BACKGROUND:High-grade soft tissue sarcomas (STSs) are heterogeneous tumours lacking robust prognostic or predictive biomarkers. Regnase-1, an immune RNase, enhances antitumour immunity by limiting immunosuppressive tumour microenvironment (TME) components (e.g., myeloid-derived suppressor cells (MDSCs)), but remains unexplored in STS. As CD68+ tumour-associated macrophages (TAMs) drive TME suppression and poor prognosis in non-translocation-driven STS, we evaluated Regnase-1 and CD68+ TAMs to assess Regnase-1 as an indicator of an immunologically activated TME. METHODS:Immunohistochemistry scoring of Regnase-1 and CD68+ TAMs was performed in 91 patients. Overall survival (OS) was assessed by Kaplan-Meier and Cox regression, and findings were validated in an independent "The Cancer Genome Atlas" Sarcoma (TCGA-SARC) cohort (n = 212). RESULTS:In UPS, Regnase-1-high predicted longer OS (17.0 months vs. not reached; p = 0.0247) and lower mortality (univariate hazard ratio (HR) = 0.3; p = 0.0343; multivariate HR = 0.4; p = 0.0413), but not after radiotherapy. CD68+ TAM-high predicted shorter OS (13.0 months vs. not reached; p = 0.0274) and higher mortality (HR = 2.0, 95% CI 1.1-3.7; p = 0.0325). Both Regnase-1 effects were reproduced in TCGA-SARC. Regnase-1-high tumours showed inflammatory/interferon enrichment, reduced TGF-β signalling, and SERPINE1 upregulation. CONCLUSIONS:Regnase-1 marked a pro-inflammatory TME and favourable outcome in UPS, but this effect may reverse upon radiotherapy.

To assess the concordance of CT-based radiological, surgical, and histopathological determination of vascular invasion in pancreatic ductal adenocarcinoma (PDAC). This retrospective single-center study included 103 treatment-naive PDAC patients (median age 68 years, male 61

Abstract Objectives In this case, we present a patient with rapidly progressive unilateral destructive orbital and midface inflammation. Initial detection of Corynebacterium kroppenstedtii was followed by a consistent course of localised necrotizing small‐vessel vasculitis, which was responsive to B‐cell depletion. Methods A 79‐year‐old woman presented with acute left periorbital pain, tearing and purulent discharge. The workup included serial microbiological cultures, fungal and mycobacterial testing, molecular diagnostics, CT/MRI/PET‐CT imaging, multiple surgical biopsies with histopathology and special stains, ANCA testing, and multidisciplinary treatments (antimicrobials, glucocorticoids, methotrexate and rituximab). The clinical course, laboratory work, imaging studies, histological analysis and response to treatment were thoroughly reviewed. Results Initial conjunctival culture revealed C. kroppenstedtii and clindamycin and vancomycin was initiated. Despite escalating antimicrobials, the patient developed progressive inflammation with sinus destruction, cutaneous fistula and cheek abscess, requiring orbital exenteration. The biopsies revealed chronic inflammation with multinucleated giant cells, focal necrosis and small‐vessel vasculitis. ANCA remained negative, and subsequent testing was negative. High‐dose prednisolone improved the patient, prompting the discontinuation of methotrexate because of pancytopenia. Rituximab‐induced remission allowed for steroid tapering and rituximab maintenance, which controlled the disease without complications. Conclusion This case illustrates a rare, localised ANCA‐negative necrotizing small‐vessel vasculitis with destructive orbital involvement and initial detection of C. kroppenstedtii. Although the pathogenic significance of this finding remains uncertain, the case highlights the importance of comprehensive microbiological and immunological evaluation in atypical destructive inflammatory disease. Sustained disease control was achieved with immunosuppressive therapy including rituximab after persistent infection had been excluded.

