PARP inhibition in UV-associated angiosarcoma preclinical models.

PURPOSE: Angiosarcoma (AS) is a rare vasoformative sarcoma, with poor overall survival and a high need for novel treatment options. Clinically, AS consists of different subtypes, including AS related to previous UV exposure (UV AS) which could indicate susceptibility to DNA damage repair inhibition. We, therefore, investigated the presence of biomarkers PARP1 (poly(ADP-ribose)polymerase-1) and Schlafen-11 (SLFN11) in UV AS. Based on experiences in other sarcomas, we examined (combination) treatment of PARP inhibitor (PARPi) olaparib and temozolomide (TMZ) in UV AS cell lines. METHODS: Previously collected UV AS (n = 47) and non-UV AS (n = 96) patient samples and two UV AS cell lines (MO-LAS and AS-M) were immunohistochemically assessed for PARP1 and SLFN11 expression. Both cell lines were treated with single agents PARPi olaparib and TMZ, and the combination treatment. Next, cell viability and treatment synergy were analyzed. In addition, effects on apoptosis and DNA damage were examined. RESULTS: In 46/47 UV AS samples (98%), PARP1 expression was present. SLFN11 was expressed in 80% (37/46) of cases. Olaparib and TMZ combination treatment was synergistic in both cell lines, with significantly increased apoptosis compared to single agent treatment. Furthermore, a significant increase in DNA damage marker γH2AX was present in both cell lines after combination therapy. CONCLUSION: We showed combination treatment of olaparib with TMZ was synergistic in UV AS cell lines. Expression of PARP1 and SLFN11 was present in the majority of UV AS tumor samples. Together, these results suggest combination treatment of olaparib and TMZ is a potential novel AS subtype-specific treatment option for UV AS patients.

Secondary angiosarcoma: A fatal complication of chronic lymphedema.

Secondary Angiosarcoma (Stewart-Treves Syndrome) is a rare malignant cutaneous lesion, which arises in chronic lymphedema of the extremity, often observed after breast cancer treatment. We reviewed the history and the oncological outcome of two patients with this disease. Multimodal therapy including hyperthermic isolated limb perfusion with TNF-alpha and Melphalan, combined with radical resection of the affected skin and subcutaneous tissue including the fascia, with large safety margins may probably lead to better survival.

Primary and secondary breast angiosarcoma: single center report and a meta-analysis.

BACKGROUND: Primary and secondary breast angiosarcoma is a rare and aggressive malignancy with limited published literature. Optimal management is mostly based on expert opinion. Our study aims to describe a single institution experience with breast angiosarcoma and evaluate other publications on this topic to further clarify prognostic outcomes and treatment modalities in this disease. METHODS: Twenty two cases of breast angiosarcoma from Roswell Park Comprehensive Cancer Center were retrospectively analyzed. Additionally, a systemic review and meta-analysis was conducted to study the association between survival outcomes, overall survival (OS), and recurrence-free survival (RFS) in both primary (PAS) and secondary breast angiosarcoma (SAS). RESULTS: 9 PAS patients (41%) and 13 SAS patients (59%) were retrospectively analyzed. No significant differences were noted in tumor characteristics and survival outcomes between PAS and SAS. Treatment modality had no significant effects on survival outcomes although adjuvant chemotherapy demonstrated a trend towards improved RFS in high grade tumors. 380 PAS and 595 SAS patients were included in the outcome meta-analysis. Survival outcomes were significantly worse with high grade tumors and tumor size of > 5 cm. Adjuvant radiation therapy demonstrated significantly better RFS, while adjuvant chemotherapy had no effect on survival outcomes. CONCLUSION: Tumor size and grade seem to be reliable predictors of survival in both PAS and SAS. Mastectomy does not seem to be adding any additional benefit to BCS. Adjuvant radiation therapy showed statistically significant RFS benefit, while adjuvant chemotherapy can be beneficial in high grade tumors.

