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Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Cranial ultrasound reliably diagnoses many neonatal brain disorders. Adding Doppler imaging expands the spectrum by providing information on the status of the vasculature and haemodynamics that may guide further diagnostic and clinical management. Doppler imaging may identify neonates with congenital or acquired vascular abnormalities such as perinatal stroke, sinuvenous thrombosis, vein of Galen malformation, dural sinus malformation, sinus pericranii, and developmental venous anomaly. These entities may need further investigation with complementary imaging modalities such as magnetic resonance imaging and magnetic resonance angiography, or conventional angiography. This review aims to help clinicians to improve their Doppler sonography knowledge and skills in order to use this helpful tool in neonates with neurological symptoms or suspected cerebral vascular abnormalities admitted to the neonatal intensive care unit., (© 2024 Mac Keith Press.)

Background: In patients with early-stage triple-negative breast cancer, the phase 3 KEYNOTE-522 trial showed significant improvements in pathological complete response and event-free survival with the addition of pembrolizumab to platinum-containing chemotherapy. Here we report the final results for overall survival., Methods: We randomly assigned, in a 2:1 ratio, patients with previously untreated stage II or III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks plus paclitaxel and carboplatin, followed by four cycles of pembrolizumab or placebo plus doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After definitive surgery, patients received adjuvant pembrolizumab (pembrolizumab-chemotherapy group) or placebo (placebo-chemotherapy group) every 3 weeks for up to nine cycles. The primary end points were pathological complete response and event-free survival. Overall survival was a secondary end point., Results: Of the 1174 patients who underwent randomization, 784 were assigned to the pembrolizumab-chemotherapy group and 390 to the placebo-chemotherapy group. At the data-cutoff date (March 22, 2024), the median follow-up was 75.1 months (range, 65.9 to 84.0). The estimated overall survival at 60 months was 86.6% (95% confidence interval [CI], 84.0 to 88.8) in the pembrolizumab-chemotherapy group, as compared with 81.7% (95% CI, 77.5 to 85.2) in the placebo-chemotherapy group (P = 0.002). Adverse events were consistent with the established safety profiles of pembrolizumab and chemotherapy., Conclusions: Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab resulted in a significant improvement, as compared with neoadjuvant chemotherapy alone, in overall survival among patients with early-stage triple-negative breast cancer. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; KEYNOTE-522 ClinicalTrials.gov number, NCT03036488.)., (Copyright © 2024 Massachusetts Medical Society.)

Therapy-induced molecular adaptation of triple-negative breast cancer is crucial for immunotherapy response and resistance. We analyze tumor biopsies from three different time points in the randomized neoadjuvant GeparNuevo trial (NCT02685059), evaluating the combination of durvalumab with chemotherapy, for longitudinal alterations of gene expression. Durvalumab induces an activation of immune and stromal gene expression as well as a reduction of proliferation-related gene expression. Immune genes are positive prognostic factors irrespective of treatment, while proliferation genes are positive prognostic factors only in the durvalumab arm. We identify stromal-related gene expression as a contributor to immunotherapy resistance and poor therapy response. The results provide evidence from clinical trial cohorts suggesting a role for stromal reorganization in therapy resistance to immunotherapy and in the generation of an immune-suppressive microenvironment, which might be relevant for future therapy approaches targeting the tumor stroma parallel to immunotherapy, such as combinations of immunotherapy with anti-angiogenic therapy., Competing Interests: Declaration of interests C.D. reports grants from European Commission H2020, grants from German Cancer Aid Translational Oncology, grants from German Breast Group, and grants from BMBF to the institution during the conduct of the study; personal fees from Novartis, personal fees from Roche, personal fees from MSD Oncology, personal fees from Daiichi Sankyo, personal fees from AstraZeneca and Molecular Health, grants from Myriad, personal fees from Merck, and other funding from Sividon Diagnostics outside the submitted work; in addition, C.D. has a patent VMScope digital pathology software with royalties paid, a patent WO2020109570A1—cancer immunotherapy pending, and a patent WO2015114146A1 and WO2010076322A1—therapy response issued. J.R. declares to be a GBG Forschungs GmbH employee. GBG Forschungs GmbH received funding for research grants from AbbVie, Amgen, AstraZeneca, BMS, Daiichi Sankyo, Gilead, Molecular Health, Novartis, Pfizer, and Roche (paid to the institution). Funding was also received (non-financial/medical writing) from Daiichi Sankyo, Gilead, Novartis, Pfizer, Roche, and Seagen (paid to the institution). GBG Forschungs GmbH has royalties in VM Scope and patents pending: EP14153692.0, EP21152186.9, and EP15702464.7. T.K. reports a patent WO2020109570A1 pending. S.R. declares to be a GBG Forschungs GmbH employee. GBG Forschungs GmbH received funding for research grants from AbbVie, Amgen, AstraZeneca, BMS, Daiichi Sankyo, Gilead, Molecular Health, Novartis, Pfizer, and Roche (paid to the institution). J.H. reports research funding from Lilly; honoraria from Lilly, Novartis, Roche, Pfizer, AstraZeneca, Seagen, Gilead, and Daiichi; consulting and advisory relationships with Lilly, Novartis, Roche, Pfizer, AstraZeneca, Gilead, and Daiichi; travel expenses from Roche, Novartis, Daiichi, and Gilead. P.J. reports research funding and travel expenses from Gilead Sciences GmbH. C.H. reports an advisory role and speakers bureau role for AstraZeneca, Roche, Novartis, and Aristo Pharma. B.V.S. is an employee of BioNTech SE and reports a patent WO2020109570A1 pending. J.-U.B. reports consultation fees, honoraria, and reimbursement for attending symposia from AstraZeneca, Amgen, Daiichi Sankyo, Eisai, Gilead, Lilly, MSD, Novartis, Pfizer, Roche, and Seagen. M.v.M. reports personal fees, honoraria, or travel grants from Amgen, AstraZeneca, Daiichi Sankyo, Genomic Health, GSK, Lilly, Molecular Health, MSD, Mylan, Novartis, Pfizer, Pierre Fabre, Roche, and Seagen. C. Schem reports speaker activities for Roche, Pfizer, Novartis, Celgen, Novartis, Exact Sciences, MSD, AstraZeneca, Lilly, and Seagen, as well as advisory boards for Roche, Astra Zeneca, Pfizer, Novartis, MSD, Amgen, Exact Sciences, Stemline, Lilly, and Novartis. T.L. reports personal fees from Amgen, Roche, Teva, Clovis, Tesaro, MSD, Novartis, Pfizer, Lilly, GSK, Gilead, AstraZeneca, Daiichi Sankyo, Stemline, and Seagen outside of the submitted work. T.L. participates in advisory boards from Amgen, MSD, Tesaro, Roche, Pfizer, Lilly, Myriad, Esai, GSK, Gilead, Daiichi Sankyo, Roche, and AstraZeneca outside of the submitted work and T.L. received travel support from Pfizer, PharmaMar, MSD, Celgene, Roche, AstraZeneca, Gilead, Daiichi Sankyo, Stemline, and Clovis outside of the submitted work. P.S. reports grants, personal fees, and non-financial support from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb Company, MSD, Incyte, Janssen-Cilag, Novartis, Takeda, Pfizer, and Roche. V.M. received speaker honoraria from AstraZeneca, Daiichi Sankyo, Eisai, GSK, Pfizer, MSD, Medac, Novartis, Roche, Seagen, Onkowissen, high5 Oncology, Medscape, Gilead, and Pierre Fabre; consultancy honoraria from Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi Sankyo, Eisai, Lilly, Sanofi, Seagen, Gilead, and Stemline; institutional research support from Novartis, Roche, Seagen, and Genentech; and travel grants from Roche, Pfizer, Daiichi Sankyo, and Gilead. L.P. has received consulting fees and honoraria for advisory board participation from Pfizer, AstraZeneca, Merck, Novartis, Bristol Myers Squibb, GlaxoSmithKline, Genentech/Roche, Personalis, Daiichi, Natera, and Exact Sciences and institutional research funding from Seagen, GlaxoSmithKline, AstraZeneca, Merck, Pfizer, and Bristol Myers Squibb. C.E.G. reports the following competing interests: Exact Sciences, Advisory Board, personal; AbbVie, Steering Committee member, institutional, co-chair of SC for BrighTNess; Daiichi Sankyo, member SC, institutional, co-chair of SC for DESTINY-Breast05; Genentech/Roche, SC member, institutional, co-chair of SC for lidERA; Genentech/Roche, coordinating PI, institutional, NSABP B-59/GeparDouze; and Genentech/Roche, SC member, institutional, co-chair of SC for KATHERINE. C.J. reports honoraria from AstraZeneca, Amgen, Daiichi Sankyo, Lilly, Roche, Pfizer, MSD Oncology, Pierre Fabre, Sanofi-Aventis, Seagen, Gilead, and Novartis and has a consulting or advisory role for Amgen, Lilly, Roche, Pfizer, Pierre Fabre, Novartis, MSD Oncology, Agendia, Seagen, Gilead, Lilly, Stemline, and Medac. V.N. declares to be a GBG Forschungs GmbH employee. GBG Forschungs GmbH received funding for research grants from AbbVie, AstraZeneca, BMS, Daiichi Sankyo, Gilead, Novartis, Pfizer, and Roche (paid to the institution). GBG Forschungs GmbH received other funding from Daiichi Sankyo, Gilead, Novartis, Pfizer, Roche, and Seagen (paid to the institution). GBG Forschungs GmbH has the following royalties/patents: EP14153692.0, EP21152186.9, EP15702464.7, EP19808852.8, and VM Scope GmbH. M.U. reports honoraria from AstraZeneca, Amgen, Daiichi Sankyo, Lilly, Roche, Pfizer, MSD Oncology, Pierre Fabre, Sanofi-Aventis, Myriad, Seagen, Gilead, and Novartis; has a consulting or advisory role for Amgen, Lilly, Roche, Pfizer, Pierre Fabre, Novartis, MSD Oncology, Agendia, Seagen, Gilead, Lily, Stemline, Genzyme, and Medac; and all honoraria and fees are paid to the employer/institution. S.L. reports grants and other funding from AbbVie; other funding from Amgen; grants and other funding from AstraZeneca; other funding from BMS; grants and other funding from Celgene; grants, non-financial support, and other funding from Daiichi Sankyo; other funding from EirGenix; other funding from Eisai Europe Ltd; other funding from GSK; grants, non-financial support, and other funding from Immunomedics/Gilead; other funding from Lilly; other funding from Merck; grants from Molecular Health; grants, non-financial support, and other funding from Novartis; grants, non-financial support, and other funding from Pfizer; other funding from Pierre Fabre; other funding from Relay Therapeutics; grants, non-financial support, and other funding from Roche; other funding from Sanofi; non-financial support and other funding from Seagen; and other funding from Olema Pharmaceuticals, outside the submitted work. In addition, S.L. has a patent EP14153692.0 pending, a patent EP21152186.9 pending, a patent EP15702464.7 issued, a patent EP19808852.8 pending, and a patent Digital Ki67 Evaluator with royalties paid., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The INGE-B trial (NCT02894398) aimed to confirm the efficacy and safety data from the PALOMA trials for patients treated first line (1L) with palbociclib (PAL) and letrozole or 1L and later line with PAL and fulvestrant. In addition, so far lacking evidence for efficacy and safety on the combination of PAL with anastrozole, exemestane (1L), or letrozole (later line) was investigated., Methods: The prospective, multicenter, multicohort phase 2 trial INGE-B enrolled adult patients with locally advanced, inoperable, or metastatic HR+/HER2- breast cancer in Germany. The primary endpoint was the clinical benefit rate (CBR) in patients with measurable disease according to RECIST v1.1. Secondary endpoints were overall response rate, progression-free survival (PFS), overall survival (OS), safety, and quality of life. Data were analyzed with descriptive statistics., Results: Between 2016 and 2018, 388 patients were enrolled at 64 German sites. Among patients with measurable disease treated with PAL in 1L (n = 157), the CBR was 63.7% (100/157). Among all patients treated with PAL 1L (n = 219), PFS was 20.1 months (95% CI 14.6-24.0), and OS was 40.9 months (95% CI 35.1-49.2). The most common grade 3/4 adverse event was neutropenia (33.4% n = 77). There were no treatment-related deaths., Conclusion: The INGE-B trial demonstrated good efficacy and tolerability of PAL with letrozole (1L) or fulvestrant (first and later line) in accordance with the PALOMA trials. In addition, the so far lacking proof of efficacy and safety of PAL in combination with anastrozole or exemestane in 1L and with letrozole in later line was provided by INGE-B., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Abstract: Although broadly used, consolidative autologous hematopoietic stem cell transplantation (auto-HCT) for relapsed/refractory (R/R) T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) has never been specifically investigated. Here, we have analyzed outcomes of auto-HCT for THRLBCL compared with diffuse large cell B-cell lymphoma not otherwise specified (DLBCL). Eligible for this retrospective registry study were adult patients with R/R THRLBCL and DLBCL, respectively, who underwent a first auto-HCT in a salvage-sensitive disease status as assessed by positron emission tomography-computed tomography between 2016 and 2021 and were registered with the European Society for Blood and Marrow Transplantation database. The primary end point was progression-free survival (PFS) 2 years after transplantation. A total of 201 patients with THRLBCL and 5543 with DLBCL were included. There were no significant differences in terms of disease status at HCT, pretreatment lines, and interval from diagnosis to transplant between the cohorts, but patients with THRLBCL were significantly younger, contained a higher proportion of men, and had a better performance status. Compared with DLBCL, THRLBCL was associated with significantly better 2-year PFS (78% vs 59%; P < .001) and overall survival (OS, 81% vs 74%; P = .02) because of a significantly lower 2-year relapse incidence (16% vs 35%; P < .001). On multivariate analysis, favorable relapse risk (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.31-0.7) and PFS (HR, 0.58; 95% CI, 0.41-0.82) of patients with THRLBCL remained significant, whereas OS benefits (HR, 0.78; 95% CI, 0.54-1.12) did not. These results were validated in a propensity score-matched analysis. These data prove auto-HCT as an effective treatment option for salvage-sensitive R/R THRLBCL., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Primary analysis of the phase III randomized AATT study showed that younger patients with peripheral T-cell lymphoma (PTCL) consolidated with autologous or allogeneic transplantation (alloSCT) had similar event-free survival (EFS) and overall survival (OS). Seven-year EFS of patients randomly assigned to alloSCT was 38% (95% CI, 25 to 52) compared with 34% (95% CI, 22 to 47) for patients randomly assigned to autologous transplantation of hematopoietic stem cells (autoSCT); OS was 55% (95% CI, 41 to 69) and 61% (95% CI, 47 to 74). Among patients undergoing alloSCT (n = 26) or autoSCT (n = 41) on study, the cumulative progression/relapse rate was 8% (95% CI, 0 to 19) and 55% (95% CI, 35 to 74). Nonrelapse mortality (NRM) was 31% (95% CI, 13 to 49) and 3% (95% CI, 0 to 8) after alloSCT and autoSCT, respectively. Fifteen of 30 patients with early progression and 11 of 20 patients with progression/relapse after autoSCT received alloSCT. Seven-year OS after salvage alloSCT was 61% (95% CI, 47 to 74); NRM was 23% (95% CI, 6 to 40). Long-term follow-up documents the strong graft versus lymphoma effect of alloSCT independent of the timing of transplantation. Survival of patients unable to undergo transplantation was dismal. AlloSCT is the treatment of choice for younger, transplant-eligible patients with relapsed/refractory PTCL. AlloSCT is currently not recommended as part of first-line consolidation.

