Angiosarcoma Research Articles

Synchronous multiple primary malignancies or transdifferentiation?-A diagnostic challenge in a case of Xeroderma pigmentosum.

A diagnosis of synchronous tumors is always questionable when they show similar histology. We present a case of synchronous tumors, i.e. melanoma (MM) arising from the scalp and angiosarcoma (AS) from the cheek in a patient of Xeroderma pigmentosum (XP). The presence of melanin in AS of the cheek led to a differential diagnosis and a possibility of transdifferentiation of malignant melanoma in the first instance. Immunohistochemistry (IHC) was negative for melanoma markers (Melan A, SOX-10 & S 100) and positive for vascular markers (ERG, CD31 & CD34) ruling out transdifferentiation and concluding the cheek swelling as angiosarcoma. The presence of non-cutaneous malignancies is rare in XP and the presence of MM in a nearby site and the melanin pigment in the cutaneous malignancy mislead the diagnosis. The morphology of the tumor was the key which led to the further workup of the case.

Comparison of clinical and MRI features of hepatic angiosarcoma and epithelioid hemangioendothelioma.

Differentiating hepatic epithelioid hemangioendothelioma (EHE) and angiosarcoma (AS), the two most common vascular tumors in the liver, is important due to disparities in their prognosis and treatment. We aimed to compare clinical and MRI features of the two tumors. This retrospective study included patients with pathologically-confirmed AS or EHE who underwent MRI using gadoxetate disodium between 2008 and 2023. Two radiologists independently reviewed MR images. Wilcoxon rank sum and Fisher's exact tests were used to compare clinical and imaging features. Overall survival was compared using restricted mean survival time at 3years. 32 patients with AS (18 women [56.3%]; median age, 68years) and 38 with EHE (24 women [63.2%]; 51years) were included. Patients with AS were generally older (81.3% ≥ 60years; P < 0.001), had more frequent laboratory abnormalities (P ≤ 0.018), and poorer overall survival (11.2 vs. 31.8months; P < 0.001) than those with EHE. On MRI, a large dominant mass accompanied by smaller nodules (14/32, 43.8%), often with ill-defined margins (15/32, 46.9%) was prevalent in AS; compared with nodules of similar sizes (24/38, 63.2%; P = 0.015) with well-defined margin (30/38, 78.9%; P = 0.002) in EHE. Cirrhotic appearance of the liver was more frequent in AS (62.5%, P < 0.001), along with decreased parenchymal enhancement on hepatobiliary phase (31.3%, P < 0.001) and ascites (37.5%, P = 0.010). AS frequently presented with avid enhancement of bizarrely-shaped foci, with a centrifugal enhancement pattern. In comparison, targetoid appearance was characteristic of EHE (78.9% on T2-weighted, 54.1% on diffusion-weighted, 65.8% on multiphase images) (P ≤ 0.002), with enhancement degree typically lower than that of the aorta. On hepatobiliary phase, all the AS exhibited hypointensity, while 39.5% of EHE showed targetoid appearance (P < 0.001). Patients aged ≥ 60years presenting with laboratory abnormalities, typically with a large dominant mass accompanied by smaller nodules, exhibiting avid, bizarre, and centrifugal enhancement-particularly in the cirrhotic-appearing liver-suggests the likelihood of AS over EHE.

Angiosarcoma: a 10-year retrospective study from a high-volume UK regional referral centre.

Angiosarcoma (AS) is a rare malignancy with considerable heterogeneity seen in its aetiology, anatomical location, and clinicopathological behaviour. Diagnosis is often delayed and prognosis poor. The purpose of this study was to perform a retrospective review of all cases of AS over 10years at a high-volume regional UK referral centre. We reviewed all cases of AS discussed at the sarcoma multidisciplinary meetings of University Hospitals Birmingham NHS Foundation Trust from September 2013 to August 2023. Demographic and clinicopathologic features at diagnosis, approaches to treatment, and outcomes were compared between four AS subtypes. A total of 130 cases were identified. The median age at diagnosis was 71years, with the majority being female (78%). The most common AS subtype was radiation-induced AS (RIAS) (n = 72; 55%), followed by primary cutaneous (n = 28; 22%), primary non-cutaneous (n = 25; 19%), and AS secondary to lymphoedema (n = 5; 4%). Metastases were present at diagnosis in 18% of patients. Treatment was with surgery in the majority of patients (71%). The median survival for the cohort was 30months (95% CI 20-40), although this differed significantly by AS subtype (p < 0.001), ranging from 5months in primary non-cutaneous AS to 76months in RIAS. RIAS is the most common AS subtype, with surgery the only potentially curative treatment modality. Overall prognosis varies significantly by subtype. An international consensus on classification of AS subtypes is required to allow meaningful comparisons across studies and/or a prospective multi-centre registry.

