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Background The inclusion of high-dimensional omics data in prediction models has become a well-studied topic in the last decades. Although most of these methods do not account for possibly different types of variables in the set of covariates available in the same dataset, there are many such scenarios where the variables can be structured in blocks of different types, e.g., clinical, transcriptomic, and methylation data. To date, there exist a few computationally intensive approaches that make use of block structures of this kind. Results In this paper we present priority-Lasso, an intuitive and practical analysis strategy for building prediction models based on Lasso that takes such block structures into account. It requires the definition of a priority order of blocks of data. Lasso models are calculated successively for every block and the fitted values of every step are included as an offset in the fit of the next step. We apply priority-Lasso in different settings on an acute myeloid leukemia (AML) dataset consisting of clinical variables, cytogenetics, gene mutations and expression variables, and compare its performance on an independent validation dataset to the performance of standard Lasso models. Conclusion The results show that priority-Lasso is able to keep pace with Lasso in terms of prediction accuracy. Variables of blocks with higher priorities are favored over variables of blocks with lower priority, which results in easily usable and transportable models for clinical practice.

Mg 2+ regulates many physiological processes and signalling pathways. However, little is known about the mechanisms underlying the organismal balance of Mg 2+ . Capitalizing on a set of newly generated mouse models, we provide an integrated mechanistic model of the regulation of organismal Mg 2+ balance during prenatal development and in adult mice by the ion channel TRPM6. We show that TRPM6 activity in the placenta and yolk sac is essential for embryonic development. In adult mice, TRPM6 is required in the intestine to maintain organismal Mg 2+ balance, but is dispensable in the kidney. Trpm6 inactivation in adult mice leads to a shortened lifespan, growth deficit and metabolic alterations indicative of impaired energy balance. Dietary Mg 2+ supplementation not only rescues all phenotypes displayed by Trpm6 -deficient adult mice, but also may extend the lifespan of wildtype mice. Hence, maintenance of organismal Mg 2+ balance by TRPM6 is crucial for prenatal development and survival to adulthood. A balanced diet contains a variety of minerals such as magnesium ions, which are required for many chemical reactions in our body. A shortage of magnesium ions is linked to many diseases and is thought to be especially harmful to babies in the womb and shortly after birth. Magnesium ion deficiency is widespread in human populations and in the US is thought to affect up to 68% of people. Despite its prominent role in human health, our understanding of how the body maintains the right balance of magnesium ions remains extremely vague. Magnesium ions can enter and leave a cell by passing through specific types of proteins that form channels in the membrane surrounding the cell. There are thought to be around ten types of these magnesium ion channels in human cells, but we do not know what roles any of them perform in the body. One such channel called TRPM6 may be particularly important because mutations in the gene that encodes this channel can cause magnesium ion deficiency in human infants. However, the loss of TRPM6 in mice disrupts how mouse embryos develop, suggesting that our current view on the role that TRPM6 plays in regulating the magnesium ion balance in humans may be too simplistic. To address this question, Chubanov et al. studied mice with mutations that disrupted the production of TRPM6 in specific tissues only. The experiments show that TRPM6 primarily operates in the placenta and intestine to regulate the balance of magnesium ions in the body. Further experiments show that the loss of TRPM6 in adult mice leads to reduced lifespan, growth defects and poor health by disrupting important biochemical reactions. Supplying the mutant mice with magnesium ion supplements improved their health and could extend lifespans of normal animals. The findings of Chubanov et al. demonstrate that TRPM6 plays a crucial role in regulating the levels of magnesium ions in mice before birth and into adulthood. The next step is to carry out large-scale experiments to investigate the effects of altering the levels of magnesium ions in human diets.