Angiosarcoma de mama radioinducido / Radiotherapy-induced angiosarcoma of the breast

El angiosarcoma radioinducido de mama tras tratamiento quirúrgico conservador y radioterapia complementaria en una paciente con cáncer de mama es una entidad poco frecuente, de difícil diagnóstico y mal pronóstico. Se presenta el caso de una mujer de 71 años, con antecedentes personales de carcinoma ductal infiltrante de mama izquierda, a la que se practicó tumorectomía y linfadenectomía axilar (pT1cpN0M0), y recibió tratamiento adyuvante con radioterapia y hormonoterapia. 77 meses después del tratamiento, la paciente consultó al presentar una lesión cutánea en la mama izquierda. Tras valoración clínica, radiológica e histológica y con el diagnóstico de angiosarcoma de mama, se practicó mastectomía izquierda. Posteriormente no recibió tratamiento complementario

Radiotherapy-induced angiosarcoma of the breast after conservative surgical treatment and complementary radiotherapy in a patient with breast cancer is a rare condition, with both difficult diagnosis and poor prognosis. We present the case of a 71-year-old woman with a personal history of infiltrating ductal carcinoma of the left breast, who underwent tumorectomy and axillary lymphadenectomy (pT1cpN0M0), and received adjuvant treatment with radiotherapy and hormone therapy. 77 months after treatment, the patient consulted with a skin lesion on her left breast. After clinical, radiological and histological assessment and with the diagnosis of angiosarcoma of the breast, a mastectomy of her left breast was performed. The patient did not receive complementary treatment

Novel Therapy for Pediatric Angiosarcoma With Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

The management of pediatric abdominopelvic angiosarcoma remains unclear due to limited clinical experience. Herein, we presented the first 2 pediatric patients with abdominal angiosarcoma who were treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) after neoadjuvant therapy. The first patient is alive with recurrent disease at 1-year follow-up and the second patient remains disease free after 1 year. CRS and HIPEC should be considered as a therapeutic option in the management of pediatric abdominal angiosarcomas. A multi-institutional international shared registry is needed to further evaluate the role of CRS and HIPEC in inducing remission of abdominopelvic angiosarcomas in the pediatric population.

Primary Colonic Angiosarcoma Seen in a Patient on Calcium Channel Blocker: A Case Report with Summary Analysis of 32 Other Cases from the Literature.

BACKGROUND Angiosarcoma is a rare malignant mesenchymal tumor of vascular endothelial cell origin. Its occurrence in the colorectal region is extremely rare. Only 32 cases of primary colorectal angiosarcoma are reported in the current literature. Angiosarcoma in association with calcium channel blocker has been rarely reported. We present such a case of a patient who had been on levamlodipine besylate, a calcium channel blocker, for over 10 years. CASE REPORT A 53-year-old female with hypertension presented with a fever, a dry cough, and hematochezia. Computed tomography (CT) scan and angiography demonstrated a 6-cm vascular mass in the ileocecal region. The clinical symptoms stopped soon after a right hemicolectomy. The histopathology with immunohistochemical studies confirmed the diagnosis of angiosarcoma. Three months after surgery, the patient had evidence of recurrence of the tumor, however, she no longer presented with a fever or a dry cough. The patient was receiving chemotherapy at the time of the report. CONCLUSIONS Colorectal angiosarcoma is a rare malignancy of endothelial origin with uncertain etiology and often has a poor prognosis. Angiosarcoma seen in a patient taking calcium channel blocker is rare but alarming. CT scan and angiography are helpful tools to raise the suspicion of the diagnosis. A definitive pathological diagnosis relies on histopathology with immunohistochemical stains of endothelial markers. Surgical resection is still the best choice of the different treatment options.

Survivin: A novel marker and potential therapeutic target for human angiosarcoma.