Angiosarcoma: clinical outcomes and prognostic factors, a single-center analysis

PurposeThis study sought to investigate oncological outcomes and prognostic factors for patients with angiosarcomas (AS).MethodsThis single-center, retrospective cohort study, analyzed histopathologically confirmed AS cases. Primarily diagnosed, locally recurrent and metastatic AS were included. Overall survival (OS), local control (LC) and local progression-free survival (LPFS) were assessed by Kaplan-Meier estimator. Multivariable Cox regression analysis was performed to detect factors associated with OS and LPFS.ResultsIn total, 118 patients with a median follow-up of 6.6 months were included. The majority presented with localized disease (62.7%), followed by metastatic (31.4%) and locally recurrent (5.9%) disease. Seventy-four patients (62.7%) received surgery, of which 29 (39.2%) were treated with surgery only, 38 (51.4%) with surgery and perioperative radiotherapy or chemotherapy, and 7 (9.4%) with surgery, perioperative radiotherapy and chemotherapy. Multivariable Cox regression of OS showed a significant association with age per year (hazard ratio (HR): 1.03, p = 0.044) and metastatic disease at presentation (hazard ratio: 3.24, p = 0.015). For LPFS, age per year (HR: 1.04, p = 0.008), locally recurrent disease at presentation (HR: 5.32, p = 0.013), and metastatic disease at presentation (HR: 4.06, p = 0.009) had significant associations. Tumor size, epithelioid components, margin status, and perioperative RT and/or CTX were not significantly associated with OS or LPFS.ConclusionOlder age and metastatic disease at initial presentation status were negatively associated with OS and LPFS. Innovative and collaborative effort is warranted to overcome the epidemiologic challenges of AS by collecting multi-institutional datasets, characterizing AS molecularly and identifying new perioperative therapies to improve patient outcomes.

TRPS1 expression in breast angiosarcoma.

Angiosarcoma (AS) of the breast, a rare mesenchymal neoplasm, exhibits distinct forms based on etiological and genetic features. While cases with typical clinical presentation and morphology allow for a straightforward diagnosis, challenges arise when clinical data are scarce, diagnostic material is limited, or morphological characteristics overlap with other tumors, including undifferentiated carcinomas. The trichorhinophalangeal syndrome protein 1 (TRPS1), once regarded as highly specific for breast carcinomas, now faces doubts regarding its reliability. This study explores TRPS1 expression in breast AS. Our investigation revealed that 60% of AS cases displayed TRPS1 labeling, contrasting with the 40% lacking expression. Scoring by four independent readers established a consensus, designating 12/35 ASs as unequivocally TRPS1-positive. However, uncertainty surrounded nine further cases due to a lack of reader agreement (being substantial as reflected by a kappa value of 0.76). These findings challenge the perceived specificity of TRPS1, shedding light on its presence in a noteworthy proportion of breast ASs. Consequently, the study underscores the importance of a comprehensive approach in evaluating breast ASs and expands the range of entities within the differential diagnosis associated with TRPS1 labeling.

Proposed diagnostic and prognostic markers of primary malignant hepatic vascular neoplasms

IntroductionPrimary malignant hepatic vascular tumors with various malignant potentials include epithelioid hemangioendothelioma (EHE) and angiosarcoma (AS), which may overlap pathologically. This study aimed to compare the pathological findings of hepatic EHE with those of AS, in association with patient outcomes.MethodsFifty-nine histologically confirmed patients with 34 EHE and 25 AS were admitted to a tertiary hospital from 2003 to 2020. Their EHE and AS pathological features were compared. Immunohistochemistry for CD31, ERG, CAMTA-1, TFE3, P53, and Ki-67 labeling was performed on paraffin-embedded blocks. Markers, along with histological findings, were analyzed for the purposes of diagnostic and prognostic significance by multivariate analysis.ResultsCAMTA-1 was 91.2% positive in EHE, but negative in AS (p = < 0.001). AS was significantly correlated to an aberrant p53 expression, high Ki-67 labeling, and high mitotic activity, compared to EHE (all, p = < 0.001). EHE can be classified as low grade (LG) and high grade (HG) using the prognostic values of mitotic activity and ki-67 labeling (sensitivity = 1, specificity = 1). Low grade-EHE showed significantly better overall survival than high grade-EHE (p = 0.020).ConclusionsImmunohistochemistry for CAMTA-1, P53, and Ki-67 labeling may help distinguish EHE and AS in histologically ambiguous cases, especially small biopsied tissue. Moreover, the combination of mitotic activity and Ki-67 labeling can be a prognostic factor for EHE with various clinical features.

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.

