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The current pharmacological pretreatment and medical treatment of nerve agent poisoning is an insufficiently addressed medical task. The prophylactic efficacy of a novel compound acting dually as an acetylcholinesterase inhibitor and NMDA receptor antagonist (K1959) and the therapeutic efficacy of a novel NMDA receptor antagonist (K2060) were evaluated in the NMRI mice model of nerve agent poisoning by tabun, soman and sarin. Their added value to the standard antidotal treatment (a combination of oxime reactivator and atropine) was also analyzed. The novel dually acting prophylactic drug (K1959) did not bring any additional benefit compared to the commonly used pyridostigmine. By contrast, an increase in the therapeutic efficacy of classic antidotal treatment was observed when the novel NMDA receptor antagonist (K2060) was combined with commonly used antidotes (oxime reactivator in combination with atropine). This novel combination reduced the acute toxicity of tabun, soman, and sarin more than two-fold, four-fold, and five-fold, respectively. These results highlight the possibility of NMDA antagonists such as K2060 as a supportive drug for the classic therapy of organophosphorus poisoning., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder that frequently leads to end-stage renal disease. In this study, we examine the indications, procedures, and outcomes of native nephrectomy (NN) in ADPKD patients at our transplant center. Drawing on 25 years of clinical practice, we aim to provide insights into the surgical management of ADPKD, focusing on the specific factors influencing NN., Materials and Methods: A retrospective study was conducted involving ADPKD patients who underwent KT and NN between 1999 and 2023. Collected data encompassed demographics and surgery parameters, such as duration, hospital stay length, blood loss, and complications. Patients were classified based on the urgency (acute/planned) of the NN and its type (unilateral/bilateral), followed by an analysis of the outcomes per group., Results: Out of 152 patients post-KT for ADPKD, 89 (58.6%) underwent NN. The procedures were predominantly unilateral (71; 64%), with bilateral NN accounting for 40 (36%) cases. NN timing relative to KT was 31 (27.9%) pretransplant, 9 (8.1%) concomitant, 51 (45.9%) posttransplant, and 10 (9%) patients undergoing the sandwich technique. Acute NN were performed in 42 cases, while 69 were planned. Acute NNs were associated with longer surgeries, greater blood loss, and a higher incidence of perioperative complications compared to planned NNs. Specifically, unilateral acute NN had a 23.8% complication rate compared to 2.9% in planned cases; bilateral acute NN showed a 28.6% complication rate versus 4.3% in planned cases., Conclusion: This investigation accentuates the significance of planning and selection in NN for ADPKD, factoring in the heightened risk of complications. Acute NN are linked to worse outcomes, including higher rates of complications. The data emphasize the necessity of tailored surgical approaches based on individual patient circumstances., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

TFE3 rearrangements characterize histogenetically, topographically, and biologically diverse neoplasms. Besides being a universal defining feature in alveolar soft part sarcoma (ASPS) and clear cell stromal tumor of the lung, TFE3 fusions have been reported in subsets of renal cell carcinoma, perivascular epithelioid cell tumor (PEComa), epithelioid hemangioendothelioma and ossifying fibromyxoid tumors. TFE3 -related neoplasms are rare in the head and neck and may pose diagnostic challenges. We herein describe 22 TFE3 fusion neoplasms affecting 11 males and 11 females aged 4 to 79 years (median, 25) and involving different head and neck sites: sinonasal cavities (n = 8), tongue (n = 4), oral cavity/oropharynx (n = 3), salivary glands (n = 2), orbit (n = 2), and soft tissue or unspecified sites (n = 3). Based on morphology and myomelanocytic immunophenotype, 10 tumors qualified as ASPS, 7 as PEComas (3 melanotic; all sinonasal), and 5 showed intermediate (indeterminate) histology overlapping with ASPS and PEComa. Immunohistochemistry for TFE3 was homogeneously strongly positive in all cases. Targeted RNA sequencing/FISH testing confirmed TFE3 fusions in 14 of 16 successfully tested cases (88%). ASPSCR1 was the most frequent fusion partner in ASPS (4 of 5 cases); one ASPS had a rare VCP::TFE3 fusion. The 6 successfully tested PEComas had known fusion partners as reported in renal cell carcinoma and PEComas ( NONO, PRCC, SFPQ , and PSPC1 ). The indeterminate tumors harbored ASPSCR1::TFE3 (n = 2) and U2AF2::TFE3 (n = 1) fusions, respectively. This large series devoted to TFE3-positive head and neck tumors illustrates the recently proposed morphologic overlap in the spectrum of TFE3 -associated mesenchymal neoplasms. While all PEComas were sinonasal, ASPS was never sinonasal and occurred in diverse head and neck sites with a predilection for the tongue. The indeterminate (PEComa-like) category is molecularly more akin to ASPS but shows different age, sex, and anatomic distribution compared with classic ASPS. We report VCP as a novel fusion partner in ASPS and PSPC1 as a novel TFE3 fusion partner in PEComa (detected in one PEComa). Future studies should shed light on the most appropriate terminological subtyping of these highly overlapping tumors., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The aim of this study was to determine the antidotal potential of the chlorinated oxime K870 compared to obidoxime, as a monotherapy and in combination with atropine, in paraoxon (POX)-poisoned rats. The treatment doses of oximes were chosen as 20% of their LD 50 values. The protective ratio (PR) of oxime K870 with atropine was significantly higher than that of obidoxime with atropine (68.8 and 125.0, respectively). In the biochemical part of the experiment POX subcutaneously (s.c.) (0.75% LD 50 ) was administered and followed by oxime K870 or obidoxime i.m. 1 min later. Acetylcholinesterase (AChE) activity was determined spectrophotometrically in cerebrum, cerebellum, brainstem, diaphragm, and erythrocytes. Carboxylesterase activity was determined in plasma and liver. Both oximes successfully reactivated AChE in brain (cerebrum, cerebellum, and brainstem), diaphragm and erythrocytes, but the oxime K870 performed better than obidoxime. Both oximes reactivated carboxylesterase, obidoxime better in plasma and oxime K870 better in liver. In conclusion, the oxime K870, when co-administered with atropine, is a more effective antidote than the obidoxime-atropine combination in POX-poisoned rats.