Abstract Background Gastric cancer remains a major global health burden, with persistently high mortality rates despite advances in multimodal treatment. Total gastrectomy (TG) constitutes a cornerstone of curative therapy; however, the factors governing early postoperative survival remain incompletely characterized. This study aimed to identify clinical and pathological predictors of 1-year overall survival (OS) following curative-intent TG, with particular emphasis on the oncological treatment strategy and tumor regression grade (TRG). Methods We retrospectively analyzed 145 patients who underwent TG between 2012 and 2023, excluding n = 4 adjuvant-only cases. To avoid statistical collinearity, multivariable Cox proportional hazards regression was performed in two sequential steps: Model 1 assessed the treatment strategy across the overall cohort (N = 145), while Model 2 evaluated TRG exclusively within the neoadjuvant-treated subgroup (n = 85). Both models incorporated the lymph node ratio (LNR) and surgical approach, and were adjusted for resection margin status (R-status), comorbidity burden (CCI), and severe postoperative complications (Clavien-Dindo ≥ III). A 60-day landmark analysis was conducted to mitigate immortal time bias. Results Completion of the perioperative chemotherapy sequence was independently associated with significantly improved 1-year OS compared to neoadjuvant therapy alone (HR = 0.20; 95% CI, 0.08–0.50; p = 0.001). This survival advantage remained highly significant in the 60-day landmark analysis (p = 0.004). Notably, 55.3% of patients who initiated neoadjuvant chemotherapy did not proceed to the adjuvant phase, primarily owing to patient refusal or medical contraindications. When evaluated exclusively within the neoadjuvant-treated subgroup, a poorer TRG demonstrated a prognostic trend toward decreased survival (HR = 1.60; 95% CI, 0.98–2.59; p = 0.059). Although severe complications (CD ≥ III) occurred in 55.9% of patients, their incidence did not differ significantly across treatment groups (p = 0.894) and did not diminish the independent prognostic value of treatment completion. The surgical approach (robotic vs. open) exerted no significant effect on 1-year OS (HR = 0.88; p = 0.745). Conclusions Completion of the perioperative chemotherapy sequence and a favorable TRG represent two distinct and critical determinants of 1-year survival following TG for gastric cancer. While residual selection bias inherent to retrospective analyses must be acknowledged, the prognostic advantage conferred by treatment completion remains robust after adjustment for surgical morbidity, R-status, and immortal time bias. These findings underscore the prognostic importance of treatment adherence and tumor chemosensitivity, and highlight the need for individualized perioperative management strategies.

Prognostic performance of mitotic index, DL score, and MJ risk models in cohorts C1 to C3.

Kaplan-Meier curves for recurrence-free survival (RFS) and overall survival (OS) in the subgroup of C2 and C3 patients with high risk score according to pathological Miettienen-Joensuu scoring system and Imatinib sensitive mutations depending on the deep Miettinen-Joensuu models. Kaplan-Meier curves for RFS (A) and OS (B) depending on the deep Miettinen-Joensuu model employing the C2 DL Score in this subgroup of the C2 subcohort. Kaplan-Meier curves for RFS (C) and OS (D) depending on the deep Miettinen-Joensuu model employing the C3 DL Score in this subgroup of the C3 subcohort. *: p < 0.05; ***: p < 0.001. Tests are log-rank tests.

Background:Gastrointestinal stromal tumor (GIST) is the most common gastrointestinal mesenchymal tumor, driven by tyrosine-protein kinase KIT and platelet-derived growth factor receptor A (PDGFRA) mutations. Specific variants, such as KIT exon 11 deletions, carry prognostic and therapeutic implications, whereas wild-type (WT) variants derive limited benefit from tyrosine kinase inhibitors (TKIs). Given the limited reproducibility of established clinicopathological risk models, deep learning (DL) applied to whole-slide images (WSIs) emerged as a promising tool for molecular classification and prognostic assessment. Patients and methods:We analyzed 8398 GIST cases from 21 centers in 7 countries, including 7238 with molecular data and 2638 with clinical follow-up. DL models were trained on WSIs to predict mutations, treatment sensitivity, and recurrence-free survival (RFS). Results:DL predicted mutational status in GIST from WSIs, with area under the curve (AUC) of 0.87 for KIT, 0.96 for PDGFRA. High performance was observed for subtypes, including KIT exon 11 del-inss 557-558 (0.67) and PDGFRA exon 18 D842V (0.93). For therapeutic categories, performance reached 0.84 for avapritinib sensitivity, 0.81 for imatinib sensitivity. DL models predicted RFS, with hazard-ratios (HR) of 8.44 (95%CI 6.14-11.61) in the overall cohort and 4.74 (95%CI 3.34-6.74) in patients receiving adjuvant therapy. Prognostic performance was comparable to pathology-based scores, with highest discrimination in the overall cohort and in patients without adjuvant therapy (9.44, 95%CI (5.87-15.20)). Conclusion:DL applied to WSIs enables prediction of molecular alterations, treatment sensitivity, and RFS in GIST, performing comparably to established risk scores across international cohorts, providing a baseline for future multimodal predictors.