P53 Overexpression May Represent an Early Marker of Clinicopathologic Progression in Vasculogenic Mesenchymal Lesions of Germ Cell Tumor Origin.

Vasculogenic mesenchymal lesions (VMLs) of germ cell tumor origin are thought to originate in postpubertal-type yolk sac tumor componentsand include a spectrum of lesions from teratoma with vasculogenic stroma (TVS), to low and high-grade vasculogenic mesenchymal tumors (VMTs). VMLs exhibit rudimentary to well-developed neoplastic vessels within primitive mesenchyme, being considered a neoplastic reiteration of embryonic vasculogenesis in the splanchnic mesoderm of the yolk sac. They occur in patients with primary mediastinal germ cell tumors after chemotherapy, and a subset progresses to "somatic-type" sarcomas [including angiosarcoma (AS)], with high-grade VMTs likely portending a higher risk. Recently, we encountered a low-grade VMT that progressed to metastatic AS during follow-up. In this case, both the low-grade VMT and the subsequent AS demonstrated p53 overexpression, suggesting that p53 alterations may precede histopathologic transformation. To test this hypothesis, we evaluated neoplasms representing the entire spectrum of VMLs using p53 immunohistochemistry (IHC; clone DO-7, Dako). Overexpression was defined as nuclear positivity in > 80% of neoplastic cells. Because the distinction between high-grade VMT and AS can be subjective in some cases, they were grouped together in a single category. Thirty-nine VMLs were assessed: 16 high-grade VMT/AS, 19 low-grade VMT, and 4 TVS. Patient age ranged from 19 to 46 years (mean, 30 years; male = 97%). Four high-grade VMT/AS and one low-grade VMT showed p53 overexpression (5/39 VMLs, 13%; 4/16 high-grade VMT/AS, 25%). These tumors included 1 unequivocal AS and 1 high-grade VMT/AS with progression to rhabdomyosarcoma. The only low-grade VMT with p53 overexpression demonstrated progression to AS. Another high-grade VMT that progressed to sarcoma demonstrated p53 overexpression in the sarcoma component, but it was excluded because the VMT was not represented in the material availableat the time of the study. Lesions with intratumoral grade heterogeneity (classified based the highest grade), demonstrated more pronounced p53 overexpression in the high-grade components. P53 overexpression is associated with disease progression in a subset of VMTs and may precede morphologic transformation to sarcoma. Routine evaluation of VMTs with p53 IHC seems justified, with overexpressors likely requiring an close clinical surveillance.

Angiosarcoma of the head and neck: A clinicopathologic study with special emphasis on diagnostic pitfalls.

Angiosarcoma (AS) is a rare malignant vascular tumor that phenotypically and functionally recapitulate normal endothelium. They constitute approximately 2-4% of soft tissue sarcomas. We present 36 cases of head and neck AS diagnosed for 11 years at a tertiary care hospital in South India to analyze the clinical, pathological, and immunophenotypic profiles with special emphasis on their differential diagnoses and diagnostic pitfalls. Head and neck AS diagnosed from January 2006 to December 2017 were included. Clinical characteristics, treatment received, and follow-up data were obtained from electronic medical records. Hematoxylin and eosin (H&E)-stained slides and immunohistochemistry (IHC) slides were reviewed, and the histomorphological features, immunohistochemical staining, and their utility in resolving differential diagnosis were assessed. Twenty-two females and 14 males were diagnosed with head and neck AS in the study period. Histomorphological patterns observed were mixed vasoformative and solid ( n = 22), pure vasoformative ( n = 13), and pure solid ( n = 1). Neoplastic cells showed epithelioid, spindly, signet cell-like, clear cell, and rhabdoid morphology. CD31 was positive in 100% of cases, and CD34 was positive in 40% of cases. Differential diagnoses included melanoma, rhabdomyosarcoma, and large-cell lymphoma. Surgery, radiotherapy, and chemotherapy were the treatment modalities used. Twelve patients developed local recurrence, and 12 patients developed metastasis on follow-up. Twenty-five patients died of disease, on an average of 24 months after diagnosis. Head and neck AS pose a significant diagnostic challenge due to their broad morphologic spectrum. Proper clinicopathologic correlation is necessary to avoid misdiagnosis.

Genomic Landscape Comparison of Cardiac versus Extra-Cardiac Angiosarcomas.

