An unusual case of primary splenic soft part alveolar sarcoma: case report and review of the literature with emphasis on the spectrum of TFE3-associated neoplasms.

BACKGROUND: Alveolar soft part sarcoma is a rare tumour of soft tissues, mostly localized in muscles or deep soft tissues of the extremities. In rare occasions, this tumour develops in deep tissues of the abdomen or pelvis. CASE PRESENTATION: In this case report, we described the case of a 46 year old man who developed a primary splenic alveolar soft part sarcoma. The tumour displayed typical morphological alveolar aspect, as well as immunohistochemical profile notably TFE3 nuclear staining. Detection of ASPSCR1 Exon 7::TFE3 Exon 6 fusion transcript in molecular biology and TFE3 rearrangement in FISH confirmed the diagnosis. CONCLUSION: We described the first case of primary splenic alveolar soft part sarcoma, which questions once again the cell of origin of this rare tumour.

Establishment and characterization of NCC-ASPS2-C1: a novel patient-derived cell line of alveolar soft part sarcoma.

Alveolar soft part sarcoma (ASPS) is a rare mesenchymal tumor characterized by rearrangement of the ASPSCR1 and TFE3 genes and a histologically distinctive pseudoalveolar pattern. ASPS progresses slowly, but is prone to late metastasis. As ASPS is refractory to conventional chemotherapy, the only curative treatment is complete surgical resection. The prognosis of advanced and metastatic cases is poor, highlighting the need for preclinical research to develop appropriate treatment options. However, ASPS is extremely rare, accounting for < 1% of all soft tissue sarcomas, and only one patient-derived ASPS cell line is available from public cell banks worldwide for research. This study reports the establishment of a novel ASPS cell line derived from the primary tumor tissue of an ASPS patient, named NCC-ASPS2-C1. This cell line retains the ASPSCR1-TFE3 fusion gene, which is characteristic of ASPS. The characterization of this cell line revealed stable growth, spheroid formation, and invasive properties. By screening a drug library using NCC-ASPS2-C1, we identified several drugs that inhibited the proliferation of ASPS cells. In conclusion, the establishment of NCC-ASPS2-C1 provides a valuable resource for advancing ASPS research and developing novel treatments for this challenging disease.

Mimicking angiogenic microenvironment of alveolar soft-part sarcoma in a microfluidic coculture vasculature chip.

Alveolar soft-part sarcoma (ASPS) is a slow-growing soft tissue sarcoma with high mortality rates that affects adolescents and young adults. ASPS resists conventional chemotherapy; thus, decades of research have elucidated pathogenic mechanisms driving the disease, particularly its angiogenic capacities. Integrated blood vessels that are rich in pericytes (PCs) and metastatic potential are distinctive of ASPS. To mimic ASPS angiogenic microenvironment, a microfluidic coculture vasculature chip has been developed as a three-dimensional (3D) spheroid composed of mouse ASPS, a layer of PCs, and endothelial cells (ECs). This ASPS-on-a-chip provided functional and morphological similarity as the in vivo mouse model to elucidate the cellular crosstalk within the tumor vasculature before metastasis. We successfully reproduce ASPS spheroid and leaky vessels representing the unique tumor vasculature to assess effective drug delivery into the core of a solid tumor. Furthermore, this ASPS angiogenesis model enabled us to investigate the role of proteins in the intracellular trafficking of bioactive signals from ASPS to PCs and ECs during angiogenesis, including Rab27a and Sytl2. The results can help to develop drugs targeting the crosstalk between ASPS and the adjacent cells in the tumoral microenvironment.

How to develop new systemic treatments in ultra-rare cancers with high unmet needs? The case of alveolar soft-part sarcoma.

Developing new drugs or generating evidence for existing drugs in new indications for ultra-rare cancers is complex and carries a high-risk of failure. This gets even harder in ultra-rare tumours, which have an annual incidence of 1 per 1,000,000 population or less. Here, we illustrate the problem of adequate evidence generation in ultra-rare tumours, using Alveolar Soft-Part Sarcomas (ASPS) - an ultra-rare sarcoma newly diagnosed in approximately 60 persons a year in the European Union - as an exemplar case showing challenges in development despite being potentially relevant for classes of agents. We discuss some possible approaches for addressing such challenges, especially focussing on constructive collaboration between academic groups, patients and advocates, drug manufacturers, and regulators to optimise drug development in ultra-rare cancers. This article, written by various European stakeholders, proposes a way forward to ultimately get better options for patients with ultra-rare cancers.

