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.

OER-073: A multicenter phase 2 study evaluating the role of pazopanib in angiosarcoma.

BACKGROUND: Angiosarcomas are rare mesenchymal sarcomas that can present as primary cutaneous or noncutaneous disease. They express a variety of vascular endothelial growth factor receptors. The authors hypothesized that the treatment of angiosarcoma with pazopanib, a multikinase inhibitor with activity against vascular endothelial growth factor receptors, would result in disease response and prolonged disease stabilization. METHODS: This was an open-label, phase 2 trial of pazopanib in patients who had incurable angiosarcoma. The co-primary end points were response according to the Response Evaluation Criteria in Solid Tumors and progression-free survival (PFS) at 3 months. The starting dose of pazopanib was 800 mg daily. RESULTS: Twenty-nine patients were accrued between 2011 and 2018, and 22 patients were evaluable for response. Toxicities were similar to those identified in prior reports. There was one partial response (3%), and the clinical benefit rate (including complete responses, partial responses, and stable disease) was 48%, which was observed more frequently in patients who had cutaneous disease. The median PFS was 14.4 weeks, and the 3-month PFS rate determined by Kaplan-Meier estimate was 54.6% (95% CI, 36.0%-82.9%), meeting the primary study objective. The Kaplan-Meier overall survival estimate was 16.1 months. CONCLUSIONS: Pazopanib therapy in patients who had incurable angiosarcoma was associated with meaningful disease control, especially in those who had cutaneous disease with limited objective responses. LAY SUMMARY: Angiosarcoma is a rare cancer that can be found on the skin or in internal organs. This study tested pazopanib, an oral targeted medication, to determine its benefit in patients with angiosarcoma who could not undergo the removal of their tumors by surgery. Pazopanib treatment was safe, and no new side effects were reported. The study showed that pazopanib controlled tumor growth in one half of patients at 3 months and was more common in angiosarcomas of the skin; it led to tumor shrinkage in a minority of patients (1 of 29).

Results of NC-6300 (Nanoparticle Epirubicin) in an Expansion Cohort of Patients with Angiosarcoma.

BACKGROUND: NC-6300 is a novel epirubicin (EPI) drug conjugated polymeric micelle developed using cutting-edge micellar nanoparticle technology. The nanoparticle epirubicin conjugates EPI to a polymer via a pH-sensitive linker which enables the selective EPI release into tumor. Tumor activity was observed in a monotherapy phase Ib trial, where two of two patients with angiosarcoma achieved a partial response. To further explore the activity of NC-6300 in angiosarcoma, an expansion cohort was undertaken. METHODS: Ten patients with angiosarcoma were enrolled in the expansion cohort. Patients were dosed using the recommended dose of 150 mg/m2 intravenously (IV) once every 3 weeks. The primary endpoint was progression-free survival. RESULTS: The most common adverse events (AEs) of any grade, regardless of the causal relationship with NC-6300, were neutropenia (90%), fatigue, and thrombocytopenia (60% each) and nausea (50%). The most common grades 3 and 4 AEs were neutropenia (80%), thrombocytopenia (40%), and anemia and leukopenia (20% each). The median progression-free survival (mPFS) for all subjects was 5.4 months. The mPFS was 3.8 months in subjects with prior anthracycline treatment and 8.2 months in subjects without prior anthracycline treatment. CONCLUSION: NC-6300 was well tolerated, showing promising activity in angiosarcoma patients without prior anthracycline treatment. NC-6300 warrants further investigation (ClinicalTrials.gov Identifier: NCT03168061).

Angiosarcoma and Vascular Surgery: A Case Report and Review of Literature.

INTRODUCTION: Angiosarcomas (AS) are rare and aggressive neoplasms originating from the endothelium: they represent less than 2% of all soft tissue sarcomas and usually have a poor prognosis. Although more often primary, different risk factors have been described and some cases are associated with vascular surgery. Materials and Methods: We present the case of an 84-year-old man who developed an AS on his thigh 3 years after a popliteal bypass with autologous saphenous vein. We performed a thorough review of the literature describing the main characteristics of the 25 cases (including ours) of AS associated with vascular surgery reported from 1981 to 2022. Results: Most of the patients were males (21 men vs 4 women) with a range age of 50-84 years. Most of AS are associated with Dacron grafts (12 cases), the overall mean time to onset is 7.8 years after surgery. The most common presenting symptoms are pain (20 cases) and weight loss (10 cases), while cutaneous presentation is uncommon; indeed, violaceous and painful papules, plaques, nodules, and skin ulceration have been found in 3 cases only. Due to unspecific symptoms, differential diagnosis is often difficult and a biopsy for histological confirmation is mandatory. Conclusion: Even if it seems to be a very rare complication, AS should always be considered in patients with compatible symptoms and who have undergone vascular surgery in the past.