Background: Antimicrobial lock therapy is recommended for preventing and treating catheter-related bloodstream infections, but different solutions have uncertain efficacy., Methods: Two locks, 1.35% taurolidine and 4% ethylenediaminetetraacetic acid (EDTA), were tested on Staphylococcus epidermidis, Staphylococcus aureus, methicillin-resistant S. aureus, Pseudomonas aeruginosa, multidrug-resistant P. aeruginosa, vancomycin-resistant Enterococcus faecium, Klebsiella oxytoca (carbapenemase producing), K. pneumoniae (extended-spectrum β-lactamase producing), Candida albicans, and Candida glabrata. Broviac catheter segments were incubated with these organisms and then exposed to various lock solutions. Colony-forming units (CFUs) were counted after 2, 4, and 24 h of incubation., Results: Taurolidine showed a significant decrease in CFUs after 2 h in S. aureus, S. epidermidis, methicillin-resistant S. aureus, vancomycin-resistant E. faecium, P. aeruginosa (both sensitive and multidrug-resistant strains), K. oxytoca, C. albicans, and C. glabrata. After 4 h, significant reductions were noted in S. aureus, S. epidermidis, methicillin-resistant S. aureus, P. aeruginosa, multidrug-resistant P. aeruginosa, K. pneumoniae, K. oxytoca, and C. albicans. Taurolidine was also effective after 24 h, especially against methicillin-resistant S. aureus and multidrug-resistant P. aeruginosa. Four percent EDTA acid showed a significant reduction in CFUs after 2 h in S. aureus, vancomycin-resistant E. faecium, P. aeruginosa, K. oxytoca, C. albicans, and C. glabrata. After 4 h, reductions occurred in P. aeruginosa, multidrug-resistant P. aeruginosa, K. oxytoca, and C. albicans and after 24 h in methicillin-resistant S. aureus, P. aeruginosa, and K. oxytoca., Conclusion: Taurolidine is more effective than 4% EDTA acid in eradicating Gram-positive and Gram-negative microorganisms and fungi., (© 2025 American Society for Parenteral and Enteral Nutrition.)

Extrapulmonary small cell neuroendocrine carcinoma (EP-SCNC) is a rare malignancy with a poor prognosis. Despite its morphological similarity to lung small cell carcinomas, its oncogenesis remains uncertain. One hundred and seventy-one EP-SCNC were enrolled in a multicenter study, and all tissue samples underwent an immunohistochemical p53 analysis. One hundred twenty-five samples were molecularly analyzed using next-generation sequencing (NGS), comprising DNA and RNA analysis. p53 normal/wild type expression was detected in 68 cases (39.8%), whereas aberrant expression was detected in 103 cases (60.2%). Molecular TP53 alteration was detected in 92 out of 125 tumors (73.6%). The TP53 mutation was shown to be prognostic and associated with shorter overall survival (p = 0.041). The multivariate analysis of p53 and TP53 mutational status found that it impacted overall survival relative to distinct sites of tumor locations (p = 0.004 and p = 0.001, respectively). Age did not influenced survival in the multivariate analysis of p53 and TP53 (p = 0.002; p < 0.001 resp.). Among tumors with paired immunohistochemical and molecular results, 108 exhibited concordance between the immunohistochemical and molecular analysis, whereas 17 were discordant. Accordingly, p53 aberrant expression was tightly associated with a TP53 mutation (p < 0.001). In discordant cases, molecular analysis revealed no alteration in three tumors with p53 overexpression. In contrast, in 14 tumors with wild-type p53 expression, TP53 genetic alteration was detected. Possible causes of discordance are discussed in this manuscript. Furthermore, the incidence of aberrant p53 expression / TP53 molecular alteration was noticeably lower in EP-SCNC than in small-cell lung carcinomas. Therefore, in EP-SCNC, other driver mutations should be sought since personalized therapy can improve patient prognosis., (© 2025. The Author(s).)

