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Gastrointestinal stromal tumors (GISTs) occur mostly sporadically. GISTs associated with a familial syndrome are very rare and are mostly wild type for KIT and platelet-derived growth factor alpha (PDGFRA). To date 35 kindreds and 8 individuals have been described with GISTs associated with germline KIT mutations. This is the third family described with a germline p.Trp557Arg mutation in exon 11 of the KIT gene. The effect of imatinib in patients harboring a germline KIT mutation has been rarely described. Moreover, in some studies imatinib treatment was withheld considering the lack of evidence for efficacy of this treatment in GIST patients harboring a germline KIT mutation. This paper describes a 52-year old patient with a de novo germline p.Trp557Arg mutation with multiple GISTs throughout the gastrointestinal tract and cutaneous hyperpigmentation. Imatinib treatment showed long-term regression of the GISTs and evident pathological response was seen after resection. Remarkably, the hyperpigmentation of the skin also diminished during imatinib treatment. Genetic screening of the family revealed the same mutation in two daughters, both with similar cutaneous hyperpigmentation. One daughter, aged 23, was diagnosed with multiple small intestine GISTs, which were resected. She was treated with adjuvant imatinib which prompted rapid regression of the cutaneous hyperpigmentation. Imatinib treatment in GIST patients harboring a germline KIT mutation shows favorable and long-term responses in both the tumor and the phenotypical hyperpigmentation. [ABSTRACT FROM AUTHOR]

Aims: Melanomas are recognised for their remarkable morphological plasticity. Some tumours may lose conventional features and/or acquire non-melanocytic characteristics, referred to as undifferentiated, dedifferentiated and transdifferentiated melanoma. Despite this phenotypical variability, melanomas typically maintain their cancer driver aberrations, affecting genes such as BRAF, NRAS and NF1. Currently, little is known about whether the DNA methylation profile follows the loss or change of differentiation or is retained despite extensive morphological transformation., Methods and Results: In this study we analysed 11 melanoma cases, comprising six males and five females, with a median age of 67 years, including five undifferentiated, four trans-differentiated and two de-differentiated melanomas. Undifferentiated and trans-differentiated tumours either arose in a patient with known melanoma and/or presented in the groin/axilla with molecular alterations consistent with melanoma. Cases with heterologous differentiation resembled chondrosarcoma, osteosarcoma, angiosarcoma and rhabdomyosarcoma both morphologically and immunohistochemically, while undifferentiated tumours resembled undifferentiated pleomorphic sarcoma. Methylome profiling was performed, and unsupervised clustering analysis revealed nine cases (five undifferentiated, three trans-differentiated and one de-differentiated) to cluster closely together with conventional melanomas from a reference set. Two cases clustered separately with a distinct group of conventional melanomas exhibiting H3K27me3 loss., Conclusions: Despite loss of differentiation and phenotypical plasticity, methylation patterns seem to be retained in undifferentiated, de-differentiated and trans-differentiated melanomas and represent useful diagnostic tools to enhance diagnostic precision in these diagnostically challenging cases., (© 2024 The Author(s). Histopathology published by John Wiley & Sons Ltd.)

Objective: To investigate imaging biomarkers of tumour response by describing changes in imaging and pathology findings after neoadjuvant radiotherapy (nRT) and exploring their correlations., Materials and Methods: Tumour diameter, volume, and tumour-to-muscle signal intensity (SI) ratio were collected before and after radiotherapy in a cohort of 107 patients with intermediate/high-grade STS and were correlated with post-radiotherapy pathology findings (percentage of necrosis, viable cells, and fibrosis) using Spearman Rank test. Pathological complete response (pCR) was defined as no residual viable cells present, whereas the presence of < 10% viable cells was defined as near-complete pathologic response (near-pCR)., Results: Median amount of necrosis, viable cells, and fibrosis after nRT were 10%, 30%, and 25%, respectively. 7% of patients achieved pCR and 22% near-pCR. No changes in tumour volume were found except for subtypes myxoid liposarcoma (mLPS) -Δ54.47%, undifferentiated pleomorphic sarcoma (UPS) +Δ24.22% and dedifferentiated liposarcoma (dLPS) +Δ35.91%. The median change of tumour-to-muscle SI ratio was -19.7% for the entire population, whereas it was -19.55% and -36.26% for UPS and mLPS, respectively. Correlations (positive and negative) were found between change in volume and the presence of necrosis or fibrosis (r s  = 0.44; r s  = -0.44), as well as between tumour-to-muscle SI ratio and viable cells (r s  = 0.33) or fibrosis (r s  = -0.28)., Conclusion: STS displays extensive heterogeneity in response patterns after nRT. In some subgroups, particularly UPS and mLPS, tumour size changes or tumour-to-muscle SI ratio are significantly linked with the percentage of viable cells, fibrosis, or necrosis., Key Points: Question How do primary soft tissue sarcomas (STS) respond to neoadjuvant therapy, and what correlations exist between pathological findings and imaging characteristics in assessing treatment response? Findings mLPS shrank post-nRT; undifferentiated pleomorphic and dLPSs enlarged. Volume increase correlated with higher necrosis and lower fibrosis; tumour-to-muscle intensity ratio correlated with viable cells. Clinical relevance These findings emphasise the extensive heterogeneity in STS response to nRT across different subtypes. Preoperative correlations between tumour volume and SI changes with necrosis, fibrosis, and viable cells can aid in more precise treatment assessment and prognostication., Competing Interests: Compliance with ethical standards. Guarantor: The scientific guarantor of this publication is Prof. Regina G. H. Beets-Tan. Conflict of interest: R.G.H.B.-T. is a member of the Scientific Editorial Board of European Radiology (section: oncology). As such, they have not participated in the selection nor review processes for this article. The remaining authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article. Statistics and biometry: Yury S. Velichko, PhD (co-author) provided statistical advice for this manuscript. No complex statistical methods were necessary for this paper. Informed consent: Written informed consent was waived by the Institutional Review Board. Ethical approval: Institutional Review Board approval was obtained. Study subjects or cohorts overlap: The present work builds upon a previous study by our group, which was limited to comparing RECIST- and Choi-based response assessments and their correlation with pathology findings and clinical outcomes (Reijers et al [16], https://doi.org/10.1080/0284186x.2023.2166427 ). Methodology: Retrospective Observational Performed at one institution, (© 2024. The Author(s), under exclusive licence to European Society of Radiology.)