Angiosarcomas (ASs) are rare malignant vascular entities that can affect several regions in our body, including the heart. Cardiac ASs comprise 25-40% of cardiac sarcomas and can cause death within months of diagnosis. Thus, our aim was to identify potential differences and/or similarities between cardiac and extra-cardiac ASs to enhance targeted therapies and, consequently, patients' prognosis. Whole-transcriptome analysis of three cardiac and eleven extra-cardiac non-cutaneous samples was performed to investigate differential gene expression and mutational events between the two groups. The gene signature of cardiac and extra-cardiac non-cutaneous ASs was also compared to that of cutaneous angiosarcomas (n = 9). H/N/K-RAS and TP53 alterations were more recurrent in extra-cardiac ASs, while POTE-gene family overexpression was peculiar to cardiac ASs. Additionally, in vitro functional analyses showed that POTEH upregulation conferred a growth advantage to recipient cells, partly supporting the cardiac AS aggressive phenotype and patients' scarce survival rate. These features should be considered when investigating alternative treatments.

Hemangiosarcoma in dogs as a potential non-rodent animal model for drug discovery research of angiosarcoma in humans.

Since the domestication of dogs 10,000 years ago, they have shared their living environment with humans and have co-evolved. The breeding process that dogs have undergone in only a few centuries has led to a significant accumulation of specific genetic alterations that could induce particular diseases in certain breeds. These canine diseases are similar to what is found in humans with several differences; therefore, comparing such diseases occurring in humans and dogs can help discover novel disease mechanisms, pathways, and causal genetic factors. Human angiosarcoma (AS) and canine hemangiosarcoma (HSA), which are sarcomas originating from endothelium, are examples of diseases shared between humans and dogs. They exhibit similar characteristics and clinical behaviors, although with some critical differences resulting from evolution. In this review, we will describe the similarities and differences in terms of clinical and molecular characteristics between human AS and canine HSA, and discuss how these similarities and differences can be applied to advance the treatment of these diseases.

Scalp Volumetric Modulated Arc Therapy Using 3D Milled Bolus: Dosimetry, Toxicity and Outcome.

Radiotherapy for scalp lesions is frequently challenging due to the competing needs for target volume coverage, sparing of numerous critical nearby OARs, and reproducible bolus setup despite the irregular and highly convex scalp geometry. Here, we evaluate the use of 3D milled bolus in treating such tumors. A retrospective analysis of scalp patients (pts) treated between 2016-2022 using 3D milled bolus and VMAT. All pts were treated with 6 MV photon beams, IGRT via daily CBCT, and 6-degree of Freedom (6-DOF) couch tops. Pts demographics, tumor characteristics, DVHs, toxicities and outcomes were evaluated. Regional control (RC) defined as control of the disease in the rest of the scalp/neck and local control (LC) defined as disease control within the PTV. A total of 23 pts were identified. Median age 74 (46-85), ECOG performance status was 0-1 in 20 pts (87%) and 92% were males. The histopathologies were squamous cell carcinoma (SCC) (61%), angiosarcoma (AS) (35%) and melanoma (4%). 35% of pts were treated with definitive intent to gross disease; the remaining 65% were treated post-operatively, 22% with microscopically positive margins and 43% with negative margins. 21% had perineural invasion (PNI), and none had lymphovascular invasion (LVI). 78% had T3/T4 and 13% had N+ disease. Median radiation dose was 66 Gy (60-69.96Gy). 44% received concurrent systemic therapy (Paclitaxel 22%, Cemiplimab 12%, Temozolomide 5%, Nivolumab 5%). In 40% of pts, the whole scalp was treated; in the remaining 60%, the median ratio of PTV volume to scalp volume was 35% (25-90%). 22% of pts (n = 5) had neck irradiation for prophylactic (3pts)/ neck lymph node involvement (2 pts). The median brain Dmax was 65 Gy (52.5-71.9), median brain mean dose was 15.4Gy (1.4-38.4), median eye Dmax was 10.9Gy (0.23-49), median cochlea mean was 8.4Gy (0.1-20.4), median lacrimal gland mean dose was 6.8Gy (0.11-38), median hippocampus Dmin was 5.9Gy (0.1-14.9) and Dmax was 10Gy (0.3-23). Most common acute side effects were grade 1-2 fatigue (100%), grade 1-2 pain (78%), grade 1 dysgeusia (22%), grade 1-2 dermatitis (74%). The only grade > = 3 adverse event was grade 3 dermatitis in 26%. Regarding long-term side effects, one pt had grade 2 osteoradionecrosis and other one developed grade 2 skin ulcer. 17% developed grade 1 memory impairment. 17% had grade 1 eye dryness. None developed brain radionecrosis. At a median follow-up was 14.4 months (1-73.5), the 1-yr LC was 96%. The 1-yr RC was 75% overall, 100% in angiosarcoma vs 62% in SCC (p = 0.18). Of the 4 regional recurrences, 1 pt had marginal recurrence along V1, 2 had neck nodal recurrence, and 1 had recurrence elsewhere in the scalp. 1-yr DMFS was 62% overall. 1-yr OS was 78% overall, 100% for AS vs 64% for SCC (P = 0.097). VMAT planning with 3D milled bolus permits technically sound radiotherapy for scalp targets with an acceptable toxicity profile and relatively favorable clinical outcomes. This approach warrants further evaluation in a larger prospective study.