Evaluation of TRIM63 RNA in situ hybridization (RNA-ISH) as a potential biomarker for alveolar soft-part sarcoma (ASPS).

Alveolar soft-part sarcoma (ASPS) is a rare soft tissue tumor with a broad morphologic differential diagnosis. While histology and immunohistochemistry can be suggestive, diagnosis often requires exclusion of other entities followed by confirmatory molecular analysis for its characteristic ASPSCR1-TFE3 fusion. Current stain-based biomarkers (such as immunohistochemistry for cathepsin K and TFE3) show relatively high sensitivity but may lack specificity, often showing staining in multiple other entities under diagnostic consideration. Given the discovery of RNA in situ hybridization (RNA-ISH) for TRIM63 as a sensitive and specific marker of MiTF-family aberration renal cell carcinomas, we sought to evaluate its utility in the workup of ASPS. TRIM63 RNA-ISH demonstrated high levels (H-score greater than 200) of expression in 19/20 (95%) cases of ASPS (average H-score 330) and was weak or negative in cases of paraganglioma, clear cell sarcoma, rhabdomyosarcoma, malignant epithelioid hemangioendothelioma, as well as hepatocellular and adrenal cortical carcinomas. Staining was also identified in tumors with known subsets characterized by TFE3 alterations such as perivascular epithelioid cell neoplasm (PEComa, average H-score 228), while tumors known to exhibit overexpression of TFE3 protein without cytogenetic alterations, such as melanoma and granular cell tumor, generally showed less TRIM63 ISH staining (average H-scores 147 and 96, respectively). Quantitative assessment of TRIM63 staining by RNA-ISH is potentially a helpful biomarker for tumors with molecular TFE3 alterations such as ASPS.

[Analysis of ultrasound images features and diagnostic model establishment of alveolar soft part sarcoma and intramuscular capillary-type hemangiomas].

Objective: The ultrasonography features of alveolar soft part sarcoma (ASPS) and intramuscular capillary-type hemangiomas (ICTH) were analyzed, and the diagnostic model of ASPS was established. Methods: A cross-sectional study was carried out. The clinical data of 52 patients [28 males and 24 females, aged (20.7±15.1) years] with pathologically confirmed ASPS and ICTH admitted to People's Hospital of Henan Province from January 2005 to February 2023 were included in the study. According to pathological types, the patients were divided into ASPS group and ICTH group. Clinical data of patients were retrospectively collected, and meaningful indicators in the univariate analysis were included in the regression analysis for screening. After comprehensive consideration of clinical significance and statistical significance, eligible indicators were selected for inclusion in the regression analysis. Binary logistic regression analysis was used to screen the factors that distinguished the pathological types of ASPS and ICTH, and the diagnostic model was established. The area under receiver operating characteristic (ROC) curve (AUC) was used to evaluate the diagnostic effectiveness of the diagnostic model in distinguishing ASPS from ICTH. Results: There were 20 patients in ASPS group, 10 males and 10 females, aged (26.9±13.5) years, and 32 patients in ICTH group, 18 males and 14 females, aged (16.8±15.0) years. The age difference between the ASPS group and the ICTH group was statistically significant (P<0.05), and there were statistically significant differences in the ultrasound imaging features of "clear boundary" "peripheral lobe" "thin blood vessels inside the lesion are straight and out of shape" "intra-lesion liquification" "peripheral thick blood vessels" and "peripheral muscle fiber disruption" between the two groups (all P<0.001).Variables with clinical and statistical significance were selected as independent variables. Binary logistic regression analysis showed that peripheral muscle fiber interruption (OR=97.358, 95%CI:6.833-1 387.249) and internal thin blood vessels were flat and out of shape (OR=0.052, 95%CI:0.003-0.921) was the correlation factor to distinguish the pathological types of ASPS and ICTH. Two ultrasonic image features of "peripheral muscle fiber interruption" and "internal thin blood vessels are straight and out of shape" were used to establish the diagnostic model. The sensitivity of "peripheral muscle fiber interruption" diagnostic model was 81.3%, and the specificity was 95.0%. The AUC was 0.811(95%CI: 0.761-0.954). The sensitivity, specificity and AUC of the diagnosis model of "internal thin vessels with flat misshape" were 90.0%, 96.9% and 0.934(95%CI: 0.830-0.984). The sensitivity, specificity and AUC of the combined diagnosis model of "peripheral muscle fiber interruption" and "internal thin blood vessel straight out of shape" were 96.9%, 90.0% and 0.974(95%CI:0.877-0.999). Conclusion: Ultrasonography can be used to distinguish ASPS from ICTH, and the combined diagnostic model based on the two ultrasonic imaging features of "peripheral muscle fiber interruption" and "internal thin blood vessel straight out of shape" can further improve the diagnostic efficiency.