Background: Previous research has suggested a heightened risk of acute myocarditis after COVID-19 infection. However, it is not clear from existing work whether this risk is higher than would be expected after comparable viral respiratory infections. This information is important to guide risk assessments and clinical practice., Methods: A retrospective cohort study of US administrative health claims was conducted to compare the rates of myocarditis after COVID-19 with that after influenza infection and describe the clinical use of diagnostic assessments.Patients with either incident COVID-19 diagnosis (between 1 January 2020 and 31 December 2021) or incident influenza diagnosis (between 1 January 2016 and 31 December 2018), with at least 12 months of continuous enrolment prior to index date and without a previous diagnosis of myocarditis were included.The primary outcome was clinically diagnosed acute myocarditis recorded after COVID-19 or influenza infection. Results are reported as covariate-adjusted subdistribution HRs from competing risk regression with COVID-19 considered as the exposure of interest and influenza as the reference group. Death was considered a competing risk., Results: 1 120 760 adult COVID-19 patients and 439 278 adult influenza patients were identified, of which 669 (0.06%) adult COVID-19 patients and 91 (0.02%) adult influenza patients received a diagnosis of myocarditis. The myocarditis rate per 1000 person-years was 0.73 (95% CI 0.67 to 0.78) for adult COVID-19 patients and 0.24 (95% CI 0.19 to 0.28) for adult influenza populations. In models comprehensively adjusted for demographic and clinical risk factors, COVID-19 diagnosis (compared with influenza diagnosis), cardiac comorbidities, being male and under the age of 30 were independently associated with an increased risk of myocarditis in the year after diagnosis., Conclusions: These findings support a distinct link between COVID-19 and myocarditis, which appears greater than after a similar viral respiratory infection. As such, a greater degree of clinical suspicion and investigation according to existing diagnostic pathways is recommended., Competing Interests: Competing interests: This study was performed as an academic and commercial partnership and funded by Bayer AG. OB, AKF and CH are Bayer AG employees. AM is an employee of Bayer Consumer Care AG. The academic authors were not paid to write this article and report no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Time-resolved 3D cine phase-contrast cardiovascular magnetic resonance (4D flow CMR) enables the characterization of blood flow using basic and advanced hemodynamic parameters. However, different confounders, e.g., different field strength, scanner configurations, or sequences, might impact 4D flow CMR measurements. This study aimed to analyze the inter-site reproducibility of 4D flow CMR to determine the influence of said confounders., Methods: A cohort of 19 healthy traveling volunteers underwent 4D flow CMR at four different sites (Sites I-III: 3 T scanner; Site IV: 1.5 T scanner; all Siemens Healthineers, Erlangen, Germany). Two protocols of one 4D flow CMR research sequence were performed, one acquiring velocity vector fields in the thoracic aorta only and one in the entire heart and thoracic aorta combined. Basic and advanced hemodynamic parameters, i.e., forward flow volume (FFV), peak and mean velocities (Vp and Vm), and wall shear stress (3D WSS), at nine different planes across the thoracic aorta (P1-P2 ascending aorta, P3-P5 aortic arch, P6-P9 descending aorta) were analyzed. Based on a second scan at Site I, mean values and tolerance ranges (TOL) were generated for inter-site comparison. Equivalency was assumed when confidence intervals of Sites II-IV lay within such TOL. Additionally, inter- and intra-observer analysis as well as a comparison between the two protocols was performed, using an intraclass correlation coefficient (ICC)., Results: Inter-site comparability showed equivalency in P1 and P2 for FFV, Vp, and Vm at all sites. Non-equivalency was present in various planes of P3-P9 and in P2 for 3D WSS in one protocol. In total, Site IV showed the most disagreements. Protocol comparison yielded excellent (>0.9) ICC in every plane for FFV, good (0.75-0.9) to excellent ICC for Vm and 3D WSS, good to excellent ICC in eight planes for Vp, and moderate (0.5-0.75) ICC in one plane for Vp. Inter- and intra-observer analysis showed excellent agreement for every parameter., Conclusions: Basic and advanced hemodynamic parameters revealed equivalency at different sites and field strength in the ascending aorta, a clinically important region of interest, under a highly controlled environment., Competing Interests: NJ was employed by Siemens Medical Solutions USA, Inc., DG was employed by Siemens Healthcare GmbH, Erlangen, Germany. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Müller, Daud, Langer, Gröschel, Viezzer, Hadler, Jin, Giese, Schmitter, Schulz-Menger and Trauzeddel.)

