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Abstract To date, several studies on genomic events underlying medulloblastoma (MB) biology have expanded our understanding of this tumour entity and led to its division into four groups—WNT, SHH, group 3 (G3) and group 4 (G4). However, there is little information about the relevance of pathogenic mitochondrial DNA (mtDNA) mutations and their consequences across these. In this report, we describe the case of a female patient with MB and a mitochondriopathy, followed by a study of mtDNA variants in MB groups. After being diagnosed with G4 MB, the index patient was treated in line with the HIT 2000 protocol with no indications of relapse after five years. Long-term side effects of treatment were complemented by additional neurological symptoms and elevated lactate levels ten years later, resulting in suspected mitochondrial disease. This was confirmed by identifying a mutation in the MT-TS1 gene which appeared homoplasmic in patient tissue and heteroplasmic in the patient’s mother. Motivated by this case, we explored mtDNA mutations across 444 patients from ICGC and HIT cohorts. While there was no statistically significant enrichment of mutations in one MB group, both cohorts encompassed a small group of patients harbouring potentially deleterious mtDNA variants. The case presented here highlights the possible similarities between sequelae caused by MB treatment and neurological symptoms of mitochondrial dysfunction, which may apply to patients across all MB groups. In the context of the current advances in characterising and interpreting mtDNA aberrations, recognising affected patients could enhance our future knowledge regarding the mutations’ impact on carcinogenesis and cancer treatment.

Abstract Background Cancer metabolism influences multiple aspects of tumorigenesis and causes diversity across malignancies. Although comprehensive research has extended our knowledge of molecular subgroups in medulloblastoma (MB), discrete analysis of metabolic heterogeneity is currently lacking. This study seeks to improve our understanding of metabolic phenotypes in MB and their impact on patients’ outcomes. Methods Data from four independent MB cohorts encompassing 1,288 patients were analysed. We explored metabolic characteristics of 902 patients (ICGC and MAGIC cohorts) on bulk RNA level. Moreover, data from 491 patients (ICGC cohort) were searched for DNA alterations in genes regulating cell metabolism. To determine the role of intratumoral metabolic differences, we examined single-cell RNA-sequencing (scRNA-seq) data from 34 additional patients. Findings on metabolic heterogeneity were correlated to clinical data. Results Established MB groups exhibit substantial differences in metabolic gene expression. By employing unsupervised analyses, we identified three clusters of group 3 and 4 samples with distinct metabolic features in ICGC and MAGIC cohorts. Analysis of scRNA-seq data confirmed our results of intertumoral heterogeneity underlying the according differences in metabolic gene expression. On DNA level, we discovered clear associations between altered regulatory genes involved in MB development and lipid metabolism. Additionally, we determined the prognostic value of metabolic gene expression in MB and showed that expression of genes involved in metabolism of inositol phosphates and nucleotides correlates with patient survival. Conclusion Our research underlines the biological and clinical relevance of metabolic alterations in MB. Thus, distinct metabolic signatures presented here might be the first step towards future metabolism-targeted therapeutic options. Graphical Abstract