Low-grade endometrial stromal sarcoma (LG-ESS) can present diagnostic challenges, due to its overlapping morphological features with other uterine mesenchymal tumors. Misdiagnosis rates remain significant, and immunohistochemical data for LG-ESS are limited to small series and inconsistent antibody panels. This study aimed to refine the IHC profile of LG-ESS by analyzing a large, molecularly confirmed series of 147 cases using a panel of 24 antibodies, including newer markers like transgelin and smoothelin. CD10 and IFITM1, key endometrial stromal markers, were expressed in 86% (92% of those extensively) and 69% (60% of those extensively) of cases, with fusion-positive tumors showing significantly higher expression. Smooth muscle markers (α-SMA, desmin, h-caldesmon, calponin, transgelin) were variably expressed, predominantly in focal or low-intensity patterns, with α-SMA reaching the highest frequency of expression (44%). However, the intensity of smooth muscle marker expression was usually very low. Smoothelin was rarely expressed. Hormone receptors were frequently positive, with PR showing a higher frequency (92% vs. 83%) and intensity than ER. Markers like S-100, HMB45, and CD117 were largely negative; all tumors were p53 wild-type, with preserved SMARCB1/SMARCA4 expression and ALK and ROS1 negativity. This work represents the largest molecularly validated IHC study on LG-ESS, providing a robust diagnostic profile for routine pathology. By addressing key diagnostic limitations and examining newer markers, our study supports a more standardized approach to diagnosing LG-ESS and underscores the value of immunohistochemical panels, particularly in fusion-negative tumors where diagnosis relies on morphological and immunohistochemical interpretation. These findings contribute critical data for improving diagnostic accuracy., Competing Interests: Declarations. Ethics approval: The study has been approved by the Ethics Committee of General University Hospital in Prague in compliance with the Helsinki Declaration (No. 2140/19 S-IV). The Ethics Committee waived the requirement for informed consent, as according to the Czech Law (Act. no. 373/11, and its amendment Act no. 202/17) it is not necessary to obtain informed consent in fully anonymized studies. Competing interests: All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript., (© 2025. The Author(s).)

Objective: Despite lack of evidence supporting efficacy, prophylactic fresh frozen plasma and Octaplas transfusions may be administered to very preterm infants to reduce bleeding risk. International variation in plasma transfusion practices in neonatal intensive care units (NICUs) is poorly understood, therefore, we aimed to describe neonatal plasma transfusion practice in Europe., Design: Prospective observational study., Setting: 64 NICUs in 22 European countries, with a 6-week study period per centre between September 2022 and August 2023., Patients: Preterm infants born below 32 weeks of gestational age., Interventions: Admission to the NICU., Main Outcome Measures: Plasma transfusion prevalence, cumulative incidence, indications, transfusion volumes and infusion rates and adverse effects., Results: A total of 92 of 1143 infants included (8.0%) received plasma during the study period, collectively receiving 177 transfusions. Overall prevalence was 0.3 plasma transfusion days per 100 admission days, and rates varied substantially across Europe. By day 28 of life, 13.5% (95% CI 10.0% to 16.9%) of infants received at least one plasma transfusion, accounted for competing risks of death or discharge. Transfusions were given for a broad range of indications, including active bleeding (29.4%), abnormal coagulation screen results (23.7%) and volume replacement/hypotension (21.5%). Transfusion volumes and infusion rates varied significantly; the most common volume was 15 mL/kg (range: 5-30 mL/kg) and the most common duration was 2 hours (range: 30 min to 6 hours)., Conclusions: We found wide variation in plasma transfusion practices in Europe, highlighting the need for evidence to inform neonatologists in daily practice and guidelines, in particular for non-bleeding indications., Trial Registration Number: ISRCTN17267090., Competing Interests: Competing interests: SGu disclosed receiving grants from Sanquin Blood Supply Foundation (PPOC21-08/L2588, RES/00264), the European Blood Alliance (EBA Grant Agreement 2021-02) and the European Society for Paediatric Research (ESPR Post-Doc Research Grant 2020). CH and TM disclosed receiving compensation from Sanquin Blood Supply Foundation. JM disclosed receiving compensation from Sanquin Blood Supply Foundation, research grants from Cooperatio and Personmed, and consulting fees from Danone, Nestlé, Baxter and Chiesi. SG disclosed receiving lecture fees from Entegrion, outside this study., (© 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.)