Human angiosarcoma is a rare malignant vascular tumor associated with extremely poor clinical outcome and generally arising in skin of the head and neck region. However, little is known about the molecular pathogeneses and useful immunohistochemical markers of angiosarcoma. To investigate the mechanisms of angiosarcoma progression, we collected 85 cases of human angiosarcoma specimens with clinical records and analyzed ISO-HAS-B patient-derived angiosarcoma cells. As control subjects, 54 cases of hemangioma and 34 of pyogenic granuloma were collected. Remarkably, consistent with our recent observations regarding the involvement of survivin expression following Hippo pathway inactivation in the neoplastic proliferation of murine hemangioendothelioma cells and human infantile hemangioma, nuclear survivin expression was observed in all cases of angiosarcoma but not in hemangiomas and pyogenic granulomas, and the Hippo pathway was inactivated in 90.3% of yes-associated protein (YAP) -positive angiosarcoma cases. However, survivin expression modes and YAP localization (Hippo pathway activation modes) were not correlated with survival. In addition, we confirmed that survivin small interference RNA (siRNA) transfection and YM155, an anti-survivin drug, elicited decreased nuclear survivin expression and cell proliferation in ISO-HAS-B cells which expressed survivin consistently. Conclusively, these findings support the importance of survivin as a good marker and critical regulator of cellular proliferation for human angiosarcoma and YM155 as a potential therapeutic agent.

Safe and Effective Sarcoma Therapy through Bispecific Targeting of EGFR and uPAR.

Sarcomas differ from carcinomas in their mesenchymal origin. Therapeutic advancements have come slowly, so alternative drugs and models are urgently needed. These studies report a new drug for sarcomas that simultaneously targets both tumor and tumor neovasculature. eBAT is a bispecific angiotoxin consisting of truncated, deimmunized Pseudomonas exotoxin fused to EGF and the amino terminal fragment of urokinase. Here, we study the drug in an in vivo "ontarget" companion dog trial as eBAT effectively kills canine hemangiosarcoma and human sarcoma cells in vitro We reasoned the model has value due to the common occurrence of spontaneous sarcomas in dogs and a limited lifespan allowing for rapid accrual and data collection. Splenectomized dogs with minimal residual disease were given one cycle of eBAT followed by adjuvant doxorubicin in an adaptive dose-finding, phase I-II study of 23 dogs with spontaneous, stage I-II, splenic hemangiosarcoma. eBAT improved 6-month survival from <40% in a comparison population to approximately 70% in dogs treated at a biologically active dose (50 µg/kg). Six dogs were long-term survivors, living >450 days. eBAT abated expected toxicity associated with EGFR targeting, a finding supported by mouse studies. Urokinase plasminogen activator receptor and EGFR are targets for human sarcomas, so thorough evaluation is crucial for validation of the dog model. Thus, we validated these markers for human sarcoma targeting in the study of 212 human and 97 canine sarcoma samples. Our results support further translation of eBAT for human patients with sarcomas and perhaps other EGFR-expressing malignancies. Mol Cancer Ther; 16(5); 956-65. ©2017 AACR.

miR-497-5p inhibits cell proliferation and invasion by targeting KCa3.1 in angiosarcoma.

Angiosarcoma is a rare malignant mesenchymal tumor with poor prognosis. We aimed to identify malignancy-associated miRNAs and their target genes, and explore biological functions of miRNA and its target in angiosarcoma. By miRNA microarrays and reverse transcription polymerase chain reaction, we identified 1 up-regulated miRNA (miR-222-3p) and 3 down-regulated miRNAs (miR-497-5p, miR-378-3p and miR-483-5p) in human angiosarcomas compared with human capillary hemangiomas. The intermediate-conductance calcium activated potassium channel KCa3.1 was one of the putative target genes of miR-497-5p, and marked up-regulation of KCa3.1 was detected in angiosarcoma biopsy specimens by immunohistochemistry. The inverse correlation of miR-497-5p and KCa3.1 also was observed in the ISO-HAS angiosarcoma cell line at the mRNA and protein levels. The direct targeting of KCa3.1 by miR-497-5p was evidenced by reduced luciferase activity due to complementary binding of miR-497-5p to KCa3.1 mRNA 3' untranslated region. For the functional role of miR-497-5p/KCa3.1 pair, we showed that application of TRAM-34, a specific KCa3.1 channel blocker, or transfection of ISO-HAS cells with KCa3.1 siRNA or miR-497-5p mimics inhibited cell proliferation, cell cycle progression, and invasion by down-regulating cell-cycle related proteins including cyclin D1, surviving and P53 and down-regulating matrix metallopeptidase 9. In an in vivo angiosarcoma xenograft model, TRAM-34 or miR-497-5p mimics both inhibited tumor growth. In conclusion, the tumor suppressor miR-497-5p down-regulates KCa3.1 expression and contributes to the inhibition of angiosarcoma malignancy development. The miR-497-5p or KCa3.1 might be potential new targets for angiosarcoma treatment.

