Background Biomarkers are desirable to characterize individual tumors and to personalize multimodal treatment in locally advanced rectal cancer patients. In this regard, monitoring of High Mobility Group Box 1 (HMGB1) protein in blood samples is of interest in radiotherapy as HMGB1 is a consensus marker for immunogenic cell death (ICD) during anticancer treatment.Patients and methods Plasma levels of HMGB1 were monitored weekly during long-term neoadjuvant chemoradiotherapy in 19 patients with locally advanced rectal cancer. HMGB1 levels were correlated with outcome and tumor volumes in magnetic resonance imaging (MRI) pre-therapeutically as well as in week 2 and week 5 of treatment. Furthermore, the association with circulating cell-free tumor DNA (ctDNA) was evaluated.Results Higher pre-therapeutic levels of HMGB1 correlated positively with bigger initial MRI volumes and higher allele frequencies of ctDNA in the corresponding baseline blood sample. Courses of HMGB1 during treatment were variable and mostly undulating. Predominant ascent was observed in four patients who showed poor pathologic response. Declining levels in week 2 / 3 were associated with bigger percentage decrease of MRI tumor volume at the end of week 2.Conclusions HMGB1 seems to be associated mostly with tumor burden as indicated by correlation with MRI volumes and ctDNA levels, rather than ICD induction or side effects as previously reported. Changes during treatment might predict clinical disease course.

PURPOSE:Given the early recurrence of brain metastasis (BM), identifying factors that drive BM progression is of clinical interest. This study investigates genetic, epigenetic, and inflammatory signatures in progressive BM following different therapeutic approaches. METHODS:A total of 153 patients who underwent surgical resection for progressive BM were grouped according to the therapeutic strategies prior to the first BM resection: prior radiation (n = 43), systemic therapy (n = 37), combined radiation and systemic treatment (n = 10), and treatment-naive patients (n = 63). Among the treatment-naive patients, 35/63 (55.5%) experienced another intracranial relapse and underwent a second resection (=relapse group), enabling paired analyses. Of these, 23/35 (65.7%) received no therapy between resections; 12/35 (34.3%) received CNS-directed radiotherapy. Tissue samples were analysed using whole-exome sequencing, DNA methylation profiling, and immunohistochemistry. RESULTS:BM resected after progression following prior cranial radiotherapy (43/153, 28.1%) showed significantly lower densities of CD3 + , CD8 + , and CD45RO + cells together with increased FOXP3 + cell density compared with treatment-naïve BM (63/153, 41.2%; median CD3 +: 71 vs. 494 cells/mm²; CD8 +: 44 vs. 187 cells/mm²; CD45RO+: 104 vs. 302 cells/mm²; FOXP3 +: 215 vs. 41 cells/mm²). In the paired analyses, progressive specimen after prior radiation were likewise associated with significantly reduced CD3 + , CD8 + , and CD45RO + and increased FOXP3 + cell densities compared with the matched baseline specimen. In contrast, no genetic alterations or differences in DNA methylation patterns between irradiated and non-irradiated matched samples were identified. CONCLUSION:Progressive BM following cranial radiotherapy demonstrated a distinct immune marker profile consistent with a more immunoregulatory, rather immunosuppressive tumour microenvironment. No therapy-associated genetic or epigenetic alterations were identified. Further prospective studies are warranted to determine whether these immune alterations reflect treatment-related effects or biological features associated with resistance following radiotherapy.

