High-dose ifosfamide (HD-IFO) remains an effective regimen for advanced bone and soft tissue sarcomas, but predictors of long-term benefit are poorly defined. This study evaluated clinical outcomes and prognostic factors using machine learning-assisted modeling in sarcoma patients treated with HD-IFO at a high-volume academic center. We retrospectively analyzed 26 patients with histologically confirmed bone or soft tissue sarcoma who received HD-IFO (≥ 12 g/m2 per cycle) between 2015 and 2025. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan–Meier method and compared across RECIST response categories using log-rank testing. Prognostic factors were identified using Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression with leave-one-out cross-validation. The top three variables were entered into multivariable logistic regression to estimate odds ratios (ORs) for OS > 24 months. Median PFS and OS from start of HD-IFO was 6.6 months (95

Evidence guiding the optimal sequencing of later-line systemic therapy in advanced soft tissue sarcoma (STS) remains limited. The aim of this study was to identify prognostic factors for overall survival (OS) beyond second-line treatment and to explore therapy sequencing in routine clinical practice. A total of 90 patients with advanced STS receiving third-line or later systemic therapy were retrospectively analyzed. Extreme gradient boosting (XGBoost) was used to identify clinical predictors of 1-year OS. The most influential variables were subsequently evaluated in multivariable Cox models for OS from the start of third- and fourth-line therapy. Sequencing analyses compared OS according to the line of administration of commonly used later-line agents. In the third-line cohort (n = 88), inferior OS was independently associated with progression on second-line therapy (hazard ratio [HR] 2.31, p = 0.005). In contrast, lipo-/leiomyosarcoma histology was associated with improved survival (HR 0.37, p = 0.002), as was a time to progression ≥ 12 months on first-line therapy (HR 0.43, p = 0.007). Findings were largely consistent in the fourth-line cohort (n = 57). Sequencing analyses suggested sustained activity of trabectedin in later lines (p = 0.023), greater benefit of earlier pazopanib use (p = 0.022), and no significant impact of treatment line for gemcitabine + docetaxel combination therapy (p = 0.12). Machine learning-guided variable selection identified clinically relevant predictors of survival in later-line STS. Prior treatment response and histology strongly influence outcomes, and exploratory sequencing analyses suggest differential timing effects across systemic therapy agents.