Plasma Metabolomics Analysis of Polyvinyl Chloride Workers Identifies Altered Processes and Candidate Biomarkers for Hepatic Hemangiosarcoma and Its Development.

BACKGROUND: High-level occupational vinyl chloride (VC) exposures have been associated with hepatic hemangiosarcoma, which typically develops following a long latency period. Although VC is genotoxic, a more comprehensive mode of action has not been determined and diagnostic biomarkers have not been established. The purpose of this study is to address these knowledge gaps through plasma metabolomics. METHODS: Plasma samples from polyvinyl chloride polymerization workers who developed hemangiosarcoma (cases, n = 15) and VC exposure-matched controls (n = 17) underwent metabolomic analysis. Random forest and bioinformatic analyses were performed. RESULTS: Cases and controls had similar demographics and routine liver biochemistries. Mass spectroscopy identified 606 known metabolites. Random forest analysis had an 82% predictive accuracy for group classification. 60 metabolites were significantly increased and 44 were decreased vs. controls. Taurocholate, bradykinin and fibrin degradation product 2 were up-regulated by greater than 80-fold. The naturally occurring anti-angiogenic phenol, 4-hydroxybenzyl alcohol, was down-regulated 5-fold. Top affected ontologies involved: (i) metabolism of bile acids, taurine, cholesterol, fatty acids and amino acids; (ii) inflammation and oxidative stress; and (iii) nicotinic cholinergic signaling. CONCLUSIONS: The plasma metabolome was differentially regulated in polyvinyl chloride workers who developed hepatic hemangiosarcoma. Ontologies potentially involved in hemangiosarcoma pathogenesis and candidate biomarkers were identified.

Diethylnitrosamine (DENA) recapitulates formation of hepatic angiosarcoma in pigs.

BACKGROUND & AIM: Primary hepatic angiosarcoma is a rare tumor with poor prognosis. The aim of this study was to generate a new angiosarcoma model to improve research on hepatic angiosarcoma. METHODS: Pigs sus scrofa were treated with different regimens of diethylnitrosamine (DENA). Tissues were analyzed by histology and immunohistochemistry. Serum parameters were determined. Angiosarcoma tissue was investigated for chromosomal aberrations by aCGH analysis. RESULTS: Animals of almost all different treatment regimens developed a multitude of variable liver lesions. Different tumor types such as granulation tissue type, cellular-like, hyalinization necrosis-like, angiosarcoma-like, dysplastic nodule-like, hepatocellular-like, glandular structure-like, and leiomyoma-like lesions were observed. Weekly treatment with 15 mg/kg for up to 52 weeks or a single shot of 200 mg/kg DENA led to the development of hepatic angiosarcomas. aCGH analysis of angiosarcoma tissue revealed increased alterations in tumors compared to non-tumorous tissue. Most of the chromosomal alterations were found on chromosomes 6, 7, 12, and 14. CONCLUSION: In this preliminary study treatment of sus scrofa with weekly injections of 15 mg/kg DENA results in a new model for primary hepatic angiosarcoma. This model may help to shed light on the pathomechanisms of primary hepatic angiosarcoma and might therefore open new treatment options.

Clinical Outcomes and Prognostic Features of Angiosarcoma: Significance of Prior Radiation Therapy.