High-throughput sequencing describes multiple alterations in individual tumors, but their functional relevance is often unclear. Clinic-close, individualized molecular model systems are required for functional validation and to identify therapeutic targets of high significance for each patient. Here, we establish a Cre-ER T2 -loxP (causes recombination, estrogen receptor mutant T2, locus of X-over P1) based inducible RNAi- (ribonucleic acid interference) mediated gene silencing system in patient-derived xenograft (PDX) models of acute leukemias in vivo. Mimicking anti-cancer therapy in patients, gene inhibition is initiated in mice harboring orthotopic tumors. In fluorochrome guided, competitive in vivo trials, silencing of the apoptosis regulator MCL1 (myeloid cell leukemia sequence 1) correlates to pharmacological MCL1 inhibition in patients´ tumors, demonstrating the ability of the method to detect therapeutic vulnerabilities. The technique identifies a major tumor-maintaining potency of the MLL-AF4 (mixed lineage leukemia, ALL1-fused gene from chromosome 4) fusion, restricted to samples carrying the translocation. DUX4 (double homeobox 4) plays an essential role in patients’ leukemias carrying the recently described DUX4-IGH (immunoglobulin heavy chain) translocation, while the downstream mediator DDIT4L (DNA-damage-inducible transcript 4 like) is identified as therapeutic vulnerability. By individualizing functional genomics in established tumors in vivo, our technique decisively complements the value chain of precision oncology. Being broadly applicable to tumors of all kinds, it will considerably reinforce personalizing anti-cancer treatment in the future. Preclinical molecular models are useful that mimic a patient´s response to targeted therapy. Here, the authors establish an in vivo inducible RNAi-mediated gene silencing system in patient-derived xenograft models of acute leukemia to identify individual vulnerabilities and therapeutic targets.

Previous studies demonstrated that splicing factor mutations are recurrent events in hematopoietic malignancies with both clinical and functional implications. However, their aberrant splicing patterns in acute myeloid leukemia remain largely unexplored. In this study, we characterized mutations in SRSF2, U2AF1, and SF3B1, the most commonly mutated splicing factors. In our clinical analysis of 2678 patients, splicing factor mutations showed inferior relapse-free and overall survival, however, these mutations did not represent independent prognostic markers. RNA-sequencing of 246 and independent validation in 177 patients revealed an isoform expression profile which is highly characteristic for each individual mutation, with several isoforms showing a strong dysregulation. By establishing a custom differential splice junction usage pipeline, we accurately detected aberrant splicing in splicing factor mutated samples. A large proportion of differentially used junctions were novel, including several junctions in leukemia-associated genes. In SRSF2(P95H) mutants, we further explored the possibility of a cascading effect through the dysregulation of the splicing pathway. Furthermore, we observed a validated impact on overall survival for two junctions overused in SRSF2(P95H) mutants. We conclude that splicing factor mutations do not represent independent prognostic markers. However, they do have genome-wide consequences on gene splicing leading to dysregulated isoform expression of several genes.

Background The current understanding of the prognostic value of routine pre-treatment laboratory parameters in patients with high-risk soft tissue sarcoma (HR-STS) is limited. We sought to analyze several inflammatory biomarkers in a large cohort of HR-STS patients undergoing neoadjuvant therapy followed by curative surgical resection. Methods 123 patients with locally advanced high-risk undifferentiated pleomorphic sarcoma (UPS), liposarcoma (LPS), leiomyosarcoma (LMS), and synovial sarcoma (SS) who underwent preoperative chemotherapy and regional hyperthermia (RHT) between 2014 and 2022 were retrospectively evaluated. The association of several pre-treatment laboratory parameters with radiologic treatment response, event-free survival (EFS), and overall survival (OS), were analyzed. Results Low pre-treatment hemoglobin (HR 2.51, p  = 0.018; HR 2.78, p  = 0.030) and lactate dehydrogenase (LDH, HR 0.29, p  = 0.0044; HR 0.23, p  = 0.010) were significantly associated with EFS and OS in the multivariable analysis. Systemic inflammatory indices such as the neutrophil-to-lymphocyte ratio (NLR) did not have a significant impact on survival. Low C-reactive protein (CRP) and high albumin values were associated with poor radiologic response according to RECIST ( p  = 0.021 and p  = 0.010, respectively). Conclusion Pre-treatment LDH and hemoglobin are strong independent predictors of survival in HR-STS patients. Systemic inflammatory indices based on circulating immune cells may not serve as reliable prognostic factors for HR-STS patients undergoing curative-intent treatment. Higher pre-treatment albumin levels and lower CRP values may reflect a reduced inflammatory status and could be associated with a poorer radiologic response to preoperative treatment.

