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Background: The aim of this study is to present short- and long-term outcomes after lower extremity bypass (LEB) surgery in patients with chronic limb-threatening ischemia and chronic kidney disease (CKD), differentiated by peripheral artery disease (PAD) Fontaine stage III and IV., Methods: Retrospective analysis of anonymized data from a nationwide German health insurance company (AOK). Data from 22,633 patients (14,523 men) who underwent LEB from 2010 to 2015 were analyzed, presenting 18,271 with CKD stage 1/2, 2,483 patients with CKD stage 3, and 1,879 with CKD stage 4/5., Results: Perioperative mortality (60-day mortality) was 7.2% for CKD stage 1/2, 12.4% for CKD stage 3, and 19.8% for CKD stage 4/5. Patients with PAD stage IV had significantly higher perioperative mortality (10.3%) than patients with PAD stage III (4.5%). The perioperative major amputation rate depended significantly on PAD stage IV (odds ratio [OR]: 2.57 confidence interval [CI]: 2.16-3.05, P < 0.001), the LEB level below the knee and crural/pedal (OR: 2.49 CI: 2.14-2.90, P < 0.001), CKD stage 4/5 (OR: 1.28, CI: 1.06-1.54, P = 0.009), and the presence of diabetes mellitus type 2 (OR: 1.19, CI: 1.05-1.36, P = 0.007). Kaplan-Meier estimated long-term survival of up to 9 years after surgery was 31.7% for patients with CKD stage 1 and 2, 14.3% for CKD stage 3, and only 10.1% for CKD stage 4 and 5 (P < 0.001). PAD Fontaine stage IV versus III (hazard ratio: 1.64, CI: 1.56-1.71, P < 0.001), but not bypass level, had an independent adverse influence on long-term survival., Conclusion: CKD and PAD stage were equally significant independent predictors of patient survival and major adverse cardiovascular events with higher PAD and CKD stages associated with less favorable long-term outcomes., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The Global Iliac Branch Study (NCT05607277) is an international, multicenter, retrospective cohort study of anatomic predictors of adverse iliac events (AIEs) in aortoiliac aneurysms treated with iliac branch devices (IBDs)., Methods: Patients with pre-IBD and post-IBD computed tomography imaging were included. We measured arterial diameters, stenosis, calcification, bifurcation angles, and tortuosity indices using a standardized, validated protocol. A composite of ipsilateral AIE was defined, a priori, as occlusion, type I or III endoleak, device constriction, or clinical event requiring reintervention. Paired t-test compared tortuosity indices and splay angles pretreatment and post-treatment for all IBDs and by device material (stainless steel and nitinol). Two-sample t-test compared anatomical changes from pretreatment to post-treatment by device material. Logistic regression assessed associations between AIE and anatomic measurements. Analysis was performed by IBD., Results: We analyzed 297 patients (286 males, 11 females) with 331 IBDs (227 stainless steel, 104 nitinol). Median clinical follow-up was 3.8 years. Iliac anatomy was significantly straightened with all IBD treatment, though stainless steel IBDs had a greater reduction in total iliac artery tortuosity index and aortic splay angle compared to nitinol IBDs (absolute reduction -0.20 [-0.22 to -0.18] vs. -0.09 [-0.12 to -0.06], P < 0.0001 and -19.6° [-22.4° to -16.9°] vs. -11.2° [-15.3° to -7.0°], P = 0.001, respectively). There were 54 AIEs in 44 IBDs in 42 patients (AIE in 13.3% of IBD systems), requiring 35 reinterventions (median time to event 41 days; median time to reintervention 153 days). There were 18 endoleaks, 29 occlusions, and 5 device constrictions. There were no strong associations between anatomic measurements and AIE overall, though internal iliac diameter was inversely associated with AIE in nitinol devices (n AIE, nitinol  = 8)., Conclusions: Purpose-built IBDs effectively treat aortoiliac disease, including that with tortuous anatomy, with a high patency rate (91.5%) and low reintervention rate (9.1%) at 4 years. Anatomic predictors of AIE are limited., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Abstract: Improved long-term survival rates after allogeneic hematopoietic cell transplantation (alloHCT) make family planning for young adult cancer survivors an important topic. However, treatment-related infertility risk poses challenges. To assess pregnancy and birth rates in a contemporary cohort, we conducted a national multicenter study using data from the German Transplant Registry, focusing on adult women aged 18 to 40 years who underwent alloHCT between 2003 and 2018. Of 2654 women who underwent transplantation, 50 women experienced 74 pregnancies, occurring at a median of 4.7 years after transplant. Fifty-seven of these resulted in live births (77%). The annual first birth rate among HCT recipients was 0.45%, which is >6 times lower than in the general population. The probability of a live birth 10 years after HCT was 3.4%. Factors associated with an increased likelihood of pregnancy were younger age at alloHCT, nonmalignant transplant indications, no total body irradiation or a cumulative dose of <8 Gy, and nonmyeloablative/reduced-intensity conditioning. Notably, 72% of pregnancies occurred spontaneously, with assisted reproductive technologies used in the remaining cases. Preterm delivery and low birth weight were more common than in the general population. This study represents the largest data set reporting pregnancies in a cohort of adult female alloHCT recipients. Our findings underscore a meaningful chance of pregnancy in alloHCT recipients. Assisted reproductive technologies techniques are important and funding should be made available. However, the potential for spontaneous pregnancies should not be underestimated, and patients should be informed of the possibility of unexpected pregnancy despite reduced fertility. Further research is warranted to understand the impact of conditioning decisions on fertility preservation., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Lung cancer has been shown to be targetable by novel immunotherapies which reactivate the immune system and enable tumor cell killing. However, treatment failure and resistance to these therapies is common. Consideration of sex as a factor influencing therapy resistance is still rare. We hypothesize that the success of the treatment is impaired by the presence of the immunosuppressive pregnancy-associated glycoprotein glycodelin that is expressed in patients with non-small-cell lung cancer (NSCLC). We demonstrate that the glycan pattern of NSCLC-derived glycodelin detected by a lectin-based enrichment assay highly resembles amniotic fluid-derived glycodelin A, which is known to have immunosuppressive properties. NSCLC-derived glycodelin interacts with immune cells in vitro and regulates the expression of genes associated with inflammatory and tumor microenvironment pathways. In tumor microarray samples of patients, high glycodelin staining in tumor areas results in an impaired overall survival of female patients. Moreover, glycodelin colocalizes to tumor infiltrating CD8+ T cells and pro-tumorigenic M2 macrophages. High serum concentrations of glycodelin prior to immunotherapy are associated with a poor progression-free survival (p < 0.001) of female patients receiving PD-(L)1 inhibitors. In summary, our findings suggest that glycodelin not only is a promising immunological biomarker for early identification of female patients that do not benefit from the costly immunotherapy, but also represents a promising immunotherapeutic target in NSCLC to improve therapeutic options in lung cancer., Competing Interests: Declaration of competing interest The authors declare no conflict of interest, (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The interest in artificial intelligence (AI) is increasing. Systematic reviews suggest that there are many machine learning algorithms in surgery, however, only a minority of the studies integrate AI applications in clinical workflows. Our objective was to design and evaluate a concept to use different kinds of AI for decision support in oncological liver surgery along the treatment path., Methods: In an exploratory co-creation between design experts, surgeons, and data scientists, pain points along the treatment path were identified. Potential designs for AI-assisted solutions were developed and iteratively refined. Finally, an evaluation of the design concept was performed with n = 20 surgeons to get feedback on the different functionalities and evaluate the usability with the System Usability Scale (SUS). Participating surgeons had a mean of 14.0 ± 5.0 years of experience after graduation., Results: The design concept was named "Aliado". Five different scenarios were identified where AI could support surgeons. Mean score of SUS was 68.2 ( ± 13.6 SD). The highest valued functionalities were "individualized prediction of survival, short-term mortality and morbidity", and "individualized recommendation of surgical strategy"., Conclusion: Aliado is a design prototype that shows how AI could be integrated into the clinical workflow. Even without a fleshed out user interface, the SUS already yielded borderline good results. Expert surgeons rated the functionalities favorably, and most of them expressed their willingness to work with a similar application in the future. Thus, Aliado can serve as a surgical vision of how an ideal AI-based assistance could look like., Competing Interests: Declaration of Competing interest The authors have no conflict of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Despite the increasing number of fenestrated and branched endovascular aortic repair (F/B-EVAR) procedures, evidence on post-operative antiplatelet therapy is very limited. This study aimed to investigate the role of single antiplatelet therapy (SAPT) vs. double antiplatelet therapy (DAPT) after F/B-EVAR in 30 day and follow up outcomes., Methods: A multicentre retrospective analysis was conducted, including F/B-EVAR patients managed from 1 January 2018 to 31 December 2022. Comparative outcomes were assessed according to post-operative antiplatelet therapy. The cohort was divided into the SAPT group (acetylsalicylic acid [ASA] or clopidogrel) and DAPT group (ASA and clopidogrel). The duration of SAPT or DAPT was one to six months. Primary outcomes were 30 day death, and cardiovascular ischaemic and major haemorrhagic events. Secondary outcomes were survival and target vessel (TV) patency during follow up., Results: A total of 1 430 patients were included: 955 under SAPT and 475 under DAPT. The 30 day mortality rate was similar (SAPT 2.1% vs. DAPT 1.5%; p = .42). Cardiovascular ischaemic events were lower in the DAPT group (SAPT 11.9% vs. DAPT 8.2%; p = .040), with DAPT being an independent protector for acute mesenteric (p = .009) and lower limb ischaemia (p = .020). No difference was found in 30 day major haemorrhagic events (SAPT 7.5% vs. DAPT 6.3%; p = .40). The mean follow up was 21.8 ± 2.9 months. Cox regression showed no survival confounders, with similar rates between groups (log rank p = .71). DAPT patients enjoyed higher TV patency (SAPT 93.4%, standard error [SE] 0.7% vs. DAPT 97.0%, SE 0.6%; log rank p = .007) at thirty six months. Cox regression revealed B-EVAR as a predictor of worse TV patency (hazard ratio 2.03, 95% confidence interval 1.36 - 3.03; p < .001). DAPT was related to higher patency within B-EVAR patients (SAPT 87.2%, SE 2.1% vs. DAPT 94.9%, SE 1.9%; p < .001)., Conclusion: DAPT after F/B-EVAR was associated with lower risk of cardiovascular ischaemic events and higher TV patency, especially in B-EVAR cases. No difference in major haemorrhagic events was observed at 30 days., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Aim: While it is currently assumed that liver assessment is only possible during normothermic machine perfusion (NMP), there is uncertainty regarding a reliable and quick prediction of graft injury during ex situ hypothermic oxygenated perfusion (HOPE). We therefore intended to test, in an international liver transplant cohort, recently described mitochondrial injury biomarkers measured during HOPE before liver transplantation., Study Design: Perfusate samples of human livers from 10 centers in 7 countries with HOPE-experience were analyzed for released mitochondrial compounds, i.e. flavin mononucleotide (FMN), NADH, purine derivates and inflammatory markers. Perfusate FMN was correlated with graft loss due to primary non-function or symptomatic non-anastomotic biliary strictures (NAS), and kidney failure, as well as liver injury after transplantation. Livers deemed unsuitable for transplantation served as negative control., Results: We collected 473 perfusate samples of human DCD (n=315) and DBD livers (n=158). Fluorometric assessment of FMN in perfusate was validated by mass spectrometry (R=0.7011,p<0.0001). Graft loss due to primary non-function or cholangiopathy was predicted by perfusate FMN values (c-statistic mass spectrometry 0.8418 (95%CI 0.7466-0.9370,p<0.0001), c-statistic fluorometry 0.7733 (95%CI 0.7006-0.8461,p<0.0001). Perfusate FMN values were also significantly correlated with symptomatic NAS and kidney failure, and superior in prediction of graft loss when compared to conventional scores derived from donor and recipient parameters, such as the donor risk index and the balance of risk score. Mitochondrial FMN values in liver tissues of non-utilized livers were low, and inversely correlated to high perfusate FMN values and purine metabolite release., Conclusions: This first international study validates the predictive value of the mitochondrial co-factor FMN, released from complex I during HOPE, and may therefore contribute to a better risk stratification of injured livers before implantation., Impact and Implications: Analysis of 473 perfusates, collected from 10 international centers during hypothermic oxygenated perfusion (HOPE), revealed that mitochondria derived flavin mononucleotide (FMN) values in perfusate is predictive for graft loss, cholangiopathy, and kidney failure after liver transplantation. This result is of high clinical relevance, as recognition of graft quality is urgently needed to improve the safe utilization of marginal livers. Ex-situ machine perfusion approaches, such as HOPE, are therefore likely to increase the number of useable liver grafts., (Copyright © 2024. Published by Elsevier B.V.)