Background: Poly (ADP ribose) polymerase inhibitors (PARPis) are a treatment option for patients with advanced high-grade serous or endometrioid ovarian carcinoma (OC). Recent guidelines have clarified how homologous recombination deficiency (HRD) may influence treatment decision-making in this setting. As a result, numerous companion diagnostic assays (CDx) have been developed to identify HRD. However, the optimal HRD testing strategy is an area of debate. Moreover, recently published clinical and translational data may impact how HRD status may be used to identify patients likely to benefit from PARPi use. We aimed to extensively compare available HRD CDx and establish a worldwide expert consensus on HRD testing in primary and recurrent OC., Methods: A group of 99 global experts from 31 different countries was formed. Using a modified Delphi process, the experts aimed to establish consensus statements based on a systematic literature search and CDx information sought from investigators, companies and/or publications., Results: Technical information, including analytical and clinical validation, were obtained from 14 of 15 available HRD CDx (7 academic; 7 commercial). Consensus was reached on 36 statements encompassing the following topics: 1) the predictive impact of HRD status on PARPi use in primary and recurrent OC; 2) analytical and clinical validation requirements of HRD CDx; 3) resource-stratified HRD testing; and 4) how future CDx may include additional approaches to help address unmet testing needs., Conclusion: This manuscript provides detailed information on currently available HRD CDx and up-to-date guidance from global experts on HRD testing in patients with primary and recurrent OC., Competing Interests: Declaration of Competing Interest Stanislas Quesada: Honoraria for lectures: GSK, AZ . Honoraria for advisory boards: GSK. Reimbursement for travel expenses: GSK, AZ, MSD, EISAI. Frédérique Penault-Llorca: Personal honoraria: AbbVie, Amgen, Astellas, AstraZeneca, Bayer, BMS, Clovis, EISAI, Exact Science, GSK, Illumina, Invitae, Lilly, MSD, Myriad, Novartis, Pfizer, Pierre-Fabre, Roche, Sanofi, Veracyte. Funding to institution for translational research: AbbVie, Astellas, AstraZeneca, Bayer, BMS, Genomic Health, Illumina, Lilly, MSD, Myriad, Nanostring, Novartis, Pfizer, Pierre-Fabre, Roche. Travel grants: AbbVie, AstraZeneca, Bayer, BMS, Gilead, MSD, Novartis, Pfizer, Roche. Xavier Matias-Guiu: Personal fees as an invited speaker: Roche Farma, Qiagen, Ferrer Internacional, Novartis, Menarini, Biocartis, Agilent-Dako, Leyca, Reig Jofre, Sysmex, MSD, Astra-Zeneca, BMS, GSK, Clovis; Advisory Boards: Astra-Zeneca, Lilly, Amgen, GSK, Janssen, Illumina, MSD. Susana Banerjee: Personal fees for advisory board membership from, AstraZeneca, Eisai, Epsilogen, GSK, ImmunoGen, Mersana, MSD, Myriad, Novartis, Oncxerna, Regeneron, Roche, Seagen, Shattuck Labs and Verastem; personal fees as an invited speaker from Abbvie, AstraZeneca , GSK, Medscape, Novacure, Peerview, Pfizer, Research to Practice and Takeda; travel expenses Verastem, AstraZeneca, GSK. Ownership of stocks/shares of PerciHealth; institutional research grants from AstraZeneca and GSK; a non-remunerated role as a PI for AstraZeneca (academic-sponsored ENGOT-GYN1/ATARI phase II international trial), GSK (academic-sponsored MONITOR-UK trial) and Verastem (ENGOTov60/GOG3052/RAMP201 phase II clinical trial – global lead); a non-remunerated leadership role as board member of the International Cancer Foundation; and a non-renumerated advisory role as a medical advisor of Ovacome Charity. Massimo Barberis: Honoraria for consulting, advisory role, speakers’ bureau, travel, accommodation, expenses from MSD Oncology, Roche/Genetech, AstraZeneca, GSK, Amgen, Thermofisher Scientifics and Illumina. Robert L. Coleman: Grants/contracts: AstraZeneca, Clovis, Genelux, Genmab, Merck, Immunogen, Roche/Genentech, Karyopharm; consulting fees from: Agenus, Alkermes, AstraZeneca, Clovis, Deciphera, Genelux, Genmab, GSK, Immunogen, OncoQuest, Onxerna, Regeneron, Karyopharm, Roche/Genentech, Novocure, Merck, Abbvie, Novocure; honoraria from lectures: AstraZeneca, Clovis, Roche/Genentech, Merck. Nicoletta Colombo: Personal fees for advisory board membership from AstraZeneca, Clovis Oncology, Eisai, GSK, ImmunoGen, Mersana, MSD/Merck, Nuvation Bio, Onxerna, Pfizer, PharmaMar, Pieris and Roche, Novocure; personal fees as an invited speaker from AstraZeneca and Novartis; institutional research grants from AstraZeneca, PharmaMar and Roche; a non-renumerated membership of the ESMO Guidelines Steering Committee; and a non-renumerated leadership role as Chair of the Alleanza Contro il Tumore Ovarico (ACTO) Scientific Committee. Anna DeFazio: Research grant support from AstraZeneca and Illumina. Consumer