Search

Gastrointestinal stromal tumors (GIST), driven by KIT and PDGFRA mutations, are the most common mesenchymal tumors of the gastrointestinal tract. Although tyrosine kinase inhibitors (TKIs) have advanced treatment, resistance mutations and off-target toxicity limit their efficacy. This study develops covalent TKIs targeting drug-resistant GIST through structure-based design, synthesis, and biological evaluation. SAR studies provided key insights into mutant KIT and PDGFRA interactions, and the first crystal structure of PDGFRA bound to a covalent inhibitor is reported. These findings highlight the promise of covalent inhibitors for overcoming resistance and advancing safer, more effective therapies for advanced GIST.

Background: The safety of minimally invasive direct coronary artery bypass (MIDCAB) has been proven. Nevertheless, reports on clinical outcomes in MIDCAB and the learning curve of this challenging technique in a non-routine off-pump coronary artery bypass (OPCAB) center are still limited. Here, we introduce our clinical outcomes of non-robotic MIDCAB., Methods: Between August 2022 and March 2024, 72 consecutive patients with a mean age of 67.4 ± 9.5 years underwent non-robotic MIDCAB (defined as off-pump bypass grafting of the left internal mammary artery to the left anterior descending artery through left-sided mini-thoracotomy). We analyzed operation time and incidence of major adverse cardiac and cerebrovascular events (MACCE). Further, subgroup analyses included body mass index (BMI) with a cut-off of 30 kg/m 2 [BMI ≧ 30: n = 18 (25.0%)] and body surface area (BSA) with a cut-off of 2.0 m 2 [BSA ≧ 2.0: n = 34 (47.2%)]., Results: All patients survived, whereas MACCE occurred in 4 patients (5.6%). By correlation analyses, no learning curve for operation time was observed in all cases analysis (p = 0.79), but MACCE (n = 4, 5.6%) exclusively observed in the first 34 patients. Furthermore, BMI ≧ 30 or BSA ≧ 2.0 was not significantly related to longer operation time (p = 0.42 and p = 0.52, respectively) and MACCE (p = 0.26 and p = 0.35, respectively). In addition, body size had no effect on operation time according to multiple regression analysis (p = 0.36)., Conclusions: Our study suggested that implementing non-robotic MIDCAB can be safely accomplished at a center with no previous routine in OPCAB surgery, even for patients with bigger body sizes. MACCE occurs more frequently in the early stages when adopting this surgical technique., Competing Interests: Declarations. Ethics approval and consent to participate: The study was conducted following the Declaration of Helsinki, and the Ethics Committee of the Medical Faculty of RWTH Aachen University, Aachen, has approved this study (ref. EK 23-263). The authors have had full access to the data and take full responsibility for the integrity of this manuscript. All authors have read and agreed to the content of this manuscript. The ethics committee waived the informed consent due to a simple retrospective study without interventions for patients. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Despite advances in precision oncology, clinical decision-making still relies on limited variables and expert knowledge. To address this limitation, we combined multimodal real-world data and explainable artificial intelligence (xAI) to introduce AI-derived (AID) markers for clinical decision support. We used xAI to decode the outcome of 15,726 patients across 38 solid cancer entities based on 350 markers, including clinical records, image-derived body compositions, and mutational tumor profiles. xAI determined the prognostic contribution of each clinical marker at the patient level and identified 114 key markers that accounted for 90% of the neural network's decision process. Moreover, xAI enabled us to uncover 1,373 prognostic interactions between markers. Our approach was validated in an independent cohort of 3,288 patients with lung cancer from a US nationwide electronic health record-derived database. These results show the potential of xAI to transform the assessment of clinical variables and enable personalized, data-driven cancer care., Competing Interests: Competing interests: V.G. receives honoraria from Bristol Myers Squibb, Pfizer, Ipsen, Eisai, Merck Sharp & Dohme (MSD) Oncology, Merck HealthCare, EUSAPharm, Apogepha and Ono Pharmaceutical; has an advisory role at BMS, Pfizer, MSD Oncology, Merck HealthCare, Ipsen, Eisai, Debiopharm, PCI Biotech, Cureteq and Oncorena; and received travel funding from Pfizer, Ipsen and Merck HealthCare. B.H. has an advisory role at ABX, AAA/Novartis, Astellas, AstraZeneca, Bayer, BMS, Janssen R&D, Lightpoint Medical and Pfizer; receives research funding from Astellas, BMS, AAA/Novartis, German Research Foundation, Janssen R&D and Pfizer; and receives travel funding from Astellas, AstraZeneca, Bayer and Janssen. D.S. receives personal fees for advisory boards of BMS, Immunocore, MSD, Neracare, Novartis, Pfizer, Philogen, Pierre Fabre, Sanofi and Regeneron; personal fees as an invited speaker from BMS, Merck Serono, MSD, Novartis, Roche and Sanofi; personal fees (financial interest) for steering committee membership from BMS and MSD; personal support (no financial interest) for steering committee membership from Novartis; institutional support as a coordinating principal investigator (no financial interest) from BMS, MSD, Novartis and Pierre Fabre; institutional support as a local principal investigator (no financial interest) from Philogen and Sanofi; institutional research grant support (financial interest) from BMS and MSD; and is an EORTC-MG Member of the Board of Directors (no financial interest). J.T.S. receives honoraria as consultant or for continuing medical education presentations from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Immunocore, MSD Sharp Dohme, Novartis, Roche/Genentech and Servier; his institution receives research funding from Abalos Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eisbach Bio and Roche/Genentech; and he holds ownership and serves on the Board of Directors of Pharma15, all outside the submitted work. M.T. receives speaker fees and personal support from AstraZeneca, Daiichi Sankyo, Novartis, Bayer, Asklepios and Edwards LifeSciences. M.W. receives honoraria and has an advisory role: Amgen, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Janssen, Novartis, Pfizer, Roche, Takeda. Research funding: Bristol-Myers Squibb, Takeda. M.S. is a consultant (compensated) for Amgen, AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Merck Serono, Novartis, Roche, Sanofi and Takeda; receives honoraria for CME presentations from Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, MSD, Novartis, Roche and Sanofi; and receives research funding (institutional) from AstraZeneca and Bristol-Myers Squibb. K.-R.M., F.K. and G.M. hold patents related to this work (9558550; 20180018553) and are co-founders of the computational pathology start-up Aignostics, Berlin. The remaining authors declare no competing interests related to this study., (© 2025. The Author(s).)

Purpose: The management of soft tissue sarcoma (STS) at reference centers with specialized multidisciplinary tumor boards (MTB) improves patient survival. The German Cancer Society (DKG) certifies sarcoma centers in German-speaking countries, promoting high standards of care. This study investigated the variability in treatment recommendations for localized STS across different German-speaking tertiary sarcoma centers., Methods: In this cross-sectional case-based survey study, 5 anonymized patient cases with imaging data of localized STS were presented to MTBs of 21 German-speaking tertiary referral hospitals. Centers provided recommendations on treatment sequence and modalities, along with the consensus level within their MTB. Agreement percentages were calculated, and consensus levels were rated on a scale of 1 to 10., Results: Five patient cases were discussed resulting in 105 recommendations. Agreement percentages for case 1 to 5 were 14.3%, 61.9%, 33.3%, 52.4% and 9.3%, with a median agreement percentage of 33.3%. Grouping pre- and postoperative therapies as "perioperative" and including recommendations with and without regional hyperthermia raised the median agreement to 47.6%. The mean consensus level within each center across all 5 cases was 9.5., Conclusion: This first case-based analysis of inter-center agreement for STS management in German-speaking countries reveals low inter-center agreement but high intra-center consensus. Our study includes nearly all tertiary sarcoma centers in German-speaking countries, affirming its strong external validity. These findings suggest potential and clinically very relevant differences in treatment standards among sarcoma centers. Enhanced case-based exchanges and collaborative efforts are needed to reduce discrepancies and standardize the management of STS patients., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no competing interest related to the presented work. Ethics approval: The study was conducted in accordance with the Declaration of Helsinki and approved by the institutional review board (EA1/126/23)., (© 2024. The Author(s).)

Dilated cardiomyopathy (DCM) is one of the main causes for end-stage heart failure. Until the transplantation, left ventricular assist devices (LVAD) have become an established treatment. We report a case of a 66-year-old patient with ischemic and DCM and suspected aortic ulcer formation. LVAD was implanted in the same session with a supracoronary aortic replacement. Bilateral cannulation of the subclavian arteries omitted the need of circulatory arrest and proximal aortic cross-clamping. Pneumonia-associated decarboxylation failure prolonged the postoperative intensive care period. The patient was finally discharged home on the 115 th postoperative day., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Background: Whole lung transpulmonary chemoembolization using a combination of doxorubicin (DXO) and degradable starch microspheres (DSM-TPCE) might be a promising treatment option in soft tissue sarcoma. To pave the way for clinical studies, this study aimed to evaluate the short-term effects of DSM-TPCE with DXO using an ex vivo isolated lung perfusion (ILP) model., Methods: Nine lung specimens retrieved from patients undergoing lobectomy underwent ex vivo ILP. In groups of three, lung specimens were either treated with sole DXO, sole DSM, or combined substances (DSM + DXO). During ex vivo ILP, histological samples were obtained from each lung every 15 min. Quantitative DXO analysis and histopathological grading of possible tissue damage using a five-point Likert scale was performed. Two-way repeated measures ANOVA tested for differences between treatment groups and changes over time., Results: We created a preclinical ex vivo ILP model to simulate the effects of DSM-TPCE. In histopathological analysis, only two specimens, treated with only DXO, showed an increase in parenchymal damage over time. No significant effect of time (3.3%, p = 0.305) or group (23.3; p = 0.331) was identified. Within the lung tissue, the DXO concentration ranged from 205 to 1,244 ng/g. No significant effects could be detected regarding different treatment groups (4.9% of total variation, p = 0.103)., Conclusion: In an ex vivo ILP model using human lung lobes, the physiological effects of DSM-TPCE with DXO could be tested. Neither increased DXO concentrations in lung tissue nor histopathological changes indicating early lung toxicity were observed., Relevance Statement: An ex vivo ILP model using human lung specimens did not show any signs of early lung toxicity after transpulmonary chemoembolization with DXO. These results support further evaluation of DSM-TPCE in phase I/II trials., Key Points: Transpulmonary chemoembolization can be investigated in an ex vivo ILP model. DSM did not increase DXO in normal lung tissue. DSM did not increase parenchymal toxicity compared to the control groups., Competing Interests: Declarations. Ethics approval and consent to participate: The study was approved by the institutional review board of the University of Duisburg Essen. Informed consent was obtained from all patients prior to surgery. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests regarding this research project., (© 2024. The Author(s).)

Purpose: Clear cell sarcoma (CCS) of tendons and aponeuroses and CCS-like malignant gastrointestinal neuroectodermal tumor/sarcoma (GINET) are characterized by frequent local and distant relapses, alongside with low efficacy of all systemic treatments. We aimed to collect a comprehensive dataset to identify prognostic factors and treatment outcomes., Methods: We performed a retrospective single center analysis for diagnosed CCS and GINET on demographic, tumor, treatment and survival data., Results: We identified 43 patients (w:25, m:18) with a median follow-up of 35mo and a 5y-OS-rate of 42%. At diagnosis the median age was 42yrs. Median tumor size was 3.6 cm (0.3-11.1 cm), and 24/26 (94%) tissues analyzed at our institute were EWSR1::ATF1-translocation-positive. Distant extremities (incl. knee or elbow) were affected in 72.5%. Of note, 79.5% received an excisional biopsy (benign histology suspected in 30.2%) leading to frequent incomplete resection. Final R0 status correlated significantly (p = 0.017) with longer survival rates compared to R + status in localized CCS (N0M0, 5-yr OS 0% vs 64%). Radiation and systemic treatment had limited antitumor effects while isolated limb perfusion was active in some patients. 18.6% of patients showed lymphatic spread and 20.9% distant metastases. Presence of initial M + was associated with a dismal survival of 1.4 years (M +) vs 7.1 years (M0; p < .001)., Conclusion: We here present one of the largest clinical cohorts of patients with CCS/GINET. Our data underscores the exceptional risk of metastatic disease even in small tumors. As systemic treatment and radiation showed limited efficacy, complete resection was the most important treatment option., Competing Interests: Declarations Conflict of interest No other potential conflicts of interest were reported. The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: The prognosis of patients with metastatic GIST and imatinib-sensitive primary mutations has significantly improved. However, limited data are available to inform patients about outcomes across different lines of treatment. This retrospective analysis aims to evaluate patient outcomes at a large German GIST referral center over the past 15 years., Patients and Methods: Overall survival (OS) and progression-free survival (PFS) were analyzed in patients with metastatic GIST, with diagnosis of metastases between 2008 and 2021, when at least three lines of treatment were available in Germany (n = 174)., Results: The median overall survival far exceeds historical data for patients with primary exon 11 and exon 9 mutations (median OS in palliative treatment with imatinib: 7.1 years; median OS in second-line palliative treatment with sunitinib: 2.9 years; median OS in third-line palliative treatment with regorafenib: 1.9 years). Among those patients who received palliative imatinib treatment, no significant difference in median OS survival was observed between those who had received perioperative imatinib for localized disease and those who did not. Furthermore, the location of metastases significantly impacted survival, whereas the time between the initial diagnosis and the diagnosis of metastases had no significant effect on survival., Conclusion: In conclusion, this study provides a novel, real-world reference for survival outcomes in patients with metastatic GIST., (© 2024. The Author(s).)