Abstract: Delays and risks associated with neurosurgical biopsies preclude timely diagnosis and treatment of central nervous system (CNS) lymphoma and other CNS neoplasms. We prospectively integrated targeted rapid genotyping of cerebrospinal fluid (CSF) into the evaluation of 70 patients with CNS lesions of unknown cause. Participants underwent genotyping of CSF-derived DNA using a quantitative polymerase chain reaction-based approach for parallel detection of single-nucleotide variants in the MYD88, TERT promoter, IDH1, IDH2, BRAF, and H3F3A genes within 80 minutes of sample acquisition. Canonical mutations were detected in 42% of patients with neoplasms, including cases of primary and secondary CNS lymphoma, glioblastoma, IDH-mutant brainstem glioma, and H3K27M-mutant diffuse midline glioma. Genotyping results eliminated the need for surgical biopsies in 7 of 33 cases (21.2%) of newly diagnosed neoplasms, resulting in significantly accelerated initiation of disease-directed treatment (median, 3 vs 12 days; P = .027). This assay was then implemented in a Clinical Laboratory Improvement Amendments environment, with 2-day median turnaround for diagnosis of CNS lymphoma from 66 patients across 4 clinical sites. Our study prospectively demonstrates that targeted rapid CSF genotyping influences oncologic management for suspected CNS tumors., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Advances in hematopoietic cell transplantation have expanded the use of alternative donors such as haploidentical family donors or mismatched unrelated donors. However, donor-specific HLA antibodies (DSA) have been recognized as a significant risk factor of primary graft failure after HLA incompatible transplantation. Therefore, screening for HLA antibodies and taking DSA into consideration in the process of donor search play an increasingly important role in donor selection. If an HLA compatible donor is not available, desensitization may enable a successful transplantation. In this review, we describe the currently most widely used methods for HLA antibody detections including their pitfalls. In addition, we summarize the results of the studies on the impact of preformed DSA on transplant outcomes and their treatment options. Many more and larger studies are needed to clarify laboratory issues as well as immunological and clinical aspects in the management of DSA., Competing Interests: Declaration of competing interest No conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Right ventricular (RV) output reserve, defined as increase of cardiac output during exercise, is reduced in patients with pulmonary arterial hypertension (PAH). Aim of this study was to evaluate the association of right heart size measured by echocardiography and invasively measured RV function at rest and during exercise in PAH patients., Methods: Adult PAH-patients who received routine haemodynamic assessment at rest and during exercise by right heart catheterisation and echocardiographic measurement of right heart size (right atrial (RA) and RV area) were included in this study. Clinical, echocardiographic, laboratory, exercise and invasive haemodynamic parameters were retrospectively analysed. The primary endpoint was to assess the association between right heart size and right ventricular function., Results: Data from 215 PAH patients (age 58.9 ± 15.9 years, 63.3% female, 62.2% double or triple combination treatment) were analysed in this cross-sectional study. Cardiac index was significantly lower for patients with enlarged RA-area > 18 cm 2 at rest, and at 25 and 50 W (all p < 0.001) and for patients with enlarged RV area > 20 cm 2 at rest, 25, 50 and 75 W (all p < 0.001). Furthermore, pulmonary vascular resistance and mPAP/CO slope (all p < 0.001) were significantly higher and pulmonary arterial compliance (all p < 0.05) was significantly lower in patients with enlarged RA or RV area. RA and RV area correlated with TAPSE/sPAP (both p < 0.001, R - 0.570 and - 0.530)., Conclusion: This study could underline that an enlargement of RA- and RV-area is associated with an impaired RV function at rest and during exercise in patients with PAH., Competing Interests: Declaration of competing interest BE: received travel fees, consulting fees, speaking fees, and/or honoraria from Janssen, MSD, Bayer and OMT, outside the submitted work. KFW, AMM: nothing to declare. CAE: received speaking fees from MSD outside the submitted work. SH: received honoraria for lectures, consultancy, or both from Actelion, AOP, Bayer/MSD, GSK, Novartis, OMT, Pfizer, and United Therapeutics out-side the submitted work. EG: has received grants and personal fees from Actelion, Bayer AG, and MSD; grants from GSK, Novartis, and United Therapeutics and personal fees from SCOPE, OrPha Swiss GmbH, and Zurich Heart House, outside the submitted work. PX: has received personal fees from MSD and OMT outside the submitted work. NB: received speaker fees from University Hospital Zurich and AOP., (Copyright © 2024. Published by Elsevier B.V.)

Background: Patients with unfavourable subset cancer of unknown primary (CUP) have a poor prognosis when treated with standard platinum-based chemotherapy. Whether first-line treatment guided by comprehensive genomic profiling (CGP) can improve outcomes is unknown. The CUPISCO trial was designed to inform a molecularly guided treatment strategy to improve outcomes over standard platinum-based chemotherapy in patients with newly diagnosed, unfavourable, non-squamous CUP. The aim of the trial was to compare the efficacy and safety of molecularly guided therapy (MGT) versus standard platinum-based chemotherapy in these patients. This was to determine whether the inclusion of CGP in the initial diagnostic work-up leads to improved outcomes over the current standard of care. We herein report the primary analysis., Methods: CUPISCO was a phase 2, prospective, randomised, open-label, active-controlled, multicentre trial done at 159 sites in 34 countries outside the USA. Patients with central eligibility review-confirmed disease (acceptable histologies included adenocarcinoma and poorly differentiated carcinoma) and an Eastern Cooperative Oncology Group performance status of 0 or 1, evaluated by CGP, who reached disease control after three cycles of standard first-line platinum-based chemotherapy were randomly assigned 3:1 via a block-stratified randomisation procedure to MGT versus chemotherapy continuation for at least three further cycles. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03498521, and follow-up is ongoing., Findings: From July 10, 2018, to Dec 9, 2022, 636 (42%) of 1505 screened patients were enrolled. Median follow-up in the treatment period was 24·1 months (IQR 11·6-35·6). Of 438 patients who reached disease control after induction chemotherapy, 436 were randomly assigned: 326 (75%) to the MGT group and 110 (25%) to the chemotherapy group. Median progression-free survival in the intention-to-treat population was 6·1 months (95% CI 4·7-6·5) in the MGT group versus 4·4 months (4·1-5·6) in the chemotherapy group (hazard ratio 0·72 [95% CI 0·56-0·92]; p=0·0079). Related adverse event rates per 100-patient-years at risk were generally similar or lower with MGT versus chemotherapy., Interpretation: In patients with previously untreated, unfavourable, non-squamous CUP who reached disease control after induction chemotherapy, CGP with subsequent MGTs resulted in longer progression-free survival than standard platinum-based chemotherapy. On the basis of these results, we recommend that CGP is performed at initial diagnosis in patients with unfavourable CUP., Funding: F Hoffmann-La Roche., Competing Interests: Declaration of interests All authors received research funding in the form of third-party medical writing assistance from F Hoffmann-La Roche. AK reports research funding for a clinical trial in CUP from Bristol Myers Squibb; research funding for a clinical trial in CUP from Molecular Health; and consulting fees, support for attending meetings or travel, or both, participation in a data safety monitoring board or advisory board from F Hoffmann-La Roche. TB was study oncologist for the CUPISCO trial for F Hoffman-La Roche and received remuneration for this work for the benefit of employer, and support for attending meetings or travel, or both. CP reports travel, accommodation, or expenses and additional costs linked to the study (paid to institution), and investigator fees from F Hoffmann-La Roche. K-KS reports grants or contracts (paid to institution for running trials) from Merck Sharp & Dohme, Roche, AstraZeneca, and Merck; consulting fees (personal) from Nouscom; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events (personal) from Merck Sharp & Dohme, Bristol Myers Squibb, Merck, Servier, Seagen, and Nouscom; support for attending meetings or travel (personal), or both, from Merck Sharp & Dohme, Bristol Myers Squibb, Roche, and Merck; and an advisory board (personal) for Mirati Therapeutics. NCo reports honoraria, advisory board membership, support for attending meetings or travel, or both, from F Hoffman-La Roche; a patent pending, application number GB2317261.2; an advisory or leadership role for CUP Foundation (Jo's Friends; unpaid); and research support to team from AstraZeneca, Orion, F Hoffmann-La Roche, Taiho, GSK, Novartis, Starpharma, Bayer, Eisai, UCB, Redx Pharmaceuticals, Stemline Therapeutics, Boehringer Ingelheim, Merck, AstraZeneca, Cancer Research UK, Orion, and LOXO-Oncology. JJdM reports support for attending meetings or travel, or both, from Bristol Myers Squibb. RAP-C reports medical writing and processing fees from Astellas, Ipsen, Roche, BeiGene, and Bristol Myers Squibb; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Eisai, Bristol Myers Squibb, Astellas, Roche, Amgen, and Eli Lilly; payment for expert testimony from AstraZeneca, Eli Lilly, and Bristol Myers Squibb; support for attending meetings or travel, or both, from Roche, Lilly, Astellas, and Bristol Myers Squibb; and participation on a data safety monitoring board or advisory board for AstraZeneca, Roche, and Ipsen. FL reports grants or contracts from Lilly and Merck Sharp & Dohme; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Lilly, Merck, Sanofi, and Roche; and support for attending meetings or travel, or both from Lilly, Merck, and Merck Sharp & Dohme. DGJR reports consulting fees from Merck, Pfizer, and Astellas; payment for honoraria, lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead and Merck Sharp & Dohme; and participation on a data safety monitoring board or advisory board for Janssen and AstraZeneca. JT reports consulting fees from Servier and Bristol Myers Squibb; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bristol Myers Squibb, Merck Sharp & Dohme, Servier, Bayer, and Ipsen; and reports support for attending meetings or travel, or both (American Society of Clinical Oncology Gastrointestinal Cancers Symposium 2022), from Zentiva and Roche. CA reports research grants from Roche, Novartis, Bristol Myers Squibb, Merck, AstraZeneca, Nektar, Johnson & Johnson, Lilly, Amgen, Incyte, and Bayer; advisory boards for Novartis, Merck, AstraZeneca, Johnson & Johnson, Lilly, Teva, Astellas, and Bristol Myers Squibb; and peakers bureaus for Bristol Myers Squibb, Johnson & Johnson, Lilly, Teva, Amgen, and Bayer. MÖ reports an advisory board, honoraria, and travel support from Janssen; additional costs linked to the study (paid to institution), investigator fees, and honoraria from F Hoffmann-La Roche; an advisory board and honoraria from Sanofi; an advisory board and honoraria for Astellas; honoraria from Novartis; travel support from Bristol Myers Squibb; and travel support and speaker support from AstraZeneca. MS reports honoraria for lectures F Hoffmann-La Roche. FB reports additional costs linked to the study and investigator fees from F Hoffmann-La Roche; an advisory board for AstraZeneca, Merck Sharp & Dohme, and Bristol Myers Squibb; speakers bureaus for AstraZeneca and Bristol Myers Squibb; and travel support or accommodation from Takeda, Merck Sharp & Dohme. SYK reports research funding (paid to institution; principal investigator since 2019) from F Hoffmann-La Roche; honorarium for lecture (May, 2023) from LG Chem; honorarium for lecture (August, 2023) from Merck Sharp & Dohme Korea; an advisory board (December, 2021) for Ono Korea; and an advisory board (December, 2022) for Guardant Health. YN reports research funding (paid to institution) from AbbVie, Ono, Daiichi Sankyo, Taiho, Pfizer, Boehringer Ingelheim, Eli Lilly, Eisai, AstraZeneca, Chugai, and Bayer; payment for honoraria, lectures, presentations, speakers’ bureaus, manuscript writing, or educational events (personal) from AstraZeneca, Eisai, Ono, Gardant, Takeda, Eli Lilly, Novartis, Pfizer, Chugai, PDR pharma, Nihon Kayaku, Taiho, Bristol Myers Squibb, Bayer, Daiichi Sankyo, and Merck Sharp & Dohme. AI reports additional costs linked to the study, investigator fees, advisory role, honoraria, and research funding from F Hoffmann-La Roche; an advisory role and honoraria from Daiichi Sankyo; an advisory role for Immune Design; an advisory role and honoraria from Epizyme; an advisory role and honoraria from Bayer and Lilly; patents, royalties, or intellectual property from Bristol Myers Squibb; honoraria from Novartis and Ipsen; and research funding from AstraZeneca–MedImmune, PharmaMar, Merck Sharp & Dohme Oncology, and Merck Serono. NCh reports being an employee and holding stocks or shares at F Hoffmann-La Roche. GD-P reports being an employee and holding stocks or shares at F Hoffmann-La Roche. CM reports being an employee of F Hoffmann-La Roche. JS reports being an employee and holding stocks or shares at F Hoffmann-La Roche. MT reports being an employee and holding stocks or shares at F Hoffmann-La Roche, and patents planned, issued, or pending (antibodies against human CSF-1R and uses thereof; modulators for HER2 signalling in HER2 expressing patients with gastric cancer) from F Hoffmann-La Roche. JSR reports being an employee of Foundation Medicine; and holding stocks or shares at Roche Holdings. HM reports research funding (paid to institution), consulting fees, and participation on a data safety monitoring board or advisory board for F Hoffmann-La Roche; and an advisory role and honoraria for lectures from Amgen, Astellas, Bayer, AstraZeneca, Merck, Stemline Therapeutics. LM reports additional costs linked to the CUPISCO trial (paid to institution), support for the presentation of the CUPISCO trial results and associated publication; and travel and accommodation expenses to attend the 2023 European Society for Medical Oncology meeting and present the CUPISCO trial results from F Hoffmann-La Roche., (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.)

Abstract: The T-box transcription factor T-bet is known as a master regulator of the T-cell response but its role in malignant B cells has not been sufficiently explored. Here, we conducted single-cell resolved multi-omics analyses of malignant B cells from patients with chronic lymphocytic leukemia (CLL) and studied a CLL mouse model with a genetic knockout of Tbx21. We found that T-bet acts as a tumor suppressor in malignant B cells by decreasing their proliferation rate. NF-κB activity, induced by inflammatory signals provided by the microenvironment, triggered T-bet expression, which affected promoter-proximal and distal chromatin coaccessibility and controlled a specific gene signature by mainly suppressing transcription. Gene set enrichment analysis identified a positive regulation of interferon signaling and negative control of proliferation by T-bet. In line, we showed that T-bet represses cell cycling and is associated with longer overall survival of patients with CLL. Our study uncovered a novel tumor suppressive role of T-bet in malignant B cells via its regulation of inflammatory processes and cell cycling, which has implications for the stratification and therapy of patients with CLL. Linking T-bet activity to inflammation explains the good prognostic role of genetic alterations in the inflammatory signaling pathways in CLL.

Purpose: MET amplification is a common resistance mechanism to EGFR inhibition in EGFR-mutant non-small cell lung cancer (NSCLC). Several trials showed encouraging results with combined EGFR and MET inhibition (EGFRi/METi). However, MET amplification has been inconsistently defined and frequently included both polysomy and true amplification., Methods: This is a multicenter, real-world analysis in patients with disease progression on EGFR inhibition and MET copy number gain (CNG), defined as either true amplification (MET to centromere of chromosome 7 ratio [MET-CEP7] ≥ 2) or polysomy (gene copy number ≥ 5, MET-CEP7 < 2)., Results: A total of 43 patients with MET CNG were included, 42 of whom were detected by FISH. Twenty-three, 7, and 14 received EGFRi/METi, METi, and SoC, respectively. Patients in the EGFRi/METi cohort exhibited a superior real-world clinical benefit rate, defined as stable disease or better, of 82% (95% confidence interval [CI], 60-95) compared to METi (29%, 4-71) and SoC (50%, 23-77). Median real-world progression-free survival was longer with EGFRi/METi with 9.8 vs. 4.3 months with METi (hazard ratio [HR], 0.19, 95% CI, 0.06-0.57) and 3.7 months with SoC (0.41, 0.18-0.91), respectively. Overall survival was numerically improved. Interaction analysis with treatment and type of CNG (amplification vs. polysomy) suggests that differences were exclusively driven by MET-amplified patients receiving EGFRi/METi (HR for OS, 0.09, 0.01-0.54)., Conclusion: In this real-world study, EGFRi/METi showed clinical benefit over METi and SoC. Future studies should focus on the differential impact of the type of MET CNG with a focus on true MET amplification as predictor of response., Competing Interests: Disclosure F. A. received support for attending meetings and speaker's honoraria from AstraZeneca, and consultant fees from IQVIA. P. C. received research funding from AstraZeneca, Amgen, Boehringer Ingelheim, Merck, Novartis, Roche, and Takeda, speaker's honoraria from AstraZeneca, Gilead, Janssen, Novartis, Roche, Pfizer, Thermo Fisher, and Takeda, support for attending meetings from AstraZeneca, Eli Lilly, Daiichi Sankyo, Janssen, Gilead, Novartis, Pfizer, Takeda, and personal fees for participating to advisory boards from AstraZeneca, Boehringer Ingelheim, Chugai, Pfizer, Novartis, MSD, Takeda and Roche, all outside the submitted work. H.-D. H. received personal fees for participating to advisory boards from Amgen, speaker's honoraria from Amgen, Boehringer Ingelheim, and Bristol-Myers Squibb. C. F. W. received personal fees for participating to advisory boards from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Lilly, Merck, MSD, Novartis, Pfizer, Roche, and Takeda, consultancy fees from Mylan/Viatris, Alvotech, Roche, support for attending meetings from Amgen, Bristol-Myers Squibb, Janssen, Lilly. A. Ri. received speaker's honoraria and consulting fees from Abbvie, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Lilly, GSK, MSD, Novartis, Pfizer, Roche/Genentech. H. Z. received support for attending meetings from Janssen, speaker's honoraria from Pierre Fabre, and Roche. A. L. received support for attending meetings from Abbvie. D. K.-G. received consultant fees from AstraZeneca, Boehringer Ingelheim, Roche, MSD, Pfizer, Bristol-Myers Squibb, GSK, Novartis, Takeda, Sanofi, and Janssen, support for attending meetings from Takeda, Boehringer-Ingelheim, Janssen. R. B. received honoraries for lectures and advisory boards for AbbVie, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Illumina, Janssen, Lilly, Merck-Serono, MSD, Novartis, Qiagen, Pfizer, Roche, Targos MP Inc. R.B. is a Co-Founder and Co-Owner of Targos Inc / Kassel (previous); Gnothis Inc / Stockholm (current); Timer Therapeutics Inc / Fulda & Freiburg (current). M. D. received personal fees for participating in advisory boards from AstraZeneca, Bayer, Diaceutics, Biocartis, Sophia Genetics, and ThermoFisher. F. C. A. has received research grants from Novartis, support for attending meetings and/or travel from Amgen, and consultant fees from IQVIA. S. H. has received research grants from Novartis and travel support from BeiGene. J. A. S. received personal fees from Boehringer Ingelheim, AstraZeneca, Roche, Bristol-Myers Squibb, Amgen, LEO pharma, Novartis, and Takeda. J. W. received speaker's honoraria and personal fees for participating in advisory boards from Amgen, AstraZeneca, Bayer, Blueprint, Bristol-Myers Squibb, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Ignyta, Janssen, Lilly, Loxo, Merck, Mirati, MSD, Novartis, Nuvalent, Pfizer, Roche, Seattle Genetics, Takeda, and Turning Point and received institutional research grants from Bristol-Myers Squibb, Janssen, Novartis, Pfizer, and AstraZeneca. M. S. received research grants from AstraZeneca, consulting fees from AstraZeneca, Bristol-Myers Squibb, MSD, Novartis, Lilly, Roche, Boehringer Ingelheim, Amgen, Takeda, Johnson, Merck-Serono, and GSK, and speaker's honoraria from AstraZeneca, Bristol-Myers Squibb, MSD, Novartis, Lilly, Roche, Boehringer Ingelheim, Amgen, Takeda, Johnson, CureVac, BioNTech, Merck-Serono, GSK, Daiichi, and Pfizer. S. M. has received research grants from Novartis and Pfizer, personal fees from Eli Lilly, Janssen, and Astra Zeneca as well as support for attending meetings and/or travel from Eli Lilly, and Janssen. A. S. has received speaker's honoraria from Agilent, Aignostics, Amgen, Astellas, Astra Zeneca, Bayer, BMS, Eli Lilly, Illumina, Incyte, Janssen, MSD, Novartis, Pfizer, Qlucore, Roche, Seagen, Servier, Takeda, and Thermo Fisher, and institutional research grants from Bayer, BMS, Chugai, and Incyte. All other authors declared no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Long noncoding RNAs (lncRNAs) have emerged as promising diagnostic biomarkers. Here, we investigated the cardiac-expressed and plasma-detectable lncRNA PDE4DIPP6 as a biomarker for non-ST-segment elevation myocardial infarction (NSTEMI), specifically assessing its potential to enhance the diagnostic