Background: Dual anti-human epidermal growth factor receptor 2 (HER2) blockade has improved the outcomes of patients with early and metastatic HER2-positive breast cancer. Here we present the final 10-year analysis of the ALTTO trial., Patients and Methods: The ALTTO trial (NCT00490139) is a prospective randomized, phase III, open-label, multicenter study that investigated the role of adjuvant chemotherapy and trastuzumab alone, in combination or sequentially with lapatinib. The primary endpoint was disease-free survival (DFS) and secondary endpoints included overall survival (OS), time to distant recurrence and safety., Results: Overall, 6281 patients with HER2-positive early breast cancer were included in the final efficacy analysis in three treatment groups: trastuzumab (T), lapatinib + trastuzumab (L + T) and trastuzumab followed by lapatinib (T→L). Baseline characteristics were well balanced between groups. At a median follow-up of 9.8 years, the addition of lapatinib to trastuzumab and chemotherapy did not significantly improve DFS nor OS. The 10-year DFS was 77% in T, 79% in L + T and 79% in T→L, and the 10-year OS was 87%, 89% and 89%, respectively. The incidence of any cardiac event was low and similar in the three treatment groups., Conclusions: With a longer follow-up, no significant improvement was observed in DFS in patients treated with dual anti-HER2 blockade with lapatinib + trastuzumab compared to trastuzumab alone. The 10-year survival rates for the combination group are consistent with other studies that have explored dual anti-HER2 therapy., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Neonatal ventriculomegaly often, but not always, follows intraventricular haemorrhage in infants born preterm. Serial cranial ultrasonography (CUS) is a very useful tool to evaluate the mechanism behind ventricular dilatation, to differentiate several types of cerebrospinal fluid retention, and to guide treatment. This review examines neonatal ventriculomegaly and its definition, pathophysiology, treatment, and prognosis from the perspective of CUS assessment. It also outlines the consensus statements formulated by the EurUS.Brain group, which are based on rounds of expert opinions on neonatal ventriculomegaly management, detailing the need and timing of ventricular access device placement, in the context of posthaemorrhagic ventricular dilation. The pathophysiology of neonatal ventriculomegaly is more complex than previously considered. CUS is a valuable, non-invasive tool to determine pathophysiology, intervention thresholds, and prognosis in neonates with ventriculomegaly. Given new insights into the existence of glymphatics and water circulation in the cerebrum, further research in that area may bring new treatment options. WHAT THIS PAPER ADDS: Cranial ultrasonography has a significant role in better understanding the complex pathophysiology of neonatal ventriculomegaly. The latest research suggests that treating posthaemorrhagic ventricular dilation in its early stages has several advantages. Proper definition, management, and a follow-up plan are essential because they can impact the infant and their family, health care providers, educational systems, and society., (© 2024 Mac Keith Press.)

Background: Carotid endarterectomy (CEA) is a well-established standard therapy for patients with symptomatic or asymptomatic high-grade carotid stenosis. The aim of carotid endarterectomy is to decrease the risk of stroke and avoid relevant functional loss. However, carotid endarterectomy is known to be associated with hemodynamic dysregulation. In this study we compared eversion CEA (E-CEA) and conventional CEA (C-CEA) regarding postoperative blood pressure values as well as preoperative and postoperative baroreceptor sensitivity in the first 7 days after surgery. The aim was to find possible factors influencing changes in baroreceptor sensitivity., Methods: Patients (111 patients were enrolled, of which 50 patients received C-CEA and 61 patients E-CEA) were prospectively enrolled in this study. For the measurement of baroreceptor sensitivity, a noninvasive Finometer measuring device from Finapres Medical System B.V. (Amsterdam, The Netherlands) was used. Measurements were performed 1 day before surgery (PRE), directly after surgery (F1), on day 1 (F2), day 2 (F3), and on day 7 (F4) postoperatively., Results: Postoperative blood pressure values were significantly higher in the E-CEA group on the day of surgery (F1) (P < 0.001) and on day 1 (F2) (P < 0.001). From day 2 (F3, F4) postoperatively, no significant difference was found between the 2 groups. The invasive blood pressure measurement in the postoperative recovery room showed significantly higher systolic blood pressure values in the E-CEA group (P = 0.001). The need of acute antihypertensive therapy was significantly higher in the recovery room in the E-CEA group (P = 0.020). With regard to changes in baroreceptor sensitivity, significantly lower baroreceptor sensitivity (BRS) values were recorded in the E-CEA group at 1 day (F2) postoperatively (P = 0.005). The regression analysis showed that the applied surgical technique and the patient's age were significant factors influencing changes in baroreceptor sensitivity., Conclusions: In this study we could confirm higher blood pressure levels after E-CEA in the first 2 days after surgery. Additionally, we identified 22 factors possibly influencing baroreceptor sensitivity: surgical technique and age. Based on the data obtained in this study, hemodynamic dysregulation after CEA (E-CEA, C-CEA) is temporary and short-term. Already after the second postoperative day, there was no significant difference between the E-CEA and E-CEA groups, this effect remained stable after 7 days., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Congenital ichthyoses (CI) comprise a heterogeneous group of genetic diseases requiring lifelong treatment and having a major effect on quality of life. Conventional treatments reduce scaling and skin discomfort; however, they usually have little or no effect on erythema and pruritus. The identification of cytokine alterations in CI raised the possibility of repurposing available biologics. Several case reports in the literature report successes using different biologics., Objective: We aimed to report the effects of biologics in real life., Methods: This was a retrospective, observational, international multicenter study of patients with CI treated with at least one biologic for a minimum of 3 months. The effect of the biologics was evaluated using an Investigator Global Assessment-Change (IGA-C) scale. A comprehensive literature search was performed in parallel., Results: A total of 98 patients were included, with a mean age of 19.7 years and both sexes equally represented. Patients with Netherton syndrome (NS) or congenital ichthyosiform erythroderma (CIE) represented the majority of patients (30% and 21.4%, respectively). Most patients (84.7%) had a severe or very severe form of CI. The most frequently used biologics were inhibitors targeting interleukin-17 (IL-17), IL-12/IL-23, or the IL-4 receptor. The mean duration of treatment was 22+20.1 months. There were 45 responders (45.9%), including 18 patients (18.3%) who were good responders; all had an erythrodermic CI subset and received one of the three main biologics. In 2 NS and CIE, IL-12/IL-23 and IL-4 receptor inhibitors tended to be most effective. Review of the literature revealed a shorter mean duration of use of biologics (11.5+8.5 months) and higher percentage of responders (85.7%), suggesting reporter bias., Conclusion: This series identified subsets of CI that may respond to biologics and will aid in designing future clinical trials of biologics for CI., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: NATALEE assessed efficacy and tolerability of 3 years of adjuvant ribociclib plus a nonsteroidal aromatase inhibitor (NSAI) compared with an NSAI alone in a broad population of patients with hormone receptor (HR)-positive/human epidermal growth factor 2 (HER2)-negative early breast cancer, including a select group without nodal involvement. This is the final preplanned analysis of invasive disease-free survival (iDFS)., Patients and Methods: Premenopausal/postmenopausal women and men were randomized 1 : 1 to ribociclib (n = 2549; 400 mg/day, 3 weeks on/1 week off for 36 months) plus NSAI (letrozole 2.5 mg/day or anastrozole 1 mg/day for 60 months) or NSAI alone (n = 2552). Men and premenopausal women also received goserelin (3.6 mg once every 28 days). Patients had anatomical stage IIA (N0 with additional risk factors or N1), IIB, or III disease. The primary endpoint was iDFS. Secondary efficacy endpoints were recurrence-free survival (RFS), distant DFS, and overall survival. This final iDFS analysis was planned after ∼500 events., Results: At data cut-off (21 July 2023), ribociclib was stopped for 1996 patients (78.3%); 1091 (42.8%) completed 3 years of ribociclib, and ribociclib treatment was ongoing for 528 (20.7%). Median follow-up for iDFS was 33.3 months. Overall, 226 and 283 iDFS events occurred with ribociclib plus NSAI versus NSAI alone, respectively. Ribociclib plus NSAI demonstrated significant iDFS benefit over NSAI alone [hazard ratio 0.749, 95% confidence interval (CI) 0.628-0.892; P = 0.0012]. The 3-year iDFS rates were 90.7% (95% CI 89.3% to 91.8%) versus 87.6% (95% CI 86.1% to 88.9%). A consistent benefit was observed across prespecified subgroups, including stage (II/III) and nodal status (positive/negative). Distant DFS and RFS favored ribociclib plus NSAI. Overall survival data were immature. No new safety signals were observed., Conclusions: With longer follow-up and most patients off ribociclib, NATALEE continues to demonstrate iDFS benefit with ribociclib plus NSAI over NSAI alone in the overall population and across key subgroups. Observed adverse events remained stable., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Neonates admitted to the intensive care unit are at risk of brain injury. Importantly, infants with signs of neurological impairment need prompt diagnosis to guide intervention. Cranial ultrasound (CUS) is the first-line imaging tool for infants born preterm. New developments in this technology, which now incorporates high-resolution equipment, have notably improved the performance of CUS in infants born at term and near-term. On the other hand, the potential of CUS as a diagnostic tool in older infants is less established. The lack of studies focusing on this topic, local protocol variability among clinical sites, and divergent opinions on CUS patterns of disease entities are the main constraints. This review provides an overview of state-of-the-art CUS as a decision-making tool under different clinical scenarios, such as neonatal encephalopathy, seizures, and suspected central nervous system infection. The CUS features that characterize several patterns supporting a diagnosis are detailed, focusing on haemorrhage and infection., (© 2024 Mac Keith Press.)