Acute myeloid leukemia (AML) is a complex disease characterized by diverse molecular pathogenesis. Genetic alterations, including germline and somatic variants in the DEAD box helicase 41 gene ( DDX41) located on chromosome 5 play an increasingly recognized role. Recent reports indicate that 5% of intensively treated adult AML patients harbor DDX41 germline mutations ( DDX41MutGL), and their precise impact remains incompletely understood. These studies suggest that DDX41MutGL may define a distinct biological subgroup, associated with e.g. older age, male gender, low blast, and low white blood cell count (WBC). To further elucidate the role of DDX41 in AML, we performed a retrospective analysis of 906 unselected adult AML patients from the AML Cooperative Group (AMLCG) registry (2015-2022), by targeted sequencing. As DDX41MutGL are typically “null mutations”, leading to reduced DDX41 expression, we additionally investigated whether DDX41 gene expression correlates or resembles the observed germline phenotype. Our analysis encompassed >1000 independent gene expression profiles (GSE37642, GSE14468, and GSE106291) of intensively treated adult AML patients. We identified a sub-cohort with low DDX41 ( DDX41-low) expression and re-analyzed them with next-generation sequencing to detect DDX41MutGL. Additionally, we correlated gene expression data with 198 DNA methylation profiles (from patients who had undergone both analyses) to identify potential epigenetic mechanisms underlying DDX41-low expression. Among the 906 patients (median age 61 years; range 18-98 years), we identified 11 unrelated individuals with suspected DDX41MutGL (VAF > 40%). Notably, the overall frequency of DDX41MutGL in the German unselected AML patient population was merely 1%, considerably lower than previously reported (p<0.0001 in comparison to Duployez et al. 2022). Characteristically, DDX41MutGL patients in this cohort were mostly male (73%), with a median age of 67 years displaying low WBC (average 1,3G/l) and a normal karyotype (80%) at initial diagnosis. Remarkably, our analysis of independent large gene expression cohorts revealed a pattern of phenotypic association in patients with decreased DDX41 expression ( DDX41-low) closely resembling those with DDX41MutGL. These associations were consistent across different datasets and included e.g. older age, low WBC, and low blast count. Furthermore, DDX41-low patients had poor overall survival. The DDX41-low subgroup constituted almost 10% of all AML patients, surpassing the reported frequencies of DDX41MutGL. In an exploratory pilot study, we screened 48 patients exhibiting the lowest DDX41 gene expression by sequencing the coding regions for DDX41 mutations but found none, suggesting alternative mechanisms, such as copy number changes, non-coding alterations or aberrant DNA methylation patterns that may replicate the phenotypic effects associated with DDX41MutGL. To further elucidate this mechanism, we correlated the gene expression of DDX41 with all DNA methylation loci (CpG sites covered by the EPIC array) on chromosome 5 using Spearman correlation analysis (GSE106291). We plotted the correlations against the sorted chromosome length, identifying a peak at a specific location corresponding to the PCDH (Protocadherin) cluster (Figure). Thus, DDX41-low was associated with reduced methylation at the PCDH loci and linked to higher PCDH gene expression. Across several data sets, we confirmed the association between higher PCDH cluster gene expression and low DDX41 expression. In summary, our study reveals that the frequency of DDX41MutGL in an unselected population of German AML patients is considerably lower than previously reported. Additionally, we found that apart from DDX41MutGL, DDX41-low exhibits a comparable clinical profile and is linked to specific methylation and gene expression patterns, with a notable emphasis on the PCDH complex located on chromosome 5. Understanding the functional implications of PCDH genes and their interaction with DDX41 in AML may significantly advance our knowledge of AML pathogenesis. Gaining insights into DDX41 alterations may open avenues for personalized therapeutic approaches and further prognostic stratification for AML patients with distinct molecular characteristics.

Immunochemotherapy induces long-term responses in patients with follicular lymphoma. However, the toxicity of chemotherapy remains a relevant challenge. The Bruton tyrosine kinase inhibitor ibrutinib has shown significant activity in patients with indolent B-cell lymphoma. Combining ibrutinib with obinutuzumab may, therefore, be an attractive chemotherapy-free option. We conducted a prospective, single-arm, multicenter phase II trial to evaluate the chemotherapy-free regimen of obinutuzumab plus ibrutinib in patients with previously untreated advanced-stage follicular lymphoma. Patients received six 21-day cycles of ibrutinib and obinutuzumab for induction and 12 additional 2-month cycles for maintenance. The primary endpoint was 1-year progression-free survival (PFS). The study was powered to detect an improvement of 10% over the 1-year PFS of 85%. Ninety-eight patients were enrolled in the trial. The median follow-up was 5.5 years. After induction, five patients (5%) had a complete response and 82 (85%) had a partial response. The 1-year PFS was 80%, missing the prospected improvement of a 1-year PFS of 85% (P=0.93). The median PFS was 4.5 years; median duration of response and overall survival were not reached. The most common adverse events of grade 3/4 were neutropenia, lung infection, hypertension, fatigue, rash and thrombocytopenia. The trial of a chemotherapy-free regimen of obinutuzumab and ibrutinib in follicular lymphoma patients failed to demonstrate a 10% improvement in the primary efficacy endpoint. However, the combination produced durable and deep responses and had an acceptable safety profile. Trial registration, EudraCT-Number: 2014-005164-15.

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 (n = 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 (AI) as first-line induction therapy without prior metastasis-directed local therapy, the median EFS and OS from the start of AI 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 (p = 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.