An Update on Radiation-Induced Angiosarcoma of the Breast: A Diagnostic and Management Challenge

Background: Post-radiation angiosarcoma (AS) of the breast, also known as radiation-associated angiosarcoma (RAAS) or radiation-induced angiosarcoma (RIAS), is a rare complication after breast radiotherapy. The diagnosis and management of post-radiation AS is challenging because of its non-specific but aggressive presentation. This study aims to examine the experience of a local health district with post-radiation AS to improve awareness of this condition. Methods: A retrospective case series was performed on patients diagnosed with post-radiation AS within Western Sydney Local Health District between 2000-2021. Eligibility criteria included patients with histologically proven breast angiosarcoma and a history of past breast radiotherapy. Results: 11 patients had post-radiation AS of the breast. The annual incidence was 1 in 18,000 of the breast radiotherapy treated population. Descriptive analysis was performed on six patients. The median age was 67 years, with a median latency period of 5.5 years. All patients presented with non-specific skin changes. Core/punch biopsy was inconclusive in five patients. Mastectomy was the mainstay of treatment. Three patients had disease recurrence. The five-year survival rate was 68%. Conclusion: Post-radiation AS of the breast is a rare disease associated with a poor prognosis due to its aggressive nature and high recurrence rate. Diagnosis is challenging with high false-negative rates associated with imaging and biopsy. It is important to maintain a high index of suspicion in patients treated with past breast radiotherapy.

Aristolochic acid (AA) exposure and telomere maintenance mechanism in liver angiosarcoma (AS).

11551 Background: Liver AS has a grave prognosis and our previous study (Chen TW et al. Cancer 2022) showed that the incidence of liver AS is higher in Asia. We aimed to investigate the etiology of liver AS and its molecular characteristics. Methods: We performed whole exome (WES) and transcriptome sequencing (RNA-seq) of AS (liver 10, scalp 5, breast 2, trunk 1, heart 1) and hepatocellular carcinoma (HCC, 9) from National Taiwan University Hospital (NTUH) and re-analyzed WES &amp; RNA-seq of AS from the Count Me In Project (CMI, 46). Somatic mutations and copy number alternation were called by Mutect2 and Sequenza from tumor-normal matched WES. Non-negative matrix factorization was used to determine mutational signature profiles and the contributions of each signature to each sample. Telomere length was estimated using TelSeq. Results: We identified four single-base-substitution (SBS) signatures using somatic mutations from 74 (AS/HCC 65/9) WES data. The dominated signature in liver AS had exceptionally high cosine similarity (93.08%) with COSMIC SBS22 (ver 3.2), which is related to AA exposure. The AA-mutation signature contributed significantly (adjusted p &lt; 0.01) to the DNA mutations in 70% (7/10), 0% (0/9), 7% (3/46), and 56% (5/9) of liver AS (NTUH), nonliver AS (NTUH), CMI AS, and HCC (NTUH), respectively. TP53 (60% vs 22% vs 32%) and ATRX (40% vs 0% vs 11%) mutations were more common in liver than nonliver AS (NTUH) or CMI, while KDR mutation rates were similar (30% vs 44% vs 22%). Among TP53 mutations from liver AS with AA signature, 86% (6/7) showed the typical A:T &gt; T:A mutation caused explicitly by AA-induced DNA damage. In liver vs nonliver AS, the median number of mutations and neoantigen burdens were 6.55 vs 0.98 (p = 0.0076) and 1572 vs 544 (p = 0.095), respectively. Although liver AS and HCC were highly associated with AA-mutation signature, liver AS had significantly longer telomeres in terms of tumor/normal telomere ratio (median 1.27 vs 1.16, p = 0.0009) but a significantly lower telomerase enzyme activity (p = 0.016). We did not find an association between ATRX mutation, or its mRNA expression level, with the extended telomere length in liver AS. Compared to nonliver AS, the activity of the telomere replication molecule BUB1 was significantly higher in liver AS (p = 0.0029). Conclusions: Our study is the first to connect AA exposure to the etiology of liver AS. The high mutation rate and distinct telomere maintenance mechanism of liver AS provides insights into future treatments.

A phase II study of talimogene laherparepvec (T-VEC) and pembrolizumab in patients with advanced sarcoma: Results of expansion cohorts.