Angiosarcoma of common iliac vein.

Angiosarcoma is a rare malignant tumour of endothelial cells. Primary angiosarcoma of venous origin is extremely rare, and has a very poor prognosis. A 63-year-old woman with retroperitoneal mass underwent en bloc resection on a part of iliac vein followed by adjuvant radiotherapy. No recurrence was detected during 3 years of follow-up.

Irradiation-induced angiosarcoma and anti-angiogenic therapy: a therapeutic hope?

Angiosarcomas are rare soft-tissue sarcomas of endothelial cell origin. They can be sporadic or caused by therapeutic radiation, hence secondary breast angiosarcomas are an important subgroup of patients. Assessing the molecular biology of angiosarcomas and identify specific targets for treatment is challenging. There is currently great interest in the role of angiogenesis and of angiogenic factors associated with tumor pathogenesis and as targets for treatment of angiosarcomas. A primary cell line derived from a skin fragment of a irradiation-induced angiosarcoma patient was obtained and utilized to evaluate cell biomarkers CD31, CD34, HIF-1 alpha and VEGFRs expression by immunocytochemistry and immunofluorescence, drugs cytotoxicity by cell counting and VEGF release by ELISA immunoassay. In addition to previous biomarkers, FVIII and VEGF were also evaluated on tumor specimens by immunohistochemistry to further confirm the diagnosis. We targeted the VEGF-VEGFR-2 axis of tumor angiogenesis with two different class of vascular targeted drugs; caprelsa, the VEGFR-2/EGFR/RET inhibitor and bevacizumab the anti-VEGF monoclonal antibody. We found the same biomarkers expression either in tumor specimens and in the cell line derived from tumor. In vitro experiments demonstrated that angiogenesis plays a pivotal role in the progression of this tumor as cells displayed high level of VEGFR-2, HIF-1 alpha strongly accumulated into the nucleus and the pro-angiogenic factor VEGF was released by cells in culture medium. The evaluation of caprelsa and bevacizumab cytotoxicity demonstrated that both drugs were effective in inhibiting tumor proliferation. Due to these results, we started to treat the patient with pazopanib, which was the unique tyrosine kinase inhibitor available in Italy through a compassionate supply program, obtaining a long lasting partial response. Our data suggest that the study of the primary cell line could help physicians in choosing a therapeutic approach for patient that almost in vitro shows chances of success and that the anti-angiogenetic agents are a reliable therapeutic opportunity for angiosarcomas patients.

Angiosarcoma de mama: a propósito de un caso / Angiosarcoma of the breast: apropos of one case

El angiosarcoma de mama constituye una neoplasia vascular maligna muy poco frecuente en la mama, con una incidencia inferior al 0,05 por ciento de entre todos los tumores primarios que asientan en la mama. Teniendo en cuenta que su edad de aparición es a partir de la tercera-cuarta década de la vida, resulta preocupante la aparición de casos a edades cada vez más tempranas. Se presenta el caso clínico de una paciente de 25 años de edad con antecedente de fibroma mamario benigno desde los 17 años que degenera en un angiosarcoma mamario...