Background: Follicular lymphoma (FL) remains a clinical challenge due to its relapsing course and difficulty in tailoring therapies to individual risk. Frontline treatment commonly includes an anti-CD20 antibody with either bendamustine or CHOP/CVP. Bendamustine has been associated with longer progression-free survival (PFS) compared to CHOP/CVP in the GALLIUM trial. However, bendamustine was also associated with more grade 3-5 infections, prolonged T-cell reduction, fatal events, and second neoplasms(Hiddemann, 2017). Additional concerns include its immunosuppressive effects and potential to impair subsequent T-cell based therapies including CAR-T cells (Iacoboni, 2024). This highlights the need to better identify patients who benefit most and least from bendamustine. Here, we used our gene mutation data to identify predictive biomarkers of bendamustine benefit and validated our findings in a large international real-life cohort. Methods: The GALLIUM trial (NCT01332968) enrolled 1,202 patients with previously untreated, advanced-stage FL (stage III/IV or bulky stage II) and ECOG 0–2, all requiring treatment per GELF criteria. Patients were randomized to receive rituximab or obinutuzumab with CHOP, CVP, or bendamustine allocated by the treating center (Marcus, 2017). Targeted sequencing of recurrently mutated genes was available for diagnostic biopsies from 418 evaluable cases. Kaplan-Meier and Cox regression analyses were used to correlate gene mutations with clinical outcomes. The median follow-up in the GALLIUM cohort was 6.9 years; 283 patients (68%) received bendamustine, 135 (33%) received CHOP or CVP. The validation cohort consisted of 473 patients from Australia (N=208), USA (N=138), and Canada (N=127). The median follow-up in the validation cohort was 5.5 years; 181 patients (38%) received bendamustine- and 292 (62%) received CHOP- or CVP-based immunochemotherapies. Results: In this updated analysis with longer follow-up, we confirmed that the previously described clinicogenetic risk model m7-FLIPI (Pastore, 2015) predicts PFS in CHOP/CVP–treated patients, but not in those receiving bendamustine. The mutation status of two of the seven m7-FLIPI genes was associated with differing PFS outcomes in patients treated with CHOP/CVP vs bendamustine: Patients with wild-type EZH2 had significantly shorter PFS with CHOP/CVP-based therapies compared to EZH2-mutated cases (HR=0.43, p=0.020); notably, no difference in PFS was observed in the bendamustine cohort. In addition, CREBBP mutations were associated with shorter PFS after CHOP/CVP (HR=2.05, p=0.037), but not after bendamustine. None of the other m7-FLIPI gene mutations predicted PFS in bendamustine-treated patients. Based on these findings, we combined the EZH2 and CREBBP mutation status to stratify patients. Only patients with both a CREBBP mutation and wild-type EZH2 showed a clinically relevant benefit from bendamustine, with significantly longer PFS compared to CHOP/CVP-treated patients (HR=0.44, p=0.00011) and similar OS (HR=0.62, p=0.27). All other patients had similar PFS with either regimen (HR=1.05, p=0.86), but we observed a trend to longer OS with CHOP/CVP (HR=2.19, p=0.11). These results were confirmed in the validation cohort: EZH2 mutations were associated with longer PFS in patients receiving CHOP/CVP (HR=0.62, p=0.025), while CREBBP mutations were associated with shorter PFS (HR 1.42, p=0.033). Again, none of the m7-FLIPI gene mutations were predictive of PFS in bendamustine-treated patients. Stratification based on EZH2 and CREBBP mutation status validated the previous results: only patients with both a CREBBP mutation and wild-type EZH2 had a PFS benefit from bendamustine (HR 0.61, p=0.027), again with similar OS (HR=0.75, p=0.48). Likewise, all other patients experienced similar PFS with either regimen (HR=1.07, p=0.73), but again had a trend towards longer OS when treated with CHOP/CVP (HR=1.75, p=0.068). Conclusion: Our findings suggest that EZH2 and CREBBP mutation status can inform treatment selection in FL. Patients with CREBBP mutations and wild-type EZH2 benefit most from bendamustine with significantly longer PFS and similar OS; all other patients had similar PFS with either regimen but a trend towards longer OS with CHOP/CVP. These data may indicate a distinct biology in FL with CREBBP mutations and wild-type EZH2, and support the use of simple mutation testing to guide personalized therapy in newly diagnosed advanced-stage patients.