Machine learning (ML) is transforming the field of image processing and analysis, from automation of laborious tasks to open-ended exploration of visual patterns. This has striking implications for image-driven life science research, particularly microscopy. In this Review, we focus on the opportunities and challenges associated with applying ML-based pipelines for microscopy datasets from a user point of view. We investigate the significance of different data characteristics - quantity, transferability and content - and how this determines which ML model(s) to use, as well as their output(s). Within the context of cell biological questions and applications, we further discuss ML utility range, namely data curation, exploration, prediction and explanation, and what they entail and translate to in the context of microscopy. Finally, we explore the challenges, common artefacts and risks associated with ML in microscopy. Building on insights from other fields, we propose how these pitfalls might be mitigated for in microscopy., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Introduction: Epithelioid hemangioendothelioma (EHE) is an ultra-rare sarcoma, marked by distinctive molecular and pathological features and with a variable clinical behavior. Its natural history is still partially understood, reliable prognostic and predictive factors are lacking and many questions are still open on the optimal management. In the context of EURACAN, a prospective registry specifically dedicated to EHE was developed and launched with the aim of providing, through high-quality prospective data collection, a better understanding of this disease., Study Design: Registry-based cohort study including only new cases of patients with a pathological and molecularly confirmed diagnosis of EHE., Objectives: To improve the understanding of EHE natural history, validate and identify new prognostic and predictive factors, clarify the activity and efficacy of currently available treatment options, describe treatment pattern., Methods: Settings and participantsIt is an hospital-based registry established in centers with expertise in EHE including adult patients with a new pathological and molecularly confirmed diagnosis of EHE starting from the 1st December 2023. The characteristics of each patient in the facility who meets the above-mentioned inclusion criteria will be collected prospectively and longitudinally with follow-up at cancer progression and / or cancer relapse or patient death. It is a secondary use of data which will be collected from the clinical records. The data collected for the registry will not entail further examinations or admissions to the facility and/or additional appointments to those normally provided for routine patient follow-up. VariablesFull details on patients and disease features, treatment and outcome will be collected, according to common clinical practice guidelines developed and shared with all the contributing centers. In addition, data on potential confounders (e.g. comorbidity; functional status etc.) will also be collected. Statistical methodsThe data analyses will include descriptive statistics and analytical analyses. Multivariable Cox's proportional hazards model and Hazard ratios (HR) for all-cause or cause-specific mortality will be used to determine independent predictors of overall survival, recurrence and progression., Results: The registry has been joined by 21 sarcoma reference centers across EU and UK, covering 10 countries. Patients' recruitment started in December 2023. The estimated completion date is December 2033 upon agreement on the achievement of all the registry objectives. The already established collaboration and participation of EHE patient's associations involved in the project will help in promoting the registry and fostering accrual., Competing Interests: Anna Maria Frezza declares institutional research funding from Advenchen Laboratories, Amgen Dompé, AROG Pharmaceuticals, Ayala Pharmaceuticals, Bayer, Blueprint Medicines, Boehriger Ingelheim, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme Inc, Foghorn Therapeutics Inc., Glaxo, Hutchison MediPharma Limited, Inhibrx, Inc., Karyopharm Pharmaceuticals, Novartis, Pfizer, PharmaMar, PTC Therapeutics, Rain Oncology, SpringWorks Therapeutics. Alexia Bertuzzi declares support for attending meeting and/or travels from Pharmamar and Istituto Gentili; support for scientific activities from Istituto Gentili. Antonella Brunello declares consulting fees or serving on advisory boards for Eli Lilly, Roche, GSK, Eisai, Pharmamar, Boehringer Ingelheim, Deciphera; payment or honoraria for educational events by GSK and Pharmamar; travel grants by Pharmamar, Istituto Gentili. Giacomo G. Baldi declares consulting fees from Eli Lilly, Pharmamar, AboutEvents; honoraria from Pharmamar, Eli Lilly, Glaxo Smith Kline, Merck Sharp & Dome, Eisai, IstitutoGentili; support for attending meetings and/or travels from Novartis, Pharmamar, Eli Lilly; participation on the advisory board from Pharmamar, Eli Lilly, Glaxo Smith Kline, Merck Sharp & Dome, Eisai. Paolo G. Casali declares institutional research funding from Advenchen Laboratories, Amgen Dompé, AROG Pharmaceuticals, Ayala Pharmaceuticals, Bayer, Blueprint Medicines, Boehriger Ingelheim, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme Inc, Foghorn Therapeutics Inc., Glaxo, Hutchison MediPharma Limited, Inhibrx, Inc., Karyopharm Pharmaceuticals, Novartis, Pfizer, PharmaMar, PTC Therapeutics, Rain Oncology, SpringWorks Therapeutics. Virginia Ferraresi declares consultancy fees or honoraria from PharmaMar, Boehringer Ingelheim, Gentili e Serb Pharmaceuticals. Matilde Ingrosso reports institutional research funding from Advenchen Laboratories, Amgen Dompé, AROG Pharmaceuticals, Ayala Pharmaceuticals, Bayer, Blueprint Medicines, Boehriger Ingelheim, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme Inc, Foghorn Therapeutics Inc., Glaxo, Hutchison MediPharma Limited, Inhibrx, Inc., Karyopharm Pharmaceuticals, Novartis, Pfizer, PharmaMar, PTC Therapeutics, Rain Oncology, SpringWorks Therapeutics. Laura Monteleone reports institutional research funding from Advenchen Laboratories, Amgen Dompé, AROG Pharmaceuticals, Ayala Pharmaceuticals, Bayer, Blueprint Medicines, Boehriger Ingelheim, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme Inc, Foghorn Therapeutics Inc., Glaxo, Hutchison MediPharma Limited, Inhibrx, Inc., Karyopharm Pharmaceuticals, Novartis, Pfizer, PharmaMar, PTC Therapeutics, Rain Oncology, SpringWorks Therapeutics. Johanna Szkandera reports participation in advisory boards or invited speaker fees for PharmaMar, Bayer, Roche, Lilly, Amgen; travel expenses coverage from PharmaMar, Roche, Lilly, Amgen, Bristol Myers Squibb; research funding from PharmaMar, Roche, Eisai. Bruno Vincenzi reports consulting fees from Eisai, Lilly, Bayer, Deciphera, PharmaMar, Blueprint, Pfizer, GSK, Accord, Abbott and research support from PharmaMar, Novartis, Lilly Silvia Stacchiotti declares advisory board roles with Bayer, Boehringer, Daiichi, Ikena, Nec Oncology, Pharma Essentia, Regeneron, Servier; invited speaker roles for Bayer, Boehringer, Gentili, Pharmamar; institutional research funding from Advenchen Laboratories, Amgen Dompé, AROG Pharmaceuticals, Ayala Pharmaceuticals, Bayer, Blueprint Medicines, Boehriger Ingelheim, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme Inc, Foghorn Therapeutics Inc., Glaxo, Hutchison MediPharma Limited, Inhibrx, Inc., Karyopharm Pharmaceuticals, Novartis, Pfizer, PharmaMar, PTC Therapeutics, Rain Oncology, SpringWorks Therapeutics. Carlo Cicala, Lorenzo D’Ambrosio, Angelo Paolo Dei Tos, Alessandro Gronchi, Nadia Hindi, Robin Jones, Iwona Lugowska, Julia Ketzer, Anna Mariuk-Jarema, Andrea Napolitano, Andri Papakonstantinou, Sandro Pasquali, Marta Sbaraglia, Federico Scolari, Elisa Crotti, Irene Benzonelli, Jean-Yves Blay, Christophe Bouvier, Javier Martin Broto, Hugh Leonard, Ninna Aggerholm-Pedersen, Andri Papakonstantinou, Giuseppe Bianchi, Federica Zuccheri, Paolo Baili, Simone Bonfarnuzzo, Domenico Campanacci, Armelle Dufresne, Sebastian Bauer, Serena Bazzurri, Stefano Gabellini, Claudia Giani, Vincenzo Giannusa, Melissa Gil-Sanjines, Teresa Grassani, Paolo Lasalvia, Stefan Lindskog, Salvatore Vizzaccaro, Nils Dieckmann, Alessandro Mazzocca, Andrei Ivanescu, Giuseppe Badalamenti, Carlo Morosi, Stephanie Elston, Kyetil Boye, Francesca Nardozza, Elisabetta Neri, Maria Nilsson and Annalisa Trama declares no conflict of interest., (Copyright: © 2024 Frezza et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Epileptogenesis is the process by which a normal brain becomes hyperexcitable and capable of generating spontaneous recurrent seizures. The extensive dysregulation of gene expression associated with epileptogenesis is shaped, in part, by microRNAs (miRNAs) - short, non-coding RNAs that negatively regulate protein levels. Functional miRNA-mediated regulation can, however, be difficult to elucidate due to the complexity of miRNA-mRNA interactions. Here, we integrated miRNA and mRNA expression profiles sampled over multiple time-points during and after epileptogenesis in rats, and applied bi-clustering and Bayesian modelling to construct temporal miRNA-mRNA-mRNA interaction networks. Network analysis and enrichment of network inference with sequence- and human disease-specific information identified key regulatory miRNAs with the strongest influence on the mRNA landscape, and miRNA-mRNA interactions closely associated with epileptogenesis and subsequent epilepsy. Our findings underscore the complexity of miRNA-mRNA regulation, can be used to prioritise miRNA targets in specific systems, and offer insights into key regulatory processes in epileptogenesis with therapeutic potential for further investigation., (© 2024. The Author(s).)

Background: Patients with ruptured gastrointestinal stromal tumour (GIST) have poor prognosis. Little information is available about how adjuvant imatinib influences survival., Methods: We explored recurrence-free survival (RFS) and overall survival (OS) of patients with ruptured GIST who participated in a randomised trial (SSG XVIII/AIO), where 400 patients with high-risk GIST were allocated to adjuvant imatinib for either 1 year or 3 years after surgery. Of the 358 patients with confirmed localised GIST, 73 (20%) had rupture reported. The ruptures were classified retrospectively using the Oslo criteria., Results: Most ruptures were major, four reported ruptures were reclassified unruptured. The 69 patients with rupture had inferior RFS and OS compared with 289 patients with unruptured GIST (10-year RFS 21% vs. 55%, OS 59% vs. 78%, respectively). Three-year adjuvant imatinib did not significantly improve RFS or OS of the patients with rupture compared with 1-year treatment, but in the largest mutational subset with KIT exon 11 deletion/indel mutation OS was higher in the 3-year group than in the 1-year group (10-year OS 94% vs. 54%)., Conclusions: About one-fifth of ruptured GISTs treated with adjuvant imatinib did not recur during the first decade of follow-up. Relatively high OS rates were achieved despite rupture., Clinical Trial Registration: NCT00116935., (© 2024. The Author(s).)