Background: One of the challenges in surgery of tumors in motor eloquent areas is the individual risk assessment for postoperative motor disorder. Previously a regression model was developed that permits estimation of the risk prior to surgery based on topographical and neurophysiological data derived from investigation with nTMS (navigated Transcranial Magnetic Stimulation). This study aims to analyze the impact of including additional neurophysiological TMS parameters into the established risk stratification model for motor outcome after brain tumor surgery., Methods: Biometric and clinical data of 170 patients with glioma in motor eloquent areas were collected prospectively. In addition, the following nTMS parameters were collected bihemispherically prior to surgery: resting motor threshold (RMT), recruitment curve (RC), cortical silent period (CSP) and a nTMS based fibertracking to measure the tumor tract distance (TTD). Motor function was quantified by Medical Research Council Scale (MRCS) preoperatively, seven days and three months postoperatively. Association between nTMS parameters and postoperative motor outcome was investigated in bivariate and multivariable analyses., Results: The bivariate analysis confirmed the association of RMT ratio with the postoperative motor outcome after seven days with higher rates of worsening in patients with RMT ratio > 1.1 compared to patients with RMT ratio ≤ 1.1 (31.6% vs. 15.1%, p = 0.009). Similarly, an association between a pathological CSP ratio and a higher risk of new postoperative motor deficits after seven days was observed (35.3% vs. 16.7% worsening, p = 0.025). A pathological RC Ratio was associated postoperative deterioration of motor function after three months (42.9% vs. 16.2% worsening, p = 0.004). In multiple regression analysis, none of these associations were statistically robust., Conclusions: The current results suggest that the RC ratio, CSP ratio and RMT ratio individually are sensitive markers associated with the motor outcome 7 days and 3 months after tumor resection in a presumed motor eloquent location. They can therefore supply valuable information during preoperative risk-benefit-balancing. However, underlying neurophysiological mechanisms might be too similar to make the parameters meaningful in a combined model., (© 2024. The Author(s).)

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Background: In KEYNOTE-522 (NCT03036488), neoadjuvant pembrolizumab plus chemotherapy and then adjuvant pembrolizumab significantly improved pathological complete response and event-free survival vs neoadjuvant chemotherapy in early-stage triple-negative breast cancer (TNBC). We report patient-reported outcomes (PROs) from KEYNOTE-522., Methods: Patients were randomized 2:1 to neoadjuvant pembrolizumab 200 mg or placebo every 3 weeks, plus 4 cycles of paclitaxel plus carboplatin and then 4 cycles of doxorubicin (or epirubicin) plus cyclophosphamide. After surgery, patients received adjuvant pembrolizumab or placebo for up to 9 cycles. European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and EORTC Breast Cancer-Specific Quality of Life Questionnaire (EORTC QLQ-BR23) were prespecified secondary objectives. Between-group differences in least squares (LS) mean change from baseline (day 1 of cycle 1 in both neoadjuvant and adjuvant phases) to the prespecified latest time point with at least 60% completion and at least 80% compliance were assessed using a longitudinal model (no alpha error assigned)., Results: Week 21 (neoadjuvant phase) and week 24 (adjuvant phase) were the latest time points at which completion/compliance rates were ≥60%/80%. In the neoadjuvant phase, between-group differences (pembrolizumab plus chemotherapy [n = 762] vs placebo plus chemotherapy [n = 383]) in LS mean change from baseline to week 21 in QLQ-C30 global health status/quality of life (GHS/QoL), emotional functioning, and physical functioning were -1.04 (95% confidence interval = -3.46 to 1.38), -0.69 (95% CI = -3.13 to 1.75), and -2.85 (95% CI = -5.11 to -0.60), respectively. In the adjuvant phase, between-group differences (pembrolizumab [n = 539] vs placebo [n = 308]) in LS mean change from baseline to week 24 were -0.41 (95% CI = -2.60 to 1.77), -0.60 (95% CI = -2.99 to 1.79), and -1.57 (95% CI = -3.36 to 0.21)., Conclusions: No substantial differences in PRO assessments were observed between neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab vs neoadjuvant placebo plus chemotherapy in early-stage TNBC., Trial Registration: ClinicalTrials.gov, NCT03036488., (© The Author(s) 2024. Published by Oxford University Press.)

Treatment of complex ischemic lower leg defects with exposure of deep anatomic structures represents a considerable challenge to involved specialties. In selected patients, limb salvage can be achieved as an alternative to major amputation by means of a combined approach including arterial reconstruction and subsequent free flap transfer. Arterial reconstruction can be performed either by endovascular or open surgical treatment (bypass reconstruction or implantation of an arteriovenous loop) preliminary to defect reconstruction using microsurgical free flap transplantation. Whereas the aim of the arterial reconstruction comprises the establishment of sufficient perfusion and creation of adequate target vessels for the free flap transfer, the selection of the appropriate flap entity depends on the extent of the wound as wells as on the presence of osteomyelitis. Arterial reconstruction and defect reconstruction can be performed as one-stage or two-stage procedure and has become an established and feasible treatment approach in centers. Evaluation of microperfusion by means of indocyanine green can further increase safety and feasibility of this method. Against this background, combined arterial reconstruction and subsequent free flap transfer provides excellent results in terms of amputation free survival and postoperative mobility. Essential is however an individualized decision making in consideration of patient selection and possible contraindications. This approach may be evaluated in mobile patients with complex wounds prior to major amputation., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Background: Several commercially available software packages exist for the analysis of three-dimensional cine phase-contrast cardiovascular magnetic resonance (CMR) with three-directional velocity encoding (four-dimensional (4D) flow CMR). Only sparse data are available on the impact of these different software solutions on quantitative results. We compared two different commercially available and widely used software packages and their impact on the forward flow volume (FFV), peak velocity (PV), and maximum wall shear stress (WSS) per plane., Materials and Methods: 4D flow CMR datasets acquired by 3 Tesla magnetic resonance imaging of 10 healthy volunteers, 13 aortic stenosis patients, and 7 aortic valve replacement patients were retrospectively analyzed for FFV, PV, and WSS using two software packages in six analysis planes along the thoracic aorta. Absolute (AD) and relative differences (RD), intraclass correlation coefficients (ICC), Bland-Altman analysis, and Spearman's correlation analysis were calculated., Results: For the FFV and PV in healthy volunteers, there was good to excellent agreement between both software packages [FFV: ICC = 0.93-0.97, AD: 0.1 ± 5.4 ml (-2.3 ± 2.4 ml), RD: -0.3 ± 8% (-5.7 ± 6.0%); PV: ICC = 0.81-0.99, AD: -0.02 ± 0.02 ml (-0.1 ± 0.1 ml), RD: -1.6 ± 2.1% (-9.3 ± 6.1%)]. In patients, the FFV showed good to excellent agreement [ICC: 0.75-0.91, AD: -1.8 ± 6.5 ml (-8.3 ± 9.9 ml), RD: -2.2 ± 9.2% (-13.8 ± 17.4%)]. In the ascending aorta, PV showed only poor to moderate agreement in patients (plane 2 ICC: 0.33, plane 3 ICC: 0.72), whereas the rest of the thoracic aorta revealed good to excellent agreement [ICC: 0.95-0.98, AD: -0.03 ± 0.07 (-0.1 ± 0.1 m/s), RD: -3.5 ± 7.9% (-7.8 ± 9.9%)]. WSS analysis showed no to poor agreement between both software packages. Global correlation analyses revealed good to very good correlation between FFV and PV and only poor correlation for WSS., Conclusions: There was good to very good agreement for the FFV and PV except for the ascending aorta in patients when comparing PV and no agreement for WSS. Standardization is therefore necessary., Competing Interests: RT received funding from Deutsche Herzstiftung (German Heart foundation) and DZHK (German Centre for Cardiovascular Research). JS-M holds institutional grants of the Charité—Universitätsmedizin Berlin. The group holds research grants from Siemens Healthineers. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Trauzeddel, Müller, Demir, Wiesemann, Daud, Schmitter, Viezzer, Hadler and Schulz-Menger.)