survey advisory committee, Verastem. Iain A. McNeish: Personal honoraria for advisory boards for AstraZeneca, GSK, Clovis Oncology, BioNTech, Roche, Episila Bio and OncoC4. Travel, accommodation and/or expenses from GSK, BioNTech and AstraZeneca. Institutional grant support from AstraZeneca. Angélica Nogueira-Rodrigues: Personal honoraria for advisory boards from Abbvie, AstraZeneca, Daiichi Sankyo, Eisai, Gilead, GSK, Immunogen, MSD, Novartis, Pfizer, Roche. President-elect for the Brazilian Society of Medical Oncology (not recompensed); Chair LACOG (not recompensed); Director of strategic planning Brazilian Group of Gynecologic Cancer (not recompensed). Ana Oaknin: Personal fees for advisory board membership from: Agenus, AstraZeneca, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals, Daiichi Sankyo, Debiopharm International, Eisai, Exelisis, F. Hoffmann-La Roche, Genmab, GSK, ImmunoGen, Itheos, MSD, Mersana Therapeutics, Myriad Genetics, Novocure, OncoXerna Therapeutics, Inc., PharmaMar, Regeneron, Sattucklabs, Seagen/Pfizer, Sutro Biopharma and Zentalis; personal fees for travel/accommodation from: AstraZeneca, PharmaMar, Roche. Sandro Pignata: Honoraria from MSD, AstraZeneca, GSK, Roche, Novartis, Pharmamar; Research funding from AstraZeneca, MSD, Roche, GSK, Pfizer. Éric Pujade-Lauraine: Personal honoraria for advisory boards/IDMC from Agenus, AstraZeneca, GSK, Incyte, MSD, Roche. Employee ARCAGY. Étienne Rouleau: served in a consulting/advisory role for AstraZeneca, Roche Diagnostics, Clovis, GSK, and BMS, and has received travel/accommodation expenses from AstraZeneca and BMS. Aleš Ryška: Honoraria for advisory services and invited lectures: Amgen, AstraZeneca, BMS, Eli-Lilly, Janssen-Cilag, MSD, Roche, Gilead, Novartis, Sanofi, Merck Serono, Bayer. Travel support: Gilead, Sanofi. Immediate past president of the European Society of Pathology (not recompensed). Nerina Van Der Merwe: Travel and accommodation expenses from AstraZeneca, Roche and Gknowmix. Toon Van Gorp: Institutional honoraria for advisory boards from AstraZeneca, BioNTech, Eisai, GSK, ImmunoGen, Incyte, MSD, OncXerna Therapeutics, Seagen, Tubulis, Zentalis. Travel, accommodation, and/or expenses from AstraZeneca, GSK, ImmunoGen, MSD, and PharmaMar. Research funding from Amgen, AstraZeneca, and Roche. Chair of BGOG (not recompensed). Ignace Vergote: Consulting Ad Boards: Akesobio, Bristol Myers Squibb, Deciphera Pharmaceuticals, Eisai, Elevar Therapeutics, F. Hoffmann-La Roche, Genmab, GSK, ITM, Jazzpharma, Karyopharm, MSD, Novocure, Oncoinvent, Sanofi, Regeneron, Seagen, Sotio, Zentalis; Consulting Data monitoring Committees: Agenus, AstraZeneca, Corcept, Exelixis, F. Hoffmann-La Roche, Immunogen, Kronos Bio, Mersana, Novartis, OncXerna, Verastem Oncology. Wilko Weichert: Honoraria: Boehringer Ingelheim, Janssen, Roche, MSD, Bristol-MyersSquibb, AstraZeneca, Pfizer, Merck KGaA, Lilly, Novartis, Takeda, Bayer, Amgen, Astellas Pharma, Illumina, Eisai, Siemens, Agilent, ADC Therapeutics, GlaxoSmithKline, MolecularHealth Consulting or Advisory Role: Roche, Pfizer, Merck Sharp & Dohme, Bristol Myers Squibb, Merck KGaA, AstraZeneca, Novartis, Boehringer Ingelheim, Agilent, Illumina, MolecularHealth, Siemens Healthcare Diagnostics, ADC Therapeutics, Astellas Pharma, Janssen, Eisai, Takeda, GlaxoSmithKline, Lilly, Amgen, Bayer. Speakers’ Bureau: Lilly, Amgen, Merck Sharp & Dohme, Pfizer, Bristol Myers Squibb, Roche, Novartis, Johnson & Johnson/Janssen, Eisai, AstraZeneca/MedImmune, Takeda, Agilent, Siemens, Astellas Pharma, Illumina, Roche, Bayer, MolecularHealth, ADC Therapeutics, Merck, Boehringer Ingelheim. Research Funding: Roche (Inst), Bristol Myers Squibb (Inst), Merck Sharp & Dohme (Inst), AstraZeneca/MedImmune (Inst). Travel, Accommodations, Expenses: Roche, Bayer, Bristol Myers Squibb, MSD, AstraZeneca, ADC Therapeutics, Astellas Pharma, MolecularHealth, Siemens, Novartis, Illumina, Agilent, Takeda, Eisai, GlaxoSmithKline, Merck, Boehringer Ingelheim, AstraZeneca, Lilly, Janssen, Pfizer. Xiaohua Wu: No potential conflicts of interest. Isabelle Ray-Coquard: Personal honoraria for advisory boards from Abbvie, Adaptimmune, Agenus, Amgen, AstraZeneca, BMS, Clovis, Corsett, Daiichi Sankyo, Deciphera, Eisai, EQRX, GSK, Immunogen, Immunocore, Merck Serono, MacroGenics, MSD, Mersana, Novartis, Onxeo, PharmaMar, Roche, Sutro Biopharma, Zentalis; Honorarium to institution for advisory boards from MSD (translational research); Funding to institution for translational research from BMS; President of GINECO (not recompensed); Chair-elect of ENGOT (not recompensed). Pascal Pujol: Consulting fees from Exact Science; Honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, HEDERADx, MSD, Novartis, Onco DNA, Predilife, and Seqone., (Copyright © 2024. Published by Elsevier Ltd.)