Abstract Background The surgical treatment of inferior patellar pole fractures can be a challenge, especially in geriatric patients, who are particularly frequently affected by osteoporosis. The objective of this biomechanical study was to compare the performance of suture anchor and transosseous suture fixation in fractures of the inferior patellar pole in context of bone mineral density. Methods Twelve fresh-frozen human cadaveric knees received a transverse osteotomy, simulating an AO/OTA 34C1.3 inferior pole fracture of the patella. These fractures were fixated with either suture anchors (SA; Corkscrew® FT 4.5 mm) or transosseous suture (TS; #2 FiberWire®). Cyclic loading tests were performed by pulling the quadriceps tendon against gravity from 90° flexion to almost full extension (5°) for 1000 cycles. Motion and fracture gap displacement were tracked until failure occurred. Subsequently, loading to failure tests followed. Differences between groups were compared using unpaired t-tests, and correlations were calculated with Pearson’s correlation coefficient. Results The suture anchor group showed significantly fewer cycles to failure than the transosseous suture group (SA: 539.0 ± 465.6 cycles, TS: 1000 ± 0 cycles, P = 0.04). Bone mineral density correlated positively with cycles to failure in the suture anchor group (Pearson’s r = 0.60, P = 0.02). No differences in fracture gap displacement could be proven after 100 cycles (SA: 4.1 ± 2.6 mm, TS: 6.5 ± 2.6 mm, P = 0.19); 500 cycles (SA: 6.4 ± 6.1 mm, TS: 9.6 ± 3.8 mm, P = 0.39); and 1000 cycles (SA: 4.0 ± 0.4 mm, TS: 11.0 ± 4.5 mm, P = 0.08). Furthermore, the mean destructive load to failure in the suture anchor group was also significantly lower than in the transosseous suture group (SA: 422.4 ± 212.2 N, TS: 825.7 ± 189.3 N, P = 0.04). Conclusions Suture anchors may be a viable alternative to transosseous suture in younger patients for clinical advantages, but in osteoporotic bone, the more stable osteosynthesis with transosseous suture continues to prove superior. Therefore, trauma surgeons might consider the use of transosseous suture in elderly patients, especially in those presenting with low bone mineral density values.

Introduction: Men are generally more susceptible to bacterial infections than women. Central venous catheters (CVCs), often used to administer systemic treatment in patients with cancer, are an important source of infection. However, little is known about sex-specific differences of CVC-related bloodstream infections (CRBSIs) in patients with cancer. This study aimed to compare CRBSIs in men versus women in a large cohort of patients with cancer. Methods: Data were derived from the SECRECY registry including nonselected patients with centrally inserted non-tunneled internal jugular or subclavian vein CVCs in 10 hematology and oncology sites in Germany. Only CRBSIs classified as definite CRBSI (dCRBSI) or probable CRBSI were included, and the combination of both was summarized as dpCRBSI. CVCs were matched 1:1 for underlying disease, anatomic site of CVC insertion, type of CVC dressing, antimicrobial coated CVC, complicated CVC insertion, and CVC in situ time by propensity score matching (PSM). Endpoints were CRBSI rates and incidences in CVCs inserted in men versus women. Results: A total of 5,075 CVCs registered from March 2013 to March 2024 were included in the analysis, of which 3,024 comprise the PSM cohort. A total of 1,512 (50.0%) CVCs were inserted in men. Underlying diseases mainly were hematological malignancies (96.4%). While there was no statistically significant difference between men and women in the dCRBSI rate (5.4% vs. 4.1%; p = 0.12) and the dCRBSI incidence (3.8 vs. 2.9/1,000 CVC days; p = 0.11), the rate of dpCRBSI (9.9% vs. 6.7%; p = 0.002) and the dpCRBSI incidence (7.0 vs. 4.7/1,000 CVC days; p = 0.002) were significantly higher in men versus women. The proportion of coagulase-negative staphylococci as causative agent of both dCRBSI and dpCRBSI was higher in men than in women (58.8% vs. 41.2%; p = 0.07 and 61.5% vs. 38.5%; p = 0.002, respectively). A multivariable regression revealed neutropenia as an independent risk factor for dCRBSI and male sex as risk factor for dCRBSI and dpCRBSI. Conclusion: In patients with hematological malignancies, men have a higher risk of CRBSI than women. This finding may be attributed to the high number of jugular vein-inserted CVCs, which in men may be associated with higher rates of skin colonization than in women. Special preventive measures such as earlier removal of CVCs in men may be studied in future. Introduction: Men are generally more susceptible to bacterial infections than women. Central venous catheters (CVCs), often used to administer systemic treatment in patients with cancer, are an important source of infection. However, little is known about sex-specific differences of CVC-related bloodstream infections (CRBSIs) in patients with cancer. This study aimed to compare CRBSIs in men versus women in a large cohort of patients with cancer. Methods: Data were derived from the SECRECY registry including nonselected patients with centrally inserted non-tunneled internal jugular or subclavian vein CVCs in 10 hematology and oncology sites in Germany. Only CRBSIs classified as definite CRBSI (dCRBSI) or probable CRBSI were included, and the combination of both was summarized as dpCRBSI. CVCs were matched 1:1 for underlying disease, anatomic site of CVC insertion, type of CVC dressing, antimicrobial coated CVC, complicated CVC insertion, and CVC in situ time by propensity score matching (PSM). Endpoints were CRBSI rates and incidences in CVCs inserted in men versus women. Results: A total of 5,075 CVCs registered from March 2013 to March 2024 were included in the analysis, of which 3,024 comprise the PSM cohort. A total of 1,512 (50.0%) CVCs were inserted in men. Underlying diseases mainly were hematological malignancies (96.4%). While there was no statistically significant difference between men and women in the dCRBSI rate (5.4% vs. 4.1%; p = 0.12) and the dCRBSI incidence (3.8 vs. 2.9/1,000 CVC days; p = 0.11), the rate of dpCRBSI (9.9% vs. 6.7%; p = 0.002) and the dpCRBSI incidence (7.0 vs. 4.7/1,000 CVC days; p = 0.002) were significantly higher in men versus women. The proportion of coagulase-negative staphylococci as causative agent of both dCRBSI and dpCRBSI was higher in men than in women (58.8% vs. 41.2%; p = 0.07 and 61.5% vs. 38.5%; p = 0.002, respectively). A multivariable regression revealed neutropenia as an independent risk factor for dCRBSI and male sex as risk factor for dCRBSI and dpCRBSI. Conclusion: In patients with hematological malignancies, men have a higher risk of CRBSI than women. This finding may be attributed to the high number of jugular vein-inserted CVCs, which in men may be associated with higher rates of skin colonization than in women. Special preventive measures such as earlier removal of CVCs in men may be studied in future. [ABSTRACT FROM AUTHOR]