Background and aims: Endoscopic submucosal dissection (ESD) has become a standard treatment for early gastric cancer (EGC), often fulfilling guideline criteria (GC) or expanded criteria (EC). When lesions exceed the EC, surgical resection is recommended. However, a subgroup of these patients are not treated surgically. The aim of this study was to investigate the long-term follow-up of patients after ESD for EGC outside the EC (out of indication; OI). Methods: Patients who were included in the prospective German ESD registry were analyzed when ESD was performed for EGC. Patients were stratified in three groups according to histopathological features (GC, EC and OI). The results were evaluated in terms of patient characteristics, procedure characteristics and follow-up data. Results: Over a 48-month period, 195 patients from 14 German centers were included. In total, 71 lesions (36.4%) met the guideline criteria, 70 lesions (35.9%) corresponded to the expanded criteria and 54 lesions (27.7%) turned out to be OI. The R0 resection rate was significantly higher for the GC and EC groups than for the OI group (94.4% vs. 84.3% vs. 55.6%, p < 0.001). Additional surgery was not performed in 72% (39/54) of patients in the OI group. During a mean follow-up of 37 months, overall survival showed no significant difference between the EC and OI groups when endoscopic follow-up was performed without additional surgery ( p = 0.064). Conclusions: The results show that a good long-term survival can be achieved after ESD for patients with OI lesions without additional surgery. The treatment decision has to be made on an individual basis, taking the patient's comorbidities and the risk of surgical resection into account.

Background: Oral anticoagulation (OAC) is key in stroke prevention in patients with atrial fibrillation (AF) but there is uncertainty regarding the optimal timing of OAC (re)initiation after stroke, as recent large randomised controlled trials have methodological weaknesses and excluded stroke patients on therapeutic anticoagulation at stroke onset as well as patients started on a vitamin K antagonist after stroke. The '1-3-6-12 days rule', based on expert consensus and referring to stroke severity, was used in clinical practice to initiate OAC after acute ischaemic stroke or transient ischaemic attack (TIA) since publication in 2013., Methods: We retrospectively assessed whether compliance to the '1-3-6-12 days rule' was associated with the composite endpoint (recurrent stroke, systemic embolism, myocardial infarction, major bleeding or all-cause death)., Results: Among 708 registry patients with known AF before stroke and hospitalisation within 72 hours after stroke, 432 were anticoagulated at stroke onset. OAC was started according to the '1-3-6-12 days rule' in 255 (39.2%) patients. Non-adherence to the '1-3-6-12 days rule' was not associated with the composite endpoint within 3 months in 661 patients who (re-)started on OAC (log-rank test: p=0.74).Results were similar for 521 patients (re)started on a non-vitamin K-dependent OAC., Conclusion: (Re)starting OAC after stroke followed the '1-3-6-12 days rule' in about 40% of all patients with AF, and more often in those anticoagulated at stroke onset. Adherence to the '1-3-6-12 days rule' did not reduce the composite clinical endpoint, if OAC was restarted within 3 months of stroke/TIA., Trial Registration Number: NCT02306824., Competing Interests: Competing interests: DGN reports speaker's honoraria and/or consulting fees from AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Novartis, Pfizer and Sanofi. PUH reports grants from Charité – Universitätsmedizin Berlin (within Mondafis; supported by an unrestricted research grant to the Charité from Bayer), research grants from German Ministry of Research and Education, German Research Foundation, research grants from Bavarian State, European Union, German Parkinson Society, German Cancer Aid, University Hospital Würzburg, German Heart Foundation, Federal Joint Committee (G-BA) within the Innovationsfonds, University Hospital Heidelberg (within RASUNOA-prime; supported by an unrestricted research grant to the University Hospital Heidelberg from Bayer, BMS, Boehringer-Ingelheim, Daiichi Sankyo), University Göttingen (within FIND-AF randomised; supported by an unrestricted research grant to the University Göttingen from Boehringer-Ingelheim) outside the submitted work; and participated on Data, Safety Monitoring Board in publicly funded studies (by German Research Foundation, German Ministry of Research, Foundations). ME reports grants from Bayer and fees paid to the Charité from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers-Squibb, Covidien, Daiichi Sankyo, Glaxo Smith Kline, Novartis, Pfizer and Sanofi,all outside the submitted work. KGH reports speaker's honoraria, consulting fees, lecture honoraria and/or study grants from Abbott, Amarin; AstraZeneca, Bayer Healthcare, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Daiichi Sankyo, Edwards Lifesciences, Medronic, Novartis, Pfizer, Portola, Premier Research, Sanofi, SUN Pharma, and W.L. Gore and Associates. PS reports speaker's honoraria from Bayer, Boehringer Ingelheim, Bristol-Myers-Squibb and Pfizer., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: We aimed to investigate the association of electrocardiogram (ECG) findings with outcomes in patients with chronic coronary syndrome., Methods: This secondary analysis of the ISCHEMIA and ISCHEMIA-CKD trials divided patients with chronic coronary syndrome into two groups, those with a normal ECG tracing and abnormal ECG tracing. Repolarization abnormalities included ST-segment depression ≥ 0.5 mm and T-wave inversion ≥ 1 mm; conduction abnormalities included left and right bundle branch block (LBBB and RBBB). The primary endpoint was cardiovascular death. Outcomes were assessed using a covariate-adjusted Cox-regression model., Results: Of 5876 patients, 2901 (49.4%) had a normal and 2975 (50.6%) an abnormal ECG tracing. An abnormal ECG tracing at baseline, compared with a normal ECG tracing, was associated with an increased risk of cardiovascular death (257 of 2975 [8.6%] vs. 97 of 2901 [3.3%], adjusted hazard ratio [aHR] 2.01, 95% CI 1.58-2.55) over a median follow-up period of 3.1 years (IQR 2.1-4.2). This finding was consistent across subgroups except for patients with black skin color and current smokers, in whom an abnormal ECG was not significantly associated with increased risk of cardiovascular death. Individual ECG abnormalities (ST-segment depression [aHR 2.0, 95% CI 1.52-2.63], T-wave inversion [aHR 1.89, 95% CI 1.40-2.54], LBBB [aHR 1.74, 95% CI 1.05-2.90], and RBBB [aHR 1.52, 95% CI 1.04-2.22]) were independently associated with an increased risk of cardiovascular death., Conclusion: In patients with chronic coronary syndrome, an abnormal ECG tracing was associated with an increased risk of cardiovascular death. Our findings underscore the importance of the ECG in cardiovascular risk stratification and prognostication., Trial Registration: NCT01471522, BioLINCC ID 14539., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported .Although dose-dense adjuvant chemotherapy administered once every 2 weeks leads to superior outcomes compared with standard regimens once every 3 weeks, the observed improvement is largely limited to studies using the suboptimal paclitaxel schedule once every 3 weeks as control. PANTHER is an international phase III trial which compared sequential epirubicin/cyclophosphamide and docetaxel administered either once every 2 or once every 3 weeks, with tailored dosing at the dose-dense schedule according to hematologic toxicity. In this end-of-study analysis, the median follow-up was 10.3 years. Compared with standard adjuvant chemotherapy, dose-dense treatment improved breast cancer recurrence-free survival (hazard ratio [HR], 0.80 [95% CI, 0.65 to 0.98]; P = .030), event-free survival (HR, 0.78 [95% CI, 0.65 to 0.94]; P = .009), and distant disease-free survival (HR, 0.79 [95% CI, 0.64 to 0.98]; P = .030) while the improvement in overall survival was not statistically significant (HR, 0.82 [95% CI, 0.65 to 1.04]; P = .109). To our knowledge, this is the first trial that confirms the benefit of a dose-dense regimen over a control regimen containing docetaxel once every 3 weeks.