AIMS: Angiosarcoma is a rare and aggressive malignancy with a poor prognosis. There is limited literature describing prognostic factors and guidelines for treatment. We aim to describe outcomes in angiosarcoma, including the impact of patient-, tumour- and treatment-related factors on prognosis. MATERIALS AND METHODS: Patients with non-metastatic angiosarcoma diagnosed between 2008 and 2017 were retrospectively reviewed. Univariable and multivariable Cox proportional hazards methods were used to evaluate factors associated with locoregional recurrence, distant failure and overall survival. The Kaplan-Meier method and log-rank statistics were used to compare outcomes among patients with and without a history of prior radiation therapy. RESULTS: The cohort included 65 patients. The median age at diagnosis was 68 years (35-93). Nineteen patients had a history of receiving prior radiation therapy at the anatomic location of their angiosarcoma. Treatment modalities included surgery (n = 19), surgery + radiation therapy (n = 12), surgery + chemotherapy (n = 8), chemotherapy + radiation therapy (n = 7) and all three modalities (n = 14). The median follow-up was 18 (2-192) months. The 2-year locoregional control, distant control and overall survival were 61.8, 63.6 and 58.9%, respectively. On multivariable analysis, a history of previous radiation therapy was associated with inferior outcomes with respect to locoregional recurrence (hazard ratio 89.67, 95% confidence interval 8.45-951.07, P < 0.001), distant failure (hazard failure 3.74, 95% confidence interval 1.57-8.91, P = 0.003) and overall survival (hazard ratio 3.89, 95% confidence interval 1.56-9.60, P = 0.003). In patients with primary angiosarcoma, the rates of locoregional control, distant control and overall survival were 72.4, 73.4 and 65.1%, respectively, compared with 31.9, 41.1 and 45.1% in patients with radiation therapy-induced angiosarcoma (P = 0.001). CONCLUSION: Angiosarcomas that arise as a result of previous radiation therapy have worse outcomes compared with primary angiosarcomas. Although selection bias and compromise of clinical care in radiation therapy-induced angiosarcoma are partially to blame, differences in genomic profiles of the tumours need to be characterised to evaluate the underlying biological differences, as this may guide future treatment management. This study adds to the existing body of literature on angiosarcoma. Results from the current study are presented alongside previously published data to further characterise outcomes and prognostic factors on this rare and aggressive malignancy.

Mortality from liver angiosarcoma, hepatocellular carcinoma, and cirrhosis among vinyl chloride workers.

BACKGROUND: Occupational exposure to vinyl chloride monomer (VCM) has been established as a cause of hepatocellular carcinoma (HCC) and liver angiosarcoma (ASL). However, some controversy remains due to conflicting results on liver cirrhosis, and to evidence on HCC based on few confirmed cases. The aim of the study is to clarify the association between VCM exposure and mortality from liver diseases. METHODS: In a cohort of 1658 workers involved in VCM production and polymerization, Poisson regression was adopted to estimate rate ratios (RR) across categories of VCM exposure for mortality due to ASL (n = 9), HCC (n = 31) confirmed by histological/clinical records, and the combination of deaths from liver cirrhosis and from liver cancer with clinical/histological evidence of cirrhosis (n = 63). RESULTS: Cumulative VCM exposure was associated with study outcomes; RRs in the highest compared to the lowest exposure category were: ASL 91.1 (95%Confidence Interval 16.8-497), HCC 5.52 (2.03-15.0), liver cirrhosis 2.60 (1.19-5.67). CONCLUSIONS: The risk of death from liver cirrhosis, as well as from HCC in the largest available series of confirmed cases, increased with VCM exposure.

Development of angiosarcoma in a mediastinal non-seminomatous germ cell tumor that exhibited growing teratoma syndrome during chemotherapy.

Herein, we report a case of an angiosarcoma in a mediastinal non-seminomatous germ cell tumor that exhibited growing teratoma syndrome during chemotherapy. A 26-year-old man presented with a giant anterior mediastinal mass, which was diagnosed as a non-seminomatous germ cell tumor. The patient was administered three cycles of chemotherapy (bleomycin, etoposide, and cisplatin), but the mass grew despite normalization of tumor markers. Massive bleeding during thoracic surgery resulted in incomplete resection, and the mass was clinically and pathologically diagnosed as growing teratoma syndrome (only mature teratoma). The residual mass continued to grow, and complete resection was subsequently achieved after a detailed analysis of its vascular anatomy using angiography. The final pathological findings revealed angiosarcoma, which indicated a rare somatic type of mediastinal non-seminomatous germ cell tumor.

Induction of hemangiosarcoma in mice after chronic treatment with S1P-modulator siponimod and its lack of relevance to rat and human.

