Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare malignant soft tissue neoplasm typically found in the distal extremities of middle-aged adults. Histologically, MIFS presents with a myxoid stroma, a mixed inflammatory infiltrate, epithelioid/spindle cells resembling virocytes, pseudolipoblasts, and emperipolesis. Genetic alterations commonly include TGFBR3-MGEA5 rearrangements and VGLL3 amplifications. Recently, YAP1::MAML2 fusions have been identified in nodular necrotizing variants of MIFS. We report a case of a 40-year-old man presenting with right thumb pain initially suspected to be tendovaginitis. Histopathologic examination revealed a variably cellular proliferation in a fibrosclerotic-myxoid stroma with epithelioid cells displaying vesicular nuclei, spindle cells, and inflammatory infiltrates. Focal extensive necrosis was present. Immunohistochemical analysis was negative for SOX10, S100, SMA, desmin, MDM2, ALK, and CD20. Molecular genetic testing identified 2 variants of YAP1::MAML2 gene fusions and an additional TRIM24::BRAF fusion. Although BRAF rearrangements have previously been reported in MIFS, identification of TRIM24 as a fusion partner represents a novel finding. The presence of YAP1::MAML2 fusions, especially in combination with a TRIM24::BRAF fusion, has not been previously described in MIFS. TRIM24 is a transcriptional coregulator involved in p53 ubiquitination and tumorigenesis. The TRIM24::BRAF fusion has been detected in various malignancies, suggesting its potential oncogenic role. This case underscores the genetic heterogeneity of MIFS and suggests the need for further studies to elucidate the clinical implications of these molecular alterations. This report expands the molecular spectrum of MIFS and highlights the diagnostic utility of advanced sequencing technologies in identifying rare gene fusions. The TRIM24::BRAF fusion may represent a potential therapeutic target, warranting further investigation.

BACKGROUND:Soft tissue sarcomas (STS) and other mesenchymal tumours belong to rare, heterogeneous neoplasms with over 150 subtypes that pose significant challenges in diagnosis and clinical decision making. While guidelines address evidence-based diagnostic and therapeutic procedures, clinical situations and scenarios without evidence remain controversial in daily practice. The 2024 Conference on Challenges in Sarcoma (CCS2024) aimed to narrow these gaps with the support of an international and multidisciplinary panel of sarcoma experts. METHODS:A Delphi process identified 200 controversial questions across eight prioritised clinical scenarios, including tenosynovial giant cell tumour, synovial sarcoma of the extremities, retroperitoneal sarcomas, angiosarcoma, phyllodes tumour, malignant peripheral nerve sheath tumour, uterine leiomyosarcoma, and atypical lipomatous tumour. RESULTS:Sixty-four experts discussed 141 controversies during the conference and reached strong consensus (> 90 %) on 24 and consensus (> 75 %) on 45 key diagnostic and therapeutic issues, while unresolved controversies emphasized the need for further research. CONCLUSIONS:CCS2024 provides a framework for clinical decision making and underscores the importance of consensus-driven approaches in the treatment of rare and complex malignancies.

Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor of intermediate malignant potential. Most cases are characterized by a WWTR1::CAMTA1 gene fusion, with YAP1::TFE3 being the second most common. We present a case of EHE in a 78-year-old woman with an RREB1::TFE3 gene fusion, which, to our knowledge, has not previously been described. The tumor was detected incidentally as a subpectoral soft tissue mass during imaging for a simultaneously diagnosed metastatic pulmonary adenocarcinoma. Aside from this, the patient's presentation was consistent with common clinical findings in EHE. Histologically, however, the tumor partly revealed an uncommon morphology: on one hand, solid areas of monomorphic epithelioid tumor cells with abundant eosinophilic cytoplasm, and on the other, regions with considerable and unusual pleomorphism and multinucleation, thus not clearly aligning with the prototypical phenotypes of the classical molecular subtypes. In summary, this case expands the molecular spectrum of EHE and supports further investigation into its molecular heterogeneity.

