Clinicopathologic and molecular correlates to neoadjuvant chemotherapy-induced pathologic response in breast angiosarcoma.

Both primary and secondary breast angiosarcoma (AS) are characterized by multifocal presentation and aggressive behavior. Despite multimodality therapy, local and distant relapse rates remain high. Therefore, neoadjuvant chemotherapy (NACT) is employed to improve the R0 resection rates and survival, but its benefits remain controversial. Herein, we investigate pathologic and molecular correlates to NACT-induced histologic response in a group of 29 breast AS, 4 primary and 25 radiation-associated (RA). The two NACT regimens applied were anthracycline- and non-anthracycline-based. The pathologic response grade was defined as: I: ≤ 50%, II: 51%-90%, III: 91%-99%, and IV: 100%. An additional 45 primary AS and 102 RA-AS treated by surgery alone were included for survival comparison. The genomic landscape was analyzed in a subset of cases and compared to a cohort of AS without NACT on a paired tumor-normal targeted DNA NGS platform. All patients were females, with a median age of 31 years in primary AS and 68 years in RA-AS. All surgical margins were negative in NACT group. The NACT response was evenly divided between poor (Grades I-II; n = 15) and good responders (Grades III-IV; n = 14). Mitotic count >10/mm2 was the only factor inversely associated with pathologic response. By targeted NGS, all 10 post-NACT RA-AS demonstrated MYC amplification, while both primary AS harbored KDR mutations. TMB or other genomic alterations did not correlate with pathologic response. All four patients with Grade IV response remained free of disease. The good responders had a significantly better disease-specific survival (p = 0.04). There was no survival difference with NACT status or the NACT regimens applied. However, NACT patients with MYC-amplified tumors showed better disease-free survival (p = 0.04) compared to MYC-amplified patients without NACT. The overall survival of NACT group correlated with size >10 cm (p = 0.02), pathologic response (p = 0.04), and multifocality (p = 0.01) by univariate, while only size >10 cm (p = 0.03) remained significant by multivariate analysis.

Characterisation of new in vitro models and identification of potentially active drugs in angiosarcoma.

Angiosarcoma is a rare soft tissue sarcoma originating from endothelial cells. Given that current treatments for advanced disease have shown limited efficacy, alternative therapies need to be identified. In rare diseases, patient-derived cell models are crucial for screening anti-tumour activity. In this study, cell line models were characterised in 2D and 3D cultures. The cell lines' growth, migration and invasion capabilities were explored, confirming them as useful tools for preclinical angiosarcoma studies. By screening a drug library, we identified potentially effective compounds: 8-amino adenosine impacted cell growth and inhibited migration and invasion at considerably low concentrations as a single agent. No synergistic effect was detected when combining with paclitaxel, gemcitabine or doxorubicin. These results suggest that this compound could be a potentially useful drug in the treatment of AGS.

Propranolol monotherapy in angiosarcoma - A window-of-opportunity study (PropAngio).

BACKGROUND: Angiosarcoma is a rare and aggressive cancer of the endothelial cells. Propranolol, a non-selective ß-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 ß-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.

Efficacy and safety of TM5614 in combination with paclitaxel in the treatment of paclitaxel-resistant cutaneous angiosarcoma: Phase II study protocol.

Cutaneous angiosarcoma (CAS) is an endothelial cell-derived, highly aggressive type of vascular tumour. Although chemoradiotherapy with paclitaxel (PTX) is recognized as a first-line therapy for CAS, second-line therapy for CAS remains controversial, and there is no standard therapy for taxane-resistant CAS. Plasminogen activator inhibitor-1 (PAI-1) is associated with poor clinical outcomes, and elevated levels of PAI-1 in both tissue and serum are correlated with poor response to therapy in various cancers, including skin cancers. Since PAI-1 protects endothelial cells from Fas ligand-mediated apoptosis, PAI-1 inhibition might induce apoptosis of endothelial cell-derived tumours such as CAS. This is a single-arm, open-label, multi-institutional, Phase 2 clinical trial to assess the efficacy and safety of PTX in combination with TM5614 (PAI-1 inhibitor) in patients with PTX-resistant CAS. PTX will be administered for 28 weeks, with oral administration of TM5614. The primary endpoint of this study will be the overall response rate (ORR) at 28 weeks after starting treatment (central image evaluation). The secondary endpoint will include the ORR at 28 weeks after starting treatment (investigator evaluation), ORR at 8 weeks and 16 weeks after initiation of treatment (central and investigator evaluation), progression-free survival, overall survival, disease control rate and safety profiles. Assuming the null hypothesis of a response rate of 13.6% and an alternative hypothesis of 45%, a minimum of 15 patients are required to achieve a two-sided, Type I error of 5% and power of 70% based on the exact binomial distribution. Data quality control will be conducted by a combination of centralized (remote) and on-site monitoring. This study will contribute to the development of novel combination therapy for PTX-resistant CAS patients, which remains an unmet clinical need.