Alveolar soft part sarcoma: a clinicopathological and immunohistochemical analysis of 26 cases emphasizing risk factors and prognosis.

OBJECTIVE: This study aimed to investigate the clinicopathological features and prognostic indicators of alveolar soft part sarcoma (ASPS). METHODS: The characteristics of 26 ASPS patients diagnosed at our hospital between January 2011 and January 2019 were retrospectively analysed. RESULTS: The data for 12 male and 14 female patients, with a median age of 27.5 years, were assessed. The clinical symptoms mainly included painless enlarged masses in deep soft tissues. ASPS had a characteristic pathological morphology. Twenty-four patients were positive for TFE3, and TFE3 gene rearrangement was detected in 12 patients. Among the 26 patients who completed follow-up, 14 had metastasis, 1 had local recurrence, and 7 died. Kaplan-Meier survival analysis revealed that prognosis was significantly correlated with sex, tumour size and metastasis (P < 0.05). Multivariate Cox regression analysis revealed that sex and metastasis were independent prognostic risk factors for patients with ASPS (P < 0.05). CONCLUSION: ASPS is a rare soft tissue sarcoma of unknown origin that occurs in young people, has a slow but metastatic course, and is associated with a poor 5-year survival rate among patients with metastasis. ASPS has character TFE3 protein and gene expression, and the diagnosis is relatively specific. The diagnosis requires comprehensive analysis of clinical history, histological morphology, and immunohistochemistry.

Atezolizumab as the First Systemic Therapy Approved for Alveolar Soft Part Sarcoma.

OBJECTIVE: The objective was to review the pharmacology, efficacy, and safety of atezolizumab (Tecentriq) for the treatment of adult and pediatric patients aged 2 years and older with unresectable or metastatic alveolar soft part sarcoma (ASPS). DATA SOURCES: A literature search was conducted using PubMed and MEDLINE databases, published abstracts, and ongoing studies from ClinicalTrials.gov between January 1, 1981, and May 31, 2023. Keywords included atezolizumab, Tecentriq, MPDL3280, immunotherapy, PD-L1, PD-1, pediatrics, sarcoma, and ASPS. STUDY SELECTION AND DATA EXTRACTION: All English-language studies involving atezolizumab for ASPS were included and discussed. DATA SYNTHESIS: Atezolizumab is an anti-programmed death-ligand 1 (PD-L1) monoclonal antibody designed to block the interaction between PD-L1 and the programmed cell death protein 1 (PD-1) receptor. Atezolizumab was granted approval by the FDA specifically for ASPS based on a phase II clinical trial in adult and pediatric patients (n = 49), which reported an overall response rate of 24% and a durable response rate at 6 and 12 months of 67% and 42%, respectively. Common grade 3/4 adverse reactions include musculoskeletal pain (8%), followed by hypertension (6%), weight gain (6%), headache (4%), and dizziness (4%). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON WITH EXISTING DRUGS: Advanced ASPS is a high-risk disease with limited treatment options. Atezolizumab appears to be a viable treatment option in ASPS demonstrating clinical efficacy and a manageable toxicity profile. CONCLUSIONS: With no other treatments that are FDA approved specifically for ASPS, and few demonstrating efficacy in the advanced setting, the approval of atezolizumab, including the first approval for pediatric patients, represents a landmark improvement to the therapeutic arsenal against this rare disease.

PEComa with ASPSCR1::TFE3 fusion: expanding the molecular genetic spectrum of TFE3-rearranged PEComa with an emphasis on overlap with alveolar soft part sarcoma.