Purpose: Normofractionated preoperative radiation therapy (nRT) with 50 Gy applied in 25 fractions represents the most widely used radiation therapy (RT) regimen in combined local treatment of soft tissue sarcomas (STSs). STSs are characterized by a low a/b ratio of 4 to 5 Gy, which may translate into a higher sensitivity for hypofractionation. Increasing data from cohorts and phase 2 trials on ultrahypofractionated RT (uhRT) regimens are available. We prospectively assessed our preoperative uhRT sarcoma patient cohort with a focus on short-term wound complications (WCs). Methods and Materials: This is a prospective registry analysis of a single-center patient cohort, treated from 03.2020 to 10.2023 with uhRT (25 Gy in 5 fractions in 1 week). The same radiation oncologists (G.S./C.G.) and surgeon (B.F.) performed the treatment (61/61 and 58/60), as well as the same reference pathologist (B.B.) confirmed all histopathologic diagnoses. WC (according to CAN-NCICSR2 trial) and intermediate local control (LC) rates were assessed and compared with outcome data of a previously published cohort of 67 extremity/trunk sarcoma patients treated with nRT by the same authors (7% WC, 98% LC at 3 years). Results: After a mean/median follow-up of 19/19 months (range, 0-46), LC at 1.5 years was 94%. Surgery was performed at a mean/ median of 20/16 days (range, 4-60) after uhRT completion. WC were observed in 7/60 operated patients (12%), and in 5/51 (10%) extremity/trunk lesions. Early tolerance was excellent, limited to G0 to G1, even in 3 patients with prior RT to the same region. Clear resection margins were achieved in 55/60 patients (92%). Pathologic necrosis of >= 95% was reported in 5% and 75% achieved less than 50% necrosis. Conclusions: These results show low rates of WC and high LC for uhRT and are comparable with our previously published nRT data. (c) 2024 The Authors. Published by Elsevier Inc. on behalf of American Society for Radiation Oncology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

This manuscript examines the synergistic potential of prospective real-world/time data/evidence (RWTD/E) and randomized controlled trials (RCTs) to enrich healthcare research and operational insights, with a particular focus on its impact within the sarcoma field. Through exploring RWTD/E’s capability to provide real-world/time, granular patient data, it offers an enriched perspective on healthcare outcomes and delivery, notably in the complex arena of sarcoma care. Highlighting the complementarity between RWTD/E’s expansive real-world/time scope and the structured environment of RCTs, this paper showcases their combined strength, which can help to foster advancements in personalized medicine and population health management, exemplified through the lens of sarcoma treatment. The manuscript further outlines methodological innovations such as target trial emulation and their significance in enhancing the precision and applicability of RWTD/E, underscoring the transformative potential of these advancements in sarcoma care and beyond. By advocating for the strategic incorporation of prospective RWTD/E into healthcare frameworks, it aims to create an evidence-driven ecosystem that significantly improves patient outcomes and healthcare efficiency, with sarcoma care serving as a pivotal domain for these developments.

Supplementary Table S7 - PDF file 93K, Correlation analysis of radiotherapy-induced immunological changes in sarcoma patients: qRT-PCR analysis was performed on 37 pairs of FFPE human sarcomas for (A) immune effector cells/ molecules, (B) immune suppressor cells/ molecules, (C) effector cytokines, (D) suppressor cytokines, (E) transcription factors and (F) CT-antigens . The delta-delta Ct values were computed for each of the target genes against each other. A bivariate correlation analysis was performed and is given by the Spearman`s rho correlation coefficient (rho) and the significance by the two-tailed P value. * Correlation is significant at the 0.05 level, ** Correlation is significant at the 0.01 level. All correlations with a significant P value are in bold

The expression of human epidermal growth factor receptor 2 (HER2) protein or gene transcripts is critical for therapeutic decision making in breast cancer. We examined the performance of a digitalized and artificial intelligence (AI)-assisted workflow for HER2 status determination in accordance with the American Society of Clinical Oncology (ASCO)/College of Pathologists (CAP) guidelines. Our preliminary cohort consisted of 495 primary breast carcinomas, and our study cohort included 67 primary breast carcinomas and 30 metastatic deposits, which were evaluated for HER2 status by immunohistochemistry (IHC) and in situ hybridization (ISH). Three practicing breast pathologists independently assessed and scored slides, building the ground truth. Following a washout period, pathologists were provided with the results of the AI digital image analysis (DIA) and asked to reassess the slides. Both rounds of assessment from the pathologists were compared to the AI results and ground truth for each slide. We observed an overall HER2 positivity rate of 15% in our study cohort. Moderate agreement (Cohen's κ 0.59) was observed between the ground truth and AI on IHC, with most discrepancies occurring between 0 and 1+ scores. Inter-observer agreement amongst pathologists was substantial (Fleiss´ κ 0.77) and pathologists' agreement with AI scores was 80.6%. Substantial agreement of the AI with the ground truth (Cohen´s κ 0.80) was detected on ISH-stained slides, and the accuracy of AI was similar for the primary and metastatic tumors. We demonstrated the feasibility of a combined HER2 IHC and ISH AI workflow, with a Cohen's κ of 0.94 when assessed in accordance with the ASCO/CAP recommendations.