Postoperative radiotherapy following surgical stabilization in patients with bone metastases is commonly recommended. The aim of the study was to validate existing prognostic scores and parameters for local control and survival in patients with bone metastases treated with surgical resection with or without radiotherapy. This retrospective single-institution study analyzed consecutive patients with bone metastases undergoing resection and/or stabilization mostly due to pathologic or impending fractures (with or without spinal compression). Additive radiotherapy was considered the standard of care. Various fractionated radiotherapy regimens have been applied; equivalent dose in 2 Gy fractions (EQD2) has been calculated to enable comparison between fractionations. Prognostic factors influencing local progression-free survival (LPFS) and overall survival (OS) were evaluated. The median follow-up was 9 months (range 1–121 months). A total of 142 patients were included. Most patients underwent surgery due to pathologic (n = 86, 60.6

PURPOSE:This updated clinical practice guideline provides a practical, evidence-based approach for the management of adult soft tissue sarcoma of the extremity and trunk wall. MATERIALS AND METHODS:The European Society for Radiotherapy and Oncology (ESTRO) formed a task force of 13 European experts, alongside 3 experts from the American Society for Radiation Oncology (ASTRO), to analyze current evidence, provide recommendations and establish expert consensus in areas lacking strong evidence. Thirteen key questions were identified, encompassing indications for radiotherapy, pre- vs. postoperative radiotherapy, treatment preparation, patient positioning, target volume delineation, dose and fractionation, adverse events assessment, and dose guidance for organs of interest. Key recommendations were formulated and tabulated for each topic, addressing all identified key questions. RESULTS:Recommendations for 13 key questions were developed. Dosing for certain subtypes or clinical scenarios has evolved. Despite advancements in imaging, radiotherapy techniques, and personalized approaches, the core principles of treatment planning remain consistent with established practices. Innovative approaches, such as preoperative hypofractionation, radiotherapy combined with systemic therapies (immunotherapy, targeted therapies), and further histotype-specific dose tailoring, show promise; however, they should not be integrated into routine practice until further evidence is obtained. CONCLUSION:Preoperative conventionally fractionated radiotherapy, delivered using highly conformal techniques and volumetric imaging, followed by surgery, remains the preferred sequencing strategy for localized soft tissue sarcoma. Multidisciplinary evaluation at expert sarcoma centers remains essential for determining the optimal treatment approach for each patient.

Abstract Background Secondary malignancies following multimodal oncological treatment are rare but represent a severe long-term complication, particularly in pediatric patients. Systematic analyses in pediatric neuro-oncology are currently lacking. Methods Based on the complete institutional pediatric neuro-oncology database, patients who developed a secondary malignancy during follow-up were identified. Extracranial secondary malignancies and meningiomas were detected using assigned ICD codes (C diagnoses excluding C71 or D32), extracted via an algorithm-based approach. Intracerebral secondary malignancies were identified through an algorithm-driven analysis of all tumor board decisions, using both keyword-based text search and a large language model. Clinical data were retrieved from the hospital patient information system. Results Among a total of 1823 patients in the pediatric neuro-oncology database, 28 patients with 34 secondary malignancies were identified. The most frequent primary tumors were medulloblastoma (n = 13), ependymoma (n = 3), and atypical teratoid/rhabdoid tumor (ATRT; n = 3). Most patients (n = 21) had been treated with craniospinal irradiation, there were only 5 patients with no documented radiotherapy. Likewise, only 7 patients had not undergone chemotherapy for the primary tumor. The most common secondary malignancies were high-grade gliomas (n = 9), meningiomas (n = 7), leukemias (n = 6), and thyroid carcinomas (n = 4). Latency periods varied substantially, ranging from 6.2 years for leukemias to 17.2 years for meningiomas. While thyroid carcinomas and meningiomas showed excellent prognosis, survival in patients with secondary high-grade gliomas was severely limited. Conclusions The applied information technology–based methods successfully identified patients with secondary malignancies within a comprehensive pediatric neuro-oncology database. The observed tumor entities correspond to expected patterns, with primary tumors amenable to curative multimodal therapy and typical secondary malignancies. Further analyses focusing on clinical risk factors and molecular characteristics of neuro-oncological secondary malignancies are planned.