Extrapulmonary small cell neuroendocrine carcinoma (EP-SCNC) is a rare malignancy with a poor prognosis. Most patients with EP-SCNC have metastatic disease upon presentation, and their average overall survival (OS) is less than 12 months. Our study aimed to conduct a complex analysis of EP-SCNC. One hundred and eighty-one EP-SCNC tissue samples were subjected to a complex analysis. One hundred and fifty-five tumors were pure EP-SCNC, while 26 were combined tumors. Immunohistochemistry for ASCL1, NEUROD1, YAP1, POU2F3, Rb1, p53, cyclin D1, p16, PTEN, DLL3, PD-L1, CD56, synaptophysin, chromogranin A, and INSM1 was performed, and 128 samples were analyzed molecularly using next generation sequencing (NGS), comprising DNA and RNA analysis. Detailed results on immunohistochemical and molecular analyses were provided for each primary origin of EP-SCNC separately. Median survival for the whole cohort of patients was 8.94 months. Patient age (≥ 70 years), tumor mutational burden (TMB) < 15, and TP53 and BRCA2 mutations were negative prognostic factors. High expression of ASCL-1 was associated with shorter OS, whereas high expression of YAP1 was associated with longer OS. Patients with genitourinary tumors had significantly better OS than those with gastrointestinal tract EP-SCNC tumors. Rb1 expression loss was detected more often in genitourinary tract SCNCs. In contrast, p16 overexpression was found more often in genitourinary tract SCNCs. POU2F3 expression was detected more often in combined tumors, whereas NEUROD1 was detected more often in pure EP-SCNC. Regarding "druggable markers," DLL3 was expressed in 66% of tumors and PD-L1 in 17.4%. Detailed analyses of different prognostic and predictive markers are needed to better understand EP-SCNC biology and create more personalized therapy to improve patient prognosis., (Copyright © 2025. Published by Elsevier Inc.)

Background: The cannulation of the internal jugular vein (IJV) is a frequent procedure in critically ill patients. According to the guidelines, real-time ultrasound navigation is recommended. Traditional techniques pose several disadvantages, such as suboptimal needle visualization. Therefore, this non-inferiority trial aimed to describe the novel approach and compare the novel lateral in-plane short-axis approach for IJV access with the conventional short-axis out-of-plane approach., Objectives: The primary objective of the trial was to prove that the first attempt success rate in the novel technique is non-inferior to the conventional technique. The secondary objectives were to demonstrate that the complication rate and the functional duration of the catheter in the novel technique are not inferior to those in the conventional technique., Methods: Patients eligible for IJV cannulation were randomly assigned to either the novel technique (Group A) or the conventional one (Group B). The procedure duration, success rate and the number of attempts required were documented. The functionality of the catheter and complications were monitored from insertion until the catheter removal. Standard descriptive statistical methods were employed for the analysis., Results: A total of 200 subjects were equally divided between Group A and Group B. For the primary outcome, there was no significant difference in first attempt success rate (Group A: 79, Group B: 77, p = 0.434). Secondary outcomes, including complications and catheter functional time, did not differ significantly between the groups. However, the novel technique demonstrated a significantly faster procedure time (Group A: 315 s, Group B: 330 s, p = 0.016). Notably, the novel approach was linked with significantly larger IJV diameter measured during the procedure (Group A: 18.2 mm, Group B: 12.1 mm, p < 0.001)., Conclusion: The novel lateral in-plane short-axis approach for IJV cannulation is a non-inferior alternative with a lower incidence of posterior vessel wall puncture compared to the conventional approach., Competing Interests: Declarations. Ethics approval and consent to participate: The trial was approved by the local ethical committee (Ethics Committee, Masaryk Hospital Usti nad Labem, Czech Republic, reference number 313/3). The trial was conducted in accordance with the Helsinki Declaration and good clinical practice. All patients agreed to be included in the clinical trial and signed an informed consent form. Consent for publication: Written informed consent for publication was obtained from the patients. Competing interests: The authors declare that they have no competing interests., (© 2025. The Author(s).)