efficacy of high-sensitivity cardiac troponin (hs-cTnT)., Methods and Results: The study enrolled individuals presenting with suspected acute coronary syndrome (ACS). LncRNA quantification was performed in plasma samples using RT-qPCR. The discriminatory performance was assessed by calculating the Area Under the Curve (AUC). Reclassification metrics, including the Integrated Discrimination Improvement (IDI) and Net Reclassification Improvement (NRI) indexes, were utilized to evaluate enhancements in diagnostic accuracy. Among the 252 patients with suspected ACS, 50.8 % were diagnosed with ACS, and 13.9 % with NSTEMI. Initially, the association of lncRNA PDE4DIPP6 with ACS was investigated. Elevated levels of this lncRNA were observed in ACS patients compared to non-ACS subjects. No association was found between lncRNA PDE4DIPP6 levels and potential confounding factors, nor was a significant correlation with hs-cTnT levels (rho = 0.071). The inclusion of lncRNA PDE4DIPP6 on top of hs-cTnT significantly improved the discrimination and classification of ACS patients, as reflected by an enhanced AUC of 0.734, an IDI of 0.066 and NRI of 0.471. Subsequently, the lncRNA PDE4DIPP6 was evaluated as biomarker of NSTEMI. Elevated levels of the lncRNA were observed in NSTEMI patients compared to patients without NSTEMI. Consistent with previous findings, the addition of lncRNA PDE4DIPP6 to hs-cTnT improved the discrimination and classification of patients, increasing the AUC from 0.859 to 0.944, with an IDI of 0.237 and NRI of 0.658., Conclusion: LncRNA PDE4DIPP6 offers additional diagnostic insights beyond hs-cTnT, suggesting its potential to improve the clinical management of patients with NSTEMI., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Few studies have explored the influence of socioeconomic status (SES) on the heat vulnerability of mental health (MH) patients. As individual socioeconomic data was unavailable, we aimed to fill this gap by using the healthcare system type as a proxy for SES. Brazilian national statistics indicate that public patients have lower SES than private. Therefore, we compared the risk of emergency department visits (EDVs) for MH between patients from both healthcare types. EDVs for MH disorders from all nine public (101,452 visits) and one large private facility (154,954) in Curitiba were assessed (2017-2021). Daily mean temperature was gathered and weighed from 3 stations. Distributed-lag non-linear model with quasi-Poisson (maximum 10-lags) was used to assess the risk. We stratified by private and public, age, and gender under moderate and extreme heat. Additionally, we calculated the attributable fraction (AF), which translates individual risks into population-representative burdens - especially useful for public policies. Random-effects meta-regression pooled the risk estimates between healthcare systems. Public patients showed significant risks immediately as temperatures started to increase. Their cumulative relative risk (RR) of MH-EDV was 7.5 % higher than the private patients (Q-Test 26.2 %) under moderate heat, suggesting their particular heat vulnerability. Differently, private patients showed significant risks only under extreme heat, when their RR became 4.3 % higher than public (Q-Test 6.2 %). These findings suggest that private patients have a relatively greater adaptation capacity to heat. However, when faced with extreme heat, their current adaptation means were potentially insufficient, so they needed and could access healthcare freely, unlike their public counterparts. MH patients would benefit from measures to reduce heat vulnerability and access barriers, increasing equity between the healthcare systems in Brazil. AF of EDVs due to extreme heat was 0.33 % (95%CI 0.16;0.50) for the total sample (859 EDVs). This corroborates that such broad population-level policies are urgently needed as climate change progresses., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease. Owing to limited available treatment options, novel pre-clinical models for target selection and drug validation are warranted. We have established and extensively characterized a primary human steatotic hepatocyte in vitro model system that could guide the development of treatment strategies for MASLD., Methods: Cryopreserved primary human hepatocytes from five donors varying in sex and ethnicity were cultured with free fatty acids in a 3D collagen sandwich for 7 days and the development of MASLD was followed by assessing classical hepatocellular functions. As proof of concept, the effects of the drug firsocostat (GS-0976) on in vitro MASLD phenotypes were evaluated., Results: Incubation with free fatty acids induced steatosis, insulin resistance, mitochondrial dysfunction, inflammation, and alterations in prominent human gene signatures similar to patients with MASLD, indicating the recapitulation of human MASLD in this system. The application of firsocostat rescued clinically observed fatty liver disease pathologies, highlighting the ability of the in vitro system to test the efficacy and potentially characterize the mode of action of drug candidates., Conclusions: Altogether, our human MASLD in vitro model system could guide the development and validation of novel targets and drugs for the treatment of MASLD., Impact and Implications: Due to low drug efficacy and high toxicity, clinical treatment options for metabolic dysfunction-associated steatotic liver disease (MASLD) are currently limited. To facilitate earlier stop-go decisions in drug development, we have established a primary human steatotic hepatocyte in vitro model. As the model recapitulates clinically relevant MASLD characteristics at high phenotypic resolution, it can serve as a pre-screening platform and guide target identification and validation in MASLD therapy., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Identification of differences in mortality risk between female and male heart transplant recipients may prompt sex-specific management strategies. Because worldwide, males of all ages have higher absolute mortality rates than females, we aimed to compare the excess risk of mortality (risk above the general population) in female vs male heart transplant recipients., Methods: We used relative survival models conducted separately in SRTR and CTS cohorts from 1988-2019, and subsequently combined using 2-stage individual patient data meta-analysis, to compare the excess risk of mortality in female vs male first heart transplant recipients, accounting for the modifying effects of donor sex and recipient current age., Results: We analyzed 108,918 patients. When the donor was male, female recipients 0-12 years (Relative excess risk (RER) 1.13, 95% CI 1.00-1.26), 13-44 years (RER 1.17, 95% CI 1.10-1.25), and ≥45 years (RER 1.14, 95% CI 1.02-1.27) showed higher excess mortality risks than male recipients of the same age. When the donor was female, only female recipients 13-44 years showed higher excess risks of mortality than males (RER 1.09, 95% CI 1.00-1.20), though not significantly (p = 0.05)., Conclusions: In the setting of a male donor, female recipients of all ages had significantly higher excess mortality than males. When the donor was female, female recipients of reproductive age had higher excess risks of mortality than male recipients of the same age, though this was not statistically significant. Further investigation is required to determine the reasons underlying these differences., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Promising as a treatment option for life-threatening ventricular arrhythmias, cardiac stereotactic body radiotherapy (cSBRT) has demonstrated early antiarrhythmic effects within days of treatment. The mechanisms underlying the immediate and short-term antiarrhythmic effects are poorly understood., Objective: We hypothesize that cSBRT has a direct antiarrhythmic effect on cellular electrophysiology through reprogramming of ion channel and gap junction protein expression., Methods: After exposure to 20 Gy of x-rays in a single fraction, neonatal rat ventricular cardiomyocytes were analyzed 24 and 96 hours postradiation to determine changes in conduction velocity, beating frequency, calcium transients, and action potential duration in both monolayers and single cells. In addition, the expression of gap junction proteins, ion channels, and calcium handling proteins was evaluated at protein and messenger RNA levels., Results: After irradiation with 20 Gy, neonatal rat ventricular cardiomyocytes exhibited increased beat rate and conduction velocity 24 and 96 hours after treatment. Messenger RNA and protein levels of ion channels were altered, with the most significant changes observed at the 96-hour mark. Upregulation of Cacna1c (Ca v 1.2), Kcnd3 (K v 4.3), Kcnh2 (K v 11.1), Kcnq1 (K v 7.1), Kcnk2 (K 2P 2.1), Kcnj2 (K ir 2.1), and Gja1 (Cx43) was noted, along with improved gap junctional coupling. Calcium handling was affected, with increased Ryr2 ryanodin-rezeptor 2 and Slc8a1 Na + /Ca 2+  exchanger expression and altered properties 96 hours posttreatment. Fibroblast and myofibroblast levels remained unchanged., Conclusion: cSBRT modulates the expression of various ion channels, calcium handling proteins, and gap junction proteins. The described alterations in cellular electrophysiology may be the underlying cause of the immediate antiarrhythmic effects observed after cSBRT., Competing Interests: Disclosures Dr Mages acknowledges educational support from Biotronik and Johnson & Johnson, while Dr Rahm acknowledges support from Boston Scientific, Johnson & Johnson, Abbott, and Medtronic. Dr Thomas has received lecture fees/honoraria from various pharmaceutical and medical device companies, including Abbott, AstraZeneca, Bayer Vital, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Johnson & Johnson, Medtronic, Novartis, Pfizer Pharma, Sanofi-Aventis, and ZOLL CMS. Dr Lugenbiel has received lecture fees from Bayer Vital, Pfizer Pharma, and Bristol Myers Squibb as well as educational support from Boston Scientific and fees/honoraria from Johnson & Johnson and Boston Scientific. The remaining authors have declared no relevant relationships. We declare that no artificial intelligence was used in preparation of the present manuscript., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Introduction: Atypical hemolytic uremic syndrome (aHUS) is a progressive rare disease that, if untreated, can result in severe organ damage and death. Ravulizumab, a next-generation terminal complement inhibitor, provides immediate, complete, and sustained complement C5 inhibition. Real-world data in patients with aHUS who switched to ravulizumab from eculizumab are lacking., Methods: The Global aHUS Registry is a multicenter study (NCT01522183) collecting data on adult or pediatric patients with an aHUS diagnosis, regardless of treatment. Patient characteristics, genetic data, hematological and renal parameters, clinical events (e.g., dialysis and kidney transplantation), and adverse events (AEs) were extracted from patients who switched to ravulizumab