Parthenolide As a Therapeutic for Disseminated Canine Neoplasms.

This study provides a unique translational research opportunity to help both humans and dogs diagnosed with diseases that carry dismal prognoses in both species: histiocytic sarcoma (HS), hemangiosarcoma (HSA), and disseminated mastocytosis/mast cell tumor (MCT). Although exceedingly rare in humans, these so called "orphan diseases" are relatively more common in dogs. For these and other more commonplace cancers like lymphoma (Lym), dogs are an excellent translational model for human disease due to remarkably similar disease biology. In this study, assays were performed to assess the therapeutic potential of parthenolide (PTL), a known canonical nuclear factor kappa B (NF-κB) signaling inhibitor with additional mechanisms of antineoplastic activity, including alteration of cellular reduction-oxidation balance. Canine cell lines and primary cells are sensitive to PTL and undergo dose-dependent apoptosis after exposure to drug. PTL exposure also leads to glutathione depletion, reactive oxygen species generation, and NF-κB inhibition in canine cells. Standard-of-care therapeutics broadly synergize with PTL. In two canine HS cell lines, expression of NF-κB pathway signaling partners is downregulated with PTL therapy. Preliminary data suggest that PTL inhibits NF-κB activity of cells and extends survival time in a mouse model of disseminated canine HS. These data support further investigation of compounds that can antagonize canonical NF-κB pathway signaling in these cancers and pave the way for clinical trials of PTL in affected dogs. As dogs are an excellent natural disease model for these cancers, these data will ultimately improve our understanding of their human disease counterparts and hopefully improve care for both species. SIGNIFICANCE STATEMENT: Disseminated neoplasms in human and canine cancers are challenging to treat, and novel therapeutic approaches are needed to improve outcomes. Parthenolide is a promising treatment for histiocytic sarcoma, hemangiosarcoma, and mast cell neoplasia.

[Adjuvant treatment of canine splenic hemangiosarcoma with autologous dendritic cell therapy - a prospective, randomized double-blind study]. / Adjuvante Behandlung des caninen Hämangiosarkoms der Milz mit der autologen dendritischen Zelltherapie ­ eine prospektive, placebokontrollierte, randomisierte Doppelblindstudie.

OBJECTIVE: Canine splenic hemangiosarcomas (HSA) are malignant mesenchymal tumors with a high tendency for metastasis. Median survival times after splenectomy followed by adjuvant chemotherapy usually range between 5 and 8 months. The aim of this prospective randomized double-blinded study was to examine the efficacy of a commercially available dendritic cell therapy (PetBioCell) following splenectomy. In addition, possible side effects of this therapy were evaluated. MATERIAL AND METHODS: Twenty-one dogs with histologically confirmed splenic HSA without metastasis (stages I or II) were included in the study. Ten dogs received the dendritic cell therapy, and 11 dogs received a placebo. Injections were administered according to the manufacturer's instructions monthly for the first 3 months and then every 3 months until death. Survival times and toxicoses of both groups were compared. RESULTS: Follow-up data were available for all 21 patients; the observation period ranging until euthanasia or metastasis-related death. One patient that had received the dendritic cell therapy was euthanized due to prostatitis and experienced the longest survival time (668 days). One dog in the placebo-group lived for 448 days after splenectomy. The median survival times in the dendritic cell therapy and the placebo group amounted to 74 and 126 days, respectively. There was no significant difference in tumor-free interval (t(18) = 1.4, p = 0.911) and survival times (t(19) = -0.094, p = 0.463) between the 2 groups. Toxicoses reported in both groups were mild and self-limiting. CONCLUSION: Immunotherapy using autologous, immature and unprimed dendritic cells according to the PetBioCell method failed to show efficacy on tumor-free interval and survival time in the presented dog population with splenic hemangiosarcoma.

Suppression or Inhibition of VEGFs on Splenic Angiosarcoma Cell with Traditional Chinese Medicine Zhi Gan Cao.