Importance:Metastases-directed stereotactic radiotherapy (SRT) is increasingly performed in patients with metastatic or oligometastatic cancer treated with immune checkpoint inhibitors (ICIs), monoclonal antibodies (mAbs), and small-molecule drugs (SMs). However, little is known about potential interactions between SRT and biological cancer therapy (BCT). Objective:To prospectively investigate adverse events associated with SRT combined with concurrent BCT. Design, Setting, and Participants:This international, prospective, multicenter, noninterventional registry cohort study (Toxicity and Efficacy of Combined Stereotactic Radiotherapy and Systemic Targeted or Immune Therapy [TOaSTT]) was conducted between July 2017 and August 2019 with a 24-month follow-up. Patients from 27 centers whose cancer was treated with metastases-directed SRT concurrently with BCT were eligible. Analyses were performed in January 2025. Exposure:Patients treated with SRT for intracranial or extracranial metastases and concurrent (within ≤30 days) BCT. Indication for treatment, decision on the radiotherapy dose and fractionation, as well as interruption of BCT, were left to the discretion of the treating clinician. Main Outcomes and Measures:The primary outcome was severe (at least grade 3) adverse events of combined modality treatment, as graded by the treating physician. Overall survival (OS) and progression-free survival (PFS) were secondary end points. Results:In total, 514 SRTs (271 cranial and 243 extracranial) concurrent with BCT were performed in 433 patients (median [IQR] age, 62 [54-70 years; 275 male [63.5%]). In 315 SRTs (61.3%) patients received ICIs, whereas in 150 SRTs (29.2%), patients received SMs and in 49 SRTs (9.5%) patients received mAbs. In 430 SRTs (83.7%), BCT had been initiated in patients before SRT, while 71 of 392 patients (18.1%) paused BCT during SRT. Severe (≥grade 3) acute adverse events were observed in 27 of 506 treatments (5.3%; 3 patients with grade 5 events), and severe late adverse events were observed in 29 of 459 patients (6.3%; 2 patients with grade 5 events). SRT with uninterrupted BCT was not associated with increased severe acute or late adverse events (odds ratio, 2.32; 95% CI, 0.87-6.22). Interruption of BCT during SRT was not associated with worse PFS and OS after correction for performance status and histologic type (hazard ratio, 0.81; 95% CI, 0.61-1.09; P = .17). Conclusions and Relevance:In this cohort study of 433 patients, severe adverse events after SRT and concurrent BCT were uncommon (<10%), continuing BCT during SRT was not associated with increased risk of severe adverse events, and interrupting BCT was not associated with worse OS when correcting for patients' performance status. These findings suggest a favorable safety profile of metastases-directed SBRT in combined modality treatment settings.

Background:Novel approaches to guide personalized treatment in glioblastoma are urgently needed. Given the poor predictive value of genetic biomarkers in glioblastoma, we are conducting a prospective clinical trial to investigate the novel approach of cultivated patient-derived tumor cells (PDCs) for ex vivo drug screening. Methods:In this randomized phase 2 study, we are testing the ability of PDC-based ex vivo drug screening to formulate a personalized recommendation for maintenance treatment in patients with newly diagnosed glioblastoma with unmethylated MGMT promoter after combined radio-chemotherapy. Based on overall survival as the primary endpoint, we plan to include 240 patients (120 per group) to show with a power of 80% that we can increase the median survival from 12 to 17 months (hazard ratio 0.7). Patients will be randomized 1:1 to either the standard group (no drug screening) or the intervention group (drug screening and personalized recommendation for maintenance treatment). In the intervention group, automated drug screening will be performed on PDCs with 28 drugs used for the treatment of solid tumors and hematological malignancies. Based on the cytotoxic activity of these drugs, as quantified by relative viability based on adenosine triphosphate levels, a molecular tumor board will recommend a personalized treatment regimen. Results:The first patient was enrolled in July 2024. Interim analysis of the ATTRACT study (NCT06512311) is expected in late 2027, and final results in 2030. Trial Registration:The ATTRACT trial is registered under the ID NCT06512311 (https://clinicaltrials.gov/study/NCT06512311).