Background: Tenosynovial giant cell tumour (TGCT) is a locally aggressive neoplasm for which few systemic treatment options exist. This study evaluated the efficacy and safety of vimseltinib, an oral, switch-control, CSF1R inhibitor, in patients with symptomatic TGCT not amenable to surgery., Methods: MOTION is a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial done in 35 specialised hospitals in 13 countries. Eligible patients were adults (aged ≥18 years) with a histologically confirmed diagnosis of TGCT for which surgical resection could potentially worsen functional limitation or cause severe morbidity. Patients were randomly assigned (2:1) with interactive response technology to vimseltinib (30 mg orally twice weekly) or placebo, administrated in 28-day cycles for 24 weeks. Patients and site personnel were masked to treatment assignment until week 25, unless progressive disease was confirmed earlier. The primary endpoint was objective response rate by independent radiological review using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST) at week 25 in the intention-to-treat population. Safety was assessed in all patients who received the study drug. The trial is registered with ClinicalTrials.gov, NCT05059262, and enrolment is complete., Findings: Between Jan 21, 2022, and Feb 21, 2023, 123 patients were randomly assigned (83 to vimseltinib and 40 to placebo). 73 (59%) patients were female and 50 (41%) were male. Nine (11%) of 83 patients assigned to vimseltinib and five (13%) of 40 patients assigned to placebo discontinued treatment before week 25; one patient in the placebo group did not receive any study drug. Objective response rate per RECIST was 40% (33 of 83 patients) in the vimseltinib group vs 0% (none of 40) in the placebo group (difference 40% [95% CI 29-51]; p<0·0001). Most treatment-emergent adverse events (TEAEs) were grade 1 or 2; the only grade 3 or 4 TEAE that occurred in more than 5% of patients receiving vimseltinib was increased blood creatine phosphokinase (eight [10%] of 83). One patient in the vimseltinib group had a treatment-related serious TEAE of subcutaneous abscess. No evidence of cholestatic hepatotoxicity or drug-induced liver injury was noted., Interpretation: Vimseltinib produced a significant objective response rate and clinically meaningful functional and symptomatic improvement in patients with TGCT, providing an effective treatment option for these patients., Funding: Deciphera Pharmaceuticals., Competing Interests: Declaration of interests VB reports institutional research funding from Deciphera Pharmaceuticals and participation on a medical advisory board for Deciphera Pharmaceuticals. SS reports institutional research funding from Abbiski, Daiichi Sankyo, and Deciphera Pharmaceuticals, and advisory board roles with Daiichi Sankyo and Deciphera Pharmaceuticals. SB reports honoraria from Blueprint Medicine, Boehringer Ingelheim, Pfizer, PharmaMar, Uptodate, and Deciphera Pharmaceuticals; consulting or advisory roles with Adcendo, Bayer, Boehringer Ingelheim, Cogent Biosciences, Daiichi Sankyo, Lilly, IDRx, and Deciphera Pharmaceuticals; institutional research funding from Adcendo, Blueprint Medicine, Incyte, and IDRx; participation on a board for the University of Aachen; unpaid board of directors positions with The Connective Tissue Oncology Society and Deutsche Sarkomstiftung; and a faculty position with the European Society for Medical Oncology. AJW reports consulting or advisory roles and institutional research funding from Daiichi Sankyo and Deciphera Pharmaceuticals. MvdS reports travel partly supported by Deciphera Pharmaceuticals. NMB reports research support from Deciphera Pharmaceuticals. AAR reports consulting or advisory roles with Boehringer Ingelheim and Medison; institutional research funding from 23andMe, Abbisko, AbbVie, Adaptimmune, Amgen, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, GSK, Inhibrx, Iterion Therapeutics, Karyopharm Therapeutics, MedImmune, Medison, Merck, Neoleukin Therapeutics, Pfizer, Rain Therapeutics, Roche/Genentech, Symphogen, and Deciphera Pharmaceuticals; and participation on an advisory board for Inhibrx. AI reports consulting or advisory roles for Bayer, Bristol Myers Squibb, Chugai Pharmaceutical, Merck, Merck Sharp & Dohme, Novartis, Parthenon, PharmaMar, and Roche; and institutional research funding from Bayer, Bristol Myers Squibb, Chugai Pharmaceutical, Merck, Merck Sharp & Dohme, Novartis, Parthenon, PharmaMar, and Roche. ALC reports honoraria from Bayer, PharmaMar, and Deciphera Pharmaceuticals. GT reports consulting or advisory roles with Daiichi Sankyo and Servier. KB reports honoraria from Incyte, Lilly, Novartis, and Deciphera Pharmaceuticals; expert testimony for Deciphera Pharmaceuticals; and advisory board participation for Bayer, GSK, and NEC OncoImmunity. JM-B reports consulting or advisory roles for Amgen, Asofarma, Boehringer Ingelheim, Bayer, GSK, Lilly, Novartis, PharmaMar, Roche, and Tecnofarma; speakers bureau involvement for PharmaMar; and institutional research funding from Adaptimmune, Amgen, Ayala Pharmaceuticals, Bayer, Blueprint Medicines, Bristol Myers Squibb, Cebiotex, Celgene, Daiichi Sankyo, Eisai, GSK, IMMIX Biopharma, Inhibrx, Karyopharm Therapeutics, Lilly, Lixte, Novartis, Pfizer, PharmaMar, Philogen, PTC Therapeutics, Rain Therapeutics, and Deciphera Pharmaceuticals; expert testimony for Amgen, Bayer, Boehringer Ingelheim, Eisai, Lilly, PharmaMar, and Roche; travel support from Novartis, Pfizer, and PharMar; advisory board participation for Asofarma and Tecnofarma; and a leadership or fiduciary role for Sarcoma Research solutions. EP reports advisory board roles with Daiichi Sankyo, SynOx, and Deciphera Pharmaceuticals. PRe reports honoraria for participation in advisory boards for Bayer, Blueprint Medicines, Boehringer Ingelheim, Clinigen, GSK, MundiBioPharma, Novartis, PharmaMar, Roche, and Deciphera Pharmaceuticals, and a leadership position for the German Sarcoma Foundation. PRu reports honoraria from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, and Sanofi; speakers bureaus for Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pfizer, and Pierre Fabre; travel support from Orphan Europe and Pierre Fabre; consulting fees from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pfizer, Philogen, and Pierre Fabre; and institutional research funding from Bristol Myers Squibb, Novartis, Pfizer, and Roche. CT, FZ, and BH report employment with and stock or other ownership interests in Deciphera Pharmaceuticals. MGS reports employment with, stock or other ownership interests in, and travel support from Deciphera Pharmaceuticals. RR-S reports employment with, stock or other ownership interests in, and patents, royalties, or other intellectual property from Deciphera Pharmaceuticals (inventor in pending patents at Deciphera Pharmaceuticals for which the rights have been transferred to Deciphera Pharmaceuticals; RR-S has not received and will not receive any royalties). MLS reports employment in a leadership role with, stock or other ownership interests in, travel support from, and patents, royalties, or other intellectual property from Deciphera Pharmaceuticals (inventor in pending patents at Deciphera Pharmaceuticals for which the rights have been transferred to Deciphera Pharmaceuticals; MLS has not received and will not receive any royalties). J-YB reports honoraria from Bayer and Deciphera Pharmaceuticals; consulting or advisory roles with Bayer and Deciphera Pharmaceuticals; institutional research funding from Bayer and Deciphera Pharmaceuticals; academic support from the French National Cancer Institute (INCA) NETSARC, INTERSARC, and EURACAN; and funding for travel, accommodation, or expenses from OSE Pharma. WDT reports advisory board roles for Aadi Biosciences, Abbisko, Amgen, AmMax Bio, Avacta, Bayer, BioAtla, Boehringer Ingelheim, C4 Therapeutics, Cogent Biosciences, Daiichi Sankyo, Foghorn Therapeutics, IMGT, Inhibrx, Ipsen, Lilly, PharmaEssentia, Servier, Sonata, and Deciphera Pharmaceuticals; owns stock or shares in Atropos and Certis Oncology Solutions; reports a patent for Companion Diagnostics for CDK4 inhibitors (14/854,329) and for Enigma and CDH18 (SKI2016–021–03); and reports institutional funding from Deciphera Pharmaceuticals. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Fibroblast activation protein-α (FAP) is often highly expressed by sarcoma cells and by sarcoma-associated fibroblasts in the tumor microenvironment. This makes it a promising target for imaging and therapy. The level of FAP expression and the diagnostic value of 68 Ga-FAP inhibitor (FAPI) PET for sarcoma subtypes are unknown. We assessed the diagnostic performance and accuracy of 68 Ga-FAPI PET in various bone and soft-tissue sarcomas. Potential eligibility for FAP-targeted radiopharmaceutical therapy (FAP-RPT) was evaluated. Methods: This prospective observational trial enrolled 200 patients with bone and soft-tissue sarcoma who underwent 68 Ga-FAPI PET/CT and 18 F-FDG PET/CT (186/200, or 93%) for staging or restaging. The number of lesions detected and the uptake (SUV max ) of the primary tumor, lymph nodes, and visceral and bone metastases were analyzed. The Wilcoxon test was used for semiquantitative assessment. The association of 68 Ga-FAPI uptake intensity, histopathologic grade, and FAP expression in sarcoma biopsy samples was analyzed using Spearman r correlation. The impact of 68 Ga-FAPI PET on clinical management was investigated using questionnaires before and after PET/CT. Eligibility for FAP-RPT was defined by an SUV max greater than 10 for all tumor regions. Results: 68 Ga-FAPI uptake was heterogeneous among sarcoma subtypes. The 3 sarcoma entities with the highest uptake (mean SUV max ± SD) were solitary fibrous tumor (24.7 ± 11.9), undifferentiated pleomorphic sarcoma (18.8 ± 13.1), and leiomyosarcoma (15.2 ± 10.2). Uptake of 68 Ga-FAPI versus 18 F-FDG was significantly higher in low-grade sarcomas (10.4 ± 8.5 vs. 7.0 ± 4.5, P = 0.01) and in potentially malignant intermediate or unpredictable sarcomas without a World Health Organization grade (not applicable [NA]; 22.3 ± 12.5 vs. 8.5 ± 10.0, P = 0.0004), including solitary fibrous tumor. The accuracy, as well as the detection rates, of 68 Ga-FAPI was higher than that of 18 F-FDG in low-grade sarcomas (accuracy, 92.2 vs. 80.0) and NA sarcomas (accuracy, 96.9 vs. 81.9). 68 Ga-FAPI uptake and the histopathologic FAP expression score ( n = 89) were moderately correlated (Spearman r = 0.43, P < 0.0002). Of 138 patients, 62 (45%) with metastatic sarcoma were eligible for FAP-RPT. Conclusion: In patients with low-grade and NA sarcomas, 68 Ga-FAPI PET demonstrates uptake, detection rates, and accuracy superior to those of 18 F-FDG PET. 68 Ga-FAPI PET criteria identified eligibility for FAP-RPT in about half of sarcoma patients., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Imatinib resistance in GI stromal tumors (GISTs) is primarily caused by secondary KIT mutations, and clonal heterogeneity of these secondary mutations represents a major treatment obstacle. KIT inhibitors used after imatinib have clinical activity, albeit with limited benefit. Ripretinib is a potent inhibitor of secondary KIT mutations in the activation loop (AL). However, clinical benefit in fourth line remains limited and the molecular mechanisms of ripretinib resistance are largely unknown., Patients and Methods: Progressing lesions of 25 patients with GISTs refractory to ripretinib were sequenced for KIT resistance mutations. Resistant genotypes were validated and characterized using novel cell line models and in silico modeling., Results: GISTs progressing on ripretinib were enriched for secondary mutations in the ATP-binding pocket (AP), which frequently occur in cis with preexisting AL mutations, resulting in highly resistant AP/AL genotypes. AP/AL mutations were rarely observed in a cohort of progressing GIST samples from the preripretinib era but represented 50% of secondary KIT mutations in patients with tumors resistant to ripretinib. In GIST cell lines harboring secondary KIT AL mutations, the sole genomic escape mechanisms during ripretinib drug selection were AP/AL mutations. Ripretinib and sunitinib synergize against mixed clones with secondary AP or AL mutants but do not suppress clones with AP/AL genotypes., Conclusion: Our findings underscore that KIT remains the central oncogenic driver even in late lines of GIST therapy. KIT-inhibitor combinations may suppress resistance because of secondary KIT mutations. However, the emergence of KIT AP/AL mutations after ripretinib treatment calls for new strategies in the development of next-generation KIT inhibitors.