Primary splenic angiosarcoma is a very rare disease that causes the development of malignant tumors in the vascular endothelium of the splenic sinuses. Moreover, the disease maintains a very low survival rate for patients to live over 5 years, which is relatively low when compared to another splenic cancer, splenic lymphomas. The treatment options for splenic angiosarcoma narrow down to surgical removal or radiation combined with chemotherapy, but both cost a lot, so discovering potential alternative treatments may eventually increase the possible survival rate. Ginseng and Zhi Gan Cao are both common herbs in Traditional Chinese Medicine (TCM); however, the price of Ginseng is much higher than that of Zhi Gan Cao. A possible reason could be the frequent studies and researches over Ginseng's active ingredient, ginsenoside rh2 or rg3 as they are both potent cancer treatments. The reason to study Zhi Gan Cao and predict its possible potential in cancer treatment is due to the similarity between its active ingredient and the active ingredient in Ginseng, namely, ginsenoside rh2 and licorice saponins. Both TCM contain the active ingredient, triterpenoid saponin, as their main composition, and the further text will predict the possible research and results that may be taken in vitro to reveal the question of whether licorice saponin has the potential to become a major treatment for splenic angiosarcoma or not.

Clinical features and prognosis of retroperitoneal hemangiosarcoma in dogs with surgical resection with or without adjuvant doxorubicin.

Retroperitoneal hemangiosarcoma (RPHSA) is a rare tumor in dogs with a poorly understood prognosis after surgery. The objectives of this study were to investigate the clinical features and prognosis of canine RPHSA that had undergone surgical resection. In this single-center, retrospective cohort study, we reviewed the medical records of dogs that had undergone surgical resection for retroperitoneal tumors and received a histopathologic diagnosis of HSA between 2005 and 2021. The median progression-free survival (PFS) and overall survival (OS) were 77.5 days and 168 days, respectively. In the present study, canine RPHSA had an aggressive biological behavior similar to visceral HSA. Further studies in larger canine populations are needed to evaluate the efficacy of adjuvant chemotherapy.

Axitinib in patients with advanced/metastatic soft tissue sarcoma (Axi-STS): an open-label, multicentre, phase II trial in four histological strata.

BACKGROUND: Axitinib is an oral vascular endothelial growth factor receptor inhibitor with anti-tumour activity in renal, thyroid, and pancreatic cancer. METHODS: Axi-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. RESULTS: Between 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. CONCLUSIONS: Axitinib showed clinical activity in all STS strata investigated. The adverse event profile was acceptable, supporting further investigation in phase III trials. CLINICAL TRIAL REGISTRATION: ISRCTN 60791336.

Identification of genomic alterations with clinical impact in canine splenic hemangiosarcoma.

Canine hemangiosarcoma (HSA) is an aggressive cancer of endothelial cells with short survival times. Understanding the genomic landscape of HSA may aid in developing therapeutic strategies for dogs and may also inform therapies for the rare and aggressive human cancer angiosarcoma. The objectives of this study were to build a framework for leveraging real-world genomic and clinical data that could provide the foundation for precision medicine in veterinary oncology, and to determine the relationships between genomic and clinical features in canine splenic HSA. One hundred and nine dogs with primary splenic HSA treated by splenectomy that had tumour sequencing via the FidoCure® Precision Medicine Platform targeted sequencing panel were enrolled. Patient signalment, weight, metastasis at diagnosis and overall survival time were retrospectively evaluated. The incidence of genomic alterations in individual genes and their relationship to patient variables including outcome were assessed. Somatic mutations in TP53 (n = 44), NRAS (n = 20) and PIK3CA (n = 19) were most common. Survival was associated with presence of metastases at diagnosis and germline variants in SETD2 and NOTCH1. Age at diagnosis was associated with somatic NRAS mutations and breed. TP53 and PIK3CA somatic mutations were found in larger dogs, while germline SETD2 variants were found in smaller dogs. We identified both somatic mutations and germline variants associated with clinical variables including age, breed and overall survival. These genetic changes may be useful prognostic factors and provide insight into the genomic landscape of hemangiosarcoma.

Efficacy and adverse events of anthracycline and propranolol combination in five dogs with stage 3 hemangiosarcoma.