AIMS: Mesenchymal neoplasms involving TFE3 gene fusions are diverse, mainly include alveolar soft part sarcoma (ASPS) that is characterised by ASPSCR1::TFE3 fusion, and a small subset of perivascular epithelioid cell tumours (PEComas) referred to as TFE3-rearranged PEComa, that most frequently harbours SFPQ::TFE3 fusion. Historically, ASPS and TFE3-rearranged PEComa are considered two distinctive entities despite their known morphological overlap. However, recent studies have suggested a potential histogenetic relationship between them, and several neoplasms that showed morphological features more closely fit PEComa rather than ASPS but harboured ASPSCR1::TFE3 fusion have been documented. In this study, we report three cases of PEComa with ASPSCR1::TFE3 fusion. METHODS AND RESULTS: Clinicopathological features were assessed and partner agnostic targeted next-generation sequencing on clinically validated platforms were performed. The patients are two females and one male with age at presentation ranging from 21 to 51 years. All three tumours were located in the viscera (rectum, kidney and cervix). On a relatively limited follow-up period (range = 9-15 months), all patients are alive without evidence of recurrent or metastatic disease. The neoplasms were composed of tight nested architecture of epithelioid clear cells separated by a delicate vascular network, two of which were associated with sheets of plump spindle cells, and none showed significant discohesive tumour morphology. Immunohistochemically, in addition to TFE3 protein, all three neoplasms demonstrated co-expression of melan-A and smooth muscle actin. RNA-sequencing identified ASPSCR1::TFE3 fusion in all three cases that were confirmed by subsequent fluorescence in-situ hybridisation analyses. CONCLUSIONS: Our study expands the molecular genetic spectrum of TFE3-rearranged PEComa and further indicates its close relationship to ASPS.

ASPSCR-1 and Sirt-5 alleviate Clonorchis liver fluke rCsNOSIP-induced oxidative stress, proliferation, and migration in cholangiocarcinoma cells.

BACKGROUND: Clonorchiasis, caused by the infection of Clonorchis sinensis (C. sinensis), is a kind of neglected tropical disease, but it is highly related to cholangiocarcinoma. It has been well known that NO from chronic inflammation responses are thought to be a major component of the damage and ultimate carcinogenesis ESPs such as nitric oxide synthase interacting protein (NOSIP) are thought to enhance the damage. The objective of this study was to identify the protein candidates interact with recombinant CsNOSIP (rCsNOSIP) and explore their role involved in CCA development or progression. METHODS: We applied HuProt microarray containing 21,000 probe sets for a systematic identification of rCsNOSIP-binding proteins and grouped binding hits by gene function. Pull-down assays were used to confirm the interaction of rCsNOSIP with alveolar soft part sarcoma (ASPSCR-1) and sirtuins 5 (Sirt-5). ASPSCR-1/Sirt-5 over-expression and siRNA knockdown experiments were employed for obtain of ASPSCR-1/Sirt-5 high or low expression (ASP-oe/Sirt5-oe or ASP-si/Sirt5-si) cholangiocarcinoma cell line (CCLP-1) cells. Nitric oxide (NO) and reactive oxygen species assay (ROS) as well as cell proliferation and wound-healing assays were performed to observe the effect of rCsNOSIP on ASP-oe/Sirt5-oe or ASP-si/Sirt5-si CCLP-1 cells. RESULTS: Seventy candidate proteins protein "hits" were detected as rCsNOSIP-binding proteins by HuProt microarray and bioinformatics analysis. Pull down assay showed that ASPSCR-1 and Sirt-5 could interact with rCsNOSIP. In addition, endotoxin-free-rCsNOSIP could increase the production of NO and ROS and promote the migration of CCLP-1 cells, while its effect on enhancing cell proliferation was not significant. Furthermore, ROS/NO production, proliferation, or migration were increased in ASP-si or Sirt5-si CCLP-1 cells but decreased in Asp-oe or Sirt5-oe CCLP-1 cells when stimulated with rCsNOSIP. CONCLUSIONS: Our findings suggest that CsNOSIP as a component of CsESPs might promote the development and invasion of CCA and Sirt5/ ASPSCR1 as host molecules might play a novel protective role against adverse stimulus during C. sinensis infection. This work supports the idea that CsESPs induce the occurrence and progression of CCA through ROS/RNS-induced oxidative and nitrative DNA damage.

Efficacy of immune checkpoint inhibitors in alveolar soft-part sarcoma: results from a retrospective worldwide registry.