Supplementary Table S2 - PDF file 1109K, TaqMan Assays.

Supplementary Table S7 - PDF file 93K, Correlation analysis of radiotherapy-induced immunological changes in sarcoma patients: qRT-PCR analysis was performed on 37 pairs of FFPE human sarcomas for (A) immune effector cells/ molecules, (B) immune suppressor cells/ molecules, (C) effector cytokines, (D) suppressor cytokines, (E) transcription factors and (F) CT-antigens . The delta-delta Ct values were computed for each of the target genes against each other. A bivariate correlation analysis was performed and is given by the Spearman`s rho correlation coefficient (rho) and the significance by the two-tailed P value. * Correlation is significant at the 0.05 level, ** Correlation is significant at the 0.01 level. All correlations with a significant P value are in bold

Patient-based health related quality of life (HRQoL) measurements are associated with an improvement in quality of care and outcomes. For a complex disease such as sarcoma, there is no disease-specific questionnaire available which covers all clinically relevant dimensions. Herein, we report on the development of an electronically implemented, sarcoma-specific instrument to assess health-related outcomes, which encompasses a combination of generic questionnaires tailored to the respective disease and treatment status covering the entire longitudinal care cycle. An interoperable digital platform was designed to provide a node between patients and physicians and to integrate the sarcoma-specific HRQoL instrument with patient and physician-based quality indicators to allow longitudinal structured real-world-time data evidence analytics. This approach enables the prediction modeling of disease, and by attributing cost tags to quality indicators, treatment effectiveness for a given disease will be directly correlated with financial expenses, which may ultimately lead to a more sustainable healthcare system.

Supplementary Table S1 - PDF file 558K, Patient information: The table summarizes patient diagnosis, survival status and the time of biopsy collection following radiotherapy. All patients received only neo-adjuvant radiotherapy (RT) and underwent surgery as part of their standard treatment regimen. N: number of patients, MPNST: malignant peripheral nerve sheath tumor, NOS: not otherwise specified

Supplementary Table S3 - PDF file 1084K, IHC quantification of Cancer Testis antigen and MHC-I expression in sarcoma patients before and after radiotherapy

Xanthogranulomatous epithelial tumor (XGET) is an extremely rare and recently described mesenchymal neoplasm characterized by a distinctive histological appearance and clinical presentation. This case report describes a unique case of XGET in a 66-year-old female patient who presented with a 5 cm mass in the dorsal distal left thigh. The clinical, radiological, and pathological findings, as well as the management and follow-up, are discussed.

Sarcomas represent a large group of rare to very rare diseases, requiring complex management with a transdisciplinary approach. Overall progress has been hampered because of discipline, institution and network fragmentation, and there is no global data harmonization or quality standards. To report on and improve quality, a common definition of quality indicators (QIs) of sarcoma care as well as the capacity to assess longitudinal real-time data is required. An international advisory board of world-renowned sarcoma experts defined six categories of QIs, totaling more than 80 quality indicators. An interoperable (web-based) digital platform was then created combining the management of the weekly sarcoma board meeting with the sarcoma registry and incorporating patient-reported outcome measures (PROMs) into the routine follow-up care to assess the entire care cycle of the patient. The QIs were then programmed into the digital platform for real-time analysis and visualization. The definition of standardized QIs covering all physician- (diagnostics and therapeutics), patient- (PROMS/PREMS), and cost-based aspects in combination with their real-time assessment over the entire sarcoma care cycle can be realized. Standardized QIs as well as their real-time assessment and data visualization are critical to improving the quality of sarcoma care. By enabling predictive modelling and introducing VBHC, precision health care for a complex disease is on the horizon.

