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Angiosarcomas are rare soft-tissue sarcomas of endothelial cell origin that have a poor prognosis. They can arise anywhere in the body, most commonly presenting as cutaneous disease in elderly white men, involving the head and neck and particularly the scalp. They can be caused by therapeutic radiation or chronic lymphoedema and hence secondary breast angiosarcomas are an important subgroup. Recent work has sought to establish the molecular biology of angiosarcomas and identify specific targets for treatment. Interest is now focused on trials of vascular-targeted drugs, which are showing promise in the control of angiosarcomas. In this review we discuss angiosarcoma and its current management, with a focus on clinical trials investigating the treatment of advanced disease.

Angiosarcomas are rare, clinically aggressive tumors with limited treatment options and a dismal prognosis. We analyzed angiosarcomas from 68 patients, integrating information from multiomic sequencing, NanoString immuno-oncology profiling, and multiplex immunohistochemistry and immunofluorescence for tumor-infiltrating immune cells. Through whole-genome sequencing (n = 18), 50% of the cutaneous head and neck angiosarcomas exhibited higher tumor mutation burden (TMB) and UV mutational signatures; others were mutationally quiet and non-UV driven. NanoString profiling revealed 3 distinct patient clusters represented by lack (clusters 1 and 2) or enrichment (cluster 3) of immune-related signaling and immune cells. Neutrophils (CD15+), macrophages (CD68+), cytotoxic T cells (CD8+), Tregs (FOXP3+), and PD-L1+ cells were enriched in cluster 3 relative to clusters 2 and 1. Likewise, tumor inflammation signature (TIS) scores were highest in cluster 3 (7.54 vs. 6.71 vs. 5.75, respectively; P < 0.0001). Head and neck angiosarcomas were predominant in clusters 1 and 3, providing the rationale for checkpoint immunotherapy, especially in the latter subgroup with both high TMB and TIS scores. Cluster 2 was enriched for secondary angiosarcomas and exhibited higher expression of DNMT1, BRD3/4, MYC, HRAS, and PDGFRB, in keeping with the upregulation of epigenetic and oncogenic signaling pathways amenable to targeted therapies. Molecular and immunological dissection of angiosarcomas may provide insights into opportunities for precision medicine.

Opinion Statement Recent clinical trials have investigated immune checkpoint inhibitors (ICIs) alone, in combination with tyrosine kinase inhibitors (TKIs), or with chemotherapy in angiosarcoma, yielding mixed results across subtypes. Single-agent ICI therapy, such as cemiplimab (ORR 27.8%), has shown responses primarily in UV- and radiation-associated angiosarcomas, likely due to their higher tumor mutation burden (TMB), while dual ICI therapy (SWOG S1609, ORR 25%) suggests potential benefit but remains limited in cutaneous disease. ICI-TKI combinations, such as cabozantinib plus nivolumab (Alliance A091902, second-line, ORR 59%), demonstrated significant efficacy in both cutaneous and non-cutaneous angiosarcomas, suggesting anti-angiogenic therapy may enhance ICI responses in tumors historically resistant to checkpoint blockade. ICI-chemotherapy combinations have been less consistent. The Alliance A091902 first-line trial (paclitaxel ± nivolumab) found no overall PFS benefit, though scalp/face angiosarcoma patients appeared to fare better, raising the question of whether ICI alone might be equally effective in this subset. The South Korean paclitaxel + avelumab trial (ORR 50%) showed promising response rates, but the lack of detailed subgroup analysis limits interpretation. Other chemotherapy-ICI combinations, such as doxorubicin plus pembrolizumab, have shown isolated responses but require further study in larger cohorts. Moving forward, better biomarkers are critical for identifying which patients benefit most from ICIs, and while TKI-ICI combinations appear to hold the most promise, chemotherapy-ICI strategies need further refinement to optimize sequencing and patient selection in angiosarcoma treatment.

BackgroundAxitinib is an oral vascular endothelial growth factor receptor inhibitor with anti-tumour activity in renal, thyroid, and pancreatic cancer.MethodsAxi-STS was a pathologically-stratified, non-randomised, open-label, multi-centre, phase II trial of continuous axitinib treatment in patients ≥16 years, performance status ≤2, with pathologically-confirmed advanced/metastatic soft tissue sarcoma (STS). Patients were recruited within four tumour strata, each analysed separately: angiosarcoma, leiomyosarcoma, synovial sarcoma, or other eligible STSs. The primary outcome was progression-free survival at 12 weeks (PFS12). A Simon’s two-stage design with activity defined as PFS12 rate of 40% determined a sample size of 33 patients per strata.ResultsBetween 31-August-2010 and 29-January-2016, 145 patients were recruited: 38 angiosarcoma, 37 leiomyosarcoma, 36 synovial sarcoma, and 34 other subtypes. PFS12 rate for each stratum analysed was 42% (95% lower confidence interval (LCI); 29), 45% (95% LCI; 32), 57% (95% LCI; 42), and 33% (95% LCI; 21), respectively. There were 74 serious adverse events including two treatment-related deaths of pulmonary haemorrhage and gastrointestinal bleeding. Fatigue and hypertension were the most common grade 3 adverse events.ConclusionsAxitinib showed clinical activity in all STS strata investigated. The adverse event profile was acceptable, supporting further investigation in phase III trials.Clinical Trial RegistrationISRCTN 60791336