Whether patients with acute myeloid leukemia (AML) harboring Nucleophosmin mutations (NPM1mut) with measurable residual disease (MRD) should undergo allogeneic stem cell transplantation (alloSCT) in complete remission (CR) remains subject of debate. This study aimed to assess whether the presence of bone marrow (BM) NPM1mut MRD, detected using a RT-qPCR assay with a sensitivity of 10-5, could influence the benefit derived from alloSCT. Data from four German transplantation centers were analyzed including 174 AML NPM1mut patients who underwent a first alloSCT between 2011-2022. Among 122 patients transplanted in complete remission (CR), pre-alloSCT MRD was positive in 54%. After alloSCT, the cumulative rate of BM MRD negativity increased from 65% by day +30 to 73% by day +100, with FLT3-ITD and ELN risk profile significantly impacting on MRD conversion rate at day +30. No significant difference in leukemia-free survival (LFS) and overall survival (OS) based on pre-transplant MRD status (3y LFS MRD+ 60% vs MRD- 74%, HR 1.5, p=0.28; 3y OS MRD+ 68% vs MRD- 78%, HR 1.42, p=0.39) was observed. Outcomes between MRD persistence and molecular relapse did not differ (p=0.8). Whereas adverse molecular risk features (HR 4.69, p=0.003) and relapsed/refractory disease (HR 2.83/3.59, p=0.005/0.001) were associated with unfavorable prognosis, administration of post-transplant maintenance improved survival in multivariable analysis (HR 0.48, p=0.06). Our findings suggest that in patients with NPM1mut AML MRD positivity as assessed per qPCR at time of transplant does not impact posttransplant outcomes of NPM1mut AML.

ABSTRACT Background Dacarbazine is currently considered the better combination partner for doxorubicin compared to ifosfamide for the treatment of leiomyosarcoma (LMS). Regional hyperthermia (RHT) combined with neoadjuvant chemotherapy has been shown to improve survival in patients with locally advanced high‐risk STS. We sought to evaluate the role of doxorubicin and dacarbazine (AD) versus doxorubicin and ifosfamide (AI) in combination with RHT in patients with LMS. Methods Patients with locally advanced high‐grade LMS, including limited metastases, eligible for RHT and first‐line treatment with either AI + RHT or AD + RHT between 2014 and 2022 were retrospectively evaluated. Endpoints were progression‐free survival (PFS) and overall survival (OS). Patients were matched using propensity scores, which were estimated with a logistic regression model accounting for tumor site, presence of metastasis, surgery, and radiotherapy. Results A total of 105 patients were included in this study, of which 101 were included in the propensity score‐matched cohort. In the matched cohort, treatment with AD + RHT was associated with a significantly improved PFS (HR 0.32, 95% CI 0.13–0.74, p = 0.0081). Multivariable analysis revealed several significant predictors of PFS, including treatment with AD + RHT (HR 0.42, 95% CI 0.19–0.92, p = 0.031). Conclusion Treatment with AD + RHT showed improved PFS and better treatment tolerability compared to AI + RHT. Our results support the use of AD instead of AI for the treatment of patients with LMS in combination with RHT.