Purpose We report the first-in-human phase Ia study to our knowledge ( ClinicalTrials.gov identifier: NCT01219699) identifying the maximum tolerated dose and assessing safety and preliminary efficacy of single-agent alpelisib (BYL719), an oral phosphatidylinositol 3-kinase α (PI3Kα)-selective inhibitor. Patients and Methods In the dose-escalation phase, patients with PIK3CA-altered advanced solid tumors received once-daily or twice-daily oral alpelisib on a continuous schedule. In the dose-expansion phase, patients with PIK3CA-altered solid tumors and PIK3CA-wild-type, estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer received alpelisib 400 mg once daily. Results One hundred thirty-four patients received treatment. Alpelisib maximum tolerated doses were established as 400 mg once daily and 150 mg twice daily. Nine patients (13.2%) in the dose-escalation phase had dose-limiting toxicities of hyperglycemia (n = 6), nausea (n = 2), and both hyperglycemia and hypophosphatemia (n = 1). Frequent all-grade, treatment-related adverse events included hyperglycemia (51.5%), nausea (50.0%), decreased appetite (41.8%), diarrhea (40.3%), and vomiting (31.3%). Alpelisib was rapidly absorbed; half-life was 7.6 hours at 400 mg once daily with minimal accumulation. Objective tumor responses were observed at doses ≥ 270 mg once daily; overall response rate was 6.0% (n = 8; one patient with endometrial cancer had a complete response, and seven patients with cervical, breast, endometrial, colon, and rectal cancers had partial responses). Stable disease was achieved in 70 (52.2%) patients and was maintained > 24 weeks in 13 (9.7%) patients; disease control rate (complete and partial responses and stable disease) was 58.2%. In patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer, median progression-free survival was 5.5 months. Frequently mutated genes (≥ 10% tumors) included TP53 (51.3%), APC (23.7%), KRAS (22.4%), ARID1A (13.2%), and FBXW7 (10.5%). Conclusion Alpelisib demonstrated a tolerable safety profile and encouraging preliminary activity in patients with PIK3CA-altered solid tumors, supporting the rationale for selective PI3Kα inhibition in combination with other agents for the treatment of PIK3CA-mutant tumors.