from eculizumab up to July 3, 2023., Results: Overall, 60 patients switched to ravulizumab (adult: n  = 43; pediatric: n  = 17); 11 patients were excluded from effectiveness and genetic analyses ( N  = 49; adult: n  = 40; pediatric: n  = 9) because they received <3 months ravulizumab treatment and/or had >1 month between eculizumab discontinuation and ravulizumab initiation. Pathogenic complement variants were identified in 11 of 49 patients (22%); the most common was a complement factor H variant ( n  = 5/49 [10%]). During ravulizumab treatment, 20 AEs occurred in 13 patients, with no unexpected AEs and only 3 treatment-related AEs (infusion reaction, headaches, and fatigue). No meningococcal infections or deaths were reported. No new events of dialysis, kidney transplantation, or thrombotic microangiopathy were reported. Renal and hematological parameters remained stable after switching to ravulizumab., Conclusion: This is the first real-world cohort analysis of data from patients treated with ravulizumab and reinforces the real-world safety and effectiveness data of ravulizumab in patients with aHUS who switched from eculizumab., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Mesenchymal stromal cells (MSCs) that are promising for cartilage tissue engineering secrete high amounts of prostaglandin E2 (PGE2), an immunoactive mediator involved in endochondral bone development. This study aimed to identify drivers of PGE2 and its role in the inadvertent MSC misdifferentiation into hypertrophic chondrocytes. PGE2 release, which rose in the first three weeks of MSC chondrogenesis, was jointly stimulated by endogenous BMP, WNT, and hedgehog activity that supported the exogenous stimulation by TGF-β1 and insulin to overcome the PGE2 inhibition by dexamethasone. Experiments with PGE2 treatment or the inhibitor celecoxib or specific receptor antagonists demonstrated that PGE2, although driven by prohypertrophic signals, exerted broad autocrine antihypertrophic effects. This chondroprotective effect makes PGE2 not only a promising option for future combinatorial approaches to direct MSC tissue engineering approaches into chondral instead of endochondral development but could potentially have implications for the use of COX-2-selective inhibitors in osteoarthritis pain management., Competing Interests: Declaration of Competing Interest The authors declare that the study was realized without any commercial or financial ties that could be interpreted as a potential conflict of interest. All authors confirm unrestricted access to all raw data, statistical analyses, and materials used in this study., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Collagen VII forms anchoring fibrils that are essential for the stability of the skin and other epithelial organs. In addition to such structural functions, it is emerging that collagen VII fills instructive functions. Collagen VII is synthesized by both epithelial cells and fibroblasts. Genetic loss of collagen VII causes dystrophic epidermolysis bullosa, which manifests with chronic skin fragility and fibrosis. Significant progress has been made in developing therapies for dystrophic epidermolysis bullosa; however, such work has also raised questions on the importance of the cellular source of collagen VII for maintenance of tissue integrity and homeostasis. Toward this end, we engineered mice that kept the physiological expression of collagen VII only in epithelial cells or in fibroblasts. Our study revealed that production of collagen VII either by keratinocytes or fibroblasts alone is sufficient for creation of mechanically robust skin. Importantly, we also show tissue-diverse dependence on epithelial and mesenchymal production of collagen VII and provide support for limited amounts of collagen VII being sufficient for tissue protection. Furthermore, a disconnect between collagen VII abundance and anchoring fibril numbers supports the concept that restoration of fully physiological collagen VII levels may not be needed to achieve complete mechanical protection of dystrophic epidermolysis bullosa skin., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Targeted tumor only sequencing has become a standard practice in cancer diagnostics. This study aims to develop an approach for robust copy number variant calling in tumor samples using only off-target region (OTR) reads. We also established a clinical use case for homologous recombination deficiency (HRD) score estimation (HRDest) using the sum of telomeric-allelic imbalance and large-scale state transition scores without the need for loss of heterozygosity information. A strong correlation was found between HRD score and the sum of telomeric-allelic imbalance + large-scale state transition in The Cancer Genome Atlas cohort (ρ = 0.99, P < 2.2 × 10 -16 ) and in a clinical in-house cohort of 34 tumors (ρ = 0.9, P = 5.1 × 10 -13 ) comparing whole-exome sequencing and targeted sequencing data. HRDest scores from 1086 clinical cases were compared with The Cancer Genome Atlas data set. There were no significant differences in HRD score distribution within the analyzed tumor types. As a control, commercially available HRD standards were also sequenced, and the HRDest scores obtained from the OTR reads were well within the HRD reference range provided by the manufacturer. In conclusion, OTR reads of tumor-only panel sequencing can be used to determine genome-wide copy number variant profiles and to approximate HRD scores., Competing Interests: Disclosure Statement O.N. reports personal fees from Novartis outside the submitted work. A.-L.V. reports personal fees from Astra Zeneca outside the submitted work. J.B. reports a grant from the German Cancer Aid outside the submitted work. S.F. reports consulting or advisory board membership for Bayer, Illumina, and Roche; honoraria from Amgen, Eli Lilly, PharmaMar, and Roche; research funding from AstraZeneca, Pfizer, PharmaMar, and Roche; and travel or accommodation expenses from Amgen, Eli Lilly, Illumina, PharmaMar, and Roche. P.S. reports personal fees from Bristol Myers Squibb, Merck Sharp & Dohme (MSD), Incyte, Janssen, Amgen, Novartis, Roche, and AstraZeneca outside the submitted work. A.S. reports grants and personal fees from Bayer and Bristol Myers Squibb; grants from Chugai; and personal fees from AstraZeneca, MSD, Takeda, Seattle Genetics, Novartis, Illumina, Thermo Fisher, Eli Lilly, and Takeda outside the submitted work. D.K. reports personal fees from AstraZeneca, Bristol Myers Squibb, Pfizer, Lilly, Agilent, and Takeda outside the submitted work. The remaining authors declare no conflict of interest., (Copyright © 2024 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Financial toxicity, defined as both the objective financial burden and subjective financial distress from a cancer diagnosis and its treatment, is a topic of interest in the assessment of the quality of life of patients with cancer and their families. Current evidence implicates financial toxicity in psychosocial, economic and other harms, leading to suboptimal cancer outcomes along the entire trajectory of diagnosis, treatment, supportive care, survivorship and palliation. This paper presents the results of a virtual consensus, based on the evidence base to date, on the screening and management of financial toxicity in patients with and beyond cancer organized by the European Society for Medical Oncology (ESMO) in 2022., Methods: A Delphi panel of 19 experts from 11 countries was convened taking into account multidisciplinarity, diversity in health system contexts and research relevance. The international panel of experts was divided into four working groups (WGs) to address questions relating to distinct thematic areas: patients with cancer at risk of financial toxicity; management of financial toxicity during the initial phase of treatment at the hospital/ambulatory settings; financial toxicity during the continuing phase and at end of life; and financial risk protection for survivors of cancer, and in cancer recurrence. After comprehensively reviewing the literature, statements were developed by the WGs and then presented to the entire panel for further discussion and amendment, and voting., Results and Discussion: A total of 25 evidence-informed consensus statements were developed, which answer 13 questions on financial toxicity. They cover evidence summaries, practice recommendations/guiding statements and policy recommendations relevant across health systems. These consensus statements aim to provide a more comprehensive understanding of financial toxicity and guide clinicians globally in mitigating its impact, emphasizing the importance of further research, best practices and guidelines., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Programmed death-ligand 1 expression currently represents the only validated predictive biomarker for immune checkpoint inhibition in metastatic NSCLC in the clinical routine, but it has limited value in distinguishing responses. Assessment of KRAS and TP53 mutations (mut) as surrogate for an immunosupportive tumor microenvironment (TME) might help to close this gap., Methods: A total of 696 consecutive patients with programmed death-ligand 1-high (≥50%), nonsquamous NSCLC, having received molecular testing within the German National Network Genomic Medicine Lung Cancer between 2017 and 2020, with Eastern Cooperative Oncology Group performance status less than or equal to 1 and pembrolizumab as first-line palliative treatment, were included into this retrospective cohort analysis. Treatment efficacy and outcome according to KRAS/TP53 status were correlated with TME composition and gene expression analysis of The Cancer Genome Atlas lung adenocarcinoma cohort., Results: Proportion of KRASmut and TP53mut was 53% (G12C 25%, non-G12C 28%) and 51%, respectively. In KRASmut patients, TP53 comutations increased response rates (G12C: 69.7% versus 46.5% [TP53mut versus wild-type (wt)], p = 0.004; non-G12C: 55.4% versus 39.5%, p = 0.03), progression-free survival (G12C: hazard ratio [HR] = 0.59, p = 0.009, non-G12C: HR = 0.7, p = 0.047), and overall survival (G12C: HR = 0.72, p = 0.16, non-G12C: HR = 0.56, p = 0.002), whereas no differences were observed in KRASwt patients. After a median follow-up of 41 months, G12C/TP53mut patients experienced the longest progression-free survival and overall survival (33.7 and 65.3 mo), which correlated with high tumor-infiltrating lymphocyte densities in the TME and up-regulation of interferon gamma target genes. Proinflammatory pathways according to TP53 status (mut versus wt) were less enhanced and not different in non-G12C and KRASwt, respectively., Conclusions: G12C/TP53 comutations identify a subset of patients with a very favorable long-term survival with immune checkpoint inhibitor monotherapy, mediated by highly active interferon gamma signaling in a proinflammatory TME., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