Background Acute leukemias represent deadly malignancies that require better treatment. As a challenge, treatment is counteracted by a microenvironment protecting dormant leukemia stem cells. Methods To identify responsible surface proteins, we performed deep proteome profiling on minute numbers of dormant patient-derived xenograft (PDX) leukemia stem cells isolated from mice. Candidates were functionally screened by establishing a comprehensive CRISPR‒Cas9 pipeline in PDX models in vivo. Results A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) was identified as an essential vulnerability required for the survival and growth of different types of acute leukemias in vivo, and reconstitution assays in PDX models confirmed the relevance of its sheddase activity. Of translational importance, molecular or pharmacological targeting of ADAM10 reduced PDX leukemia burden, cell homing to the murine bone marrow and stem cell frequency, and increased leukemia response to conventional chemotherapy in vivo. Conclusions These findings identify ADAM10 as an attractive therapeutic target for the future treatment of acute leukemias. Highlights - Ultra-deep proteomics of minute leukemia stem cells uncovers increased cell adhesion. - In vivo PDX CRISPR-Cas9 screens identify ADAM10 as essential for leukemia in mice. - ADAM10 knockout impairs the leukemia-niche interaction and stem cell numbers. - Therapeutic targeting of ADAM10 reduces PDX leukemia fitness and augments therapy.

Purpose Epithelioid hemangioendothelioma (EHE) represents an ultra-rare, translocated vascular sarcoma with a heterogeneous course of disease. The optimal systemic treatment for patients with advanced EHE remains unclear. We sought to evaluate the value of pazopanib (PAZ) as a first-line treatment in metastatic EHE. Methods Thirteen patients with metastatic EHE and PAZ as a first-line treatment at our institution between 2012 und 2023 were reviewed and analyzed with regard to clinical outcomes. Results At a median follow-up of 51.4 months, the median progression-free survival (PFS) and overall survival (OS) were 35.1 and 53.8 months, respectively. In patients with documented prior tumor progression ( n  = 10), the median PFS and OS were 12.6 and 105 months, respectively. In patients with serosal effusion/ systemic symptoms ( n  = 4), the median PFS and OS were 6.1 and 10.3 months. The clinical benefit rate of the overall cohort was 62% with no complete or partial responses. Two of four patients experienced a reduction of symptoms (pain and ascites reduction/hemoptysis, respectively) under treatment with PAZ. Toxicity was mainly gastrointestinal and manageable with dose reductions. Permanent treatment interruption due to toxicity was necessary in one patient. Conclusion This is the first study to systematically report survival outcomes for PAZ as a first-line treatment in patients with metastatic EHE. PAZ is active and safe in patients with metastatic EHE and may be considered as an alternative to sirolimus for specific patient subgroups. RECIST criteria should be questioned for evaluation of treatment response in EHE.

Background The prognostic and predictive value of obesity and sarcopenia remains poorly defined in patients with high-risk soft tissue sarcoma (HR-STS). We sought to correlate clinical outcomes with CT-based body composition parameters in patients with HR-STS undergoing a multimodal preoperative therapy. The impact of radiologic and histopathologic response to preoperative treatment was correlated with individual fat and muscle distribution. Methods Patients with locally advanced non-abdominal HR-STS and treatment with preoperative chemotherapy + regional hyperthermia (RHT) +/- radiotherapy (RT) followed by surgery between 2015 and 2022 were retrospectively evaluated. Body composition parameters measured on baseline CT scans were correlated with clinical outcomes including event-free survival (EFS) and overall survival (OS) as well as radiologic and histopathologic treatment response. Results A total of 85 patients were included. Body composition parameters showed no significant correlation with radiologic or histopathologic treatment response. High total fat indices such as the total fat index (TFI, HR 3.56, p  = 0.005) and high total fat to muscle ratio (FMR, HR 3.22, p  = 0.020) were strongly associated with poor OS. Parameters for sarcopenia including skeletal muscle index (SMI) were not significantly linked to survival outcomes. Conclusion High fat indices and a high FMR are strong predictors of poor OS in patients with HR-STS. Larger studies are warranted to further clarify the prognostic impact of sarcopenia and the predictive value of body composition parameters on preoperative treatment response.