Endocrine-based combination therapy with an inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6 inhibitors) is currently the first-line therapy of choice for patients with hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-), locally advanced or metastatic breast cancer (mBC). The efficacy and safety of the treatment with palbociclib, the first CDK4/6 inhibitor approved for this indication, have been confirmed in large randomized controlled clinical trials (RCTs) with strictly defined patient cohorts. Since then, many relevant questions about CDK4/6 inhibition with palbociclib for mBC have been investigated in RCTs and real-world studies. Based on this evidence, palbociclib is widely used in clinical practice since many years because of its efficacy and good tolerability. The aim of this review is to summarize findings from RCTs and RWE considering clinically relevant aspects such as safety, tolerability, quality of life and efficacy with a focus on specific questions and patient characteristics. A critical discussion and review of the overall evidence for endocrine-based therapy with the CDK4/6 inhibitor palbociclib can contribute to support therapy decisions in daily clinical practice., Competing Interests: Conflict of Interest Ruckhäberle, Eugen: Honoraria or fees from: Amgen, Roche, Celgene, Gilead, Pfizer, Novartis, AstraZeneca, MSD, Teva, TESARO, Pharmamar, Pierre Fabre, Exact Sciences, Janssen-Cilag, Lilly, Clovis Oncology, Onkowissen. Travel support: Pfizer, Roche, Eisai, Pierre Fabre. Research support: Roche. Schmidt, Marcus: Personal fees from AstraZeneca, BioNTech, Daiichi Sankyo, Eisai, Exact Sciences, Gilead, Lilly, Menarini Stemline, Molecular Health, MSD, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, Roche, and Seagen. His institution has received research funding from AstraZeneca, BioNTech, Eisai, Genentech, German Breast Group, Novartis, Palleos, Pantarhei Bioscience, Pierre Fabre, and Seagen. In addition, he has a patent for EP 2390370 B1 and a patent for EP 2951317 B1 issued. Welt, Anja: Fees from MSD, Roche, Novartis, Pfizer, Seagen, Lilly, Menarini Stemline, Pierre Fabre, iOMEDICO, Eisai, RCC, MCI, Interplan. Harbeck, Nadia: Honoraria for lectures and/or consulting: AstraZeneca, Daiichi Sankyo, Gilead, Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Seagen, Viatris, Zuelligpharma. Other: Co-Director West German Study Group (WSG). Wöckel, Achim: Amgen, AstraZeneca, Celgene, Lilly, Novartis, Pfizer, Roche, MSD, Genomic Health, Organon, Seagen, Exact Sciences, Gilead, Daiichi Sankyo, Stemline. Gluz, Oleg: Honoraria/consulting: Roche, Celgene, Amgen, Seagen, Novartis, Lilly, Pfizer, MSD, Exact Sciences, Gilead, AstraZeneca, Molecular Health, Pierre Fabre, Eisai, Agendia. Travel support: Daiichi Sankyo, Roche, Pfizer. Non-Profit: Gesellschafter Westdeutsche Studiengruppe GmbH. Park-Simon, Tjoung-Won: Roche, AstraZeneca, GSK, Pfizer, Daiichi Sankyo, Lilly, MSD, NCO, Eisai, Seagen, Exact Sciences, Novartis, Gilead, Onkowissen, ONKO-Internetportal. Meeting support: Amgen, Roche, Celgene, Gilead, Pfizer, Novartis, AstraZeneca, MSD, Teva, TESARO, GSK, Clovis Oncology, Pharmamar, Pierre Fabre, Gedeon Richter, Eisai, Daiichi Sankyo, Hexal, Ribosepharm, Schering, BMS, Janssen-Cilag, Olympus, Seagen, Genomic Health. Travel support: Pfizer, Roche, Eisai, Pierre Fabre, MSD, Gilead, Stryker. Research support: Roche. Untch, Michael: Honoraria: AstraZeneca, Art tempi, Amgen, Daiichi Sankyo, Lilly, Roche, Pfizer, MSD Oncology, Pierre Fabre, Sanofi-Aventis, Myriad, Seagen, Gilead, Novartis, Menarini Stemline. Consulting or advisory role: Amgen, Lilly, Roche, CD Pharma, Pfizer, Pierre Fabre, Novartis, MSD Oncology, Agendia, Seagen, Gilead, Menarini Stemline, Genzyme. All honoraria and fees to the employer/institution. Lux, Michael Patrick: Honoraria from Lilly, Pfizer, Roche, MSD, Hexal, Novartis, AstraZeneca, Eisai, Exact Sciences, Agendia, Daiichi Sankyo, Grünenthal, Gilead, Pierre Fabre, Pharmamar, Samantree, Endomag, and medac for advisory boards, lectures, and travel support., (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/).)

Follicular lymphoma (FL) is the most common indolent B-cell non-Hodgkin lymphoma (NHL), accounting for nearly one-third of all NHL. The therapeutic landscape for patients with FL has significantly expanded over the past decade, but the disease continues to be considered incurable. Hematopoietic cell transplantation (HCT) is potentially curative in some cases. Recently, the emergence of chimeric antigen receptor T-cell therapy (CAR-T) for patients with relapsed/refractory (R/R) FL has yielded impressive response rates and long-term remissions, but definitive statement on the curative potential of CAR-T is currently not possible due to limited patient numbers and relatively short follow up. A consensus on the contemporary role, optimal timing, and sequencing of HCT (autologous or allogeneic) and cellular therapies in FL is needed. As a result, the American Society of Transplantation and Cellular Therapy (ASTCT) Committee on Practice Guidelines endorsed this effort to formulate consensus recommendations to address this unmet need. The RAND-modified Delphi method was used to generate 15 consensus statements/recommendations. These clinical practice recommendations will help guide clinicians managing patients with FL. Of note, the use of bispecific antibodies in R/R FL was not in the scope of this project., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Patients with inherited ichthyosis suffer from scaling due to mutations affecting the epidermal barrier. Symptomatic treatment with ointments, bathing and mechanical scale removal can alleviate the disease, but therapy is time and cost intensive., Objectives: We investigated costs, time and disease burden of ichthyoses. The study addresses difficulties of the healthcare situation for patients with ichthyoses and reveals potential improvements., Materials and Methods: We developed a questionnaire addressing time and financial effort for the treatment. Additionally, we collected data of the Dermatology Life Quality Index (DLQI) and the Pruritus Life Quality (5PLQ) questionnaires to determine the impact of ichthyosis and associated pruritus on quality of life (QoL)., Results: We recruited 144 patients with ichthyosis (median age: 23; 53.5% female) from the Department of Dermatology in Muenster (Germany) and the German patient support group including common, rare and syndromic subtypes. Eighty-seven percent reported applying topical therapeutics at least once per day, 66.4% several times with an overall median duration of 15 min. Highest single expenditure of time was due to balneotherapy (n = 115; median bathing time: 40 min). In 81.9%, the health insurance did not completely cover the costs for topical treatment causing additional financial burden to the patient with a median of 71 € per quarter, herein creams being the largest cost factor (50 €). Patients with Netherton syndrome showed the highest median expenditure (170 €). The QoL impairment under treatment was moderate (median DLQI: 8.5 points). Pruritus was prevalent in 79.9% and showed a distinct impact on QoL (median 5PLQ: 7.5 points) without any significant difference between the subtypes (p = 0.37)., Conclusion: Patients suffering from ichthyoses have a large and lifelong overall burden in mild and severe subtypes. Since continuous topical treatment is required, financial and psychosocial support needs to be considered beyond dermatological care., (© 2024 European Academy of Dermatology and Venereology.)

Background: Active inflammatory bowel disease (A-IBD) but not remission (R-IBD) has been associated with an increased risk of cardiovascular death and hospitalization for heart failure., Objectives: Using cardiovascular magnetic resonance (CMR), this study aims to assess adverse myocardial remodeling in patients with IBD in correlation with disease activity., Methods: Forty-four IBD patients without cardiovascular disease (24 female, median-age: 39.5 years, 26 A-IBD, 18 R-IBD) and 44 matched healthy volunteers (HV) were prospectively enrolled. The disease stage was determined by endoscopic and patient-reported criteria. Participants underwent CMR for cardiac phenotyping: cine imaging and strain analysis were performed to assess ventricular function. T1 mapping, extracellular volume and late-gadolinium enhanced images were obtained to assess focal and diffuse myocardial fibrosis. Simultaneous T1 and T2 elevation (T1 > 1049.3 ms, T2 > 54 ms) was considered to indicate a myocardial segment was inflamed., Results: 16/44 (16.4%) IBD patients described dyspnea on exertion and 10/44 (22.7%) reported chest pain. A-IBD patients showed impaired ventricular function, indicated by reduced global circumferential and radial strain despite preserved left-ventricular ejection fraction. 16% of all IBD patients had focal fibrosis in a non-ischemic pattern. A-IDB patients had increased markers of diffuse left ventricular fibrosis (T1-values: A-IBD: 1022.0 ± 34.83 ms, R-IBD: 1010.10 ± 32.88 ms, HV: 990.61 ± 29.35 ms, p < .01). Significantly more participants with A-IDB (8/26, 30.8%) had at least one inflamed myocardial segment than patients in remission (0/18) and HV (1/44, 2.3%, p < .01). Markers of diffuse fibrosis correlated with disease activity., Conclusion: This study, using CMR, provides evidence of myocardial involvement and patterns of adverse left ventricular remodeling in patients with IBD., Clinical Trial Registration: ISRCTN30941346., (© 2024. The Author(s).)