Most primary retroperitoneal soft tissue tumors are malignant, with liposarcomas and leiomyosarcomas being the most common. However, other sarcomas and benign tumors can also occur in this location. Pathologic evaluation of retroperitoneal sarcomas (RPS) presents unique challenges. Sarcomas are a heterogeneous group with overlapping microscopic features, making accurate classification essential for prognosis and evolving targeted therapies. Core biopsies often capture only a small portion of the tumor, which may result in underestimation of key features such as differentiation, necrosis, and proliferation, leading to undergrading. Surgical management is complicated by the RPS's tendency to involve adjacent organs. Resections are often large and en bloc, and formalin fixation can obscure anatomic landmarks, making it difficult to identify and assess true surgical margins. In addition to the standard data elements required for cancer staging, specific pathologic features of RPS should be reported to aid in prognosis and treatment planning. This position paper/consensus statement was developed by members of the Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG) based on evidence and expert opinion. A detailed description of specimen handling, specimen sampling, and the inclusion of the key diagnostic elements required for an accurate pathology report are provided. The aim of this manuscript is to offer a comprehensive critical reappraisal of the role of pathologic evaluation of surgical specimens in RPS surgery, as well as to propose a standard pathology report to harmonize reporting and facilitate future data collection and interpretation for future research development.

DL predicts treatment sensitivity and supports clinical decision-making in GIST. A, Standard clinical workflow from initial diagnosis to treatment selection in patients with GIST. B, Proposed integration of the DL model into the diagnostic–therapeutic pathway, enabling early triage of patients for further molecular analysis or tailored treatment selection. C, AUC with 95% CI for DL-based prediction of treatment sensitivity, reported for the internal validation cohort (pink), external validation cohort (green), and an external biopsy-only validation cohort (light green). D, Confusion matrices for avapritinib and imatinib sensitivity, shown at the optimal threshold by Youden’s index (green) and at the threshold yielding the highest F1 score (pink).

Predictive performance of the DL models for selected molecular mutations in GIST.

Metastatic cancers of unknown primary (CUP) pose significant diagnostic and therapeutic challenges. We present the case of a 63-year old male patient with a CUP showing neuroendocrine differentiation, metastasized to the iliac bone, bone marrow, supraclavicular and retroperitoneal lymph nodes. Immunohistochemical and molecular profiling revealed strong pan-neurotrophic tyrosine kinase (Trk) expression without NTRK-gene fusion, corroborating the neural cell origin. Following molecular tumor board (MTB) discussion, genome-wide methylation profiling suggested the diagnosis of a neuroblastoma but results were below diagnostic thresholds. Subsequent imaging and laboratory findings confirmed an INRGSS stage M neuroblastoma, a rare finding in older adults. Despite multimodal therapy, including polychemotherapy and immunotherapy according to pediatric GPOH neuroblastoma guidelines, disease progression necessitated an experimental approach. Comprehensive molecular analysis and MTB discussion revealed several potential treatment targets, leading to subsequent treatment including dinutuximab beta, nivolumab, cabozantinib, I-131-mIBG radionuclide therapy and alpelisib, unfortunately, all followed by disease progression. This case demonstrates the potential of comprehensive molecular analysis including methylation profiling for diagnosis and treatment guidance in rare tumors. Additional research is urgently required to improve outcomes in elderly patients with neuroblastoma.

Most primary retroperitoneal soft tissue tumors are malignant, with liposarcomas and leiomyosarcomas being the most common. However, other sarcomas and benign tumors can also occur in this location. Pathologic evaluation of retroperitoneal sarcomas (RPS) presents unique challenges. Sarcomas are a heterogeneous group with overlapping microscopic features, making accurate classification essential for prognosis and evolving targeted therapies. Core biopsies often capture only a small portion of the tumor, which may result in underestimation of key features such as differentiation, necrosis, and proliferation, leading to undergrading. Surgical management is complicated by the RPS's tendency to involve adjacent organs. Resections are often large and en bloc, and formalin fixation can obscure anatomic landmarks, making it difficult to identify and assess true surgical margins. In addition to the standard data elements required for cancer staging, specific pathologic features of RPS should be reported to aid in prognosis and treatment planning. This position paper/consensus statement was developed by members of the Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG) based on evidence and expert opinion. A detailed description of specimen handling, specimen sampling, and the inclusion of the key diagnostic elements required for an accurate pathology report are provided. The aim of this manuscript is to offer a comprehensive critical reappraisal of the role of pathologic evaluation of surgical specimens in RPS surgery, as well as to propose a standard pathology report to harmonize reporting and facilitate future data collection and interpretation for future research development.