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. 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. 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). 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 myeloid leukemia (AML) is a heterogenous malignancy and efficient treatment strategies for high-risk patients are still lacking. To facilitate preclinical and translational leukemia research, e.g. to test novel therapeutics in vivo, we generate patient-derived xenograft (PDX) samples. We had transplanted more than 100 primary adult AML samples into immune-compromised NSG mice. Furthermore, we received PDX samples primografted in other labs of pediatric and adult patients. However, only around 20% of primary samples (i.e. “high score samples”) show a robust and reliable serial engraftment and can be genetically modified, facilitating repetitive, reproducible and convenient in vivo experiments. Aims: (i) Identifying factors influencing reliable serial engraftment; (ii) Characterizing high score samples functionally and genetically; (iii) Performing in vivo (therapy) trials. Methods: We generated 23 high score AML PDX samples characterized by (i) a serial, fast, reliable and systemic engraftment, and (ii) the capacity to be genetically engineered. These samples were characterized by DNA panel sequencing (seq), whole exome seq, low coverage whole genome seq, RNA seq, methylation profiling, karyotyping, and immunophenotyping. Furthermore, samples were transplanted repetitively, and capacity for serial engraftment was analyzed. Last, samples were used for diverse in vivo trials, e.g. long-term chemotherapy trials. Results: High score samples originated mainly from relapsed AML cases (18/23, p<0.05). Overall survival (OS) of patients whose cells yielded high score samples was dramatically lower compared to OS of patients whose cells did not engraft or meet the criteria of high score samples (p<0.01). Analysis of AML-related mutations, gene fusions, translocations, copy number alterations and immunophenotype revealed that high score AML PDX samples resembled primary patient cells of both, initial diagnosis and relapsed disease, and - in contrast to established AML cell lines - covered many different genetic and genomic alterations. Within the WHO classification of 2022, most samples belonged to one of the three groups “AML with NPM1 mutation” (n=8), “AML with KMT2A rearrangement” (n=7), or “AML, myelodysplasia-related” (n=6). High score samples were serially transplanted into recipient mice, with up to fifteen repetitive transplantations. Importantly, we did not lose a sample in serial re-transplantations, indicating that leukemia initiating cells proliferated within the murine niche for many months (median 412 days). On the contrary, under in vitro conditions, cells could be kept for some days to weeks, but ultimately died. With every engraftment, PDX cells can be amplified by a factor 30-fold or higher, depending on the sample, allowing the production of indefinite numbers of PDX cells. Engraftment capacity and engraftment time were influenced by several factors; thawed PDX cells and injection of cell numbers below 500,000 cells had a reduced engraftment rate and a longer passaging time compared to freshly isolated cells or higher cells numbers. Serial re-passaging or expression of transgenes did, however, not influence engraftment. While murine gender influenced engraftment capacity of some samples, with male mice being less supportive, mouse age did not, and even older mice with more than 20 weeks of age allowed reliable engraftment. High score AML PDX samples were further used in preclinical in vivo therapy trials. Stable luciferase expression allowed sensitive disease monitoring, facilitating real-time analysis of drug effects and of growth kinetics before and after treatment. Bioluminescence imaging revealed that azacitidine, in contrast to cytarabine, had a delayed effect on tumor burden. Both drugs, however, showed a sustained effect on the cells even after stop of long-term therapy, indicated by a reduced growth rate after treatment. Conclusion and Outlook: High score AML PDX models represent highly aggressive primary patients' cells. By serial engraftment and genetic engineering, we can produce indefinite numbers of these cells, which represent a valuable and unique tool for sophisticated molecular and functional studies. Our well characterized AML PDX cohort allows repetitive and reproducible preclinical trials, and luciferase expression facilitates reliable monitoring of long-term therapy trials.

