takeda, Zai Lab, and Clovis; research grant/funding (institution) from Roche, Novartis, GSK, and Aravive; and steering committee member (personal) for MSD. CM reports honoraria/consulting fees (personal) from Roche, Novartis, Amgen, MSD, PharmaMar, AstraZeneca, GSK, and Seagen; participation on an advisory board from Roche, Novartis, Amgen, MSD, PharmaMar, AstraZeneca, GSK, and Seagen; and travel expenses from Roche and AstraZeneca. SN reports honoraria (self) from AstraZeneca, Chugai, Mochida, MSD, Takeda, and Terumo; and research grant (self) from AstraZeneca. IV reports consulting fees from Agenus, Akesobio, AstraZeneca, BMS, Deciphera Pharmaceuticals, Eisai, Elevar Therapeutics, F. Hoffmann-La Roche, Genmab, GSK, Immunogen, Jazzpharma, Karyopharm, Mersana, MSD, Novocure, Novartis, Oncoinvent, OncXerna, Sanofi, Seagen, Sotio, Verastem Oncology, and Zentalis; contracted research funding (via KULeuven) from Oncoinvent AS; corporate sponsored research funding from Amgen and Roche; and accommodation and travel expenses from Karyopharm. NC reports research grants from AstraZeneca, PharmaMar, and Roche; honoraria for lectures from AstraZeneca, Tesaro, Novartis, Clovis Oncology, MSD, GSK, and Eisai; honoraria for advisory boards from Roche, PharmaMar, AstraZeneca, Clovis Oncology, MSD, GSK, Tesaro, Pfizer, BIOCAD, ImmunoGen, Mersana Therapeutics, Eisai, and OncXerna Therapeutics; and is a steering committee member on ESMO clinical guidelines and a scientific committee chair for Acto Onlus. JM reports honoraria from AstraZeneca and GSK. FS reports honoraria from AstraZeneca, GSK Tesaro, MSD, Sandoz (Novartis), and Clovis Oncology; and institutional financial support from Roche, GSK Tesaro, AstraZeneca, Immunogen, MSD, Incyte, and Agenus. JS reports grants or contracts from Roche Pharma, AstraZeneca, Bayer, Clovis, GSK, Lilly, Tesaro, consulting fees from Tesaro, Merck, Pfizer, PharmaMar, Clovis Oncology, AstraZeneca, Roche Pharma, GSK, MSD, Eisai, Novocure, Oncoinvent, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Tesaro, GSK, PharmaMar, AstraZeneca, Clovis, Bayer, Roche, PharmaMar, Vifor Pharma, Hexal AG, Novartis Pharma. DL reports consultancy fees (personal) from AstraZeneca, Clovis Oncology, Genmab, GSK, Immunogen, MSD, PharmaMar, Novartis, and Seagen; membership on an advisory board (personal) from AstraZeneca, Clovis Oncology, Corcept, Genmab, GSK, Immunogen, MSD, Oncoinvest, PharmaMar, Seagen, and Sutro; research funding (institutional) from AstraZeneca, Clovis Oncology, Genmab, GSK, Immunogen, Incyte, MSD, Novartis, PharmaMar, Roche, and Seagen; and travel support from Roche, PharmaMar, AstraZeneca, Clovis Oncology, and GSK. EMGA reports consulting fees from AstraZeneca–MSD, Clovis Oncology, GSK–Tesaro, PharmaMar, and Roche; speaker bureau/expert testimony honorarium from AstraZeneca–MSD, PharmaMar, Roche, GSK–Tesaro, and Clovis Oncology; and travel support from Roche, GSK–Tesaro, and Baxter. GB reports consulting or advisory board roles for AstraZeneca, Roche, and GSK; and has received funding for medical conferences from AstraZeneca, Roche, and GSK. CLP reports advisory/consultancy honoraria from Pfizer, AstraZeneca, Roche, and Daiichi–Sanko; and other travel/accommodation/medical congress expenses from Roche, Novartis, Pfizer, Pierre Fabre, and MSD. PB reports honoraria from Roche, AstraZeneca, and GSK; and congress and travel support from GSK and PharmaMar. AL reports advisory board fees from AstraZeneca, MSD, and Tesaro; speaker honoraria from Clovis Oncology and Roche; and participation in a medical congress for Novartis, Pfizer, MSD, Lilly, and Roche. AB reports honoraria for lectures and advisory boards from AstraZeneca, Roche, and Tesaro. JM reports advisory board fees (personal) from Daiichi Sankyo, Gilead, and Eli Lilly; and non-financial traveling facilities from Pfizer. AEB reports advisory board fees from AstraZeneca, MSD, and GSK; speaker honoraria from AstraZeneca and Olympus; and participation in a medical congress for PharmaMar and AstraZeneca. MR reports advisory board fees (personal) from AstraZeneca, GSK, and Immunocore; advisory board fees and research grant (personal/institution) from MSD; and research grant (institution) from BMS. TWPS reports honoraria (advisory role, expert testimony and lectures, participation in clinical trials, other financial relationships, e.g. travel) from AstraZeneca, Daiichi-Sankyo, Exact Sciences, Gilead, GSK, Lilly, MSD, NCO, Novartis, Pfizer, Roche, and Seagen. CD reports participation on a data safety monitoring board or advisory board for MSD, Eisai, and AstraZeneca. DD reports consulting or advisory roles (personal) for AstraZeneca, GSK/Tesaro, Roche, Eisai Germany, and MSD Oncology; travel expenses from AstraZeneca; and honoraria from Roche, AstraZeneca, GSK/Tesaro, MSD, Intuitive Surgical, and KLS Martin. BY reports consulting fees (personal) from MSD, AstraZeneca, GSK–Tesaro, Bayer, Roche–Genentech, ECS Progastrin, Novartis, LEK, Amgen, Clovis Oncology, Merck Serono, BMS, SEAGEN, and Myriad. EPL reports lecture fees, speaker’s bureau fees, and travel support from AstraZeneca, Tesaro, and Roche; lecture fees from Clovis Oncology, Incyte, and Pfizer; and is employed by ARCAGY Research. PH reports honoraria from AstraZeneca, Roche, Clovis Oncology, Stryker, MSD Oncology, Zai Lab, Lilly, Sotio, Eisai, and GSK; consulting/advisory roles from AstraZeneca, Roche, Tesaro, Merck, GSK, Clovis Oncology, and Immunogen; and research funding (institution) from AstraZeneca, Roche, Genmab, GSK, Immunogen, and Clovis Oncology. All other authors have declared no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)