Myxoid liposarcoma (MLPS) is a rare subtype of soft tissue sarcoma. This entity has a specific clinical behavior, characterized with a distinct pattern of hematogenous spread, as well as with a unique radiosensitivity and chemosensitivity. Oncologic results, metastatic patterns and treatment response after multimodal therapy were evaluated in a unicentric patient cohort. Patients with myxoid liposarcoma were retrospectively analyzed in a single institution analysis (n = 31). Oncologic outcomes were evaluated in 28 patients with localized MLPS treated with multimodal therapy in curative intent. Metastatic pattern was analyzed in additional 3 patients with initially metastatic disease. In patients treated with concomitant MR-guided hyperthermia in the preoperative setting (n = 7), tumor size response was evaluated longitudinally during radio(-chemo)therapy in thermometry MRIs and before surgery (based on preoperative imaging). The median follow-up was 4.1 ± 1.0 years. The most common anatomic localization was the lower extremity (78.6

Further evaluation of HER3 expression in BM of breast and lung cancer.

Differentially methylated CpG sites in HER3+ vs HER3- breast cancer samples (HER2+ cohort)

Background: A significant proportion of women in reproductive age are diagnosed with diffuse gliomas, resulting in the need to address the safety of pregnancy in patient consultation. However, data on glioma progression after and during pregnancy are sparse and controversial. Methods: Female adult patients in their reproductive years (>= 18 years and <46 years) with histological diagnosis of glioma between 01/01/2000 and 01/12/2019 from 2 academic centers have been included in the study. Reclassification according to the 2021 WHO classification of CNS tumours was performed. The cohort was divided into 3 groups, defined as (A) nulliparae, (B) primi-/multiparae before glioma diagnosis, and (C) primi-/multiparae after glioma diagnosis. Survival analyses were performed in a time-dependent manner with parity as timedependent covariate. Results: 159/368 females met our inclusion criteria, resulting in 47 (29.6 %) nulliparae, 88 (55.3 %) primi-/ multiparae before glioma diagnosis and 24 (15.1 %) primi-/multiparae after glioma diagnosis. Median follow-up was 127.4 months (range 0.7-341.9), and median overall survival and progression free survival were 247.6 months (range 0.4-269.1) and 67.9 months (range 0.7-341.9), respectively. Overall, 113/159 (71.1 %) patients had tumour progression and 53/159 (33.3 %) deceased. In total, 57.4 % of the nullipara, 76.1 % of the primi-/ multipara before glioma diagnosis and 79.1 % of the primi-/multipara after glioma diagnosis groups experienced tumour progression (p > 0.05). In multivariate time-dependent analysis, primi-/multiparae after glioma diagnosis presented with shorter progression free (HR 2.45, p = 0.0079), but not overall survival (HR 0.54, p > 0.05) in comparison to the other two groups. Conclusion: Pregnancy after glioma diagnosis was associated with shorter progression free survival. Longer follow-up as well as larger cohorts are needed to investigate a potential impact on overall survival.

Kaplan-Meier curves of patients with BM of A) Luminal-BCa B) HER2+ BCa C) TN-BCa, and D) NSCLC patients stratified according to the intensity of HER3 expression determined by IHC.

The prognosis of diffuse gliomas previously classified as “lower-grade” is heterogeneous and complicates clinical decisions. We aimed to investigate the molecular profile of clinical outliers to gain insight into biological drivers of long and short-term survivors. Here, patients aged ≥ 18 years and diagnosed with diffuse glioma, WHO grade II/2 or III/3 were included. Short-term survivors (STS) were defined as overall survival (OS) < 1 years, and long-term survivors (LTS) as OS > 10 years. DNA methylation profiling was performed using the Illumina EPIC 850k platform. In total, 385 patients (294 LTS, 91 STS) were included. Median overall survival was 234 months (95