Cutaneous angiosarcoma (cAS) is a rare malignant neoplasm with variable clinical presentation. Although a distinct vascular tumour, cAS shares many overlapping histopathological features with other vasoformative and epithelioid tumours or ‘mimickers’. cAS shows aggressive behaviour and carries a grave prognosis, thus early diagnosis is of paramount importance to achieve the best possible outcomes. Recently, several genetic studies were conducted leading to the identification of novel molecular targets in the treatment of cAS. Herein, we present a comprehensive review of cAS with discussion of its clinical, histopathological and molecular aspects, the differential diagnosis, as well as current therapies including ongoing clinical trials.

Angiosarcomas are highly aggressive soft tissue tumors with poor prognosis in both humans and dogs. In dogs, visceral hemangiosarcoma offers a relevant spontaneous model for evaluating novel therapies. Surgery alone yields a median survival of 1–3 months, and treatment with doxorubicin (DOX), alone or in combination (e.g., with propranolol), modestly extends median survival time to 5–7 months, with a 1-year survival of around 10%. We developed a conjugate vaccine technology, called immune Boost (iBoost), and hypothesized that combining DOX with an iBoost vaccine targeting extracellular vimentin (eVim) could improve survival without added toxicity. Twenty-three dogs with visceral hemangiosarcoma received six cycles of DOX every two weeks post-splenectomy, alongside four doses every other week of eVim iBoost immunotherapy, followed by maintenance vaccinations every two months. Outcomes were compared to historical controls treated with DOX alone. Compared to the control group the median overall survival time increased from 136 to 235 days (NS), restricted mean survival time at one year increased with 81 days (p = 0.02) and 1-year survival rate was 44% versus 14% (p = 0.0344). The combination was well-tolerated, with no systemic vaccine-related toxicity. Adding dog eVim vaccine to DOX appears to improve survival without added toxicity in dogs with hemangiosarcoma. These results support further clinical development, including evaluation in human angiosarcoma.

Background We report here a correlation analysis conducted along with a phase II trial assessing bevacizumab in combination with weekly paclitaxel. Methods Circulating pro/anti-angiogenic factors were assessed on day 1 (D1) and day 8 (D8). The prognostic value for progression-free survival (PFS) was evaluated using a Cox model with biomarkers as continuous variables. Results Among the 51 patients enrolled and treated in this trial, biomarker analysis was performed for 42: 18 in Arm A (single-agent) and 24 in Arm B (combination). With a median follow-up of 46 months, PFS was 5.5 versus 5.7 months, respectively ( p  = 0.75). According to univariate analysis, factors associated with a poor PFS were as follows: visceral angiosarcoma, de novo angiosarcoma, and high PlGF and low VEGF-C baseline values. In multivariate analysis, de novo angiosarcoma (HR = 2.5; p  = 0.024) and baseline VEGF-C value (HR = 0.7; p  = 0.003) were significant prognostic factors. We observed a significant increase in circulating PlGF (< 0.001) and a decrease in VEGF (< 0.001) during bevacizumab treatment. An increase in FGF was associated with a poor outcome. Conclusions De novo angiosarcoma and a low baseline level of VEGF-C were found to be associated with a poor prognosis. Addition of bevacizumab induces major changes in circulating biomarkers (VEGF and PlGF) in a short timeframe without impacting PFS. Trial registration Retrospectively registered on EudraCT N° 2009–017020-59 and NCT01303497 (February 24, 2011).