11570 Background: The open-label, single-center phase II study of T-VEC and pembrolizumab in patients with advanced sarcoma met its primary endpoint and demonstrated a best objective response rate of 30% at 24 weeks per RECIST v1.1 (Kelly CM, et al, Jama Oncology, 2020). Responses were seen in undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma, (MFS), epithelioid sarcoma (ES), cutaneous angiosarcoma (AS), and undifferentiated sarcoma not otherwise specified. Here, we report the efficacy observed in three histology specific expansion cohorts: 1) UPS/MFS, 2) cutaneous AS and 3) ES. Methods: Patients refractory to ≥ 1 prior line of systemic therapy or declined standard of care systemic therapy received pembrolizumab intravenously and intratumoral T-VEC injections on day 1 of a 21-day cycle. The primary endpoint was best objective response (ORR, complete and partial responses per RECIST v 1.1) by 24 weeks estimated for each subtype-specific cohort. Secondary objectives included: adverse events (AEs, TRAEs), median PFS and correlatives. Results: Twenty-one patients enrolled in the expansion cohorts: median age 72 years (range: 39-85), male 57%, ≤ 1 prior line of therapy (43%). Treatment was well tolerated in twenty patients; one patient discontinued study therapy due to grade 3 immune mediated hepatitis. Nineteen patients were evaluable for efficacy (one patient withdrew from the study and another discontinued treatment before week 24). Subtype specific best ORR by 24 weeks per RECIST v 1.1: UPS/MFS – 11% (n = 1/9)[95% CI: 0.0-0.48]; AS – 43% (n = 3/7)[95% CI: 0.1-0.82]; ES – 0% (n = 0/3). The best ORR overall for the AS cohort was 71% (n = 5/7)[95% CI: 0.03-0.95]. Median PFS (weeks) was 14.9 [CI:7-111] for UPS/MFS and 54 [95% CI: 3- not reached] for AS (Table). Conclusions: TVEC and pembrolizumab demonstrated acceptable safety and promising anti-tumor activity in cutaneous AS [head &amp; neck (n = 4) and Stewart-Treves syndrome involving the upper extremity (n = 1)]. Five AS patients experienced a partial response with durable disease control, remaining on study for 1-2 years or more. Two delayed responses were observed in the AS cohort after the pre-specified 24-week criteria. One AS responder progressed on immune checkpoint inhibition prior to study entry. Correlative analyses are ongoing. Clinical trial information: NCT03069378 . [Table: see text]

Interim results of a phase II trial of first line retifanlimab (R) plus gemcitabine and docetaxel (GD) in patients (pts) with advanced soft tissue sarcoma (STS).

11518 Background: GD is an alternative to doxorubicin in the front line setting in advanced STS. In the Phase I portion of this study, the PD-1 antibody R, plus GD, was generally well tolerated. We hypothesized that R+GD would be more effective than historical controls treated with GD alone. Methods: This is an ongoing open-label single-center study of R+GD in pts with treatment-naïve unresectable or metastatic high-grade STS. G (900 mg/m2) is administered on days 1 and 8 and D (75 mg/m2) on day 8, in 21-day cycles. R (375 mg flat dose) is administered on day 1 starting in cycle 2 and continued as monotherapy ‘maintenance’ after completion of 6 cycles of GD. Up to fifty pts can accrue into five histology-specific cohorts of 10 pts each. The primary endpoint is to estimate the progression-free survival (PFS) rate at 24 weeks. Secondary endpoints included safety, best overall response rate (RR) by RECIST 1.1, disease control rate (DCR), and duration of response (DOR). Subgroup analyses to evaluate all endpoints within each histology-specific cohort are preplanned. An early stopping rule for excessive toxicity will halt accrual if a prespecified severe adverse event rate is surpassed. Results: As of January 11, 2023, 43 pts were enrolled and treated with R+GD. The leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma (UPS)/myxofibrosarcoma (MFS), dedifferentiated liposarcoma (DDLPS), and other STS cohorts (n = 10 pts each) were fully accrued. Three of 10 angiosarcoma (AS) pts were enrolled. Median age was 59.5 (range 21 – 81) and 27 (63%) were male. Two DDLPS patients were not yet evaluable for response. Of 41 evaluable pts, the best overall RR was 22% (95% confidence interval [CI]) 11 – 38). Confirmed responses were seen in UPS/MFS (n = 4), LMS (2), AS (2), and follicular dendritic cell sarcoma (1). Three pts (LMS, ossifying fibromyxoid tumor, AS) had an unconfirmed PR, for a best RR of 29% (95% CI 16 – 46). Median PFS was 32.7 weeks (95% CI 26.4 – not estimable [NE]) and median DOR was 24 weeks (95% CI 15 – NE). Safety was evaluated in all 43 pts and the early stopping rule was not triggered. Eighteen (42%) pts had at least one Grade (Gr) 3 or 4 treatment-related adverse event (TRAE). The most common ( &gt; 5%) were anemia (16%), neutropenia (9%), febrile neutropenia (7%), lung infection (7%), and leukopenia (7%). Seven pts (16%) had pneumonitis: one Gr 1, four Gr 2, and two Gr 3. Six pts (14%) stopped treatment due to toxicity, including five with pneumonitis. Conclusions: The median PFS of R+GD appears promising compared to historical controls, although the primary endpoint analysis is pending completion of accrual. There was a higher incidence of pneumonitis with the combination compared to GD alone. Future studies of this combination will need to carefully consider the benefits and risks after the final efficacy and safety analyses are performed. Clinical trial information: NCT04577014 .