Mesenchymal chondrosarcoma is a rare and aggressive sarcoma subtype with high risk for distant metastases and poor prognosis. Currently NCCN- and ESMO-Guidelines recommend using Ewing sarcoma protocols as standard treatment. Nevertheless, in localized disease overall 5-year survival rates are below 50% whereas in metastatic spread median progression-free survival rates of only 5 months can be expected. Here we present a patient with metastatic osseous spread of mesenchymal chondrosarcoma that showed a sustained clinical improvement and a good partial response on imaging over a period of one year when treated with the multi-tyrosine kinase inhibitor cabozantinib. Although we cannot explain the exact mechanism underlying this treatment effect, tumors with similar genetic patterns might respond to the same therapy as well.

The ratio of malignancy in suspicious soft tissue and bone neoplasms (RMST) has not been often addressed in the literature. However, this value is important to understand whether biopsies are performed too often, or not often enough, and may therefore serve as a quality indicator of work-up for a multidisciplinary team (MDT). A prerequisite for the RMST of an MDT is the assessment of absolute real-world data to avoid bias and to allow comparison among other MDTs. Analyzing 950 consecutive biopsies for sarcoma-suspected lesions over a 3.2-year period, 55% sarcomas were confirmed; 28% turned out to be benign mesenchymal tumors, and 17% non-mesenchymal tumors, respectively. Of these, 3.5% were metastases from other solid malignancies, 1.5% hematologic tumors and 13% sarcoma simulators, which most often were degenerative or inflammatory processes. The RMST for biopsied lipomatous lesions was 39%. The ratio of unplanned resections was 10% in this series. Reorganizing sarcoma work-up into integrating practice units (IPU) allows the assessment of real-world data with absolute values over the geography, thereby enabling the definition of quality indicators and addressing cost efficiency aspects of sarcoma care.

Abstract Objective It is hypothesized that in the treatment of patients with soft tissue sarcomas (STS) the interval from establishing the diagnosis until initiation of treatment is relevant for the overall survival. Therefore, time to treatment initiation (TTI) was defined as a quality indicator for monitoring the treatment standard. The primary objective of this study was to find out how long (in days) it takes from establishing the sarcoma diagnosis through biopsy until initiation of treatment in patients suffering from STS. Secondary objectives were defined as the comparison between the different dignities, the different institutions and how the Swiss Sarcoma Network (SSN) cohort compares to the international standard. Methods This is a retrospective analysis of prospectively collected data from the SSN. All patients being presented to the MDT/SB within a four-year period from 2018 to 2022 were included in this study. TTI and secondary objectives were determined using non-parametric summary statistics and presented as median and interquartile range. Ethic approval was granted for this study. Results In total 383 patients were recorded in the respective time period in the SSN. In this study 278 patients with a malignant or intermediate STS according to WHO2020 were included. There were 66% (n=185) with a malignant and 44% (n=93) with an intermediate STS. The median TTI was 23 (8-52) days. In the malignant group, the median TTI was 21 (5-43) days and in the intermediate group 32 (11-59) days. In the different institutions the median TTI's were 10 (-6-30), 28 (12-78), 24 (10-58), 24 (10-53) and 12 (-12-54) days. Conclusion In the SSN cohort the overall median TTI was 23 days. In the literature, a TTI delay of more than 42 days led to a slightly reduced overall survival. Compared to the international standard, we conclude that within the SSN network, patients face an adequate waiting time until treatment initiation with no potential restrictions to overall survival.

The urgent need to restructure healthcare delivery to address rising costs has been recognised. Value-based health care aims to deliver high and rising value for the patient by addressing unmet needs and controlling costs. Sarcoma is a rare disease and its care is therefore usually not organised as an institutional discipline. It comprises a set of various diagnostic entities and is highly transdisciplinary. A bottom-up approach to establishing sarcoma integrated practice units (IPUs) faces many challenges, but ultimately allows the scaling up of quality and outcomes of patient care, specific knowledge, experience and education. The key for value-based health care - besides defining the shared value of quality - is an integrated information technology platform that allows transparency by sharing values, brings all stakeholders together in real-time, and offers the opportunity to assess quality of care and outcomes, thereby ultimately saving costs. Sarcoma as a rare disease may serve as a model of how to establish IPUs through a supraregional network by increased connectivity, to advance patient care, to improve science and education, and to control costs in the future, thereby restructuring healthcare delivery. This article describes how the value-based health care delivery principles are being adopted and fine-tuned to the care of sarcoma patients, and already partially integrated in seven major referral hospitals in Switzerland.