Background: The process of kidney transplantation remains the optimal treatment for end-stage renal disease, offering improved quality of life and increased survival rates compared to long-term dialysis. However, despite advances in surgical techniques, immunosuppression regimens, and post-operative care, there are still significant challenges in predicting the organ's status and long-term outcomes of transplantation. Among the many factors that influence graft survival, the quality of the donated organ plays a fundamental role. There is an ongoing need for accurate and reliable biomarkers. Syndecan-1 is found in the endothelial glycocalyx and shed at a higher rate into the blood during systemic pathological conditions. The aim of this study is to evaluate the potential of serum syndecan-1 levels as a biomarker for assessing donor kidney quality and to investigate its correlation with donor characteristics and short-term outcomes in kidney recipients., Material and Methods: We investigated serum syndecan-1 levels in 80 deceased donors and correlated them with donor characteristics and short-term outcomes (defined as delayed graft function - defined as the need for dialysis within the first week post-transplantation and renal function at 3 months post-transplantation - assessed using serum creatinine levels) in 104 corresponding kidney recipients. This single-center retrospective observational cohort study was conducted from April to December 2021., Results: The donor pool consisted of 65% males with a median age of 53 years. Of these, 45 donors (56%) were classified as extended criteria donors. Higher syndecan-1 levels correlated with the last creatinine levels before organ procurement (R = 0.32, p = 0.01) and were marginally higher in donors with acute kidney injury (p = 0.07). However, syndecan-1 levels were not associated with short-term outcomes in kidney recipients (renal function at 3 months)., Conclusions: The data suggests syndecan-1 could be a potential biomarker for assessing donor kidney quality, although its implications on recipient outcomes require further study. This pilot investigation underscores the importance of syndecan-1 in evaluating organ quality but highlights the necessity for more extensive research to validate these findings and explore their implications in transplant success., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Pavel Navratil reports was provided by University Hospital Hradec Kralove. If there are other authors, they 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 © 2025 Elsevier Inc. All rights reserved.)

Purpose: Patients with high-grade serous ovarian carcinoma (HGSOC) are virtually insensitive to immune checkpoint inhibitors (ICI) employed as standalone therapeutics, at least in part reflecting microenvironmental immunosuppression. Thus, conventional chemotherapeutics and targeted anticancer agents that not only mediate cytotoxic effects but also promote the recruitment of immune effector cells to the HGSOC microenvironment stand out as promising combinatorial partners for ICIs in this oncological indication., Experimental Design: We harnessed a variety of transcriptomic, spatial, and functional assays to characterize the differential impact of neoadjuvant paclitaxel-carboplatin on the immunological configuration of paired primary and metastatic HGSOC biopsies as compared to neoadjuvant chemotherapy (NACT)-naïve HGSOC samples from five independent patient cohorts., Results: We found NACT-driven endoplasmic reticulum stress and calreticulin exposure in metastatic HGSOC lesions culminates with the establishment of a dense immune infiltrate including follicular T cells (TFH cells), a prerequisite for mature tertiary lymphoid structure (TLS) formation. In this context, TLS maturation was associated with an increased intratumoral density of ICI-sensitive TCF1+PD1+ CD8+ T cells over their ICI-insensitive TIM-3+PD1+ counterparts. Consistent with this notion, chemotherapy coupled with a PD1-targeting ICI provided a significant survival benefit over either therapeutic approach in syngeneic models of HGSOC bearing high (but not low) tumor mutational burden., Conclusions: Altogether, our findings suggest that NACT promotes TLS formation and maturation in HGSOC lesions, de facto preserving an intratumoral ICI-sensitive T-cell phenotype. These observations emphasize the role of rational design, especially relative to the administration schedule, for clinical trials testing chemotherapy plus ICIs in patients with HGSOC. See related commentary by Bravo Melgar and Laoui, p. 10., (©2024 The Authors; Published by the American Association for Cancer Research.)

Adenoid cystic carcinomas (AdCC) of salivary gland origin have long been categorized as fusion-defined carcinomas owing to the almost universal presence of the gene fusion MYB::NFIB, or less commonly MYBL1::NFIB. Sinonasal AdCC is an aggressive salivary gland malignancy with no effective systemic therapy. Therefore, it is urgent to search for potentially targetable genetic alterations associated with AdCC. We have searched the authors' registries and selected all AdCCs arising in the sinonasal tract. The tumors were examined histologically, immunohistochemically, by next generation sequencing (NGS) and/or fluorescence in situ hybridization (FISH) looking for MYB/MYBL1 and/or NFIB gene fusions or any novel gene fusions and/or mutations. In addition, all tumors were tested for HPV by genotyping using (q)PCR. Our cohort comprised 88 cases of sinonasal AdCC, predominantly characterized by canonical MYB::NFIB (49 cases) and MYBL1::NFIB (9 cases) fusions. In addition, noncanonical fusions EWSR1::MYB; ACTB::MYB; ESRRG::DNM3, and ACTN4::MYB were identified by NGS, each of them in 1 case. Among nine fusion-negative AdCCs, FISH detected