A high incidence of hemangiosarcoma (HSA) was observed in mice treated for 2 years with siponimod, a sphingosine-1-phosphate receptor 1 (S1P1) functional antagonist, while no such tumors were observed in rats under the same treatment conditions. In 3-month rat (90 mg/kg/day) and 9-month mouse (25 and 75 mg/kg/day) in vivo mechanistic studies, vascular endothelial cell (VEC) activation was observed in both species, but VEC proliferation and persistent increases in circulating placental growth factor 2 (PLGF2) were only seen in the mouse. In mice, these effects were sustained over the 9-month study duration, while in rats increased mitotic gene expression was present at day 3 only and PLGF2 was induced only during the first week of treatment. In the mouse, the persistent VEC activation, mitosis induction, and PLGF2 stimulation likely led to sustained neo-angiogenesis which over life-long treatment may result in HSA formation. In rats, despite sustained VEC activation, the transient mitotic and PLGF2 stimuli did not result in the formation of HSA. In vitro, the mouse and rat primary endothelial cell cultures mirrored their respective in vivo findings for cell proliferation and PLGF2 release. Human VECs, like rat cells, were unresponsive to siponimod treatment with no proliferative response and no release of PLGF2 at all tested concentrations. Hence, it is suggested that the human cells also reproduce a lack of in vivo response to siponimod. In conclusion, the molecular mechanisms leading to siponimod-induced HSA in mice are considered species specific and likely irrelevant to humans.

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.

Carcinogenicity of quinoline by drinking-water administration in rats and mice.

The carcinogenicity of quinoline was examined by administrating quinoline in the drinking water to groups of 50 F344/DuCrj rats and 50 Crj: BDF1 mice of each sex. In rats, the doses of quinoline were 0, 200, 400, and 800 ppm for males and 0, 150, 300, and 600 ppm for females. In male rats, administration of quinoline was terminated at week 96 due to high mortality caused by tumors. There were significant increases of hepatocellular adenomas, hepatocellular carcinomas, hepatocellular adenomas and/or carcinomas (combined), and liver hemangiomas, hemangiosarcomas, hemangiomas and/or hemangiosarcomas (combined) in both male and female rats, and nasal esthesioneuroepitheliomas and sarcoma NOS (not otherwise specified) in males. In mice, doses of quinoline were 0, 150, 300 and 600 ppm for both males and females. Administration of quinoline was terminated at week 65 in males and at week 50 in females due to high mortality caused by tumors. There were marked increases of hemangiomas, hemangiosarcomas, and hemangiomas and/or hemangiosarcomas (combined) in the retroperitoneum, mesenterium, and liver in males, and in the retroperitoneum, mesenterium, peritoneum, and subcutis in females. Additionally, histiocytic sarcomas were statistically increased in the livers of female mice. Thus the present studies provided clear evidence of carcinogenic activity of quinoline administered in the drinking water in both rats and mice.

From the Cover: Fenretinide, Troglitazone, and Elmiron Add to Weight of Evidence Support for Hemangiosarcoma Mode-of-Action From Studies in Mice.

Pharmaceuticals and chemicals produce hemangiosarcomas (HS) in mice, often by nongenotoxic, proliferative mechanisms. A mode-of-action (MOA) for hemangiosarcoma was proposed based on information presented at an international workshop (Cohen et al., Hemangiosarcoma in rodents: Mode-of-action evaluation and human relevance. Toxicol. Sci. 111, 4-18.). Five key elements of the MOA were articulated and included hypoxia, macrophage activation, increased angiogenic growth factors, dysregulated angiogenesis/erythropoiesis, and endothial cell proliferation. The goal of the current study was to add to the weight-of-evidence for the proposed MOA by assessing these key elements with 3 different compounds of varying potency for HS induction: fenretinide (high), troglitazone (intermediate), and elmiron (low). Multiple endpoints, including hypoxia (hyproxyprobe, transcriptomics), endothelial cell (EC) proliferation, and clinical and anatomic pathology, were assessed after 2, 4, and 13-weeks of treatment in B6C3F1 mice. All 3 compounds demonstrated strong evidence for dysregulated erythropoiesis (decrease in RBC and a failure to increase reticulocytes) and macrophage activation (4- to 11-fold increases); this pattern of hematological changes in mice might serve as an early biomarker to evaluate EC proliferation in suspected target organs for potential HS formation. Fenretinide demonstrated all 5 key elements, while troglitazone demonstrated 4 and elmiron demonstrated 3. Transcriptomics provided support for the 5 elements of the MOA, but was not any more sensitive than hypoxyprobe immunohistochemistry for detecting hypoxia. The overall transcriptional evidence for the key elements of the proposed MOA was also consistent with the potency of HS induction. These data, coupled with the previous work with 2-butoxyethanol and pregablin, increase the weight-of-evidence for the proposed MOA for HS formation.