Breast Angiosarcoma is a malignant vascular neoplasm rare in the breast with an incidence of less than 0.05 percent of all primary tumors in the breast that seat. Given its age of onset is from the third to fourth decade of life, it is disturbing to the occurrence of increasingly early ages. We describe the case of a patient 25 years old with a history of benign breast fibroid from the 17 years that degenerates into a breast angiosarcoma...

Angiosarcoma de cuero cabelludo: revisión de la literatura a propósito de un caso / Angiosarcoma of the scalp: clinical case and literature review

El angiosarcoma es una neoplasia maligna originada en el endotelio vascular. Puede afectar cualquier parte del cuerpo. Es un tumor infrecuente que representa aproximadamente el 2 por ciento de los sarcomas de partes blandas. El angiosarcoma de cuero cabelludo es una forma diferenciada dentro de los angiosarcomas; suele tener una evolución insidiosa, por lo que sus manifestaciones clínicas pueden ser muy variadas. A continuación se presenta el caso de un paciente de sexo femenino que presentó un angiosarcoma de cuero cabelludo. Se realiza una revisión de la literatura, con particular énfasis en las claves diagnósticas clínicas y de tratamiento.

Angiosarcoma is a malignant tumor originated in the vascular endothelium. It can affect any part of the body. It is a rare tumor that represents about 2 percent of soft tissue sarcomas. Scalp angiosarcoma is a distinct form within the angiosarcomas; usually has an insidious evolution and clinical manifestations vary. We present the clinical case of a female patient who presented a scalp angiosarcoma. A review of the literature is presented with particular emphasis on key clinical diagnosis and treatment.

Galectin-3 as a potential therapeutic target in tumors arising from malignant endothelia.

Angiosarcoma (ASA) in humans and hemangiosarcoma (HSA) in dogs are deadly neoplastic diseases characterized by an aggressive growth of malignant cells with endothelial phenotype, widespread metastasis, and poor response to chemotherapy. Galectin-3 (Gal-3), a beta-galactoside-binding lectin implicated in tumor progression and metastasis, endothelial cell biology and angiogenesis, and regulation of apoptosis and neoplastic cell response to cytotoxic drugs, has not been studied before in tumors arising from malignant endothelia. Here, we tested the hypothesis that Gal-3 could be widely expressed in human ASA and canine HSA and could play an important role in malignant endothelial cell biology. Immunohistochemical analysis demonstrated that 100% of the human ASA (10 of 10) and canine HSA (17 of 17) samples analyzed expressed Gal-3. Two carbohydrate-based Gal-3 inhibitors, modified citrus pectin (MCP) and lactulosyl-l-leucine (LL), caused a dose-dependent reduction of SVR murine ASA cell clonogenic survival through the inhibition of Gal-3 antiapoptotic function. Furthermore, both MCP and LL sensitized SVR cells to the cytotoxic drug doxorubicin to a degree sufficient to reduce the in vitro IC(50) of doxorubicin by 10.7-fold and 3.6-fold, respectively. These results highlight the important role of Gal-3 in the biology of ASA and identify Gal-3 as a potential therapeutic target in tumors arising from malignant endothelial cells.

Association of liver hemangiosarcoma and secondary iron overload in B6C3F1 mice--the National Toxicology Program experience.

The literature evidencing the role of iron in promoting a range of neoplasms in humans and animals prompted us to search for a possible association between chemically induced hemosiderosis and hemangiosarcomas in the liver of mice in selected studies conducted by the National Toxicology Program (NTP). Its historical control database was examined for studies in which treatment-related liver hemangiosarcoma was noted; 130 consecutive NTP studies in B6C3F1 mice from Technical Report (TR)-340 to TR-493 were evaluated. Three compounds (2-butoxyethanol, p-nitroaniline, and para-chloroaniline) were associated with a relatively high incidence of Kupffer cell pigmentation consisting of hemosiderin in both sexes; only the male mice developed a relatively low incidence of treatment-related hemangiosarcoma. With a fourth compound (o-nitroanisole), a relatively low incidence (16/50, high-dose males) of chemical-related hemosiderosis was noted, with no associated increase of hemangiosarcoma. Two chemicals (pentachlorophenol and tetrafluoroethylene) increased the incidence of liver hemangiosarcoma in male and female mice, with no increase in Kupffer cell pigmentation. The overall association between liver hemangiosarcoma and Kupffer cell pigmentation was highly significant (p < 0.001). The cause for hemosiderosis in all cases was the erythrocytic hemolytic effect of the compounds. The reason for the sex-increased susceptibility for development of hemangiosarcoma is unknown but may be due to a hormone-related, reduced antioxidative defensive capacity through modulation of the activities of antioxidative enzymes.