Purpose: The efficacy of the selective KIT/PDGFRA inhibitor avapritinib (300 mg once daily) was explored in patients with non-PDGFRA-mutant gastrointestinal stromal tumors (GISTs) from the phase I NAVIGATOR and phase I/II CS3007-001 trials., Patients and Methods: Adults with unresectable/metastatic, KIT-only-mutant GISTs and progression following ≥1 tyrosine kinase inhibitors (TKIs) were included in this post hoc analysis. Baseline mutational status was identified in tumor and plasma. Primary endpoints were objective response rate (ORR) and progression-free survival (PFS) by blinded independent radiology review per modified RECIST v1.1 in patients harboring KIT activation-loop mutations (KIT exons 17 or 18) without ATP binding-pocket mutations (KIT exons 13 or 14; ALposABPneg), and other KIT mutations (OTHERS)., Results: Sixty KIT ALposABPneg and 100 KIT OTHERS predominantly heavily pretreated patients (61.3% with ≥3 prior TKIs) were included. ORR was significantly higher in KIT ALposABPneg than KIT OTHERS patients (unadjusted: 26.7% vs. 12.0%; P = 0.0852; adjusted: 31.4% vs. 12.1%; P = 0.0047). Median PFS (mPFS) was significantly longer in KIT ALposABPneg patients compared with KIT OTHERS patients (unadjusted: 9.1 vs. 3.5 months; P = 0.0002; adjusted: 9.1 vs. 3.4 months; P < 0.0001), and longer in second- versus later-line settings (19.3 vs. 5.6-10.6 months). Benefit with avapritinib was observed in patients with KIT exon 9 mutations in the ≥4 line settings (mPFS: 5.6 and 3.7 months for 4 line and >4 line, respectively)., Conclusions: Avapritinib showed greater antitumor activity in patients with GISTs harboring KIT ALposABPneg mutations versus KIT OTHERS, and may be considered in the former subpopulation. Patients with KIT exon 9 mutations may also benefit in ≥4 line settings., (©2023 American Association for Cancer Research.)

Objectives: Malignant triton tumours (MTTs) are rare but aggressive subtypes of malignant peripheral nerve sheath tumours (MPNSTs) with a high recurrence rate and 5-year survival of 14%. Systematic imaging data on MTTs are scarce and mainly based on single case reports. Therefore, we aimed to identify typical CT and MRI features to improve early diagnosis rates of this uncommon entity., Methods: A systematic review on literature published until December 2022 on imaging characteristics of MTTs was performed. Based on that, we conducted a retrospective, monocentric analysis of patients with histopathologically proven MTTs from our department. Explorative data analysis was performed., Results: Initially, 29 studies on 34 patients (31.42 ± 22.6 years, 12 female) were evaluated: Literature described primary MTTs as huge, lobulated tumours (108 ± 99.3 mm) with central necrosis (56% [19/34]), low T1w (81% [17/21]), high T2w signal (90% [19/21]) and inhomogeneous enhancement on MRI (54% [7/13]). Analysis of 16 patients (48.9 ± 13.8 years; 9 female) from our institution revealed comparable results: primary MTTs showed large, lobulated masses (118 mm ± 64.9) with necrotic areas (92% [11/12]). MRI revealed low T1w (100% [7/7]), high T2w signal (100% [7/7]) and inhomogeneous enhancement (86% [6/7]). Local recurrences and soft-tissue metastases mimicked these features, while nonsoft-tissue metastases appeared unspecific., Conclusions: MTTs show characteristic features on CT and MRI. However, these do not allow a reliable differentiation between MTTs and other MPNSTs based on imaging alone. Therefore, additional histopathological analysis is required., Advances in Knowledge: This largest published systematic analysis on MTT imaging revealed typical but unspecific imaging features that do not allow a reliable, imaging-based differentiation between MTTs and other MPNSTs. Hence, additional histopathological analysis remains essential., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Institute of Radiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

INTRIGUE was an open-label, phase 3 study in adult patients with advanced gastrointestinal stromal tumor who had disease progression on or intolerance to imatinib and who were randomized to once-daily ripretinib 150 mg or sunitinib 50 mg. In the primary analysis, progression-free survival (PFS) with ripretinib was not superior to sunitinib. In clinical and nonclinical studies, ripretinib and sunitinib have demonstrated differential activity based on the exon location of KIT mutations. Therefore, we hypothesized that mutational analysis using circulating tumor DNA (ctDNA) might provide further insight. In this exploratory analysis (N = 362), baseline peripheral whole blood was analyzed by a 74-gene ctDNA next-generation sequencing-based assay. ctDNA was detected in 280/362 (77%) samples with KIT mutations in 213/362 patients (59%). Imatinib-resistant mutations were found in the KIT ATP-binding pocket (exons 13/14) and activation loop (exons 17/18). Mutational subgroup assessment showed 2 mutually exclusive populations with differential treatment effects. Patients with only KIT exon 11 + 13/14 mutations (ripretinib, n = 21; sunitinib, n = 20) had better PFS with sunitinib versus ripretinib (median, 15.0 versus 4.0 months). Patients with only KIT exon 11 + 17/18 mutations (ripretinib, n = 27; sunitinib, n = 25) had better PFS with ripretinib versus sunitinib (median, 14.2 versus 1.5 months). The results of this exploratory analysis suggest ctDNA sequencing may improve the prediction of the efficacy of single-drug therapies and support further evaluation of ripretinib in patients with KIT exon 11 + 17/18 mutations. ClinicalTrials.gov identifier: NCT03673501., (© 2024. The Author(s).)

Fibroblast activation protein α (FAPα) is expressed at high levels in several types of tumors. Here, we report the expression pattern of FAPα in solitary fibrous tumor (SFT) and its potential use as a radiotheranostic target. Methods: We analyzed FAPα messenger RNA and protein expression in biopsy samples from SFT patients using immunohistochemistry and multiplexed immunofluorescence. Tracer uptake and detection efficacy were assessed in patients undergoing clinical 68 Ga-FAPα inhibitor (FAPI)-46 PET, 18 F-FDG PET, and contrast-enhanced CT. 90 Y-FAPI-46 radioligand therapy was offered to eligible patients with progressive SFT. Results: Among 813 patients and 126 tumor entities analyzed from the prospective observational MASTER program of the German Cancer Consortium, SFT ( n = 34) had the highest median FAPα messenger RNA expression. Protein expression was confirmed in tumor biopsies from 29 of 38 SFT patients (76%) in an independent cohort. Most cases showed intermediate to high FAPα expression by immunohistochemistry (24/38 samples, 63%), which was located primarily on the tumor cell surface. Nineteen patients who underwent 68 Ga-FAPI-46 PET imaging demonstrated significantly increased tumor uptake, with an SUV max of 13.2 (interquartile range [IQR], 10.2), and an improved mean detection efficacy of 94.5% (SEM, 4.2%), as compared with 18 F-FDG PET (SUV max , 3.2 [IQR, 3.1]; detection efficacy, 77.3% [SEM, 5.5%]). Eleven patients received a total of 34 cycles (median, 3 cycles [IQR, 2 cycles]) of 90 Y-FAPI-46 radioligand therapy, which resulted in disease control in 9 patients (82%). Median progression-free survival was 227 d (IQR, 220 d). Conclusion: FAPα is highly expressed by SFT and may serve as a target for imaging and therapy. Further studies are warranted to define the role of FAPα-directed theranostics in the care of SFT patients., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

A heart transplant is the gold standard therapy for patients with end-stage heart failure. In this case report, situs inversus totalis and congenitally corrected transposition of the great arteries led to a unique and complex preoperative setting. Extended donor organ harvesting, donor graft rotation of 45° to the right and post-operative stenting of the superior vena cava were essential steps in the interdisciplinary management of this case. The patient was transferred to the intensive care unit with moderate inotropic support. He was discharged to rehabilitation on postoperative day 89 and eventually underwent an additional renal transplant 14 months after the cardiac transplant., (© The Author 2024. Published by MMCTS on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

MicroRNAs have emerged as important regulators of the gene expression landscape in temporal lobe epilepsy. The mechanisms that control microRNA levels and influence target choice remain, however, poorly understood. RNA editing is a post-transcriptional mechanism mediated by the adenosine acting on RNA (ADAR) family of proteins that introduces base modification that diversifies the gene expression landscape. RNA editing has been studied for the mRNA landscape but the extent to which microRNA editing occurs in human temporal lobe epilepsy is unknown. Here, we used small RNA-sequencing data to characterize the identity and extent of microRNA editing in human temporal lobe epilepsy brain samples. This detected low-to-high editing in over 40 of the identified microRNAs. Among microRNA exhibiting the highest editing was miR-376a-3p, which was edited in the seed region and this was predicted to significantly change the target pool. The edited form was expressed at lower levels in human temporal lobe epilepsy samples. We modelled the shift in editing levels of miR-376a-3p in human-induced pluripotent stem cell-derived neurons. Reducing levels of the edited form of miR-376a-3p using antisense oligonucleotides resulted in extensive gene expression changes, including upregulation of mitochondrial and metabolism-associated pathways. Together, these results show that differential editing of microRNAs may re-direct targeting and result in altered functions relevant to the pathophysiology of temporal lobe epilepsy and perhaps other disorders of neuronal hyperexcitability., Competing Interests: K.L.E.H., J.C.K. and D.C.H. declare an invention under assessment for patent filing by RCSI. All other authors declare no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Somatic KIT activating mutations drive most gastrointestinal stromal tumors (GISTs). Disease progression eventually develops with first-line imatinib, commonly due to KIT secondary mutations, and different kinase inhibitors have various levels of treatment efficacy dependent on specific acquired resistance mutations. Ripretinib is a broad-spectrum switch-control KIT/PDGFRA tyrosine kinase inhibitor for patients with advanced GIST who received prior treatment with three or more kinase inhibitors, including imatinib. Exploratory baseline circulating tumor DNA analysis from the second-line INTRIGUE trial determined that patients with advanced GIST previously treated with imatinib harboring primary KIT exon 11 mutations and secondary resistance mutations restricted to KIT exons 17/18 had greater clinical benefit with ripretinib versus sunitinib. We describe the rationale and design of INSIGHT (NCT05734105), an ongoing Phase III open-label study of ripretinib versus sunitinib in patients with advanced GIST previously treated with imatinib exclusively harboring KIT exon 11 + 17/18 mutations detected by circulating tumor DNA. Clinical Trial Registration: NCT05734105 (ClinicalTrials.gov).

Purpose: The phase III, open-label, prospective, multicenter, randomized Ewing 2008R1 trial (EudraCT2008-003658-13) was conducted in 12 countries to evaluate the effect of zoledronic acid (ZOL) maintenance therapy compared with no add-on regarding event-free survival (EFS, primary endpoint) and overall survival (OS) in standard-risk Ewing sarcoma (EWS)., Patients and Methods: Eligible patients had localized EWS with either good histologic response to induction chemotherapy and/or small tumors (<200 mL). Patients received six cycles of VIDE induction and eight cycles of VAI (male) or eight cycles of VAC (female) consolidation. ZOL treatment started parallel to the sixth consolidation cycle. Randomization was stratified by tumor site (pelvis/other). The two-sided adaptive inverse-normal four-stage design (planned sample size 448 patients, significance level 5%, power 80%) was changed after the first interim analysis using the Müller-Schäfer method., Results: Between April 2010 and November 2018, 284 patients were randomized (142 ZOL/142 no add-on). With a median follow-up of 3.9 years, EFS was not significantly different between ZOL and no add-on group in the adaptive design (HR, 0.74; 95% CI, 0.43-1.28, P = 0.27, intention-to-treat). Three-year EFS rates were 84.0% (95% CI, 77.7%-90.8%) for ZOL vs. 81.7% (95% CI, 75.2%-88.8%) for no add-on. Results were similar in the per-protocol collective. OS was not different between groups. The 3-year OS was 92.8% (95% CI, 88.4%-97.5%) for ZOL and 94.6% (95% CI, 90.9%-98.6%) for no add-on. Noticeable more renal, neurologic, and gastrointestinal toxicities were observed for ZOL (P < 0.05). Severe renal toxicities occurred more often in the ZOL arm (P = 0.003)., Conclusions: In patients with standard-risk localized EWS, there is no additional benefit from maintenance treatment with ZOL., (©2023 American Association for Cancer Research.)