The identification of monogenic causes for cornification disorders has enhanced our understanding of epidermal differentiation and skin barrier function. Autosomal dominant lamellar ichthyosis is a rare condition, and ASPRV1 was the only gene linked to autosomal dominant lamellar ichthyosis to date. We identified a heterozygous variant (ENST00000686631.1:c.1372G>T, p.[Val458Phe]) in the NKPD1 gene in 7 individuals from a 4-generation German pedigree with generalized lamellar ichthyosis by whole-exome sequencing. Segregation analysis confirmed its presence in affected individuals, resulting in a logarithm of the odds score of 3.31. NKPD1 encodes the NKPD1 protein, implicated in the plasma membrane; its role in human disease is as yet unknown. Skin histology showed moderate acanthosis and compact orthohyperkeratosis, and the ultrastructure differed clearly from that in ASPRV1-autosomal dominant lamellar ichthyosis. Although NKPD1 mRNA expression increased during keratinocyte differentiation, stratum corneum ceramides exhibited no significant changes. However, affected individuals showed an elevated ratio of protein-bound ceramides to omega-esterified ceramides. This highlights NKPD1's role in autosomal dominant lamellar ichthyosis, impacting ceramide metabolism and skin lipid barrier formation, as demonstrated through functional characterization., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Vulnerability to infectious diseases in refugees is dependent on country of origin, flight routes, and conditions. Information on specific medical needs of different groups of refugees is lacking. We assessed the prevalence of infectious diseases, immunity to vaccine-preventable diseases, and chronic medical conditions in children, adolescents, and adult refugees from Ukraine who arrived in Germany in 2022., Methods: Using different media, we recruited Ukrainian refugees at 13 sites between 9-12/2022. An antigen test for acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection, serologies for a range of vaccine-preventable diseases, as well as interferon gamma release assays (IGRAs) for tuberculosis (TB), and SARS-CoV-2 were performed. We assessed personal and family history of chronic medical conditions, infectious diseases, vaccination status, and conditions during migration., Results: Overall, 1793 refugees (1401 adults and 392 children/adolescents) were included. Most participants were females (n = 1307; 72·3%) and from Eastern or Southern Ukraine. TB IGRA was positive in 13% (n = 184) of the adults and in 2% (n = 7) of the children. Serology-based immunological response was insufficient in approximately 21% (360/1793) of the participants for measles, 32% (572/1793) for diphtheria, and 74% (1289/1793) for hepatitis B., Conclusions: We show evidence of low serological response to vaccine-preventable infections and increased LTBI prevalence in Ukrainian refugees. These findings should be integrated into guidelines for screening and treatment of infectious diseases in migrants and refugees in Germany and Europe. Furthermore, low immunity for vaccine-preventable diseases in Ukrainians independent of their refugee status, calls for tailor-made communication efforts., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Sepsis is characterised by a dysregulated host immune response to infection. Despite recognition of its significance, immune status monitoring is not implemented in clinical practice due in part to the current absence of direct therapeutic implications. Technological advances in immunological profiling could enhance our understanding of immune dysregulation and facilitate integration into clinical practice. In this Review, we provide an overview of the current state of immune profiling in sepsis, including its use, current challenges, and opportunities for progress. We highlight the important role of immunological biomarkers in facilitating predictive enrichment in current and future treatment scenarios. We propose that multiple immune and non-immune-related parameters, including clinical and microbiological data, be integrated into diagnostic and predictive combitypes, with the aid of machine learning and artificial intelligence techniques. These combitypes could form the basis of workable algorithms to guide clinical decisions that make precision medicine in sepsis a reality and improve patient outcomes., Competing Interests: Declaration of interests SC reports personal fees from Pfizer, AstraZeneca, Swedish Orphan Biovitrum (SOBI), GSK, and Merck Sharp & Dohme (MSD). MK reports personal fees from ARTCLINE, Atriva, AOP pharma, Inflammatix, and 4TEEN4; and discloses institutional funding from MediSieve, 4TEEN4, Adrenomed, Spinghotec, Cytosorbents, and Inflammatix. MAW reports personal fees from MSD, Gilead, Pfizer, Shionogi, Eumedica, Coulter, Biotest, Sedana, SOBI, and Böhringer; and patent EPA17198330 “Delta-Like Ligand 1 for diagnosing severe infections”. IM-L reports personal fees from MSD, Pfizer, and Gilead. GL reports personal fees from SOBI. EJG-B discloses institutional funding from Abbott, bioMérieux, InflaRx, Johnson & Johnson, MSD, SOBI, XBiotech, Horizon 2020 Marie Skłodowska-Curie International Training Network “the European Sepsis Academy”, Horizon 2020 European Grants ImmunoSep and RISCinCOVID, and Horizon Health European Grants EPIC-CROWN-2. MSW has received unrestricted funding from Sartorius and reports personal fees from GRIFOLS, Gilead, and Amomed. MO is president of the European Shock Society and Deputy Editor of Intensive Care Medicine Experimental. JFB-M reports personal fees from GSK, PROFARMA programme, Ministry of Industry Spain, GSK-MODUS programme, and Inflammatix; and patents on the following biomarkers related to management of severe infections: PCT/EP2018/064363 “MMP-8 as a marker for identifying infectious disease”, PCT/EP2018/052499 “Pro-ADM as marker indicating an adverse event”, WO2020030745 “Pro-ADM for prognosing the risk of a medical condition requiring hospitalisation in patients with symptoms of infectious disease”, and EP20383140.9 “In vitro method for predicting mortality in COVID-19 patients” (based on detecting N-antigenaemia of SARS-CoV-2 in plasma). JCS discloses institutional funding from Orion Pharma, Abbott Nutrition International, B Braun Medical, CSEM, Edwards Lifesciences Services, Kenta Biotech, Maquet Critical Care, Omnicare Clinical Research, Nestle, Pierre Fabre Pharma, Pfizer, Bard Medica, Abbott, Anandic Medical Systems, Pan Gas Healthcare, Bracco, Hamilton Medical, Fresenius Kabi, Getinge Group Maquet, Dräger, Teleflex Medical, GSK, MSD, Eli Lilly and Company, Baxter, Astellas, AstraZeneca, CSL Behring, Novartis, Covidien, Philips Medical, Prolong Pharmaceuticals and Nycomed, Phagenesis, and Cytel, outside of the submitted work. JCS is Chair of the Clinical Advisory Board of Hemotune. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Scope: The current tools for tuberculosis (TB) treatment monitoring, smear microscopy and culture, cannot accurately predict poor treatment outcomes. Research into new TB treatment monitoring tools (TMTs) is growing, but data are unreliable. In this article, we aim to provide guidance for studies investigating and evaluating TB TMT for use during routine clinical care. Here, a TB TMT would guide treatment during the course of therapy, rather than testing for a cure at the regimen's end. This article does not cover the use of TB TMTs as surrogate endpoints in the clinical trial context., Methods: Guidelines were initially informed by experiences during a systematic review of TB TMTs. Subsequently, a small content expert group was consulted for feedback on initial recommendations. After revision, feedback from substantive experts across sectors was sought., Questions Addressed by the Guideline and Recommendations: The proposed considerations and recommendations for studies evaluating TB TMTs for use during the treatment in routine clinical care fall into eight domains. We provide specific recommendations regarding study design and recruitment, outcome definitions, reference standards, participant follow-up, clinical setting, study population, treatment regimen reporting, and index tests and data presentation. Overall, TB TMTs should be evaluated in a manner similar to diagnostic tests, but TB TMT accuracy must be assessed at multiple timepoints throughout the treatment course, and TB TMTs should be evaluated in study populations who have already received a diagnosis of TB. Study design and outcome definitions must be aligned with the developmental phase of the TB TMT under evaluation. There is no reference standard for TB treatment response, so different reference standards and comparator tests have been proposed, the selection of which will vary depending on the developmental phase of the TMT under assessment. The use of comparator tests can assist in generating evidence. Clarity is required when reporting of timepoints, TMT read-outs, and analysis results. Implementing these recommendations will lead to higher quality TB TMT studies that will allow data to be meaningfully compared, thereby facilitating the development of novel tools to guide individual TB therapy and improve treatment outcomes., (Copyright © 2024 World Health Organization. Published by Elsevier Ltd.. All rights reserved.)

Objectives: The Orphan Drug Act (ODA) incentivizes drug development for rare diseases with limited sales potential. Partial orphans-drugs used to treat rare and common diseases-frequently turn into multi-billion dollar blockbusters. This study analyzes partial orphan cancer drugs' development, approval, and economics., Methods: 170 drugs with US Food and Drug Administration approval for 455 cancer indications were identified (2000-2021). 110 full, 22 partial, and 38 non-orphan drugs were compared regarding their approval, benefits, trials, epidemiology, price, beneficiaries, and spending with data from regulatory documents, Global Burden of Disease study, and Medicare and Medicaid., Results: Full orphans, relative to partial and non-orphans, were more frequently monotherapies for hematologic cancers supported by smaller single-arm trials treating diseases with a lower incidence and higher severity. The time from first to second indication approval was 1 year shorter for partial than full orphans. Full orphans offered a greater overall survival (median: 4.0 vs 2.8 vs 2.8 months, P < .001) and progression-free survival benefit (median: 5.1 vs 2.5 vs 3.6 months, P < .001). Monthly prices were higher for full and partial than non-orphan drugs (median: $17 177 vs $13 284 vs $12 457, P < .001). Beneficiaries (8790 vs 4390 vs 1730) and spending ($570 vs $305 vs $156 million) per drug were greater for partial than non-and full orphans., Conclusions: Although partial orphans' benefits, trials, and economics are more similar to non-than full orphans, they receive all of the ODA's benefits and are swiftly extended to new indications; resulting in greater spending. A maximum ODA revenue/patient threshold could limit expenditure on partial orphans., Competing Interests: Author Disclosures Links to the disclosure forms provided by the authors are available here., (Copyright © 2024. Published by Elsevier Inc.)