Honokiol, a small molecular weight natural product, inhibits angiogenesis in vitro and tumor growth in vivo.

Natural products comprise a major source of small molecular weight angiogenesis inhibitors. We have used the transformed endothelial cell line SVR as an effective screen of natural product extracts to isolate anti-angiogenesis and anti-tumor compounds. Aqueous extracts of Magnolia grandiflora exhibit potent activity in our SVR proliferation assays. We found that the small molecular weight compound honokiol is the active principle of magnolia extract. Honokiol exhibited potent anti-proliferative activity against SVR cells in vitro. In addition, honokiol demonstrated preferential inhibition of primary human endothelial cells compared with fibroblasts and this inhibition was antagonized by antibodies against TNF alpha-related apoptosis-inducing ligand. In vivo, honokiol was highly effective against angiosarcoma in nude mice. Our preclinical data suggests that honokiol is a systemically available and non-toxic inhibitor of angiogenesis and should be further evaluated as a potential chemotherapeutic agent.

Treatment of murine angiosarcoma with etoposide, TNP-470 and prednisolone.

To develop effective therapies for angiosarcoma, we investigated the anti-tumor effects of etoposide (ETO), TNP-470 and prednisolone (PSL) using an established murine angiosarcoma cell line (ISOS-1). We examined the direct anti-tumor and anti-angiogenic effects of these drugs on ISOS-1 cells and normal murine microvascular endothelial cells (mECs) in vitro. Cell growth of ISOS-1 was inhibited significantly by ETO, moderately by TNP-470, and not at all by PSL (IC(50): 0.25 microg/ml, 10 microg/ml, >8000 microg/ml, respectively). One the other hand, cell growth of mECs was inhibited significantly by TNP-470, slightly by PSL, and negligibly by ETO (IC(50): 0.85 ng/ml, 0.7 microg/ml, 10 microg/ml, respectively). In an in vivo assay, tumor growth of ISOS-1 was significantly inhibited by more than 2.5 mg/kg of ETO dose-dependently, and by more than 30 mg/kg of TNP-470, and 100 mg/kg of PSL individually. Combination treatments of ETO+TNP-470 and TNP-470+PSL showed synergistic enhancement of inhibition (% control inhibition: ETO vs. TNP-470 vs. ETO+TNP-470: 55 versus 55 vs. 16%) (% control inhibition: TNP-470 vs. PSL vs. TNP-470+PSL: 41 vs. 86 vs. 21%). ETO+PSL combination treatment, however, failed to show significant enhancement of anti-tumor effects. In conclusion, our results indicated that TNP-470 may be a very effective drug for angiosarcoma treatment, especially in combination with ETO or PSL. We eagerly anticipate the use of TNP-470 in clinical treatment of angiosarcoma.

[Angiosarcoma of the nasal septum]. / Angiosarkom des Nasenseptums.

This is a report on a female patient, 37 years old, with a polypous, sessile tumor on the nasal septum covered by smooth mucous membrane. She was treated with local excision. The histological diagnosis was an angiosarcoma, confirmed by immunohistological stain with factor VIII-like antigen, thrombomodulin, and UEA. She currently remains free of the disease 12 months after diagnosis. Angiosarcoma in the head and neck area and especially the localization in the nasal septum are extremely rare. Prognosis, differential diagnosis, metastasis formation, and therapy of this tumor are presented.