Gamma delta (γδ) T cells represent a minor fraction of human T cell repertoire but play an important role in mediating anti-infectious and anti-tumorous effects in the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We performed a prospective study to analyze the effect of different transplant modalities on immune reconstitution of γδ T cells and subsets. CD3, CD4 and CD8 T cells were analyzed in parallel. Secondly, we examined the impact of γδ T cell reconstitution on clinical outcomes including acute Graft-versus-Host-Disease (aGvHD) and viral infections. Our cohort includes 49 pediatric patients who received unmanipulated bone marrow grafts from matched unrelated (MUD) or matched related (MRD) donors. The cohort includes patients with malignant as well as non-malignant diseases. Cell counts were measured using flow cytometry at 15, 30, 60, 100, 180 and 240 days after transplantation. Cells were stained for CD3, CD4, CD8, CD45, TCR αβ , TCRγδ, TCRVδ1, TCRVδ2, HLA-DR and combinations. Patients with a MRD showed significantly higher Vδ2+ T cells than those with MUD at timepoints +30, +60, +100 (p<0.001, respectively) and +180 (p<0.01) in univariate analysis. These results remained significant in multivariate analysis. Patients recovering with a high relative abundance of total γδ T cells and Vδ2+ T cells had a significantly lower cumulative incidence of grade II-IV aGvHD after transplantation (p=0.03 and p=0.04, respectively). A high relative abundance of Vδ2+ T cells was also associated with a lower incidence of EBV infection (p=0.02). Patients with EBV infection on the other hand showed higher absolute Vδ1+ T cell counts at days +100 and +180 after transplantation (p=0.046 and 0.038, respectively) than those without EBV infection. This result remained significant in a multivariate time-averaged analysis (q<0.1). Our results suggest a protective role of γδ T cells and especially Vδ2+ T cell subset against the development of aGvHD and EBV infection after pediatric HSCT. Vδ1+ T cells might be involved in the immune response after EBV infection. Our results encourage further research on γδ T cells as prognostic markers after HSCT and as possible targets of adoptive T cell transfer strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Müller, Alasfar, Preuß, Zimmermann, Streitz, Hundsdörfer, Eggert, Schulte, von Stackelberg and Oevermann.)