Background: Large Impella systems (5.0 or 5.5; i.e., Impella 5+) (Abiomed Inc., Danvers, MA, USA) help achieve better clinical outcomes through relevant left ventricular unloading in acute cardiogenic shock (CS). Here, we report our experience with Impella 5+, while focusing on the clinical outcomes depending on individual case scenarios in patients with acute CS., Methods: This single-center retrospective observational study included 100 Impella 5+ implantations conducted on patients with acute CS from November 2018 to October 2021. After excluding 10 reimplantation cases, 90 cases were enrolled for further analysis., Results: In-hospital and 30-day mortality rates were 56.7% (n = 51) and 48.9% (n = 44), respectively. In-hospital mortality was lower in patients with acute myocardial infarction (AMI) than in non-AMI patients (p = 0.07). Young age and low lactate levels were the independent predictors of successful transition and survival after permanent mechanical circulatory support/heart transplantation (pMCS/HTX) (age, p = 0.03; lactate level, p = 0.04; survived after pMCS/HTX, n = 11; died on Impella, n = 41). During simultaneous utilization of venoarterial extracorporeal membrane oxygenation therapy and Impella 5+, termed ECMELLA therapy, high dose of noradrenaline was a predictive factor for in-hospital mortality by multivariate analysis (n = 0.02)., Conclusions: Our results suggest that enhanced Impella support might have better clinical outcomes among acute CS patients supported with large Impella, those with AMI than those with no AMI. Young age and low lactate levels were predictors of successful bridging to pMCS/HTX and favorable clinical outcomes thereafter. The clinical outcomes of ECMELLA therapy might depend on noradrenaline dose at the time of Impella 5+ implantation., (© 2023 The Authors. Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Purpose: In the INTRIGUE trial, ripretinib showed no significant difference versus sunitinib in progression-free survival for patients with advanced gastrointestinal stromal tumour (GIST) previously treated with imatinib. We compared the impact of these treatments on health-related quality of life (HRQoL)., Patients and Methods: Patients were randomised 1:1 to once-daily ripretinib 150 mg or once-daily sunitinib 50 mg (4 weeks on/2 weeks off). Patient-reported outcomes were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer-30 (EORTC QLQ-C30) questionnaire at day (D)1, and D29 of all cycles until treatment discontinuation. Change from baseline was calculated. Time without symptoms or toxicity (TWiST) was estimated as the mean number of days without progression, death, or grade ≥3 treatment-emergent adverse events per patient over 1 year of follow-up., Results: Questionnaire completion at baseline was 88.1% (199/226) for ripretinib and 87.7% (199/227) for sunitinib and remained high for enrolled patients throughout treatment. Patients receiving sunitinib demonstrated within-cycle variation in self-reported HRQoL, corresponding to the on/off dosing regimen. Patients receiving ripretinib reported better HRQoL at D29 assessments than patients receiving sunitinib on all scales except constipation. HRQoL was similar between treatments at D1 assessments, following 2 weeks without treatment for sunitinib patients. TWiST was greater for ripretinib patients (173 versus 126 days)., Conclusion: Patients receiving ripretinib experienced better HRQoL than patients receiving sunitinib during the dosing period and similar HRQoL to patients who had not received sunitinib for 2 weeks for all QLQ-C30 domains except constipation. Ripretinib may provide clinically meaningful benefit to patients with advanced GIST previously treated with imatinib., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Attia reports institutional research funding from AB Science, Adaptimmune, Advenchen Laboratories, Ayala Pharmaceuticals, Bavarian Nordic, Bayer, Blueprint Medicines, Boehringer Ingelheim, BTG, C4 Therapeutics, CBA Pharma, Deciphera Pharmaceuticals, Eli Lilly & Co, Epizyme, FORMA Therapeutics, Genmab, GlaxoSmithKline, Gradalis, Incyte, InhibRx, Karyopharm Therapeutics, Merck, Monopar Therapeutics, Novartis, Noxopharm, Philogen, PTC Therapeutics, Rain Therapeutics, Salarius Pharmaceuticals, Springworks, Takeda, Theseus Pharmaceuticals, TRACON Pharmaceuticals and Trillium Therapeutics; and personal research funding from the Desmoid Tumour Research Foundation. Dr. Bauer reports honoraria from Novartis; advisory board fees from Roche; consulting fees from Adcendo, Bayer, Blueprint Medicines, Boehringer Ingelheim, Cogent Biosciences, Daiichi Sankyo, Deciphera Pharmaceuticals, Eli Lilly & Co, Exelixis, GlaxoSmithKline, Incyte, Nanobiotix, Novartis and PharmaMar; institutional research funding from Novartis; and travel support from PharmaMar. Dr. Becker has no financial interests to disclose. Dr. Blay reports leadership at Innate Pharma; honoraria from AstraZeneca, Bayer, Bristol Myers Squibb, Deciphera Pharmaceuticals, Ignyta, Merck, PharmaMar and Roche; consulting fees from Bayer, Blueprint Medicines, Deciphera Pharmaceuticals, Karyopharm Therapeutics, PharmaMar and Roche; institutional research funding from AstraZeneca, Bristol Myers Squibb, Bayer, Deciphera Pharmaceuticals, GlaxoSmithKline, Merck, Novartis, OSE Pharma, PharmaMar and Roche; and travel support from Roche. Dr. Boye reports honoraria from Eli Lilly & Co and Novartis; consulting fees from Bayer and GlaxoSmithKline; and institutional research funding from Eli Lillly & Co and Merck. Dr. Chi reports consulting fees from Deciphera Pharmaceuticals, Exelixis, NewBay, Novartis and Zai Lab; institutional research funding from Deciphera Pharmaceuticals and Pfizer/Array; and is a shareholder of Oric Pharma.Dr. Druta reports consulting fees from Eisai and Eli Lilly & Co; and speaker’s bureau fees from Eisai and Eli Lilly & Co. Dr. Gelderblom reports institutional research funding from Daiichi Sankyo, Deciphera Pharmaceuticals, Ipsen and Novartis. Dr. George reports consulting fees from Bayer, Blueprint Medicines, Daiichi Sankyo, Deciphera Pharmaceuticals, Eli Lilly & Co, Kayothera, Immunicum, MORE Health, Research to Practice and UpToDate; institutional research funding from BioAtla, Blueprint Medicines, Daiichi Sankyo, Deciphera, Eisai, IDRX, Merck, Springworks, Theseus Pharmaceuticals and TRACON Pharma; honoraria from CStone Pharmaceuticals; patents, royalties, or other intellectual property with UpToDate; other financial relationships with Research to Practice and WCG/Ayala; and is a shareholder of Abbott Laboratories. Dr. Goldstein reports consulting fees from Deciphera Pharmaceuticals. Dr. Harrow is an employee and shareholder of Deciphera Pharmaceuticals. Dr. Heinrich reports honoraria from Novartis; consulting fees from Blueprint Medicines, Deciphera Pharmaceuticals, Novartis and Theseus Pharmaceuticals; and a patent on the treatment of GIST licensed to Novartis. Dr. Jones reports consulting fees from Adaptimmune, Astex, Athenex, Bayer, Boehringer Ingelheim, Blueprint Medicines, Clinigen, Eisai, Eli Lilly & Co, Epizyme, Daiichi Sankyo, Deciphera Pharmaceuticals, Immunedesign, Immunicum, Karma Oncology, Merck, Mundipharma, PharmaMar, Springworks, SynOx, TRACON Pharmaceuticals and UpToDate. Dr. Kang reports consulting fees from ALX Oncology, Amgen, Novartis, Blueprint Medicines, Bristol Myers Squibb, Daehwa, Macrogenics, Surface Oncology and Zymeworks. Dr. Le Cesne reports honoraria from Bayer, Deciphera Pharmaceuticals, and PharmaMar. Dr. Razak reports consulting fees from Adaptimmune, Bayer, GlaxoSmithKline, Medison, Inhibrx; and research funding from AbbVie, Adaptimmune, Amgen, Blueprint Medicines, Bristol Myers Squibb, Daiichi Sankyo, Deciphera Pharmaceuticals, GlaxoSmithKline, Iterion Therapeutics, Karyopharm Therapeutics, Merck, MedImmune, Neoleukin Therapeutics, Pfizer, Roche/Genentech, Rain Therapeutics and Symphogen; and served as expert testimony for Medison. Dr. Reichmann is an employee and shareholder of Deciphera Pharmaceuticals. Dr. Ruiz-Soto is an employee of Deciphera Pharmaceuticals; a shareholder of Deciphera Pharmaceuticals and Immunogen; and is an inventor in three patents with Immunogen and pending patents at Deciphera Pharmaceuticals, the rights for which have been transferred to Immunogen and Deciphera, respectively; Dr. Ruiz-Soto has not received and will not receive royalties from these patents. Dr. Rutkowski reports honoraria from AstraZeneca, Bristol Myers Squibb, Merck, Novartis, Pierre Fabre, and Sanofi. Dr. Sanchez reports honoraria from AstraZeneca, Novartis, Pfizer and Roche; and research funding from Pfizer, Novartis and Roche. Dr. Serrano reports honoraria from Bayer and Blueprint Medicines; institutional research funding from Bayer, Deciphera Pharmaceuticals, Karyopharm Therapeutics and Pfizer; consulting fees from Blueprint Medicines, Cogent Biosciences, Deciphera Pharmaceuticals and Immunicum; and travel support from Bayer, Eli Lilly & Co, Novartis, Pfizer and PharmaMar. Dr. Siontis reports consulting fees from Deciphera Pharmaceuticals and institutional research funding from Advenchen and Deciphera Pharmaceuticals. Dr. Sherman reports employment, leadership, and stock or other ownership interests of Deciphera Pharmaceuticals and Pieris Pharmaceuticals. Dr. Somaiah reports consulting fees from Aadi Biosciences, Boehringer Ingelheim and Epizyme and research funding from Advenchen, Ascentage, AstraZeneca, Cogent, Deciphera Pharmaceuticals, GlaxoSmithKline, and Innovent. Dr. Steeghs reports consulting fees from Boehringer Ingelheim, Cogent Biosciences, Ellipses Pharma and Luszana; institutional research funding from AbbVie, Actuate Therapeutics, Amgen, Array, Ascendis Pharma, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Cantargia, CellCentric, Cogent, Cresecendo Biologics, Cytovation, Deciphera Pharmaceuticals, Eli Lilly & Co, Exelixis, Genentech, GlaxoSmithKline, Incyte, InteRNA, Janssen, Kinnate Biopharma, Luszana, Merck, Merus, Molecular Partners, Navire Pharma, Novartis, Numab Therapeutics, Pfizer, Relay Pharmaceuticals, Revolution Medicine, Roche, Sanofi, Seattle Genetics, Taiho and Takeda. Dr. Trent reports consulting fees from Adcendo, AADI Bioscience, Cogent, Deciphera Pharmaceuticals, Daiichi Sankyo and Foghorn Therapeutics. Dr. von Mehren reports consulting fees from Deciphera Pharmaceuticals, GlaxoSmithKline and Moleculin; institutional research funding from ASCO, Ayala, Deciphera Pharmaceuticals, Genmab, Gradalis, Novartis, Solaris Health, Sumitomo Pharma Oncology and Theseus Pharmaceuticals; and another financial relationship with NCCN. Dr. Zalcberg reports leadership at ICON Group, Lipotek and Praxis; honoraria from Deciphera Pharmaceuticals, Halozyme, Gilead Sciences, Merck Serono, Specialised Therapeutics and Targovax; consulting fees from 1Globe Health Institute, Centre for Emerging and Neglected Diseases (CEND), Deciphera Pharmaceuticals, FivePHusion, Genor BioPharma, Halozyme, Lipotek, Merck, Merck Serono, Novotech, Revolution Medicine, Specialised Therapeutics and Targovax; institutional research funding from AstraZeneca, Bristol Myers Squibb, Eisai, Ipsen, IQVIA, Medtronic, Merck Serono, Mylan and Pfizer; stock or other ownership of Amarin Corporation, Biomarin, Concert Pharmaceuticals, Frequency Therapeutics, Gilead Sciences, Madrigal Pharmaceuticals, Moderna Therapeutics, Novavax, Opthea, Orphazyme, Twist Bioscience, UniQure and Zogenix; and travel support from AstraZeneca, Deciphera Pharmaceuticals, Merck, Merck Serono and Sanofi., (Copyright © 2023 Deciphera Pharmaceuticals LLC. Published by Elsevier Ltd.. All rights reserved.)