Acute lymphoblastic leukemia (ALL) represents the most frequent malignancy in children, and relapse/refractory (r/r) disease is difficult to treat, both in children and adults. In search for novel treatment options against r/r ALL, we studied inhibitor of apoptosis proteins (IAP) and Smac mimetics (SM). SM‐sensitized r/r ALL cells towards conventional chemotherapy, even upon resistance against SM alone. The combination of SM and chemotherapy‐induced cell death via caspases and PARP, but independent from cIAP‐1/2, RIPK1, TNFα or NF‐κB. Instead, XIAP was identified to mediate SM effects. Molecular manipulation of XIAP in vivo using microRNA‐30 flanked shRNA expression in cell lines and patient‐derived xenograft (PDX) models of r/r ALL mimicked SM effects and intermediate XIAP knockdown‐sensitized r/r ALL cells towards chemotherapy‐induced apoptosis. Interestingly, upon strong XIAP knockdown, PDX r/r ALL cells were outcompeted in vivo , even in the absence of chemotherapy. Our results indicate a yet unknown essential function of XIAP in r/r ALL and reveal XIAP as a promising therapeutic target for r/r ALL. Synopsis Smac mimetics sensitize relapsed/refractory acute leukemia (r/r ALL) cell lines towards chemotherapy, independently from TNFα, RIPK1, NFκB and cIAP1/2 signaling. Knockdown in PDX models shows that XIAP harbors an essential function in vivo and represents an important therapeutic target for r/r ALL. r/r ALL cell lines are sensitized to standard chemotherapy by co‐treatment with Smac mimetics (SM). TNFα, RIPK1, NFκB and cIAP1/2 are dispensable for apoptosis induced by the combination of SM and conventional chemotherapy in r/r ALL. To study the role of XIAP in vivo , a miR30‐based, fluorochrome‐guided system was established, with distinct promoters inducing different knockdown strengths. Moderate XIAP knockdown mimics the effects of SM and sensitizes r/r ALL to chemotherapy, making XIAP an interesting therapeutic target to enhance chemotherapy. In PDX models in vivo , strong XIAP knockdown alone reduces ALL growth, demonstrating that XIAP harbors an essential function and represents an interesting therapeutic target in r/r ALL. Graphical Abstract Smac mimetics sensitize relapsed/refractory acute leukemia (r/r ALL) cell lines towards chemotherapy, independently from TNFα, RIPK1, NFκB and cIAP1/2 signaling. Knockdown in PDX models shows that XIAP harbors an essential function in vivo and represents an important therapeutic target for r/r ALL.

Background: The prognosis of patients with advanced soft tissue sarcoma (STS) remains dismal. Trofosfamide (TRO) has been proposed as a well-tolerated oral maintenance therapy. This retrospective analysis aims to determine the value of this therapy. Methods: Fifty-nine patients with advanced STS who received TRO maintenance therapy between 2016 and 2022 were reviewed and analysed regarding clinical parameters and outcomes. Results: The median age was 48 years; the most common histological subtype was synovial sarcoma (n = 22,37%), and 71% of patients (n = 42) presented with metastatic disease. No radiological evidence of disease (NED) before the start of maintenance was reported in 36% of patients (п = 21). The median follow-up was 38.2 months with a median maintenance duration of 9.0 months. The median event-free survival (EFS) and overall survival (OS) were 9.5 and 33.2 months, respectively. In metastatic patients achieving NED before the initiation of TRO, the median EFS was 29.4 months, while the median OS was not reached. In metastatic patients with anthracycline + ifosfamide (Al) as first-line induction therapy without prior metastasis-directed local therapy, the median EFS and OS from the start of Al were 13.9 and 26.8 months, respectively. Multivariate analysis of the overall cohort demonstrated that NED before the start of maintenance was significantly associated with a prolonged EFS (p = 0.024, hazard ratio [HR] = 0.26), and G2 histology correlated with longer OS (р = 0.030, HR = 0.16, reference: G3). Interpretation: Oral maintenance therapy with TRO appears to improve outcomes in patients with advanced STS. Metastatic patients who achieve NED through prior metastasectomy may particularly benefit from TRO maintenance.