Sensitivity and specificity for treatment-sensitivity prediction.

Abstract Gastrointestinal stromal tumor (GIST) is the most common gastrointestinal mesenchymal tumor, driven by tyrosine–protein kinase (KIT) and platelet-derived growth factor receptor A (PDGFRA) mutations. Specific variants, such as KIT exon 11 deletions, carry prognostic and therapeutic implications, whereas wild-type variants derive limited benefit from tyrosine kinase inhibitors. Given the limited reproducibility of established clinicopathologic risk models, deep learning (DL) applied to whole-slide images (WSI) emerged as a promising tool for molecular classification and prognostic assessment. We analyzed 8398 GIST cases from 21 centers in seven countries, including 7,238 with molecular data and 2,638 with clinical follow-up. DL models were trained on WSIs to predict mutations, treatment sensitivity, and recurrence-free survival (RFS). DL predicted mutational status in GIST from WSIs, with area under the curve of 0.87 for KIT and 0.96 for PDGFRA, and high performance was observed for subtypes, including KIT exon 11 del–inss 557 to 558 (0.67) and PDGFRA exon 18 D842V (0.93). For therapeutic categories, performance reached 0.84 for avapritinib sensitivity and 0.81 for imatinib sensitivity. DL models predicted RFS, with hazard ratios of 8.44 in the overall cohort and 4.74 in patients receiving adjuvant therapy. Prognostic performance was comparable with pathology-based scores, with highest discrimination in the overall cohort and in patients without adjuvant therapy. DL applied to WSIs enables prediction of molecular alterations, treatment sensitivity, and RFS in GIST, performing comparably with established risk scores across international cohorts, providing a baseline for future multimodal predictors. Significance: Deep learning on histology predicts KIT and PDGFRA mutations and stratifies recurrence-free survival in a large international cohort of gastrointestinal stromal tumors from multiple centers.

Sensitivity, specificity, and F1-score for molecular mutation prediction.

Predictive performance of the DL models for treatment-sensitivity categories in GIST.

Statistical pipeline for recurrence-free survival (RFS) analysis. (A) Data partitioning. Boxes with light dashed contours corresponded to the patients with available DL Scores while boxes with solid thick contours to the patient included in the survival analysis. (B) Methodological approach performed in C1, C2 and C3 to obtain deep learning (DL) scores and to develop survival models in the Training cohorts using the Cox proportional hazard (CPH) algorithm and to compare them. Other abbreviations: ext.val: external validation, int. val: internal validation, M.J.: Miettinen-Joensuu. *Covariables were: age, sex, adjuvant TKI therapy and mutational status for C1; and age, sex and mutational status for C2 and C3.

Solitary fibrous tumor (SFT) is a rare soft-tissue sarcoma with limited treatment options, especially in advanced or metastatic cases. Fibroblast activation protein α (FAPα) is overexpressed in certain sarcomas, including SFTs, making it a promising target for diagnostics and radiopharmaceutical therapy (RPT). We present the cases of 3 patients with metastatic SFTs who, after exhausting standard treatments, underwent molecular profiling and showed elevated FAPα expression. Methods: Messenger RNA and protein expression of FAPα were examined in biopsy samples from 3 patients participating in the Molecularly Aided Stratification for Tumor Eradication Research program, a multicenter observational study focused on biology-driven stratification of adults with advanced cancer. Messenger RNA expression levels were quantified as transcripts per million, with RNA extraction, sequencing, and data processing performed using established protocols. Protein expression was assessed and stained with FAPα immunohistochemistry using a recombinant anti-FAPα antibody. Following the recommendation of the molecular tumor board, these patients received 90Y-labeled fibroblast activation protein inhibitor (FAPI)-46 RPT because of the high uptake observed in 68Ga-FAPI-46 PET/CT scans. Results: 90Y-FAPI-46 RPT led to substantial clinical benefits, including metabolic resolution and symptom relief, with disease control confirmed using RECIST and PERCIST. Treatment was well-tolerated, with only minor adverse events observed. Conclusion: Our findings underscore the utility of FAPα screening as a predictive biomarker and the potential of FAP-targeted RPT as a viable treatment for advanced SFT.

Figure S3 shows a reciprocal regulation of YAP1/TAZ-TEAD and β-catenin-TCF in SySa cells via luciferase assays.