Gastrointestinal stromal tumors (GISTs) frequently show KIT mutations, accompanied by overexpression and aberrant localization of mutant KIT (MT-KIT). As previously established by multiple studies, including ours, we confirmed that MT-KIT initiates downstream signaling in the Golgi complex. Basic leucine zipper nuclear factor 1 (BLZF1) was identified as a novel MT-KIT-binding partner that tethers MT-KIT to the Golgi complex. Sustained activation of activated transcription factor 6 (ATF6), which belongs to the unfolded protein response (UPR) family, alleviates endoplasmic reticulum (ER) stress by upregulating chaperone expression, including heat shock protein 90 (HSP90), which assists in MT-KIT folding. BLZF1 knockdown and ATF6 inhibition suppressed both imatinib-sensitive and -resistant GIST in vitro. ATF6 inhibitors further showed potent antitumor effects in GIST xenografts, and the effect was enhanced with ER stress-inducing drugs. ATF6 activation was frequently observed in 67% of patients with GIST (n = 42), and was significantly associated with poorer relapse-free survival (P = 0.033). Overall, GIST bypasses ER quality control (QC) and ER stress-mediated cell death via UPR activation and uses the QC-free Golgi to initiate signaling., (© 2023. The Author(s).)

Purpose: Limited data are available about the influence of KIT and PDGFRA mutations on overall survival (OS) of patients with gastrointestinal stromal tumor (GIST) treated with adjuvant imatinib., Patients and Methods: The Scandinavian Sarcoma Group XVIII/AIO multicenter trial accrued 400 patients with a high risk for GIST recurrence after macroscopically complete surgery between February 4, 2004, and September 29, 2008. The patients received adjuvant imatinib 400 mg/day for either 1 year or 3 years based on random allocation. We analyzed using conventional sequencing KIT and PDGFRA mutations centrally from 341 (85%) patients who had localized, centrally confirmed GIST, and correlated the results with recurrence-free survival (RFS) and OS in exploratory analyses., Results: During a median follow-up time of 10 years, 164 RFS events and 76 deaths occurred. Most patients were re-treated with imatinib when GIST recurred. Patients with KIT exon 11 deletion or indel mutation treated with 3 years of adjuvant imatinib survived longer than patients treated for 1 year [10-year OS 86% versus 64%, respectively; HR, 0.34; 95% confidence interval (CI), 0.15-0.72; P = 0.007], and also had longer RFS (10-year RFS 47% versus 29%; HR, 0.48; 95% CI, 0.31-0.74; P < 0.001). Patients with KIT exon 9 mutation had unfavorable OS regardless of the duration of adjuvant imatinib., Conclusions: Compared with 1 year of imatinib, 3 years of adjuvant imatinib led to 66% reduction in the estimated risk of death and a high 10-year OS rate in the subset of patients with a KIT exon 11 deletion/indel mutation., (©2023 The Authors; Published by the American Association for Cancer Research.)

Background: Pulmonary metastasectomy (PM) is a widely accepted surgical procedure. This study aims to investigate postoperative morbidity and mortality after PM and develop a score to predict high-risk patients., Methods: We retrospectively investigated all patients undergoing a PM in our institution from November 2012 to January 2023. Complications were defined as the diagnosis of any new disease after the PM up to 30 days after the operation., Results: 1284 patients were identified. At least one complication occurred in 145 patients (11.29%). Only one patient died during the hospital stay. Preoperative cardiovascular comorbidities (OR: 2.99, 95% CI: 1.412-3.744, p = 0.01), major lung resections (OR: 2.727, 95% CI: 1.678-4.431, p < 0.01), repeated pulmonary metastasectomy (OR: 1.759, 95% CI: 1.040-2.976, p = 0.03) and open thoracotomy (OR: 0.621, 95% CI: 0.415-0.930, p = 0.02) were identified as independent factors for postoperative complications. Based on the above independent factors for postoperative morbidity, the Essen score was developed (overall correct classification: 94.6%, ROC-Analysis: 0.828, 95% CI: 0.795-0.903)., Conclusion: PM is a safe surgical procedure with acceptable morbidity and low mortality. The aim of the Essen score is to identify patients that are associated with risk for postoperative complications after PM.

Background: The International Thymic Malignancy Interest Group (ITMIG) proposed an internationally accepted division of the mediastinum into three compartments based on computed tomography (CT): anterior (prevascular), middle (visceral) and posterior (paravertebral) compartment. There is no generally accepted definition for the term "giant" when applied to middle mediastinal lesions. We defined the term "giant" and described our surgical experience in treating patients with giant lesions of the middle mediastinum., Methods: CT imaging of patients operated in our center from January 2016 to August 2021 for mediastinal lesions was reviewed. Lesions were categorized to one of the ITMIG-defined compartments. Lesion size at diagnosis was measured at its largest diameter on axial CT imaging. Giant middle mediastinal lesions were defined as lesions having a size ≥90 th percentile of our middle mediastinal lesion cohort. Patients with giant middle mediastinal lesions were further analyzed., Results: Thirty-six patients (23%) had lesions located in the middle mediastinal compartment. Most common diagnoses were mediastinal cysts (n=10, 28%), metastatic lesions (n=6, 17%), lymphomas (n=5, 14%), and sarcomas (n=3, 8%). Ninetieth percentile lesion size was 73 mm. As per definition, four patients had giant middle mediastinal lesions. All these four lesions were of mesenchymal origin including oesophageal leiomyoma, synovial sarcoma, leiomyosarcoma and undifferentiated round cell sarcoma. Resection was performed through posterolateral thoracotomy or sternotomy, with or without cardiopulmonary bypass., Conclusions: The term "giant" could be defined as a mass larger or equal to 73 mm. This definition selected specifically lesions with mesenchymal origin and may therefore guide diagnostic algorithm and patient management., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-22-49/coif). The authors have no conflicts of interest to declare., (2023 Mediastinum. All rights reserved.)

Systemic pan-tumor analyses may reveal the significance of common features implicated in cancer immunogenicity and patient survival. Here, we provide a comprehensive multi-omics data set for 32 patients across 25 tumor types for proteogenomic-based discovery of neoantigens. By using an optimized computational approach, we discover a large number of tumor-specific and tumor-associated antigens. To create a pipeline for the identification of neoantigens in our cohort, we combine DNA and RNA sequencing with MS-based immunopeptidomics of tumor specimens, followed by the assessment of their immunogenicity and an in-depth validation process. We detect a broad variety of non-canonical HLA-binding peptides in the majority of patients demonstrating partially immunogenicity. Our validation process allows for the selection of 32 potential neoantigen candidates. The majority of neoantigen candidates originates from variants identified in the RNA data set, illustrating the relevance of RNA as a still understudied source of cancer antigens. This study underlines the importance of RNA-centered variant detection for the identification of shared biomarkers and potentially relevant neoantigen candidates., (© 2023. The Author(s).)

There remains an urgent need for new therapies for treatment-resistant epilepsy. Sodium channel blockers are effective for seizure control in common forms of epilepsy, but loss of sodium channel function underlies some genetic forms of epilepsy. Approaches that provide bidirectional control of sodium channel expression are needed. MicroRNAs (miRNA) are small noncoding RNAs which negatively regulate gene expression. Here we show that genome-wide miRNA screening of hippocampal tissue from a rat epilepsy model, mice treated with the antiseizure medicine cannabidiol, and plasma from patients with treatment-resistant epilepsy, converge on a single target-miR-335-5p. Pathway analysis on predicted and validated miR-335-5p targets identified multiple voltage-gated sodium channels (VGSCs). Intracerebroventricular injection of antisense oligonucleotides against miR-335-5p resulted in upregulation of Scn1a , Scn2a , and Scn3a in the mouse brain and an increased action potential rising phase and greater excitability of hippocampal pyramidal neurons in brain slice recordings, consistent with VGSCs as functional targets of miR-335-5p. Blocking miR-335-5p also increased voltage-gated sodium currents and SCN1A, SCN2A , and SCN3A expression in human induced pluripotent stem cell-derived neurons. Inhibition of miR-335-5p increased susceptibility to tonic-clonic seizures in the pentylenetetrazol seizure model, whereas adeno-associated virus 9-mediated overexpression of miR-335-5p reduced seizure severity and improved survival. These studies suggest modulation of miR-335-5p may be a means to regulate VGSCs and affect neuronal excitability and seizures. Changes to miR-335-5p may reflect compensatory mechanisms to control excitability and could provide biomarker or therapeutic strategies for different types of treatment-resistant epilepsy.

The theranostic use of fibroblast activation protein inhibitors (FAPIs) is a novel approach in oncology. Sarcomas are a heterogenous group of rare malignant tumors. Prognosis remains poor in advanced/metastatic disease due to limited therapeutic options. Sarcoma frequently demonstrate high expression of fibroblast activation protein alpha on the tumor cells themselves, in contrast to other solid tumors, where it is mainly expressed on cancer-associated fibroblasts. Consequently, high in vivo uptake of FAPI in PET is observed in sarcoma. Moreover, retrospective case reports and series demonstrated feasibility of FAPI radioligand therapy with signs of tumor response., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: When brain cancer relapses, treatment options are scarce. The use of molecularly matched targeted therapies may provide a feasible and efficacious way to treat individual patients based on the molecular tumor profile. Since little information is available on this strategy in neuro-oncology, we retrospectively analyzed the clinical course of 41 patients who underwent advanced molecular testing at disease relapse., Methods: We performed Sanger sequencing, targeted next generation sequencing, and immunohistochemistry for analysis of potential targets, including programmed death ligand 1, cyclin D1, phosphorylated mechanistic target of rapamycin, telomerase reverse transcriptase promoter mutation, cyclin-dependent kinase inhibitor 2A/B deletion, or BRAF-V600E mutation. In selected patients, whole exome sequencing was conducted., Results: The investigation included 41 patients, of whom 32 had isocitrate dehydrogenase (IDH) wildtype glioblastoma. Molecular analysis revealed actionable targets in 31 of 41 tested patients and 18 patients were treated accordingly (matched therapy group). Twenty-three patients received molecularly unmatched empiric treatment (unmatched therapy group). In both groups, 16 patients were diagnosed with recurrent IDH wildtype glioblastoma. The number of severe adverse events was comparable between the therapy groups. Regarding the IDH wildtype glioblastoma patients, median progression-free survival (mPFS) and median overall survival (mOS) were longer in the matched therapy group (mPFS: 3.8 versus 2.0 months, p = 0.0057; mOS: 13.0 versus 4.3 months, p = 0.0357)., Conclusion: These encouraging data provide a rationale for molecularly matched targeted therapy in glioma patients. For further validation, future study designs need to additionally consider the prevalence and persistence of actionable molecular alterations in patient tissue., (© 2022. The Author(s).)

To investigate the pathogenic mechanisms of calcified aortic valve disease (CAVD), it is necessary to develop a new three-dimensional model that contains valvular interstitial cells (VIC) and valvular endothelial cells (VEC). For this purpose, ovine aortic valves were processed to isolate VIC and VEC that were dissolved in an alginate/gelatin hydrogel. A 3D-bioprinter (3D-Bioplotter ® Developer Series, EnvisionTec, Gladbeck, Germany) was used to print cell-laden tissue constructs containing VIC and VEC which were cultured for up to 21 days. The 3D-architecture, the composition of the culture medium, and the hydrogels were modified, and cell viability was assessed. The composition of the culture medium directly affected the cell viability of the multicellular tissue constructs. Co-culture of VIC and VEC with a mixture of 70% valvular interstitial cell and 30% valvular endothelial cell medium components reached the cell viability best tested with about 60% more living cells compared to pure valvular interstitial cell medium ( p = 0.02). The tissue constructs retained comparable cell viability after 21 days ( p = 0.90) with different 3D-architectures, including a "sandwich" and a "tube" design. Good long-term cell viability was confirmed even for thick multilayer multicellular tissue constructs. The 3D-bioprinting of multicellular tissue constructs with VEC and VIC is a successful new technique to design tissue constructs that mimic the structure of the native aortic valve for research applications of aortic valve pathologies.