Background: Canine hemangiosarcoma (HSA), which originates from endothelial cells, is one of the most common malignant neoplasms that frequently develop metastatic lesions. Although anthracycline-based HSA treatment strategies have been widely investigated, reliable therapy for dogs with clinically advanced-stage HSA (stage 3 HSA) has not been established yet. Recently, several studies have demonstrated that propranolol, a beta-adrenergic receptor antagonist, exhibits anti-tumor effects against tumors originating from vascular endothelial cells, indicating the possibility that propranolol is a candidate adjunctive agent for anthracycline-based therapy in dogs with stage 3 HSA. This study aimed to evaluate the clinical efficacy and adverse events (AEs) of anthracycline and propranolol combination in stage 3 HSA-affected dogs. Case Description: We retrospectively investigated five dogs diagnosed with stage 3 HSA which were administered with both anthracycline and propranolol during the same period between January 2020 and August 2021. Clinical benefit was observed in four of five HSA dogs (one of complete response, one of partial response, and two of stable disease) with gross metastatic lesions by anthracycline and propranolol combination. Notably, some or all of the metastatic lesions were reduced in two cases. In all five dogs administered with anthracycline and propranolol combination, no serious and irreversible AEs were observed. Conclusion: Our findings demonstrate the efficacy and safety of anthracycline and propranolol combination in stage 3 HSA-affected dogs. Further studies are needed to establish treatment protocols based on anthracycline and propranolol combination for dogs with advanced HSA.

Clinical benefit of switching from paclitaxel to docetaxel or vice versa in cutaneous angiosarcoma patients resistant to first taxane chemotherapy.

Cutaneous angiosarcoma (CAS) is a rare soft-tissue sarcoma of vascular endothelial origin. Paclitaxel (PTX) and docetaxel (DTX) are used as systemic chemotherapy; however, chemoresistance often occurs in CAS. Switching one taxane to the other (i.e., PTX to DTX, or vice versa) is an option when the first taxane is no longer effective in malignant cancers such as ovarian or breast cancer. However, the efficacy of the same strategy in CAS has not been reported. Herein, we report the clinical response of switching one taxane-based chemotherapy to the other in CAS patients with resistance to the first taxane. Twelve CAS patients were included for analyses. In all patients, the median overall survival from the start of the first taxane treatment was 29.0 months (range, 6.47-58.5). During the first taxane, the median PFS for all patients was 5.96 months (1.81-47.1). Similarly, the median (range) PFS for all patients during the second taxane was 5.87 months (1.60-18.2). Furthermore, the median OS was 22.7 months (PTX to DTX) and 39.5 months (DTX to PTX) (p = 0.307). The median PFS during the first taxane was 5.14 (PTX to DTX) and 12.5 months (DTX to PTX), respectively (p = 0.380). The median PFS during the second taxane was 3.5 (PTX to DTX) and 7.1 months (DTX to PTX), respectively (p = 0.906). The objective response rate, defined as the sum of complete response (CR) and partial response (PR) rates, was 16.7%. The disease control rate, defined as the sum of CR, PR, and stable disease rates, was 50%. The frequency of adverse events during the second taxane was the same between the two groups (p > 0.999). Our report suggests that CAS patients could benefit from the second taxane treatment if the tumor is resistant to the first taxane.

Use of intralesional cisplatin to successfully treat distal limb haemangiosarcoma in a foal.

A 4-month old, 200 kg, grey warmblood colt presented for a firm, non painful mass on the distal medial aspect of the left third metatarsus. Excisional biopsy revealed a diagnosis of haemangiosarcoma. Equine haemangiosarcoma is uncommon and only limited reports of successful treatment are available. The prognosis for survival is therefore considered to be poor. After two separate incidences of recurrence with incomplete excision of the tumour, intralesional treatment with cisplatin without excision or debulking was performed on three separate occasions. Intralesional cisplatin injection was performed at monthly intervals for three treatments. Four years post treatment with cisplatin, the horse remained in remission. This case report describes the diagnostic and treatment challenges for successful treatment of a primary haemangiosarcoma on the distal limb of a warmblood foal using intralesional cisplatin chemotherapy.

New molecular targets in canine hemangiosarcoma-Comparative review and future of the precision medicine.