Background: In 2022, the European Society of Cardiology updated guidelines for preoperative evaluation. The aims of this study were to quantify: (1) the impact of the updated recommendations on the yield of pathological findings compared with the previous guidelines published in 2014; (2) the impact of preoperative B-type natriuretic peptide (NT-proBNP) use for risk estimation on the yield of pathological findings; and (3) the association between 2022 guideline adherence and outcomes., Methods: This was a secondary analysis of MET-REPAIR, an international, prospective observational cohort study (NCT03016936). Primary endpoints were reduced ejection fraction (EF<40%), stress-induced ischaemia, and major adverse cardiovascular events (MACE). The explanatory variables were class of recommendations for transthoracic echocardiography (TTE), stress imaging, and guideline adherence. We conducted second-order Monte Carlo simulations and multivariable regression., Results: In total, 15,529 patients (39% female, median age 72 [inter-quartile range: 67-78] yr) were included. The 2022 update changed the recommendation for preoperative TTE in 39.7% patients, and for preoperative stress imaging in 12.9% patients. The update resulted in missing 1 EF <40% every 3 fewer conducted TTE, and in 4 additional stress imaging per 1 additionally detected ischaemia events. For cardiac stress testing, four more investigations were performed for every 1 additionally detected ischaemia episodes. Use of NT-proBNP did not improve the yield of pathological findings. Multivariable regression analysis failed to find an association between adherence to the updated guidelines and MACE., Conclusions: The 2022 update for preoperative cardiac testing resulted in a relevant increase in tests receiving a stronger recommendation. The updated recommendations for TTE did not improve the yield of pathological cardiac testing., (Copyright © 2024 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Abstract: Primary hemophagocytic lymphohistiocytosis (pHLH) is a life-threatening hyperinflammatory syndrome that develops mainly in patients with genetic disorders of lymphocyte cytotoxicity and X-linked lymphoproliferative syndromes. Previous studies with etoposide-based treatment followed by hematopoetic stem cell transplantation (HSCT) resulted in 5-year survival of 50% to 59%. Contemporary data are lacking. We evaluated 88 patients with pHLH documented in the international HLH registry from 2016-2021. In 12 of 88 patients, diagnosis was made without HLH activity, based on siblings or albinism. Major HLH-directed drugs (etoposide, antithymocyte globulin, alemtuzumab, emapalumab, ruxolitinib) were administered to 66 of 76 patients who were symptomatic (86% first-line etoposide); 16 of 57 patients treated with etoposide and 3 of 9 with other first-line treatment received salvage therapy. HSCT was performed in 75 patients; 7 patients died before HSCT. Three-year probability of survival (pSU) was 82% (confidence interval [CI], 72%-88%) for the entire cohort and 77% (CI, 64%-86%) for patients receiving first-line etoposide. Compared with the HLH-2004 study, both pre-HSCT and post-HSCT survival of patients receiving first-line etoposide improved, 83% to 91% and 70% to 88%. Differences to HLH-2004 included preferential use of reduced-toxicity conditioning and reduced time from diagnosis to HSCT (from 148 to 88 days). Three-year pSU was lower with haploidentical (4 of 9 patients [44%]) than with other donors (62 of 66 [94%]; P < .001). Importantly, early HSCT for patients who were asymptomatic resulted in 100% survival, emphasizing the potential benefit of newborn screening. This contemporary standard-of-care study of patients with pHLH reveals that first-line etoposide-based therapy is better than previously reported, providing a benchmark for novel treatment regimes., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Myeloid neoplasms with germline predisposition have been recognized increasingly over the past decade with numerous newly described disorders. Penetrance, age of onset, phenotypic heterogeneity, and somatic driver events differ widely among these conditions and sometimes even within family members with the same variant, making risk assessment and counseling of these individuals inherently difficult. In this review, we will shed light on high malignant penetrance (e.g., CEBPA, GATA2, SAMD9/SAMD9L, and TP53) versus variable malignant penetrance syndromes (e.g., ANKRD26, DDX41, ETV6, RUNX1, and various bone marrow failure syndromes) and their clinical features, such as variant type and location, course of disease, and prognostic markers. We further discuss the recommended management of these syndromes based on penetrance with an emphasis on somatic aberrations consistent with disease progression/transformation and suggested timing of allogeneic hematopoietic stem cell transplant. This review will thereby provide important data that can help to individualize and improve the management for these patients., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: The aim of the present study was to assess the long-term course of OHRQoL and the impact of the loading protocol in patients receiving a single mandibular implant supporting a complete denture over a period of five years., Methods: In this multicenter RCT, a total of 158 edentulous patients were initially included and were randomly allocated immediately after placement of a mandibular midline implant to either immediate loading (IL) or to conventional loading (CL) with submerged healing. The assessment of OHRQoL was performed with the 49-item Oral Health Impact Profile (OHIP) at baseline and 1, 4, 12, 24, and 60 months after loading. At 5-year follow-up, 100 patients (mean age: 69.2 years; 45.0% female) with completed OHIP were available for analyses. A mixed-effects model with patients as random effect and an unstructured covariance matrix was developed to address repeated outcome measurement., Results: The OHRQoL improved substantially after loading, indicated by a decrease of mean OHIP summary scores from 51.0 points at baseline, by 14.2 (95%-CI: 9.4 - 19.1; p<0.001) points to 37.2 points at 1-month follow-up, and by continuous improvement to 20.4 OHIP points at final follow-up. Considering constant treatment effects, the loading protocol had no significant effect on OHIP scores (-3.7, 95%-CI: -9.4 - 2.2; p = 0.204). Time effect was statistically significant with -0.21 (95%-CI: -0.28 - -0.15; p<0.001) points per month., Conclusion: Both the immediate and conventional loading of a single mandibular midline implant supporting a complete denture offer long-lasting high levels of OHRQoL, with no significant or clinically relevant long-term differences., Clinical Significance: The study firstly presents long-term data for OHRQoL by investigating the loading protocol of single mandibular implant-supported complete dentures. Since immediate loading has been associated with a reduced implant survival rate for this concept, information on patient benefits is essential for evidence-based decision making., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Abstract: CD19 chimeric antigen receptor (CAR) T cells and CD20 targeting T-cell-engaging bispecific antibodies (bispecs) have been approved in B-cell non-Hodgkin lymphoma lately, heralding a new clinical setting in which patients are treated with both approaches, sequentially. The aim of our study was to investigate the selective pressure of CD19- and CD20-directed therapy on the clonal architecture in lymphoma. Using a broad analytical pipeline on 28 longitudinally collected specimen from 7 patients, we identified truncating mutations in the gene encoding CD20 conferring antigen loss in 80% of patients relapsing from CD20 bispecs. Pronounced T-cell exhaustion was identified in cases with progressive disease and retained CD20 expression. We also confirmed CD19 loss after CAR T-cell therapy and reported the case of sequential CD19 and CD20 loss. We observed branching evolution with re-emergence of CD20+ subclones at later time points and spatial heterogeneity for CD20 expression in response to targeted therapy. Our results highlight immunotherapy as not only an evolutionary bottleneck selecting for antigen loss variants but also complex evolutionary pathways underlying disease progression from these novel therapies., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Objective: Despite the publication of various national/international guidelines, several questions concerning the management of patients with asymptomatic (AsxCS) and symptomatic (SxCS) carotid stenosis remain unanswered. The aim of this international, multi-specialty, expert-based Delphi Consensus document was to address these issues to help clinicians make decisions when guidelines are unclear., Methods: Fourteen controversial topics were identified. A three-round Delphi Consensus process was performed including 61 experts. The aim of Round 1 was to investigate the differing views and opinions regarding these unresolved topics. In Round 2, clarifications were asked from each participant. In Round 3, the questionnaire was resent to all participants for their final vote. Consensus was reached when ≥75% of experts agreed on a specific response., Results: Most experts agreed that: (1) the current periprocedural/in-hospital stroke/death thresholds for performing a carotid intervention should be lowered from 6% to 4% in patients with SxCS and from 3% to 2% in patients with AsxCS; (2) the time threshold for a patient being considered "recently symptomatic" should be reduced from the current definition of "6 months" to 3 months or less; (3) 80% to 99% AsxCS carries a higher risk of stroke compared with 60% to 79% AsxCS; (4) factors beyond the grade of stenosis and symptoms should be added to the indications for revascularization in AsxCS patients (eg, plaque features of vulnerability and silent infarctions on brain computed tomography scans); and (5) shunting should be used selectively, rather than always or never. Consensus could not be reached on the remaining topics due to conflicting, inadequate, or controversial evidence., Conclusions: The present international, multi-specialty expert-based Delphi Consensus document attempted to provide responses to several unanswered/unresolved issues. However, consensus could not be achieved on some topics, highlighting areas requiring future research., Competing Interests: Disclosures D.P.M. has given talks, acted as a consultant or attended conferences sponsored by Amgen and Novo Nordisk. J.F.M. receives funding from the United States National Institute of Neurologic Disorders and Stroke for work related to running the CREST-2 clinical trial (U01NS080168) and the CREST-2 Long-term Observational Extension study (U01NS119169). E.A.S. has received research grants from the United States Food and Drug Administration, BD, Boston Scientific, Cook, CSI, Laminate Medical, Medtronic and Philips; has received consulting/speaking fees from Abbott, Bayer, BD, Boston Scientific, Cook, Cordis, CSI, Inari, Infraredx, Medtronic, Philips, Shockwave and VentureMed. H.