Background: Uveal melanoma is a disease characterized by constitutive activation of the G alpha pathway and downstream signaling of protein kinase C (PKC) and the mitogen-activated protein kinase (MAPK) pathway. While limited clinical activity has been observed in patients with metastatic disease with inhibition of PKC or MEK alone, preclinical data has demonstrated synergistic antitumor effects with concurrent inhibition of PKC and MEK., Method: We conducted a phase Ib study of the PKC inhibitor sotrastaurin in combination with the MEK inhibitor binimetinib in patients with metastatic uveal melanoma using a Bayesian logistic regression model guided by the escalation with overdose control principle (NCT01801358). Serial blood samples and paired tumor samples were collected for pharmacokinetic (PK) and pharmacodynamic analysis., Results: Thirty-eight patients were treated across six dose levels. Eleven patients experienced DLTs across the five highest dose levels tested, most commonly including vomiting (n=3), diarrhea (n=3), nausea (n=2), fatigue (n=2) and rash (n=2). Common treatment related adverse events included diarrhea (94.7%), nausea (78.9%), vomiting (71.1%), fatigue (52.6%), rash (39.5%), and elevated blood creating phosphokinase (36.8%). Two dose combinations satisfying criteria for the maximum tolerated dose (MTD) were identified: (1) sotrastaurin 300 mg and binimetinib 30 mg; and, (2) sotrastaurin 200 mg and binimetinib 45 mg. Exposure to both drugs in combination was consistent with single-agent data for either drug, indicating no PK interaction between sotrastaurin and binimetinib. Stable disease was observed in 60.5% of patients treated. No patient achieved a radiographic response per RECIST v1.1., Conclusions: Concurrent administration of sotrastaurin and binimetinib is feasible but associated with substantial gastrointestinal toxicity. Given the limited clinical activity achieved with this regimen, accrual to the phase II portion of the trial was not initiated., Competing Interests: The handling editor JK declared a past co-authorship with the authors JL, SH, SP-N, RC. SB reports COI with Blueprint Medicines, Incyte, and Novartis RF-institutional, PharmaMar, Eli Lilly & Co, Novartis Honoraria, Adcendo, Bayer, Blueprint Medicines, Böhringer Ingelheim, Daiichi Sankyo, Deciphera, Eli Lilly & Co, GSK, Exelixis, Nanobiotix, Novartis, Roche SAB, JL reports personal fees from Eisai, Novartis, Incyte, Merck, touchIME, touchEXPERTS, Pfizer, Royal College of Physicians, Cambridge Healthcare Research, Royal College of General Practitioners, VJOncology, Agence Unik, BMS, iOnctura, Apple Tree, Merck, BMS, Eisai, Debipharm, Incyte, Pierre Fabre, BMS, Ipsen, Roche, EUSA Pharma, Novartis, Aptitude, AstraZeneca, GSK, Eisai, Calithera, Ultimovacs, Seagen, Merck, eCancer, Inselgruppe, Pfizer, Goldman Sachs and MSD. He reports grants from Achilles, BMS, MSD, Nektar, Novartis, Pfizer, Roche, Immunocore, Aveo and Pharmacyclics. He reports institutional research support from BMS, MSD, Novartis, Pfizer, Achilles Therapeutics, Roche, Nektar Therapeutics, Covance, Immunocore, Pharmacyclics and Aveo. SH reports grants and personal fees from Bristol-Myers Squibb, personal fees from Merck, personal fees from EMD Serono, grants and personal fees from Novartis, personal fees from Surface, personal fees from Compass Therapeutics, personal fees from Apricity, personal fees from Sanofi, personal fees from Pionyr, personal fees from 7 Hills Pharma, personal fees from Torque, personal fees from Bicara, personal fees from Checkpoint Therapeutics, personal fees from Genentech/Roche, personal fees from Bioentre, personal fees from Gossamer, personal fees from Iovance, personal fees from Trillium, personal fees from Catalym, personal fees from Immunocore, personal fees from Amgen, personal fees from Kairos, personal fees from Eisai, personal fees from Rheos, personal fees from Zumutor, personal fees from Corner Therapeuitcs, outside the submitted work; In addition, Dr. Hodi has a patent Methods for Treating MICA-Related Disorders #20100111973 with royalties paid, a patent Tumor antigens and uses thereof #7250291 issued, a patent Angiopoiten-2 Biomarkers Predictive of Anti-immune checkpoint response #20170248603 pending, a patent Compositions and Methods for Identification, Assessment, Prevention, and Treatment of Melanoma using PD-L1 Isoforms #20160340407 pending, a patent Therapeutic peptides #20160046716 pending, a patent Therapeutic Peptides #20140004112 pending, a patent Therapeutic Peptides #20170022275 pending, a patent Therapeutic Peptides #20170008962 pending, a patent on Therapeutic Peptides, Patent number: 9402905 issued, a patent METHODS OF USING PEMBROLIZUMAB AND TREBANANIB pending, a patent Vaccine compositions and methods for restoring NKG2D pathway function against cancers, patent number 10279021 issued, a patent Antibodies that bind to MHC class I polypeptide-related sequence A, patent number 10106611 issued, and a patent ANTI-GALECTIN ANTIBODY BIOMARKERS PREDICTIVE OF ANTI-IMMUNE CHECKPOINT AND ANTI-ANGIOGENESIS RESPONSES. EK has consultancy/advisory relationships with Bristol-Myers Squibb, Novartis, Merck, Pierre Fabre, EISAI, Bayer, Genzyme-Sanofi, Ipsen and Lilly, and received research grants not related to this paper from Novartis, Pierre Fabre and Bristol-Myers Squibb. GS has consultancy/advisory relationships with Bionaut Labs, Ellipses Pharma, Gencirq, Epizyme, Array BioPharma, Apexigen, Oncogenuity, OnCusp Therapeutics, Concarlo, Shanghai Pharma, Astex Pharmaceuticals, January Therapeutics, Sellas Life Sciences, PureTech Health and Killys Therapeutics. He reports stock and other ownership interests in GenCirq, Bionaut Labs and January Therapuetics. He reports travel support from Array BioPharma and Epizyme. He receives research funding from Astex Pharmaceuticals. He reports institutional research support from Incyte, Calithera Biosciences, Lilly, Daiichi Sankyo, Fortress Biotech, Karyopharm Therapeutics, Oxford BioTherapeutics, Astex, Pharmaceuticals, TopAlliance Biosciences Inc, Adaptimmune, SpringWorks Therapeutics and TRACON Pharma. EC has consultancy/advisory relationships with Nanobiotx, Janssen-Cilag, Roche/Genentech, TargImmune Therapeutics, Servier, Bristol-Myers Squibb, Amunix, Adecendo, Anaveon, AstraZeneca/MedImmune, Chugai Pharma, MonTa, MSD Oncology, Nouscom, Novartis, OncoDNA, T-Knife, Elevation Oncology, PharmaMar. He has stock and other ownership interests in START and Oncoart Associated. He has leadership in START, PharmaMar, the EORTC, Sanofi and BeiGene. PY-R is an employee of Novartis. SP-N has consultancy/advisory relationships with Immunocore. RC has consultancy/advisory relationships with Alkermes, Aura Biosciences, Bristol Myers Squibb, Castle Biosciences, Chimeron, Delcath, Eisai, Hengrui, Ideaya, Immunocore, InxMed, Iovance, Merck, Novartis, Oncosec, Pierre Fabre, PureTech Health, Regeneron, Rgenix, Sanofi Genzyme, Sorrento Therapeutics and Trisalus. He reports institutional research support from Amgen, Astellis, AstraZeneca, Bristol-Myers Squibb, Corvus, Ideaya, Immunocore, Iovance, Merck, Mirati, Novartis, Pfizer, Plexxikon, Regeneron and Roche/Genentech. The remaining author declares 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 Bauer, Larkin, Hodi, Stephen, Kapiteijn, Schwartz, Calvo, Yerramilli-Rao, Piperno-Neumann and Carvajal.)

Background: The Tenosynovial giant cell tumor Observational Platform Project (TOPP) registry is an international prospective study that -previously described the impact of diffuse-type tenosynovial giant cell tumour (D-TGCT) on patient-reported outcomes (PROs) from a baseline snapshot. This analysis describes the impact of D-TGCT at 2-year follow-up based on treatment strategies., Material and Methods: TOPP was conducted at 12 sites (EU: 10; US: 2). Captured PRO measurements assessed at baseline, 1-year, and 2-year follow-ups were Brief Pain Inventory (BPI), Pain Interference, BPI Pain Severity, Worst Pain, EQ-5D-5L, Worst Stiffness, and -Patient-Reported Outcomes Measurement Information System. Treatment interventions were no current/planned treatment (Off-Treatment) and systemic treatment/surgery (On-Treatment)., Results: A total of 176 patients (mean age: 43.5 years) were included in the full analysis set. For patients without active treatment strategy -(Off-Treatment) at baseline (n = 79), BPI Pain Interference (1.00 vs. 2.86) and BPI Pain Severity scores (1.50 vs. 3.00) were numerically favorable in patients remaining Off-Treatment compared with those who switched to an active treatment strategy at year 1. From 1-year to 2-year -follow-ups, patients who remained Off-Treatment had better BPI Pain Interference (0.57 vs. 2.57) and Worst Pain (2.0 vs. 4.5) scores compared with patients who switched to an alternative treatment strategy. In addition, EQ-5D VAS scores (80.0 vs. 65.0) were higher in patients who remained -Off-Treatment between 1-year and 2-year follow-ups compared with patients who changed treatment strategy. For patients receiving systemic treatment at baseline, numerically favorable scores were seen in patients remaining on systemic therapy at 1-year follow-up: BPI Pain Interference (2.79 vs. 5.93), BPI Pain Severity (3.63 vs. 6.38), Worst Pain (4.5 vs. 7.5), and Worst Stiffness (4.0 vs. 7.5). From 1-year to 2-year follow-up, EQ-5D VAS scores (77.5 vs. 65.0) were higher in patients who changed from systemic treatment to a different treatment strategy., Conclusion: These findings highlight the impact D-TGCT has on patient quality of life, and how treatment strategies may be influenced by these outcome measures. (ClinicalTrials.gov number: NCT02948088)., (© The Author(s) 2023. Published by Oxford University Press.)

Aim: Describing the treatment patterns, outcomes by line of treatment (LOT), and healthcare resource utilization (HCRU) in patients with metastatic synovial sarcoma (mSS). Patients & methods: In this descriptive, non-interventional, retrospective cohort study, physicians from five European countries reported on patients with recent pharmacological treatment for mSS. Results: Among 296 patients with mSS, 86.1, 38.9 and 8.4% received 1 LOT (1L), 2 LOTs (2L) and 3+ LOTs (L3+), respectively. Common regimens were doxorubicin/ifosfamide-based (37.4%) for 1L and trabectedin-based for 2L (29.7%). For 1L, median time to next treatment was 13.1 and 6.0 months for living and deceased patients, respectively. Median OS was 22.0, 6.0 and 4.9 months in all patients, 2L and 3L, respectively. HCRU data showed median one inpatient hospital admission, 3 days in hospital and four outpatient visits yearly. Conclusion: This large-scale study documents high unmet needs in patients previously treated for mSS and for more effective therapies.