Human angiosarcoma and canine hemangiosarcoma reveal similarities not only in their aggressive clinical behaviour, but especially in molecular landscape and genetic alterations involved in tumorigenesis and metastasis formation. Currently, no satisfying treatment that allows for achieving long overall survival or even prolonged time to progression does not exist. Due to the progress that has been made in targeted therapies and precision medicine the basis for a new treatment design is to uncover mutations and their functions as possible targets to provide tailored drugs for individual cases. Whole exome or genome sequencing studies and immunohistochemistry brought in the last few years important discoveries and identified the most common mutations with probably crucial role in this tumour development. Also, despite a lack of mutation in some of the culprit genes, the cancerogenesis cause may be buried in main cellular pathways connected with proteins encoded by those genes and involving, for example, pathological angiogenesis. The aim of this review is to highlight the most promising molecular targets for precision oncology treatment from the veterinary perspective aided by the principles of comparative science. Some of the drugs are only undergoing laboratory in vitro studies and others entered the clinic in the management of other cancer types in humans, but those used in dogs with promising responses have been mentioned as priorities.

Treatment for taxane-resistant cutaneous angiosarcoma: A multicenter study of 50 Japanese cases.

Cutaneous angiosarcoma (CAS) is a rare and highly aggressive type of vascular tumor. Although chemoradiotherapy with taxanes is recognized as a first-line therapy for CAS, second-line therapy for CAS remains controversial. From the above findings, the efficacy and safety profiles of taxane-switch (change paclitaxel to docetaxel or vise), eribulin methylate, and pazopanib regimens in second-line chemotherapy were evaluated retrospectively in 50 Japanese taxane-resistant CAS patients. Although there was no significant difference in progression-free survival (P = 0.3528) among the regimens, the incidence of all adverse events (AEs) (P = 0.0386), as well as severe G3 or more AEs (P = 0.0477) was significantly higher in the eribulin methylate group and pazopanib group than in the taxane-switch group. The present data suggest that switching to another taxane should be considered for the treatment of taxane-resistant CAS in second-line therapy based on the safety profiles.

Timely adjuvant chemotherapy improves outcome in dogs with non-metastatic splenic hemangiosarcoma undergoing splenectomy.

Timely delivery of adjuvant chemotherapy has been shown to be advantageous in many human cancers and canine osteosarcoma. Adjuvant chemotherapy has been shown to improve outcome for canine splenic hemangiosarcoma. The aim of this retrospective study was to investigate whether timely adjuvant chemotherapy administration resulted in better outcome in dogs with non-metastatic splenic hemangiosarcoma undergoing splenectomy. Medical records were searched for dogs with non-metastatic, splenic hemangiosarcoma that received splenectomy and adjuvant chemotherapy. The number of days from surgery to the first chemotherapy dose (StoC) was evaluated to identify the cut-off value associated with the best survival advantage. StoC and other possible prognostic factors were tested for influence on time to metastasis (TTM) and overall survival (OS). Seventy dogs were included. Median StoC was 20 days (range: 4-70). The time interval associated with the greatest survival benefit was 21 days. Median TTM and OS of dogs with StoC ≤ 21 days were significantly longer than those with StoC >21 days (TTM: 163 vs. 118 days, p = .001; OS: 238 vs. 146 days, p < .001). On multivariable analysis, StoC >21 days was the only variable significantly associated with increased risk of tumour progression (HR 2.1, p = .010) and death (HR 2.3; p = .008). Starting adjuvant chemotherapy within 21 days of surgery may be associated with a survival benefit in dogs with non-metastatic splenic hemangiosarcoma, possibly due to the early targeting of newly recruited metastatic cells after surgery.

The Complex Management of the Breast Angiosarcoma: A Retrospective Study.

BACKGROUND/AIM: Breast angiosarcoma is a rare and aggressive disease with a poor prognosis. Two subtypes have been identified: primary angiosarcoma (PBA) and secondary breast angiosarcoma (SBA). In this retrospective analysis, we describe and compare our institute experience with the data existing in the literature. MATERIALS AND METHODS: We included in our analysis 29 patients who received a diagnosis of PBA or SBA between 2006 and 2019. RESULTS: All patients received surgery as frontline treatment, but only 6 patients underwent to adjuvant treatment. Neoadjuvant chemotherapy was administered 2 patients. The preferred chemotherapeutic regimen was taxanes with or without gemcitabine and associated with anthracyclines. A lower median RFS and OS were reported in patients with PBA compared to those with SBA, but the difference observed was not statistically significant. Patients with PBA had a lower median age at the diagnosis (38 vs. 75). CONCLUSION: In our analysis, we have shown a lower median RFS and OS in patients with PBA compared with those with SBA, and a significantly younger age at diagnosis in patients affected by PBA.