Visceral haemangiosarcoma is considered clinically aggressive in dogs, with perceived poor prognosis often leading to euthanasia at presentation. This study aimed to determine survival times and prognostic factors in dogs with haemangiosarcoma under first-opinion care. Dogs clinically diagnosed with haemangiosarcoma in first-opinion practice in 2019 were identified in VetCompass electronic health records and examined to capture variables potentially associated with survival. Median survival time (MST) from diagnosis was calculated for the whole population, those histopathologically confirmed and based on primary tumour location. Binary logistic regression was used to explore differences between dogs that died on the day of diagnosis and those that survived ≥1 day. Cox proportional hazards modelling explored factors associated with time to death in dogs surviving ≥1 day. Across all cases (n = 788), overall MST was 9.0 days (95%CI:5.0–15.0, range: 0–1789) and proportional 1-year survival was 12.0% (95%CI:9.7–15.0%). Dogs with splenic (MST = 4.0 days, 95%CI 0.0–9.0) and cutaneous haemangiosarcoma (MST = 119.0 days,95%CI:85.0–248.0) had MST greater than 0 days. Of dogs with a histopathological diagnosis of haemangiosarcoma, overall MST was longer at 105 days (95% CI 84–133 days) and additionally, location-specific MST were longer. For both clinically diagnosed cases and histopathologically confirmed cases, increasing tumour size was associated with increased hazard of death while cutaneous location and surgery were associated with reduced hazard of death. A very short survival time was identified for haemangiosarcoma under first-opinion care. Although survival time was longest for cutaneous cases, the actualised prognosis was poor overall for haemangiosarcoma. However, a common prevailing view of extremely poor prognosis for haemangiosarcoma could be promoting frequent euthanasia at presentation and therefore leading to a self-fulfilling prophecy and low survival times. Further exploration of the potential effect of perceived prognosis is warranted. This study provides valuable information for contextualised care and dialogues with clients in first-opinion practice.

MYC, a proto-oncogene located on chromosome 8q24, is involved in the control of cell proliferation and differentiation. Previous studies have documented high-level MYC gene amplification and MYC overexpression by immunohistochemistry (IHC) in post-irradiation angiosarcomas, but not in primary cutaneous angiosarcoma (AS-C) or in other radiation-associated vascular proliferations, such as atypical vascular lesions. Prompted by our recent finding of MYC amplification in a primary hepatic AS, we analyzed a large number of well-characterized AS-C for MYC amplification and protein overexpression. Formalin-fixed, paraffin-embedded blocks from 38 AS-C were retrieved from our archives and were examined by IHC analysis and fluorescence in-situ hybridization (FISH), using a commercially available antibody and probe. For FISH analysis, the number of copies of MYC was compared with the control gene, CEN8 (MYC/CEN8 ratio). All cases occurred on sun-exposed skin; no patient was known to have a history of therapeutic irradiation. Possible associations between survival and a wide variety of clinicopathological variables were evaluated using the log-rank test. By IHC analysis, MYC overexpression was present in 9/38 (24%) AS-C (2–3+: 6 cases, 16%; 1+: 3 cases, 8%). By FISH analysis, 2/5 (40%) informative cases with 2–3+ immunostaining showed high-level gene amplification. One additional case with 3+ immunostaining showed higher level aneusomy of chromosome 8 (5–8 MYC and CEN8). Two out of fourteen (14%) IHC-negative cases also carried MYC amplification (one high level and one lower level). Low copy number gain of chromosome 8 (3–5 MYC and CEN8) was observed in AS-C with or without MYC expression. MYC amplification and MYC protein overexpression were not correlated with clinical outcome. We have shown, for the first time, MYC gene amplification and protein overexpression in primary (non-radiation-associated) AS of the skin. MYC protein overexpression in cases lacking gene amplification likely reflects other mechanisms of MYC activation. The study of a larger number of AS-C showing MYC amplification may be necessary to determine whether the behavior of such cases differs from their more common non-amplified counterparts.

The objectives of this study were to evaluate the risk and predictive factors of splenic malignancy and hemangiosarcoma in dogs undergoing splenectomy at a surgical specialty clinic. Medical records, hematologic results, surgical reports, and histopathologic results from 182 dogs that underwent splenectomy for the treatment of splenic masses or nodules were reviewed retrospectively. The majority of dogs (57.7%) had benign splenic diagnoses with no malignancy. Hemangiosarcoma was diagnosed in 32.4% of the dogs. A final multivariable model indicated that thrombocytopenia, anemia, and a smaller diameter of the largest splenic nodule were risk factors for hemangiosarcoma (P<0.001), and hemoperitoneum (P = 0.01) was an additional risk factor when nodule diameter was not evaluated. There were 91 dogs that had hemoperitoneum, and 60.4% of those dogs had malignant splenic lesions. Of the 33 dogs that underwent a splenectomy for incidentally identified splenic lesions, 93.9% had benign splenic lesions. Breed size was not a significant predictor of splenic malignancy risk; however, all 6 of the German shepherds included in the study had a hemangiosarcoma diagnosis. Overall prevalence of splenic malignancy including HSA may be overestimated in some canine populations.