Background: Angiosarcoma is a rare and aggressive cancer of the endothelial cells. Propranolol, a non-selective β-blocker, was able to initiate apoptosis in angiosarcoma cell lines and its anti-tumor activity has been described in several case reports. The aim of this trial was to prospectively evaluate the anti-tumor activity of propranolol monotherapy in patients with angiosarcoma before proceeding to standard of care treatment., Methods: Propranolol was dosed 80 mg to 240 mg/day for 3 to 6 weeks according to a dose titration schedule. The primary endpoint was clinical response (response according to RECIST 1.1 or stable disease with improvement of cutaneous lesions) in at least three patients. Exploratory objectives included histologic response (>30% decrease in Ki-67), FDG PET response, and β-receptor expression levels., Results: Fourteen patients were enrolled. The median duration of treatment was 26 days (range 21-42 days). The median highest propranolol dose was 160 mg/day (range 80 - 240 mg). Two patients showed clinical response (14%, 95% CI 3-100%). One of these patients showed a partial metabolic response on PET-CT. None of the tumors showed histologic response. The most common adverse event was grade 1/2 bradycardia (86%). There were no grade ≥ 3 adverse events. ADRB2 was overexpressed in 16 out of 18 tumors, in both responders and non-responders. None of the tumors showed ADRB1 overexpression., Conclusions: This window-of-opportunity trial did not show clinical efficacy of propranolol monotherapy. However, two out of 14 patients did show clinical benefit. ADRB1/2 expression did not correlate with clinical response., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The aim of this study was to assess the association between radiological and histopathological response after neoadjuvant radiotherapy (nRT) in soft tissue sarcoma (STS), as well as the prognostic value of the different response evaluation methods on the oncological outcome., Methods: A retrospective cohort of patients with localized STS of the extremity and trunk wall, treated with nRT followed by resection were included. The radiological response was assessed by RECIST 1.1 (RECIST) and MR-adapted Choi (Choi), histopathologic response was evaluated according to the EORTC-STBSG recommendations. Oncological outcome parameters of interest were local recurrence-free survival (LRFS), disease metastases-free survival (DMFS), and overall survival (OS)., Results: For 107 patients, complete pre- and postoperative pathology and imaging datasets were available. Most tumors were high-grade (77%) and the most common histological subtypes were undifferentiated pleomorphic sarcoma/not otherwise specified (UPS/NOS, 40%), myxoid liposarcoma (MLS, 21%) and myxofibrosarcoma (MFS, 16%). When comparing RECIST to Choi, the response was differently categorized in 58%, with a higher response rate (CR + PR) with Choi. Radiological responders showed a significant lower median percentage of viable cells (RECIST p  = .050, Choi p  = .015) and necrosis (RECIST p  < .001), and a higher median percentage of fibrosis (RECIST p  = .005, Choi p  = .008), compared to radiological non-responders (SD + PD). RECIST, Choi, fibrosis, and viable cells were not significantly associated with altered oncological outcome, more necrosis was associated with poorer OS ( p  = .038)., Conclusion: RECIST, Choi and the EORTC-STBSG response score show incongruent results in response evaluation. The radiological response was significantly correlated with a lower percentage of viable cells and necrosis, but a higher percentage of fibrosis. Apart from necrosis, radiological nor other histopathological parameters were associated with oncologic outcomes.

With more than 70 different histological sarcoma subtypes, accurate classification can be challenging. Although characteristic genetic events can largely facilitate pathological assessment, large-scale molecular profiling generally is not part of regular diagnostic workflows for sarcoma patients. We hypothesized that whole genome sequencing (WGS) optimizes clinical care of sarcoma patients by detection of diagnostic and actionable genomic characteristics, and of underlying hereditary conditions. WGS of tumor and germline DNA was incorporated in the diagnostic work-up of 83 patients with a (presumed) sarcomas in a tertiary referral center. Clinical follow-up data were collected prospectively to assess impact of WGS on clinical decision making. In 12/83 patients (14%), the genomic profile led to revision of cancer diagnosis, with change of treatment plan in eight. All twelve patients had undergone multiple tissue retrieval procedures and immunohistopathological assessments by regional and expert pathologists prior to WGS analysis. Actionable biomarkers with therapeutic potential were identified for 30/83 patients. Pathogenic germline variants were present in seven patients. In conclusion, unbiased genomic characterization with WGS identifies genomic biomarkers with direct clinical implications for sarcoma patients. Given the diagnostic complexity and high unmet need for new treatment opportunities in sarcoma patients, WGS can be an important extension of the diagnostic arsenal of pathologists.