Preclinical cancer research requires robust model systems, especially for poor prognosis entities like acute myeloid leukemia (AML), a highly aggressive blood cancer. Here, primary tumor cells from 137 AML patients of all age groups were transplanted into immune compromised mice to generate patient-derived xenografts (PDX). From these, 23 models enable robust, virtually endless serial re-transplantation and are amenable to lentiviral genetic engineering (*PDX AML models). These models primarily originate from patients with highly aggressive, relapsed disease. Comprehensive genomic, transcriptomic, and epigenomic analyses confirmed that they replicate primary AML biology more faithfully than conventional cell lines. Notably, *PDX AML models include AML subgroups that are underrepresented or absent in existing model systems, such as cytogenetically normal or IDH1/2 -mutant AML. They withstand freeze-thaw cycles, making them suitable for broad distribution and reproducibility across research institutions. Luciferase-based in vivo imaging enables real-time monitoring of tumor progression and treatment responses in preclinical trials. Surprisingly, long-term treatment, including repeated cytarabine therapy over a period of one year, showed a gradual reduction in leukemia cell proliferation, which decreased continuously after each treatment block. Collectively, our *PDX models represent a robust, versatile, and relevant platform that holds great promise to accelerate translational research for the benefit of cancer patients. ![Figure][1] Key Points ### Competing Interest Statement TH: Travel support: Jazz Pharmaceuticals; Participation on Advisory Board: Servier and Jazz Pharmaceuticals; honoraria for speakers: Astellas Pharma. All other authors declare no competing interest. European Research Council, https://ror.org/0472cxd90, 681524 Deutsche Forschungsgemeinschaft, https://ror.org/018mejw64, 537701335, SFB 1709/1 2025 - 533056198 German Cancer Aid, https://ror.org/01wxdd722, Mildred Scheel Professorship Deutsche José Carreras Leukämie-Stiftung, https://ror.org/00826gz80, DJCLS 15 R/2021, DJCLS 02 R/2023 Bettina Bräu Stiftung Dr. Helmut Legerlotz Stiftung [1]: pending:yes

Pulmonary metastasectomy (PM) is the most frequently performed local ablative therapy for leiomyosarcoma (LMS), synovial sarcoma (SyS), and undifferentiated pleomorphic sarcoma (UPS). This study aimed to assess surgical feasibility, outcome, and clinical prognostic factors, as well as the value of a peri-interventional systemic therapy. This multicenter retrospective study enrolled 77 patients with LMS, SyS, or UPS who underwent first-time complete resection of isolated lung metastases between 2009 and 2021. Disease-free survival (DFS), overall survival (OS), and clinical prognostic factors were analyzed. After the first PM, the median DFS was 7.4 months, and the median OS was 58.7 months. A maximal lesion diameter greater than 2 cm was associated with reduced DFS in both the univariable (hazard ratio [HR], 2.29; p = 0.006) and multivariable (HR, 2.60; p = 0.005) analyses. The univariable analysis identified a maximal lesion diameter greater than 2 cm as an adverse prognostic factor for OS (HR, 5.6; p < 0.001), whereas a treatment-free interval longer than 12 months was associated with improved OS (HR, 0.42; p = 0.032). The addition of systemic therapy was associated with a trend toward improved DFS for patients with lesions larger than 2 cm (HR, 0.29; p = 0.063). Severe postoperative complications (grade ≥IIIa) occurred in 2

Primary cardiac sarcomas (PCS) are rare, aggressive malignancies with poor prognosis and limited evidence guiding optimal management. We aimed to evaluate clinical and histopathological parameters in a single-center PCS cohort. Thirty-three patients diagnosed with PCS between 2002 and 2024 were retrospectively reviewed. Clinical outcomes and prognostic factors were analyzed. Event-free survival (EFS) was defined as the time from initial diagnosis to the first occurrence of disease progression, recurrence, or death. Overall survival (OS) was calculated from initial diagnosis to death. The median age at diagnosis was 45 years, with angiosarcoma representing the most common histological subtype (n = 9, 27