-H.E. is a local Principal Investigator for the ROADSTER 2 trial and a scientific committee member of SPACE-1, SPACE-2 and ACST-2. T.R. is funded by grants from the National Institutes of Health (R01 MD012467, R01 NS029993, R01NS040807, 1U24NS107267), and the National Center for Advancing Translational Sciences (UL1 TR002736, KL2 TR002737). J.S.M. has received institutional research grants from Abbott, Cook, Endologix, Gore and Medtronic., (Copyright © 2023 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Purpose: To apply multi-shot high-resolution multi inversion spin and gradient echo (MI-SAGE) acquisition for simultaneous liver T 1 , T 2 and T 2 * mapping., Methods: Inversion prepared spin- and gradient-echo EPI was developed with ascending slice order across measurements for efficient acquisition with T 1 , T 2 , and T 2 ⁎ weighting. Multi-shot EPI was also implemented to minimize distortion and blurring while enabling high in-plane resolution. A dictionary-matching approach was used to fit the images to quantitative parameter maps, which were compared to T 1 measured by modified Look-Locker (MOLLI), T 1 measured by variable flip angle (VFA), T 2 measured by multiple echo time-based Half Fourier Single-shot Turbo spin-Echo (HASTE), T 2 measured by radial turbo-spin-echo (rTSE) and T 2 ⁎ measured by multiple gradient echo (MGRE) sequences., Results: The multi-shot variant of the sequence achieved higher in-plane resolution of 1.7 × 1.7 mm 2 with good image quality in 28 s. Derived quantitative maps showed comparable values to conventional mapping methods. As measured in phantom and in vivo, MOLLI, MESE and MGRE give closest values to MISAGE. VFA, HASTE and rTSE show obvious overestimation., Conclusions: The proposed multi-shot inversion prepared spin- and gradient-echo EPI sequence allows for high-resolution quantitative T 1 , T 2 and T 2 liver tissue characterization in a single breath-hold scan., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Chronic pancreatitis (CP) causes suffering and socioeconomic burden. This study evaluated perioperative results and patient-reported outcomes (PRO) in CP patients treated with duodenum-preserving pancreatic head resection (DPPHR)., Methods: Data were analyzed of CP patients undergoing DPPHR between 01/2001-10/2014. PROs were measured using a specifically designed questionnaire and the EORTC QLQ-C30/PAN26. Associations between treatment variables and PROs were examined., Results: Of 332 patients who received DPPHR, most (n = 251, 75.6%) underwent the Berne modification. Surgical morbidity was 21.5% (n = 71) and 90-day mortality 1.5% (n = 5). Median follow-up was 79.9 months, 5-year survival 90.5%, and 1.8% of patients developed pancreatic cancer. Of 283 patients alive, 178 (62.9%) returned questionnaires. Referral for surgery was self-initiated (38.0% of cases), by gastroenterologists (27.5%) and by general practitioners (21.1%). QoL improved in 78.7% of patients, remained stable in 12.1%, and worsened in 9.1%. Median Izbicki scores decreased from 90 to 5 points after surgery (p < 0.0001). Time from diagnosis to DPPHR was an independent, proportional predictor of a higher postoperative Izbicki score (p = 0.04)., Conclusion: DPPHR is an effective, safe treatment for CP. A delay in surgery decreases surgical effectivity, hence CP patients should be referred to surgery early to ensure satisfactory outcomes., (Copyright © 2023 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Since the finding and correction of an error in previous spiroware software versions commonly used with the Exhalyzer D for multiple-breath washout (MBW) analysis, there has been an ongoing discussion about its impact on MBW results. In this study, we reanalyzed previously published findings with the corrected spiroware version 3.3.1. In total, 31 infants and preschool children with cystic fibrosis (CF) (mean age 2.3 ± 0.8 years) and 20 healthy controls (mean age 2.3 ± 1.1 years) underwent consecutive sulfure hexafluoride (SF 6 )- and nitrogen (N 2 )-MBW. In addition, children with CF underwent chest magnetic resonance imaging (MRI) on the same day. After reanalysis of MBW data, the corrected N 2 -lung clearance index (LCI) decreased by 10-15% in both groups (P = 0.001) but remained significantly higher than the SF 6 -LCI (P<0.01). Diagnostic agreement between the MBW results remained moderate with a persistent correlation between SF 6 - and N 2 -MBW. The corrected upper limit of normal of the N 2 -LCI changed classification of nine children with CF, eight of which were within the normal range after correction. The correlation between the different LCI values and the chest MRI scores remained significant with strongest correlation with the MRI perfusion score. Consequently, the corrected N 2 -LCI is significantly lower than the previous N 2 -LCI, but key results published before are not affected by the reanalysis., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

As cancer therapies increase in effectiveness and patients' life expectancies improve, balancing oncologic efficacy while reducing acute and long-term cardiovascular toxicities has become of paramount importance. To address this pressing need, the Cardiology Oncology Innovation Network (COIN) was formed to bring together domain experts with the overarching goal of collaboratively investigating, applying, and educating widely on various forms of innovation to improve the quality of life and cardiovascular healthcare of patients undergoing and surviving cancer therapies. The COIN mission pillars of innovation, collaboration, and education have been implemented with cross-collaboration among academic institutions, private and public establishments, and industry and technology companies. In this report, we summarize proceedings from the first two annual COIN summits (inaugural in 2020 and subsequent in 2021) including educational sessions on technological innovations for establishing best practices and aligning resources. Herein, we highlight emerging areas for innovation and defining unmet needs to further improve the outcome for cancer patients and survivors of all ages. Additionally, we provide actionable suggestions for advancing innovation, collaboration, and education in cardio-oncology in the digital era., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier Inc.)

Background: Brain metastases (BMs) are a key challenge in the management of anaplastic lymphoma kinase-rearranged non-small-cell lung cancer (ALK+ NSCLC), but prognostic scores are complicated or rely on data before the era of tyrosine kinase inhibitors (TKIs). This study aimed to validate the novel ALK-Brain Prognostic Index (ALK-BPI), which was originally proposed based on 44 TKI-treated ALK+ NSCLC patients from Karolinska University Hospital, using an external clinical cohort., Patients and Methods: TKI-treated ALK+ NSCLC patients with BM from Heidelberg (n = 82, cohort 1) were retrospectively analyzed alone and together with the original Karolinska cohort (n = 126, cohort 2). Cox regression models were used to determine the association of clinical variables and scores with overall survival (OS) after BM diagnosis (BM-related OS)., Results: Both cohorts showed a similar median age (58 years), roughly balanced sex distributions (52%-56% females), and Eastern Cooperative Oncology Group performance status (PS) 0-2 for most patients (87%-92%) at the time of BM development, which were present already at initial diagnosis in 36%-38% of the patients. Most patients had received next-generation ALK inhibitors (54%-63%), while 55%-56% of patients did not receive any radiotherapy. The ALK-BPI identified poor-risk patients (i.e. featuring ≥ 2/3 risk factors: PS > 2, male sex, development of BM after initial diagnosis) with a significantly shorter BM-related OS than other patients in both cohorts: 32/82 in cohort 1 with 21.3 versus 62.2 months in median [hazard ratio (HR) = 2.5, P < 0.001]; 59/126 in cohort 2 with 23.1 versus 67.2 months in median (HR = 2.6, P < 0.001). The five-parameter Lung-molGPA score did not achieve statistical significance and/or clear prognostic separation in all four groups, while the Disease-Specific Graded Prognostic Assessment score did not show consistent results., Conclusions: The ALK-BPI is a reliable tool for easy prognostic dichotomization of TKI-treated ALK+ NSCLC patients with BM in daily clinical practice, without the complexity of previous models., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Narcissistic personality traits have been theorised to negatively affect depressive symptoms, therapeutic alliance, and treatment outcome, even in the absence of narcissistic personality disorder. We aimed to examine how the dimensional narcissistic facets of admiration and rivalry affect depressive symptoms across treatment modalities in two transdiagnostic samples., Methods: We did a naturalistic, observational prospective cohort study in two independent adult samples in Germany: one sample pooled from an inpatient psychiatric clinic and an outpatient treatment service offering cognitive behavioural treatment (CBT), and one sample from an inpatient clinic providing psychoanalytic interactional therapy (PIT). Inpatients treated with CBT had an affective or psychotic disorder. For the other two sites, data from all service users were collected. We examined the effect of core narcissism and its facets admiration and rivalry, measured by Narcissistic Admiration and Rivalry Questionnaire-short version, on depressive symptoms, measured by Beck's Depression Inventory and Patient Health Questionnaire-Depression Scale, at baseline and after treatment in patients treated with CBT and PIT. Primary analyses were regression models, predicting baseline and post-treatment depression severity from core narcissism and its facets. Mediation analysis was done in the outpatient CBT group for the effect of the therapeutic alliance on the association between narcissism and depression severity after treatment., Findings: The sample included 2371 patients (1423 [60·0%] female and 948 [40·0%] male; mean age 33·13 years [SD 13·19; range 18-81), with 517 inpatients and 1052 outpatients in the CBT group, and 802 inpatients in the PIT group. Ethnicity data were not collected. Mean treatment duration was 300 days (SD 319) for CBT and 67 days (SD 26) for PIT. Core narcissism did not predict depression severity before treatment in either group, but narcissistic rivalry was associated with higher depressive symptom load at baseline (β 2·47 [95% CI 1·78 to 3·12] for CBT and 1·05 [0·54 to 1·55] for PIT) and narcissistic admiration showed the opposite effect (-2·02 [-2·62 to -1·41] for CBT and -0·64 [-1·11 to -0·17] for PIT). Poorer treatment response was predicted by core narcissism (β 0·79 [0·10 to 1·47]) and narcissistic rivalry (0·89 [0·19 to 1·58]) in CBT, whereas admiration showed no effect. No effect of narcissism on treatment outcome was discernible in PIT. Therapeutic alliance mediated the effect of narcissism on post-treatment depression severity in the outpatient CBT sample., Interpretation: As narcissism affects depression severity before and after treatment with CBT across psychiatric disorders, even in the absence of narcissistic personality disorder, the inclusion of dimensional assessments of narcissism should be considered in future research and clinical routines. The relevance of the therapeutic alliance and therapeutic strategy could be used to guide treatment approaches., Funding: IZKF Münster., Translation: For the German translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are strongly associated with obesity, metabolic syndrome, and insulin resistance (IR)., Objective: The aim of this study was to investigate the effects of metabolic surgery on pancreatic beta cell function and IR in patients with obesity and NAFLD., Setting: University Hospital, Germany., Methods: Liver biopsies were taken intraoperatively from 112 patients undergoing sleeve gastrectomy (n = 68) or Roux-en-Y gastric bypass (n = 44) and analyzed histologically for the presence of simple steatosis (NAFL) or NASH. Clinical and biochemical parameters were collected over up to 2 years. Beta cell function and IR were assessed using the homeostasis model assessment of beta-cell function (HOMA2-%B) and insulin resistance (HOMA2-IR) index., Results: NASH was present in 53.6% (n = 60) of the patients and NAFL in 25.9% (n = 29). Liver enzymes, adiponectin/leptin ratio, triglycerides, and HbA1C were improved at 6 months, 1, and 2 years after surgery. HOMA2-IR was significantly lower in patients without NAFLD while HOMA2-IR did not differ between patients with NAFL and/or NASH. HOMA2-%B was highest in the NAFLD group and lowest in patients with NASH. While there was no change in HOMA2-%B and HOMA2-IR in the No-NAFLD group, HOMA2-%B decreased and IR improved in the NAFL and NASH groups., Conclusion: Insufficient compensatory beta-cell function may contribute to the progression from NAFL alongside with IR to NASH. Our findings suggest that bariatric surgery decreases IR while at the same time reducing compensatory insulin oversecretion. These results are associated with beneficial changes in adipose tissue function after bariatric surgery., (Copyright © 2023 American Society for Metabolic and Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)