[Mortality study update of workers exposed to vinyl chloride in plants located in Ferrara and Ravenna (Emilia-Romagna Region, Northern Italy)]. / Aggiornamento dello studio di mortalità nelle coorti di lavoratori ex esposti a cloruro di vinile monomero a Ferrara e Ravenna.

OBJECTIVES: to update the mortality study of subjects exposed to vinyl chloride in the phases of synthesis of the monomer and polymerization in the plants of Ferrara and Ravenna (Emilia-Romagna Region, Northern Italy). DESIGN: both for the whole cohort and for the two plants, standardized mortality ratios (SMRs), with 95% confidence intervals (95%CI), were calculated for different death causes, then stratified by duration and latency, periods of the beginning of work and cumulative exposure (ppm-years). SETTING AND PARTICIPANTS: the cohort includes 1,540 subjects (469 in Ferrara hired from 1953 to 1999; 1,071 in Ravenna hired from 1959 to 2000), with at least six months of work. RESULTS: by the end of the follow-up (31.12.2013), 348 deaths occurred. Overall observed mortality, contrasted to that expected based on Emilia-Romagna Region mortality rates, appeared to be lower than expected in the whole cohort (348 cases, SMR: 0.85; 95%CI 0.77-0.95) and in Ravenna (173 cases, SMR: 0.71; 95%CI 0.61-0.83). Mortality for all neoplasms was in excess in Ferrara (79 cases, SMR: 1.27; 95%CI 1.02-1.58), but lower than expected in Ravenna (83 cases, SMR: 0.80; 95%CI 0.64-0.99). An excess in mortality was observed in the whole cohort (16 cases, SMR: 1.74; 95%CI 1.07-2.85) and in Ferrara for liver cancer (7 cases, SMR: 2.12; 95%CI 1.02-4.46), and only in Ferrara for respiratory tract cancer (30 cases, SMR: 1.45; 95%CI 1.02-2.07) and larynx cancer (4 cases, SMR: 3.35; 95%CI 1.26-8.92). In the whole cohort, SMR for liver cancer was in excess since a cumulative exposure of 5,000 ppm-year and 12 cases belong to the job title of autoclave workers (12 cases, SMR 4.6; 95%CI 2.6-8.0), duration of work higher than 20 years (8 cases, SMR 2.4; 95%CI 1.2-4.9), and latency higher than 40 years (7 cases, SMR 2.5; 95%CI 1.2-5.2). The excess in mortality for lung cancer is statistically significant for and with cumulative exposure higher than 7,330 ppm-years (6 cases, SMR 3.2 95%CI 1.4-7.0). There are not excesses among subjects hired after 1971. CONCLUSIONS: the study findings confirm and expand the ones of previous studies. It was not possible to apply a best evidence approach to the study of liver cancer, and consequently it is not possible to distinguish between hepatic angiosarcoma and hepatocellular carcinoma. The evidence of a causal link between vinyl chloride exposure and liver cancer is anyhow confirmed. The causal link between vinyl chloride exposure and lung cancer must be further investigated.

Sequential development of hepatocellular carcinoma and liver angiosarcoma in a vinyl chloride-exposed worker.

Strong experimental and clinical evidences have definitely linked occupational vinyl chloride exposure to development of angiosarcoma of the liver. In contrast, despite the International Agency for Research on Cancer having included vinyl chloride among the causes of hepatocellular carcinoma, the association between vinyl chloride exposure and hepatocellular carcinoma remains debated. This issue is relevant, because occupational exposure to high levels of vinyl chloride may still occur. We report a unique case of sequential occurrences of hepatocellular carcinoma and angiosarcoma of the liver, in a vinyl chloride-exposed worker without cirrhosis and any known risk factor for chronic liver disease. Both the hepatocellular carcinoma and the surrounding normal liver showed micronucleus formation, which reflects genotoxic effect of vinyl chloride. Angiosarcoma showed a KRAS G12D point mutation, which is considered to be characteristic of vinyl chloride-induced angiosarcoma. This case supports the pathogenic role of vinyl chloride in both hepatocellular carcinoma and angiosarcoma development.