The outcome of patients with acute myeloid leukemia (AML) worsens with increasing age. Dichotomization into “younger” and “older” patients is clinically routine and often dictates treatment options. We aimed to delineate whether molecular genetic features and/or outcome measures support assorting patient populations by age, including division into “younger” and “older” groups. We analyzed 2823 adult AML patients enrolled onto frontline chemotherapy-based clinical protocols of two cooperative study groups from USA and Germany who were profiled molecularly via targeted sequencing platforms. Frequencies of gene mutations and cytogenetic findings were depicted in 5-year age increments. Clinical outcomes of 2756 AML patients were analyzed with respect to molecular features, genetic-risk groups and age. Age-associated distributions of gene mutations and cytogenetic abnormalities were similar in both cohorts. There was almost linear shortening of overall survival with increasing age among all patients (P < 0.001) and within 2022 European LeukemiaNet-defined genetic-risk groups, with survival decreasing as age increased (favorable-risk, P < 0.001; intermediate-risk, P < 0.001; adverse-risk, P < 0.001). Although mutational profiles and outcomes of the youngest patients differed from those of older patients, there was no age cut-off identifying “younger” and “older” patients. These findings support more age-associated flexibility for drug approval and trial eligibility.

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.

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. 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. 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. 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.

Clinical outcome of patients with acute myeloid leukemia (AML) is associated with demographic and genetic features. Although the associations of acquired genetic alterations with patients’ sex have been recently analyzed, their impact on outcome of female and male patients has not yet been comprehensively assessed. We performed mutational profiling, cytogenetic and outcome analyses in 1726 adults with AML (749 female and 977 male) treated on frontline Alliance for Clinical Trials in Oncology protocols. A validation cohort comprised 465 women and 489 men treated on frontline protocols of the German AML Cooperative Group. Compared with men, women more often had normal karyotype, FLT3 -ITD, DNMT3A , NPM1 and WT1 mutations and less often complex karyotype, ASXL1 , SRSF2 , U2AF1 , RUNX1 , or KIT mutations. More women were in the 2022 European LeukemiaNet intermediate-risk group and more men in adverse-risk group. We found sex differences in co-occurring mutation patterns and prognostic impact of select genetic alterations. The mutation-associated splicing events and gene-expression profiles also differed between sexes. In patients aged <60 years, SF3B1 mutations were male-specific adverse outcome prognosticators. We conclude that sex differences in AML-associated genetic alterations and mutation-specific differential splicing events highlight the importance of patients’ sex in analyses of AML biology and prognostication.

Rituximab, gemcitabine and oxaliplatin (R-GemOx) has demonstrated to be effective and safe in lymphoma patients. We aimed to determine the maximum tolerated dose (MTD) of oxaliplatin in combination with rituximab and gemcitabine and to explore the efficacy and safety of R-GemOx in relapsed or refractory (r/r) indolent and mantle cell lymphoma (MCL). In this single-arm, phase I/II trial, we enrolled 55 patients with r/r indolent lymphoma and MCL not suitable for autologous stem-cell transplantation. Patients received 4 cycles of R-GemOx. In the dose escalation group, 70 mg/m 2 of oxaliplatin was applied and interindividually increased by 10 mg/m 2 until the MTD was reached together with fixed doses of rituximab and gemcitabine. At the oxaliplatin MTD, an extension cohort was opened. Primary aim was to detect an overall response rate (ORR) greater than 65% (α = 0.05). Oxaliplatin 70 mg/m 2 (MTD) was chosen for the extension cohort after 3 of 6 patients experienced a DLT at 80 mg/m 2 . Among 46 patients evaluable for the efficacy analysis ORR was 72% (33/46), missing the primary aim of the study ( p = 0.21). After a median follow-up of 7.9 years, median PFS and OS were 1.0 and 2.1 years. Most frequent grade ≥ 3 adverse events were cytopenias. R-GemOx induces decent response rates in r/r indolent lymphoma and MCL, though novel targeted therapies have largely replaced chemotherapy in the relapse setting. Particularly in MCL, R-GemOx might be an alternative option in late relapses or as bridging to CAR-T-cells. This study was registered with ClinicalTrials.gov on Aug 4th, 2009, number NCT00954005.