Is there a role for adjuvant therapy in radiation-induced angiosarcoma of the breast? A case report and review of the literature.

Angiosarcoma (AS) of the breast is very rare, accounting for 1% of all soft tissue breast tumors. AS may present as primary tumors of the breast or as secondary lesions usually associated with previous radiotherapy. Commonly, secondary AS affects older women (median age 67-71 years) with a clinical history of breast cancer. The preferred site of onset of RIAS is the edge of radiation fields, where radiation doses and tumor necrosis may be heterogeneous, resulting in a DNA damage and instability. Radical surgery is the treatment of choice, but no clear consensus exists on surgical management of breast AS. We describe an atypical case of relapsed RIAS after radical mastectomy, treated with new surgery and, considering the higher risk of recurrence, subsequent adjuvant chemotherapy with weekly paclitaxel. The frequency of radiation-induced angiosarcomas (RIAS) after breast-conserving surgery and radiotherapy has been increased to 0.14-0.5% among long survivors. Nevertheless, even if RIAS continues to be prognostically an extremely unfavorable cancer due to a high rate of recurrence, distant spread, and median overall survival (OS) of about 60 months, the benefits of loco-regional breast radiotherapy are clearly higher than the risk in developing angiosarcoma.

Profiling Docetaxel in Plasma and Urine Samples from a Pediatric Cancer Patient Using Ultrasound-Assisted Dispersive Liquid-Liquid Microextraction Combined with LC-MS/MS.

In recent years, therapeutic drug monitoring (TDM) has been applied in docetaxel (DOC)-based anticancer therapy to precisely control various pharmacokinetic parameters, including the concentration of DOC in biofluids (e.g., plasma or urine), its clearance, and its area under the curve (AUC). The ability to determine these values and to monitor DOC levels in biological samples depends on the availability of precise and accurate analytical methods that both enable fast and sensitive analysis and can be implemented in routine clinical practice. This paper presents a new method for isolating DOC from plasma and urine samples based on the coupling of microextraction and advanced liquid chromatography with tandem mass spectrometry (LC-MS/MS). In the proposed method, biological samples are prepared via ultrasound-assisted dispersive liquid-liquid microextraction (UA-DLLME) using ethanol (EtOH) and chloroform (Chl) as the desorption and extraction solvents, respectively. The proposed protocol was fully validated according to the Food and Drug Administration (FDA) and the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) requirements. The developed method was then applied to monitor the DOC profile in plasma and urine samples collected from a pediatric patient suffering from cardiac angiosarcoma (AS) with metastasis to lungs and mediastinal lymph nodes, who was receiving treatment with DOC at a dose of 30 mg/m2 body surface area. Due to the rarity of this disease, TDM was carried out to determine the exact levels of DOC at particular time points to ascertain which levels were conducive to maximizing the treatment's effectiveness while minimizing the drug's toxicity. To this end, the concentration-time profiles of DOC in the plasma and urine samples were determined, and the levels of DOC at specific time intervals up to 3 days after administration were measured. The results showed that DOC was present at higher concentrations in the plasma than in the urine samples, which is due to the fact that this drug is primarily metabolized in the liver and then eliminated with the bile. The obtained data provided information about the pharmacokinetic profile of DOC in pediatric patients with cardiac AS, which enabled the dose to be adjusted to achieve the optimal therapeutic regimen. The findings of this work demonstrate that the optimized method can be applied for the routine monitoring of DOC levels in plasma and urine samples as a part of pharmacotherapy in oncological patients.