rearrangements in MYB (7 cases), NFIB (1 case), and EWSR1 (1 case). Six AdCCs lacked fusions or gene rearrangements, while 11 cases were unanalyzable. Mutational analysis was performed by NGS in 31/88 (35%) AdCCs. Mutations in genes with established roles in oncogenesis were identified in 21/31 tumors (68%), including BCOR (4/21; 19%), NOTCH1 (3/21; 14%), EP300 (3/21; 14%), SMARCA4 (2/21; 9%), RUNX1 (2/21; 9%), KDM6A (2/21; 9%), SPEN (2/21; 9%), and RIT1, MGA, RB1, PHF6, PTEN, CREBBP, DDX41, CHD2, ROS1, TAF1, CCD1, NF1, PALB2, AVCR1B, ARID1A, PPM1D, LZTR1, GEN1, PDGFRA, each in 1 case (1/21; 5%). Additional 24 cases exhibited a spectrum of gene mutations of uncertain pathogenetic significance. No morphologic differences were observed between AdCCs with MYBL1::NFIB and MYB::NFIB fusions. Interestingly, mutations in the NOTCH genes were seen in connection with both canonical and noncanonical fusions, and often associated with high-grade histology or metatypical phenotype, as well as with poorer clinical outcome. Noncanonical fusions were predominantly observed in metatypical AdCCs. These findings emphasize the value of comprehensive molecular profiling in correlating morphologic characteristics, genetic landscape, and clinical behavior in AdCC., (Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: The recommended threshold for the time spent on continuous glucose monitoring (CGM) is established at 70%. However, glucose outcomes in children with type 1 diabetes (CwD) using CGM for a different proportion of time within this threshold have not been evaluated yet. The study aims to compare glycemic parameters among CwD who spent 70%-89% and ≥90% on CGM using the population-wide data from the Czech national pediatric diabetes registry ČENDA. Methods: CwD aged <19 years who used real-time CGM >70% of the time and did not change the type of therapy throughout the year 2023 were included and divided into two groups based on the time they spent on CGM-70%-89% versus ≥90%. HbA1c, times in standard glycemic ranges, mean glucose, and coefficient of variability (CV) were compared between the groups and by treatment modalities. Results: Data from 1977 CwD (1035 males and 942 females) were evaluated. Among them, 404 participants (20.4%) used CGM 70%-89% of the time, and 1573 participants (79.6%) ≥90% of the time. Compared with the 70-89% group, the ≥90% CGM users achieved significantly lower HbA1c levels (51 mmol/mol, 6.8% vs. 58 mmol/mol, 7.4%, P < 0.001), higher time in range (72% vs. 60%, P < 0.001), and lower mean glucose and CV (8.1 mmol/L, 146 mg/dL vs. 9.1 mmol/L, 164 mg/dL and 37% vs. 40%, respectively, both P < 0.001). Analogous results were seen irrespective of the treatment modality. The differences persisted after propensity score adjustment. Conclusion: CGM use for ≥90% is associated with tighter glycemic control compared with 70%-89% use. Therefore, it is essential to motivate CwD to use CGM for the longest possible time and search for suitable options to overcome barriers in uninterrupted CGM monitoring.

Introduction: Approximately one-third of all AML patients have a mutation in the Fms-like tyrosine kinase 3 ( FLT3 ) gene, which is associated with a poor prognosis in these individuals. The 2017 approval of midostaurin, the first FLT3 inhibitor, spurred extensive development of more potent and selective inhibitors with an improved safety profile., Areas Covered: This review analyzes patent inventions for the treatment of AML using FLT3 inhibitors, covering developments from the earliest to the most recent, disclosed in 2024. Our search using the global Espacenet database identified numerous compounds with low nanomolar inhibitory concentrations against FLT3-ITD and FLT3-TKD mutants. These compounds have shown promise in preclinical studies. Co-inhibition strategies and combinatorial therapies to overcome resistance and enhance anti-leukemic efficacy are also discussed., Expert Opinion: Recent patents highlight advances in the field of FLT3 inhibitors with a focus on overcoming resistance, improving selectivity and potency. Future strategies may include third-generation inhibitors such as type III allosteric inhibitors, irreversible inhibitors, or PROTACs. Personalized medicine approaches utilizing genetic profiling to tailor therapies are emphasized. Exploration of novel combination regimens with emerging therapies like CAR T-cell therapy, immune checkpoint inhibitors, and small molecules targeting critical AML pathways is ongoing to further enhance anti-leukemic efficacy.

Infectious diseases, including bacterial, fungal, and viral, have once again gained urgency in the drug development pipeline after the recent COVID-19 pandemic. Tuberculosis (TB) is an old infectious disease for which eradication has not yet been successful. Novel agents are required to have potential activity against both drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis (Mtb), the causative agent of TB. In this study, we present a series of 2-phenyl-N-(pyridin-2-yl)acetamides in an attempt to investigate their possible antimycobacterial activity, cytotoxicity on the HepG2 liver cancer cell line, and-as complementary testing-their antibacterial and antifungal properties against a panel of clinically important pathogens. This screening resulted in one compound with promising antimycobacterial activity-compound 12, MIC Mtb H37Ra  = 15.625 μg/mL (56.26 μM). Compounds 17, 24, and 26 were further screened for their antiproliferative activity against human epithelial kidney cancer cell line A498, human prostate cancer cell line PC-3, and human glioblastoma cell line U-87MG, where they were found to possess interesting activity worth further exploration in the future., (© 2025 The Author(s). Chemical Biology & Drug Design published by John Wiley & Sons Ltd.)