Background: Intensified systemic chemotherapy has the highest primary cure rate for advanced-stage, classical Hodgkin lymphoma but this comes with a cost of severe and potentially life long, persisting toxicities. With the new regimen of brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD), we aimed to improve the risk-to-benefit ratio of treatment of advanced-stage, classical Hodgkin lymphoma guided by PET after two cycles., Methods: This randomised, multicentre, parallel, open-label, phase 3 trial was done in 233 trial sites across nine countries. Eligible patients were adults (aged ≤60 years) with newly diagnosed, advanced-stage, classical Hodgkin lymphoma (ie, Ann Arbor stage III/IV, stage II with B symptoms, and either one or both risk factors of large mediastinal mass and extranodal lesions). Patients were randomly assigned (1:1) to four or six cycles (21-day intervals) of escalated doses of etoposide (200 mg/m 2 intravenously on days 1-3), doxorubicin (35 mg/m 2 intravenously on day 1), and cyclophosphamide (1250 mg/m 2 intravenously on day 1), and standard doses of bleomycin (10 mg/m 2 intravenously on day 8), vincristine (1·4 mg/m 2 intravenously on day 8), procarbazine (100 mg/m 2 orally on days 1-7), and prednisone (40 mg/m 2 orally on days 1-14; eBEACOPP) or BrECADD, guided by PET after two cycles. Patients and investigators were not masked to treatment assignment. Hierarchical coprimary objectives were to show (1) improved tolerability defined by treatment-related morbidity and (2) non-inferior efficacy defined by progression-free survival with an absolute non-inferiority margin of 6 percentage points of BrECADD compared with eBEACOPP. An additional test of superiority of progression-free survival was to be done if non-inferiority had been established. Analyses were done by intention to treat; the treatment-related morbidity assessment required documentation of at least one chemotherapy cycle. This trial was registered at ClinicalTrials.gov (NCT02661503)., Findings: Between July 22, 2016, and Aug 27, 2020, 1500 patients were enrolled, of whom 749 were randomly assigned to BrECADD and 751 to eBEACOPP. 1482 patients were included in the intention-to-treat analysis. The median age of patients was 31 years (IQR 24-42). 838 (56%) of 1482 patients were male and 644 (44%) were female. Most patients were White (1352 [91%] of 1482). Treatment-related morbidity was significantly lower with BrECADD (312 [42%] of 738 patients) than with eBEACOPP (430 [59%] of 732 patients; relative risk 0·72 [95% CI 0·65-0·80]; p<0·0001). At a median follow-up of 48 months, BrECADD improved progression-free survival with a hazard ratio of 0·66 (0·45-0·97; p=0·035); 4-year progression-free survival estimates were 94·3% (95% CI 92·6-96·1) for BrECADD and 90·9% (88·7-93·1) for eBEACOPP. 4-year overall survival rates were 98·6% (97·7-99·5) and 98·2% (97·2-99·3), respectively., Interpretation: BrECADD guided by PET after two cycles is better tolerated and more effective than eBEACOPP in first-line treatment of adult patients with advanced-stage, classical Hodgkin lymphoma., Funding: Takeda Oncology., Competing Interests: Declaration of interests PB reports consulting fees from Takeda, BMS, Roche, Amgen, Novartis, Celgene, Miltenyi Biotech, and Gilead; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda, Novartis, BMS, Roche, MSD, Celgene, Miltenyi Biotech, Gilead, and AbbVie; and funding for scientific research from Takeda Oncology, MSD, and Novartis. JF reports funding and consulting fees from Takeda Oncology and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda Oncology and Roche Pharma. RG reports consulting fees from Celgene, Novartis, Roche, Takeda, AbbVie, Astra Zeneca, MSD, Merck, Gilead, Daiichi Sanko, and Sanofi; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, AbbVie, Gilead, Daiichi Sankyo, and Sanofi; support for attending meetings or travel from Roche, Amgen, Janssen, Astra Zeneca, Novartis, BMS, AbbVie, and Daiichi Sankyo; participating on a data safety monitoring board or advisory board for Celgene, Novartis, Roche, BMS, Takeda, AbbVie, Astra Zeneca, Janssen, MSD, Merck, Gilead, Daiichi Sankyo, and Sanofi; and stock or stock options from Novo Nordisk and Lilly. MHe reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda. AH reports payment for speakers bureau, funding, and travel support from, and participation on an advisory board for Takeda. FK reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events, and support for attending meetings or travel from Takeda. MHä reports consulting fees from Pfizer, Incyte, Roche, Amgen, Sanofi/Aventis, Sobi, Kite/Gilead, Janssen, and BMS and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Sobi, Novartis, Kite/Gilead, Falk Foundation, and BMS. UN reports consulting fees for the institution from Janssen-Cilag, Celgene (BMS), Takeda, AstraZeneca, Roche, Novartis, Incyte, BeiGene, Kyowa Kiin, Gileag, and Pierre Fabre; payment or honoraria for lectures, presentations, speakers bureaus, manuscript, writing or educational events for the institution from Celgene (BMS), Novartis, Takeda, and Gilead; support to the institution for attending meetings or travel from Janssen, Roche, Gilead, and Takeda; and participating on a data safety monitoring board or advisory board for Janssen-Cilag, Celgene (BMS), Takeda, AstraZeneca, Roche, Novartis, Incyte, BeiGene, Kyowa Kiin, Gileag, and Pierre Fabre. JM reports consulting fees from MSD. AZi reports payment for presentations from Novartis, Oncopeptides, Takeda, Incyte, and Roche and travel support from Oncopeptides, Roche, and Novartis. AF reports consulting fees and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda. AV reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Roche, BMS, and AbbVie; support for attending meetings or travel from Janssen, Kite/Gilead, BMS, and AbbVie; and participation on a data safety monitoring board or advisory board from Roche, BMS, AbbVie, and Kite/Gilead. SS reports travelling support from AbbVie and Jazz and reports support for attending meetings or travel from and having a leadership or fiduciary role in another board, society, committee or advocacy group (paid or unpaid) with Pfizer, Amgen, and Novartis. VV reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda and participation on an advisory board for Takeda and MSD. AK reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Roche, Celgene, AbbVie, Sobi, BMS, and Takeda and support for attending meetings or travel from AbbVie, BeiGene, Sobi, Takeda, EUSA Pharma, Novartis, and Alexion. KT-G reports consulting fees and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda. PK reports travel support from Roche Pharmaceuticals and Takeda. BvT reports institutional grants or contracts from Esteve, Merck Sharp & Dohme, Novartis, and Takeda; consulting fees from Allogene, Amgen, BMS/Celgene, Cerus, Gilead Kite, Incyte, IQVIA, Janssen-Cilag, Lilly, Merck Sharp & Dohme, Miltenyi, Novartis, Noscendo, Pentixapharm, Pfizer, Pierre Fabre, Qualworld, Roche, Sobi, and Takeda; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, AstraZeneca, BMS/Celgene, Gilead Kite, Incyte, Lilly, Merck Sharp & Dohme, Novartis, Roche, and Takeda; support for attending meetings or travel from AbbVie, AstraZeneca, Gilead, Kite, Lilly, Merck Sharp & Dohme, Pierre Fabre, Roche, Takeda, and Novartis; payment from Takeda and Regeneron (INSIGHTFUL study); payment to institution from the Olympia 3 study; and participation on a data safety monitoring board or advisory board for Takeda and Regeneron. SB reports consulting fees from Galapagos; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events and consultation from Takeda; support for attending meetings or travel from Takeda; having a leadership role in another board, society, committee, or advocacy group (paid or unpaid), and holding stock or stock options for Liqomics. KB reports funding and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda Oncology. MF reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Celgene, BMS, Takeda, and Janssen. AZo reports Takeda stocks and being an employee of Takeda Oncology. SK reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events, payment for expert testimony, and support for attending meetings or travel from, and participating on a data safety monitoring board or advisory board for Takeda. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Although major amputations can often be avoided due to evolving methods of endovascular and surgical revascularizations techniques, in patients with chronic limb-threatening ischemia, it is still necessary in some cases. Aim of this study was the detection of wound healing disorders through intraoperative microcirculation measurements in major limb amputations., Materials and Methods: In this single-center clinical study, patients with an indication for major amputation were enrolled prospectively. Cause of amputation, patients' comorbidities including cardiovascular risk profile were assessed. Macrocirculation, as well as microcirculation were assessed. Microcirculation measurements were performed by fluorescence angiography with the administration of indocyanine green. A preoperative measurement was obtained at the amputation level, followed by three additional measurements of the amputation stump postoperatively. Wound healing was monitored and correlated with the microcirculatory findings, based on the perfusion parameters ingress and ingress rate, calculated in the indocyanine green fluorescence video sequences of the amputation stumps., Results: Forty-five patients were enrolled, including 19 (42%) below-the-knee amputations and 26 (58%) above-the-knee amputations. When considering the need for revision, a change in the microperfusion parameters was observed postoperatively. The mean value for ingress was significantly lower directly postoperatively in stumps requiring revisions (5 ± 0 A.U. versus 40.5 ± 42.5 A.U., p  < 0.001). The mean value of ingress rate behaved similarly (0.15 ± 0.07 A.U./s versus 2.8 ± 5.0 A.U./s, p  = 0.005). The evaluation of indocyanine green measurements when wound healing disorders occurred also showed nonsignificant differences in the mean values., Conclusion: Fluorescence angiography after major lower limb amputations appears to be an option of depicting microperfusion. Especially, the early postoperative detection of reduced perfusion can indicate a subsequent need for revision. Therefore, this method could possibly serve as a tool for intraoperative quality control after major limb amputation., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Autologous(auto-) and allogeneic(allo-) hematopoietic stem cell transplantation (HSCT) are key treatments for relapsed/refractory diffuse large B-cell lymphoma (DLBCL), although their roles are challenged by CAR-T-cells and other immunotherapies. We examined the transplantation trends and outcomes for DLBCL patients undergoing auto-/allo-HSCT between 1990 and 2021 reported to EBMT. Over this period, 41,148 patients underwent auto-HSCT, peaking at 1911 cases in 2016, while allo-HSCT saw a maximum of 294 cases in 2018. The recent decline in transplants corresponds to increased CAR-T treatments (1117 cases in 2021). Median age for auto-HSCT rose from 42 (1990-1994) to 58 years (2015-2021), with peripheral blood becoming the primary stem cell source post-1994. Allo-HSCT median age increased from 36 (1990-1994) to 54 (2015-2021) years, with mobilized blood as the primary source post-1998 and reduced intensity conditioning post-2000. Unrelated and mismatched allo-HSCT accounted for 50% and 19% of allo-HSCT in 2015-2021. Three-year overall survival (OS) after auto-HSCT improved from 56% (1990-1994) to 70% (2015-2021), p < 0.001, with a decrease in relapse incidence (RI) from 49% to 38%, while non-relapse mortality (NRM) remained unchanged (4%). After allo-HSCT, 3-year-OS increased from 33% (1990-1999) to 46% (2015-2021) (p < 0.001); 3-year RI remained at 39% and 1-year-NRM decreased to 19% (p < 0.001). Our data reflect advancements over 32 years and >40,000 transplants, providing insights for evaluating emerging DLBCL therapies., (© 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: Neuroblastoma is the most common extracranial solid tumour in children. Relapsed or refractory neuroblastoma is associated with a poor outcome. We assessed the combination of irinotecan-temozolomide and dasatinib-rapamycin (RIST) in patients with relapsed or refractory neuroblastoma., Methods: The multicentre, open-label, randomised, controlled, phase 2, RIST-rNB-2011 trial recruited from 40 paediatric oncology centres in Germany and Austria. Patients aged 1-25 years with high-risk relapsed (defined as recurrence of all stage IV and MYCN amplification stages, after response to treatment) or refractory (progressive disease during primary treatment) neuroblastoma, with Lansky and Karnofsky performance status at least 50%, were assigned (1:1) to RIST (RIST group) or irinotecan-temozolomide (control group) by block randomisation, stratified by MYCN status. We compared RIST (oral rapamycin [loading 3 mg/m 2 on day 1, maintenance 1 mg/m 2 on days 2-4] and oral dasatinib [2 mg/kg per day] for 4 days with 3 days off, followed by intravenous irinotecan [50 mg/m 2 per day] and oral temozolomide [150 mg/m 2 per day] for 5 days with 2 days off; one course each of rapamycin-dasatinib and irinotecan-temozolomide for four cycles over 8 weeks, then two courses of rapamycin-dasatinib followed by one course of irinotecan-temozolomide for 12 weeks) with irinotecan-temozolomide alone (with identical dosing as experimental group). The primary endpoint of progression-free survival was analysed in all eligible patients who received at least one course of therapy. The safety population consisted of all patients who received at least one course of therapy and had at least one post-baseline safety assessment. This trial is registered at ClinicalTrials.gov, NCT01467986, and is closed to accrual., Findings: Between Aug 26, 2013, and Sept 21, 2020, 129 patients were randomly assigned to the RIST group (n=63) or control group (n=66). Median age was 5·4 years (IQR 3·7-8·1). 124 patients (78 [63%] male and 46 [37%] female) were included in the efficacy analysis. At a median follow-up of 72 months (IQR 31-88), the median progression-free survival was 11 months (95% CI 7-17) in the RIST group and 5 months (2-8) in the control group (hazard ratio 0·62, one-sided 90% CI 0·81; p=0·019). Median progression-free survival in patients with amplified MYCN (n=48) was 6 months (95% CI 4-24) in the RIST group versus 2 months (2-5) in the control group (HR 0·45 [95% CI 0·24-0·84], p=0·012); median progression-free survival in patients without amplified MYCN (n=76) was 14 months (95% CI 9-7) in the RIST group versus 8 months (4-15) in the control group (HR 0·84 [95% CI 0·51-1·38], p=0·49). The most common grade 3 or worse adverse events were neutropenia (54 [81%] of 67 patients given RIST vs 49 [82%] of 60 patients given control), thrombocytopenia (45 [67%] vs 41 [68%]), and anaemia (39 [58%] vs 38 [63%]). Nine serious treatment-related adverse events were reported (five patients given control and four patients given RIST). There were no treatment-related deaths in the control group and one in the RIST group (multiorgan failure)., Interpretation: RIST-rNB-2011 demonstrated that targeting of MYCN-amplified relapsed or refractory neuroblastoma with a pathway-directed metronomic combination of a multkinase inhibitor and an mTOR inhibitor can improve progression-free survival and overall survival. This exclusive efficacy in MYCN-amplified, relapsed neuroblastoma warrants further investigation in the first-line setting., Funding: Deutsche Krebshilfe., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)

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.)

Background : Arterio-venous fistulas (AVF) are used as first-line access for hemodialysis (HD) in the pediatric population. The aim of this investigation was to describe a single-center experience in the creation of AVF, together with its patency in children. Methods : This single-center retrospective study included all patients aged ≤18 years with AVFs created between 1993 and 2023. The collected data included patients' demographics, hemodialysis history, intraoperative data, and required reinterventions in order to determine the impact of these variables on primary, primary-assisted, and secondary patency. Results : Fifty-seven patients were analyzed with a median age of 15 years (range, 7-18 years). Fifty-four forearm and four upper arm fistulas were performed. The median follow-up was 6.9 years (range, 0-23 years). The primary failure rate was 10.5%. The primary patency rate was 67.6%, 53.6%, 51.4%, and 38.1% after 1, 3, 5, and 10 years; primary-assisted patency was 72.9%, 62.8%, 60.6%, and 41.5%; and secondary patency was 87.3%, 81.3%, 76.8%, and 66.6% after 1, 3, 5, and 10 years in the studied population. Conclusions : AVFs showed an acceptable rate of primary failure and excellent long-term patency. In this context, AVFs are an appropriate option for HD access, especially in pediatric patients.