Abstract 6064: Patient-partnered research enables germline characterization of angiosarcoma predisposition genes

Abstract Background: Angiosarcoma (ASC) represents 1-2% of soft tissue sarcomas. Due to its rarity, to date, no large-scale studies have been done to systematically identify ASC-predisposition genes and the broader landscape of pathogenic germline variants in patients with ASC remains unclear. Methods: Through the Angiosarcoma Project, an ongoing patient-partnered research approach that allows patients living anywhere in the U.S. or Canada with angiosarcoma to participate through a website, blood and saliva samples were collected from more than 300 patients and whole-exome-sequencing was performed. Machine-learning frameworks were used to identify germline short variants (SNPs, indels) and rare germline copy number variants (CNVs). The pathogenicity of variants in 107 curated cancer-predisposition and sarcoma-related genes were evaluated according to the ACMG guidelines. A short-variant-based gene-burden analysis was then performed using 223 unrelated ASC patients and 4557 ancestry-matched unrelated cancer-free controls. Results: In total, 38 patients (17.04%) carried at least one pathogenic short variant, including 37 carrying germline heterozygous pathogenic variants in POT1 (9, 4.04%), BRCA2 (3, 1.35%), CHEK2 (3, 1.35%), MUTYH (3, 1.35%), BRCA1 (2, 0.90%), PRF1 (2, 0.90%), ERCC3 (1, 0.45%), TP53 (2, 0.90%), ATM (1, 0.45%), TSHR (1, 0.45%), TSC2 (1, 0.45%), SDHA (1, 0.45%), SBDS (1, 0.45%), MSH6 (1, 0.45%), MITF (1, 0.45%), MET (1, 0.45%), LZTR1 (1, 0.45%), FH (1, 0.45%), ERCC2 (1, 0.45%), XPC (1, 0.45%). In addition, one patient harbored pathogenic short variants in both BRCA1 and ERCC3. In the 8 unique CNVs detected in 10 (4.55%) patients, 6 were classified as pathogenic including 3 heterozygous duplications overlapping MSH2, LZTR1, SMARCB1, and 3 heterozygous deletions overlapping NF1, MSH2, and WRN. Two unique heterozygous duplications met VUS criteria including one overlapping ERCC2 and one overlapping SMARCB1. In a comparison between ASC patients and cancer-free controls of predominantly European ancestry, we found ASC patients tobe 40 times more likely to carry a pathogenic variant in POT1 (OR: 42.91, CI: [15.40-174.08], q &amp;lt; 0.001, p &amp;lt; 0.001), while TP53 was nominally significant (OR: 7.37, CI: [1.19 - 41.13], p = 0.037). Conclusion: We confirmed prior observations of POT1 being responsible for ASC and called for attention to investigate the effect of germline CNVs in ASC. Overall, the elucidation of various germline elements associated with ASC risk highlighted the value and importance of patient-partnered research, particularly for rare cancers, and the analysis support using germline testing of patients for more precise clinical management. Citation Format: Hoyin Chu, Marissa Hollyer, Seunghun Han, Sabrina Y. Camp, Riaz Gillani, Eliezer Van Allen, Nikhil Wagle, Corrie A. Painter, Saud H. AlDubayan. Patient-partnered research enables germline characterization of angiosarcoma predisposition genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6064.

Sarcomas in fluid cytology: Experience from a tertiary care centre in India

Cytological evaluation of fluids for sarcomatous exfoliation is extremely rare. However, recently studies have come up describing characteristics of sarcomatous malignancies exfoliating into fluids but study from an Indian experience is still lacking. Description of clinico-pathological landscape in known cases of sarcomas, involving body fluid with emphasis on cytomorphologic details. Study includes cases reported as positive for involvement by sarcoma on fluid cytology including pleural, ascitic and cerebrospinal fluid (CSF) specimens between Jan 2016 to June 2022. Cases were retrieved and reviewed for cytomorphologic features which were subsequently correlated with its parent histology and IHC. IHC was applied on cell blocks for two cases where involvement was doubtful. In total, 21 fluid samples/cases including 4 CSF, 6 ascitic and 11 pleural fluid specimens were incorporated. Case spectrum comprised of 6 cases of Ewing Sarcoma (ES), 3 cases of rhabdomyosarcoma (RMS), 3 cases of osteosarcoma (OS), 2 cases of malignant peripheral nerve sheath tumor (MPNST), 2 cases of synovial sarcoma (SS), a case each of chondrosarcoma (CS), leiomyosarcoma (LMS) angiosarcoma (AS) and two cases of other malignancies with exfoliation of their sarcomatous component. Two cases presented as isolated latent metastasis so an IHC panel was applied to exclude involvement by secondary malignancy and prove involvement by primary diagnosed sarcoma.Majority of exfoliated sarcomas presented with epithelioidto pleomorphic morphology where at times it becomes obligatory to rule out occurrence of a secondary malignancy. It’s the first study from an Indian institute’s perspective that reflects upon such diversity of sarcomas with variability in morphology on exfoliation which can be overwhelming for a cytopathologist at times. IHC panel might be used when clinical background is unknown or when involvement is uncertain. More studies are needed that can help come up with recommendations that address such problems.