Abstract Aims Since its introduction, alcohol septal ablation (PTSMA) was discussed as treatment option only in elderly symptomatic patients with hypertrophic obstructive cardiomyopathy (HOCM). We report on long‐term follow‐up after PTSMA with respect to patient's age. Methods and results Between May 2000 and June 2017, we treated 952 consecutive HOCM patients with PTSMA; 133 (14.0%) patients were

Over the past decade, cancer immunotherapy with immune checkpoint inhibitors (ICIs) has significantly improved the outcome of many malignancies. However, with the broad use of ICIs, neurological immune related adverse events (irAE) are increasingly recognized. ICI-induced encephalitis (ICI-iE) is a particularly severe irAE, often leading to treatment termination, long-term sequalae or death. Despite its high morbidity and mortality, data on clinical features and diagnostic criteria are limited.We aimed to define clinical, radiologic and laboratory characteristics of ICI-iE and identify factors that discriminate it from anti-leucine-rich glioma-inactivated (anti-LGI)-1 encephalitis and herpes simplex virus (HSV)-1 encephalitis – two alternative causes of encephalitis – to increase the awareness of ICI-iE and improve its diagnosis and management.To that end, we retrospectively collected 30 cases of ICI-iE that were reported to the Side Effect Registry Immuno-Oncology (SERIO) and 46 cases of anti-LGI1 encephalitis or herpes simplex virus (HSV)-1 encephalitis that presented to a large German neurological referral center (Charité Universitätsmedizin Berlin) between January 2015 and September 2021. Signs and symptoms, imaging and electroencephalogram features, laboratory findings and outcome measures were assessed using standardized case report forms as well as patients’ medical records and compared between the groups.The data reported here represents the largest primary cohort of patients with ICI-iE to date and the first comparison with other types of encephalitis. As all three disorders – ICI-iE, HSV-1 encephalitis and anti-LGI1 encephalitis – are rare neurological entities, this dataset can be used as a reference in future clinical studies on ICI-induced neurotoxicity, neurological autoimmune disorders, and central nervous system infections.

Abstract Background Infection with SARS‐CoV‐2 leads to COVID‐19, the course of which is highly variable and depends on numerous patient‐specific risk factors. Patients with tumor diseases are considered to be more susceptible to severe COVID‐19; however, they also represent a heterogeneous group of individuals with variable risk. Identifying specific risk factors for a severe course of COVID‐19 in patients with cancer is of great importance. Methods Patients diagnosed with solid tumors or hematological malignancies and PCR‐confirmed SARS‐CoV‐2 infection were included into the multicentric ADHOK (Arbeitsgemeinschaft der Hämatologen und Onkologen im Krankenhaus e.V.) coronavirus tumor registry. Detailed information about the patients’ cancer disease, treatment, and laboratory parameters prior to infection, was collected retrospectively. The outcome of the SARS‐CoV‐2 infection was graded according to the WHO. Results A total of 195 patients (68% with solid neoplasms and 32% with hematological malignancies) were included in the registry. Overall, the course of the SARS‐CoV‐2 infection varied greatly, as 69% of all patients were either asymptomatic or encountered a mild to moderate course, while 23% of the cohort died from COVID‐19. In multivariable analysis, preinfection laboratory parameters (determined at least 10 days and a median of 21 days before the first documentation of SARS‐CoV‐2 infection) significantly correlated with severe course of the disease. Out of these, the absolute neutrophil count prior to infection showed the strongest association with COVID‐19‐related death. Conclusion The course of COVID‐19 in patients with tumor diseases is highly variable. Preinfection laboratory parameters may aid to identify patients at risk for severe COVID‐19 at an early stage prior to infection with the virus. German Clinical Trials Register identification: DRKS00023012.