For advanced cancer inpatients, the established standard for gathering information about symptom burden involves a daily assessment by nursing staff using validated assessments. In contrast, a systematic assessment of patient-reported outcome measures (PROMs) is required, but it is not yet systematically implemented. We hypothesized that current practice results in underrating the severity of patients' symptom burden. To explore this hypothesis, we have established systematic electronic PROMs (ePROMs) using validated instruments at a major German Comprehensive Cancer Center. In this retrospective, non-interventional study, lasting from September 2021 to February 2022, we analyzed collected data from 230 inpatients. Symptom burden obtained by nursing staff was compared to the data acquired by ePROMs. Differences were detected by performing descriptive analyses, Chi-Square tests, Fisher's exact, Phi-correlation, Wilcoxon tests, and Cohen's r. Our analyses pointed out that pain and anxiety especially were significantly underrated by nursing staff. Nursing staff ranked these symptoms as non-existent, whereas patients stated at least mild symptom burden (pain: mean NRS/epaAC = 0 (no); mean ePROM = 1 (mild); p < 0.05; r = 0.46; anxiety: mean epaAC = 0 (no); mean ePROM = 1 (mild); p < 0.05; r = 0.48). In conclusion, supplementing routine symptom assessment used daily by nursing staff with the systematic, e-health-enabled acquisition of PROMs may improve the quality of supportive and palliative care.

Soft tissue sarcomas (STS) may arise as a consequence of germline variants in cancer predisposition genes (CPGs). We believe that elucidating germline sarcoma predisposition is critical for understanding disease biology and therapeutic requirements. Participation in surveillance programs may allow for early tumor detection, early initiation of therapy and, ultimately, better outcomes. Among children, adolescents, and adults diagnosed with soft-tissue sarcomas and examined as part of published germline sequencing studies, pathogenic/likely pathogenic (P/LP) variants in CPGs were reported in 7-33% of patients. P/LP germline variants were detected most frequently in TP53, NF1 and BRCA1/2. In this review, we describe reported associations between soft tissue sarcomas and germline variants in CPGs, with mentioning of locally aggressive and benign soft tissue tumors that have important associations with cancer predisposition syndromes. We also discuss recommendations for diagnostic germline genetic testing. Testing for sarcoma-predisposing germline variants should be considered as part of the routine clinical workup and care of any child, adolescent, or adult diagnosed with STS and take into account consequences for the whole family., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Purpose: Optimization of local therapies in synovial sarcoma (SS) considered unresectable at diagnosis is needed. We evaluated the effects of neoadjuvant versus adjuvant radiation versus surgery only on long-term outcomes., Methods: Patients with macroscopic SS tumors before chemotherapy (IRS-group-III) in the trials CWS-81, CWS-86, CWS-91, CWS-96, CWS-2002-P and SoTiSaR-registry were analyzed. Local therapies were scheduled after 3 neoadjuvant chemotherapy cycles., Results: Median age of 145 patients was 14.5 years. 106 survivors had median follow-up of 7.0 years. Tumor site was 96 extremities, 19 head-neck, 16 shoulder/hip, 14 trunk. Tumors were < 3 cm in 16, 3-5 cm in 28, 5-10 cm in 55, > 10 cm in 34 patients. In a secondary resection during chemotherapy, R0-status was accomplished in 82, R1 in 30, R2 in 21 (12 missing). Radiotherapy was administered to 115 (R0 61, R1 29, R2 20, missing 5), thereof 57 before and 52 after tumor resection. 23 were treated with surgery only. For all patients, 5 year event-free (EFS) and overall survival (OS) was 68.9% ± 7.6 (95%CI) and 79.1% ± 6.9. To establish independent significance, tumor site, size, surgical results and sequencing of local therapies were analyzed in a Cox regression analysis. Variables associated with EFS and OS are site, size and sequencing of local therapies. Variables associated with local recurrence are site, surgical results and sequencing of local therapies. The only variable associated with suffering metastatic recurrence is tumor size., Conclusion: Differences in sequencing of local therapy procedures are independently associated with outcomes. Best local control is achieved when tumors are irradiated pre-operatively and undergo R0 or R1 resection thereafter., (© 2022. The Author(s).)

Resection margin adequacy plays a critical role in the local control of sarcomas. Fluorescence-guided surgery has increased complete resection rates and local recurrence-free survival in several oncological disciplines. The purpose of this study was to determine whether sarcomas exhibit sufficient tumor fluorescence (photodynamic diagnosis (PDD)) after administration of 5-aminolevulinic acid (5-ALA) and whether photodynamic therapy (PDT) has an impact on tumor vitality in vivo. Sixteen primary cell cultures were derived from patient samples of 12 different sarcoma subtypes and transplanted onto the chorio-allantoic membrane (CAM) of chick embryos to generate 3-dimensional cell-derived xenografts (CDXs). After treatment with 5-ALA, the CDXs were incubated for another 4 h. Subsequently accumulated protoporphyrin IX (PPIX) was excited by blue light and the intensity of tumor fluorescence was analyzed. A subset of CDXs was exposed to red light and morphological changes of both CAMs and tumors were documented. Twenty-four hours after PDT, the tumors were excised and examined histologically. High rates of cell-derived engraftments on the CAM were achieved in all sarcoma subtypes and an intense PPIX fluorescence was observed. PDT of CDXs resulted in a disruption of tumor-feeding vessels and 52.4% of CDXs presented as regressive after PDT treatment, whereas control CDXs remained vital in all cases. Therefore, 5-ALA mediated PDD and PDT appear to be promising tools in defining sarcoma resection margins (PDD) and adjuvant treatment of the tumor bed (PDT).

Objective: The EPAZ study (NCT01861951) showed recently that pazopanib was non-inferior to doxorubicin in patients ≥60 years treated in first line for advanced soft tissue sarcoma . The current post-hoc analysis aimed to assess the prognostic impact of frailty., Methods: Geriatric assessments were evaluated at baseline. Age >75 years, liposarcoma, ECOG = 2, G8 ≤14, instrumental activities of daily living (IADL) ≥1 and Charlson Comorbidity Index ≥2 were tested for their impact on progression-free survival (PFS), overall survival (OS), CTCAE grade 3/4 adverse events (AEs) or serious AEs (SAEs), using univariate and multivariate analysis models., Results: univariate analysis showed an increased risk of grade 3/4 AEs and SAEs for ECOG = 2, G8 score ≤14 or IADL ≥1, independent of treatment. The multivariate analysis exhibited for pazopanib a significantly reduced risk for grade 3/4 AEs (HR 0.53; p = 0.033), and in patients with G8 ≤14 an increased risk for SAEs (HR 2.67; p = 0.011). In the multivariate analysis, G8 ≤14 was a negative prognostic factor for PFS (HR 1.82; p = 0.009) and IADL ≥1 for OS (HR 2.02; p = 0.007). ECOG = 2 was the strongest negative predictor for PFS (HR 4.39; p = 0.001) and OS (HR 3.74; p = 0.004). Neither age nor Charlson Comorbidity Index showed any impact on PFS, OS, incidence of grade 3/4 AEs or SAEs., Conclusions: This post hoc analysis demonstrated that age is not a denominator for outcome or toxicity in elderly patients with soft tissue sarcoma . Instead, geriatric and functional assessments should be used to counsel patients and tailor therapy to individual needs. Moreover, pazopanib has a reduced risk for grade 3/4 AEs compared to doxorubicin., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The blood-brain barrier (BBB) is a physiological barrier maintaining a specialized brain micromilieu that is necessary for proper neuronal function. Endothelial tight junctions and specific transcellular/efflux transport systems provide a protective barrier against toxins, pathogens, and immune cells. The barrier function is critically supported by other cell types of the neurovascular unit, including pericytes, astrocytes, microglia, and interneurons. The dysfunctionality of the BBB is a hallmark of neurological diseases, such as ischemia, brain tumors, neurodegenerative diseases, infections, and autoimmune neuroinflammatory disorders. Moreover, BBB dysfunction is critically involved in epilepsy, a brain disorder characterized by spontaneously occurring seizures because of abnormally synchronized neuronal activity. While resistance to antiseizure drugs that aim to reduce neuronal hyperexcitability remains a clinical challenge, drugs targeting the neurovasculature in epilepsy patients have not been explored. The use of novel imaging techniques permits early detection of BBB leakage in epilepsy; however, the detailed mechanistic understanding of causes and consequences of BBB compromise remains unknown. Here, we discuss the current knowledge of BBB involvement in temporal lobe epilepsy with the emphasis on the neurovasculature as a therapeutic target., (© 2023 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Background: Acute aortic dissection type A (AADA) is associated with high perioperative morbidity and mortality. A novel non-covered hybrid prosthesis (AMDS, CryoLife, Kennesaw, USA) can be easily implanted to stabilize the true lumen. However, the role of AMDS for patients requiring additional aortic root surgery has not been described., Methods: Between 2010 and 2020 a total of n = 370 patients underwent surgery for AADA in our department. Of those, n = 120 underwent treatment for aortic root in addition to proximal arch replacement without resection of the aorta beyond the innominate artery (Control, n = 111) and were compared to patients who received additional AMDS implantation (AMDS, n = 9)., Results: Aortic valve repair was performed in 48.6% (Control) and in 55.6% of AMDS patients. Cardiopulmonary bypass (Control: 248 ± 76 min, AMDS: 313 ± 53 min, P < 0.01) time as well as circulatory arrest time of the lower body (Control: 30 ± 15 min, AMDS: 52 ± 12 min, P < 0.01) was prolonged in the AMDS group. Nevertheless, postoperative in-hospital morbidity such as dialysis (Control: 22.4%, AMDS: 11.1%, P = 0.68) and stroke (Control: 17.0%, AMDS: 22.2%, P = 0.65) were comparable. In-hospital death (Control: 21.8%, AMDS: 11.1%, P = 0.68) and the compound end-point MACCE (Control: 38.7%, AMDS: 44.4%, P = 0.74) did also not differ., Conclusions: Addressing the arch by implantation of AMDS prolongs cardiopulmonary bypass and circulatory arrest time, however without relevant impairments of short-term outcome. Combining root surgery with replacement of the proximal aortic arch and AMDS implantation seems feasible and safe as it did not impair the early postoperative outcome., (© 2023. The Author(s).)

Tenosynovial giant cell tumour (TGCT) is a rare, locally aggressive, mesenchymal tumor arising from the joints, bursa and tendon sheaths. TGCT comprises a nodular- and a diffuse-type, with the former exhibiting mostly indolent course and the latter a locally aggressive behavior. Although usually not life-threatening, TGCT may cause chronic pain and adversely impact function and quality of life (QoL). CSFR1 inhibitors are effective with benefit on symptoms and QoL but are not available in most countries. The degree of uncertainty in selecting the most appropriate therapy and the lack of guidelines on the clinical management of TGCT make the adoption of new treatments inconsistent across the world, with suboptimal outcomes for patients. A global consensus meeting was organized in June 2022, involving experts from several disciplines and patient representatives from SPAGN to define the best evidence-based practice for the optimal approach to TGCT and generate the recommendations presented herein., 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 © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Ripretinib is a novel switch-control kinase inhibitor that inhibits KIT and PDGFRA signaling. In the INVICTUS phase 3 trial, ripretinib increased median progression-free survival and prolonged overall survival vs. placebo in ≥ fourth-line advanced GIST. Here, we report prespecified analysis of quality of life (QoL) as assessed by patient-reported outcome (PRO) measures and an exploratory analysis evaluating the impact of alopecia on QoL., Methods: In the INVICTUS trial (NCT03353753), QoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30; physical function, role function, overall health, and overall QoL) and the EuroQoL 5-Dimension 5-Level (EQ-5D-5 L; visual analogue scale). Analysis of covariance (ANCOVA) models compared changes in scores from baseline to treatment cycle 2, day 1 within and between ripretinib and placebo. Within the ripretinib arm, repeated measures models assessed the impact of alopecia on QoL., Results: Patients receiving ripretinib maintained QoL (as assessed by the EORTC QLQ-C30 and EQ-5D-5 L PRO measures) from baseline to cycle 2, day 1 whereas QoL declined with placebo, resulting in clinically significant differences between treatments (nominal P < 0.01). The most common treatment-emergent adverse event with ripretinib was alopecia; however, QoL was similarly maintained out to treatment cycle 10, day 1 in patients receiving ripretinib who developed alopecia and those who did not., Conclusion: PRO assessments in the INVICTUS trial suggest that patients on ripretinib maintain their QoL out to C2D1, unlike patients receiving placebo. Longitudinal QoL was maintained for patients receiving ripretinib out to cycle 10, day 1 (approximately 8 months; past the point of median progression-free survival with ripretinib [6.3 months]), even if the patients developed alopecia., Trial Registration: ClinicalTrials.gov Identifier: NCT03353753 ; first posted: November 27, 2017., (© 2022. The Author(s).)