Heterozygous p53 knockout mouse model for dehydropyrrolizidine alkaloid-induced carcinogenesis.

Dehydropyrrolizidine alkaloids (DHPA) are a large, structurally diverse group of plant-derived protoxins that are potentially carcinogenic. With worldwide significance, these alkaloids can contaminate or be naturally present in the human food supply. To develop a small animal model that may be used to compare the carcinogenic potential of the various DHPAs, male heterozygous p53 knockout mice were administered a short-term treatment of riddelliine 5, 15 or 45 mg kg(-1) bodyweight day(-1) by oral gavage for 14 days, or dosed a long-term treatment of riddelliine 1 mg kg(-1) bodyweight day(-1) in pelleted feed for 12 months. Exposure to riddelliine increased the odds of tumor development in a dose-responsive manner (odds ratio 2.05 and Wald 95% confidence limits between 1.2 and 3.4). The most common neoplastic process was hepatic hemangiosarcoma, which is consistent with published lifetime rodent riddelliine carcinogenesis studies. Angiectasis (peliosis hepatis) and other previously unreported lesions were also identified. The results of this research demonstrate the utility of the heterozygous p53 knockout mouse model for further investigation of comparative carcinogenesis of structurally and toxicologically different DHPAs and their N-oxides.

Surveillance for angiosarcoma of the liver among vinyl chloride workers.

OBJECTIVE: We report the results of our angiosarcoma of the liver (ASL) registry to assess the occurrence, the impact of exposures to vinyl chloride, and to quantify latency. METHODS: We examined more than 73,000 death certificates of North American workers employed between 1940 and 2008. RESULTS: We found 13 deaths of ASL among workers with vinyl chloride exposure. All 13 occurred at single plant among workers with high vinyl chloride exposure. The mean latency after first exposure was 36.5 years ranging from 24 to 56 years. No ASL deaths occurred among workers with vinyl chloride exposures after 1974, when exposures were reduced. CONCLUSIONS: We may have seen the last case of ASL among workers exposed to vinyl chloride. Nevertheless, given the long latency of this cancer, continued surveillance seems prudent.

Hepatic angiosarcoma occurring 65 years after thorium dioxide (Thorotrast) exposure: imaging, surgical and histo- pathologic findings of a historical case.

We report the CT, surgical and histopathologic findings of a rare case of Hepatic Angiosarcoma (HAS) diagnosed in a 85-year old women 65 years afterThorotrast (Th232) exposure for angiography. At the early arterial phase of dynamic MDCT, peripheral curvilinear and central nodular puddling of contrast produced in the 8 cm tumor.Then progressive contrast filling of the tumor was observed on the delayed scans. Associated pathognomonic signs related to previous Th232 exposure were also found comprising diffuse intrahepatic reticular bands of calcifications, numerous calcified epigastric lymph nodes and a calcified shrunken spleen. Emergency laparotomy was performed because of associated hemoperitoneum. With a delay of 65 years afterThorotrast exposure, this historical case probably represents, to our knowledge, the most delayed presentation of Th232 related HAS ever published.

A vinyl chloride-exposed worker with an adrenal gland angiosarcoma: a case report.

Adrenal epithelioidangiosarcoma (AEA) is a rare neoplasm that accounts for less than 1% of sarcomas. Due to its rarity, it can easily be misdiagnosed, both by the clinician and the pathologist. Data on the patient's occupational history was collected and analyzed. The bibliographic data was found on the PUBMED bibliographic search site after entering the word "extrahepaticangiosarcoma". We report a case of adrenal epithelioidangiosarcoma (AEA) in a 68 yr-old Caucasian male factory worker exposed to Vinyl Chloride (VC) for 15 yr. He underwent surgery, chemotherapy and radiotherapy. Hepatic angiosarcoma is a known consequence of VC exposure, but occupational causality of extra-hepatic angiosarcoma is controversial. Extra-hepatic angiosarcomas have been reported in VC workers, but never AEA. Cancerogenic effects of VC involve all endothelial areas of the body and extra-hepatic endothelial tumors may also be caused by this substance. This is the first published report of AEA diagnosed in a worker exposed to VC.