Abstract Autophagy is an intracellular recycling pathway with implications for intracellular homeostasis and cell survival. Its pharmacological modulation can aid chemotherapy by sensitizing cancer cells toward approved drugs and overcoming chemoresistance. Recent translational data on autophagy modulators show promising results in reducing tumor growth and metastasis, but also reveal a need for more specific compounds and novel lead structures. Here, we searched for such autophagy-modulating compounds in a flow cytometry-based high-throughput screening of an in-house natural compound library. We successfully identified novel inducers and inhibitors of the autophagic pathway. Among these, we identified arzanol as an autophagy-modulating drug that causes the accumulation of ATG16L1-positive structures, while it also induces the accumulation of lipidated LC3. Surprisingly, we observed a reduction of the size of autophagosomes compared to the bafilomycin control and a pronounced accumulation of p62/SQSTM1 in response to arzanol treatment in HeLa cells. We, therefore, speculate that arzanol acts both as an inducer of early autophagosome biogenesis and as an inhibitor of later autophagy events. We further show that arzanol is able to sensitize RT-112 bladder cancer cells towards cisplatin (CDDP). Its anticancer activity was confirmed in monotherapy against both CDDP-sensitive and -resistant bladder cancer cells. We classified arzanol as a novel mitotoxin that induces the fragmentation of mitochondria, and we identified a series of targets for arzanol that involve proteins of the class of mitochondria-associated quinone-binding oxidoreductases. Collectively, our results suggest arzanol as a valuable tool for autophagy research and as a lead compound for drug development in cancer therapy.

We retrospectively studied 125 patients with acute myeloid leukemia and trisomy 4 (median age at diagnosis, 58 years; range, 16-77 years) treated between 2000 and 2019 within a multicenter study. Trisomy 4 was the sole abnormality in 28 (22%) patients and additional abnormalities were present in 97 (78%) patients. Twenty-two (22%) and 15 (15%) of 101 tested patients harbored NPM1 and FLT3-ITD mutations. Two (3%) of 72 tested patients had double CEBPA mutations. Data on response to intensive anthracycline-based induction therapy were available for 119 patients. Complete remission was achieved in 67% (n=80) and the early death rate was 5% (n=6). Notably, patients with trisomy 4 as sole abnormality had a complete remission rate of 89%. Allogeneic hematopoietic cell transplantation was performed in 40 (34%) patients, of whom 19 were transplanted in first complete remission. The median follow-up of the intensively treated cohort was 5.76 years (95% confidence interval [95% CI]: 2.99-7.61 years). The 5-year overall survival and relapse-free survival rates were 30% (95% CI: 22-41%) and 27% (95% CI: 18-41%), respectively. An Andersen-Gill regression model on overall survival revealed that favorable-risk according to the European LeukemiaNet classification (hazard ratio [HR]=0.34; P=0.006) and trisomy 4 as sole abnormality (HR=0.41; P=0.01) were favorable factors, whereas age with a difference of 10 years (HR=1.15; P=0.11), female gender (HR=0.74; P=0.20) and allogeneic hematopoietic cell transplantation (HR=0.64; P=0.14) did not have an significant impact. In our cohort, patients with trisomy 4 as their sole abnormality had a high complete remission rate and favorable clinical outcome. Allogeneic hematopoietic cell transplantation did not seem to improve overall survival.

Summary: Autophagy, apoptosis, and necroptosis are stress responses governing the ultimate fate of a cell. However, the crosstalk between these cellular stress responses is not entirely understood. Especially, it is not clear whether the autophagy-initiating kinase ULK1 and the cell-death-regulating kinase RIPK1 are involved in this potential crosstalk. Here, we identify RIPK1 as a substrate of ULK1. ULK1-dependent phosphorylation of RIPK1 reduces complex IIb/necrosome assembly and tumor necrosis factor (TNF)-induced cell death, whereas deprivation of ULK1 enhances TNF-induced cell death. We observe that ULK1 phosphorylates multiple sites of RIPK1, but it appears that especially phosphorylation of S357 within the intermediate domain of RIPK1 mediates this cell-death-inhibiting effect. We propose that ULK1 is a regulator of RIPK1-mediated cell death. : Wu et al. show that the autophagy-inducing kinase ULK1 phosphorylates the necroptosis-regulating kinase RIPK1 within its intermediate domain at Ser357. This phosphorylation reduces the assembly of the death-inducing complex IIb/necrosome and, thus, TNF-induced cell death. Keywords: ULK1, RIPK1, RIPK3, autophagy, necroptosis, TNF, MLKL, necrosome, complex I, complex II