BACKGROUND: Conventional cytotoxic drugs are not effective in alveolar soft-part sarcoma (ASPS). Immune checkpoint (programmed cell death protein 1/programmed death-ligand 1) inhibitors (ICIs) are promising drugs in ASPS. A worldwide registry explored the efficacy of ICI in ASPS. MATERIALS AND METHODS: Data from adult patients diagnosed with ASPS and treated with ICI for advanced disease in expert sarcoma centers from Europe, Australia and North America were retrospectively collected, including demographics and data related to treatments and outcome. RESULTS: Seventy-six ASPS patients, with a median age at diagnosis of 25 years (range 3-61 years), were registered. All patients received ICI for metastatic disease. Immunotherapy regimens consisted of monotherapy in 38 patients (50%) and combination in 38 (50%) (23 with a tyrosine kinase inhibitor). Among the 68 assessable patients, there were 3 complete responses and 34 partial responses, translating into an overall response rate of 54.4%. After a median follow-up of 36 months [95% confidence interval (CI) 32-40 months] since the start of immunotherapy, 45 (59%) patients have progressed on ICI, with a median progression-free survival (PFS) of 16.3 months (95% CI 8-25 months). Receiving ICI in first line (P = 0.042) and achieving an objective response (P = 0.043) correlated with a better PFS. Median estimated overall survival (OS) from ICI initiation has not been reached. The 12-month and 24-month OS rates were 94% and 81%, respectively. CONCLUSIONS: This registry constitutes the largest available series of ASPS treated with ICI. Our results suggest that the ICI treatment provides long-lasting disease control and prolonged OS in patients with advanced ASPS, an ultra-rare entity with limited active therapeutic options.

Severe immediate hypersensitivity to gadolinium contrast agent after targeted treatment in a patient with alveolar soft part sarcoma: A case report and review of literature.

RATIONALE: Gadolinium-based contrast agents (GBCAs), benefiting from good tolerance and safety, become the priority contrast agents in magnetic resonance imaging. Serious hypersensitivity reactions caused by GBCAs are rare, but occur occasionally. The "immune surveillance" theory proposes that lowered immune function exists in patients with malignance, which decrease the occurrence of atopy. Natural immunosurveillance that enhanced by effective treatment of malignance may increase the risk of hypersensitivity. PATIENT CONCERNS: A 29-year-old female patient suffering from intensive pain with left leg mass was admitted in our hospital. DIAGNOSES: The patient was diagnosed with alveolar soft part sarcoma by histopathology and revealed destruction of the left fibula and lung metastasis by computed tomography scan, and treated with anlotinib hydrochloride, a multi-targeted tyrosine kinase inhibitor. After 4 cycles of effective targeted therapy, the patient developed severe immediate hypersensitivity due to gadopentetate dimeglumine-enhanced magnetic resonance imaging. INTERVENTIONS AND OUTCOMES: The vital signs of the patient returned to normal after rescue. Since then, the patient has not used gadolinium contrast agent again, and currently the condition is stable and still alive. LESSONS: Severe immediate hypersensitivity might be occurred by gadolinium contrast agent in patients with malignance after effective treatment. We explored the potential mechanism of GBCA-inducing hypersensitivity in detail, by especially focusing on the changes of immune environment. Furthermore, we propose new ideas for the safe use of GBCAs in patients with malignancies.

Alveolar soft part sarcoma in a child - a case report.

BACKGROUND: Alveolar soft part sarcoma (ASPS) is a very rare mesenchymal malignancy of uncertain origin. It mostly affects young people, with about a quarter of cases being diagnosed in children. CASE: An 11-year-old girl had a painless subcutaneous "lump" in the left elbow area. Imaging exams revealed a solid soft-tissue intramuscular mass of suspicious appearance. A surgical excision of lesion was performed. The biopsy consisted of a lobular tumor measuring 35 × 20 × 12 mm. Histology revealed an epithelioid-cell population arranged in organoid pseudoalveolar pattern. It immunohistochemically expressed TFE3 and harbored the ASPSCR1:: TFE3 gene fusion. A diagnosis of ASPS was established. Subsequently, a wide re-excision of the scar was performed without microscopic residual tumor. The patient is currently without evidence of local recurrence or metastasis. CONCLUSION: ASPS is considered an aggressive and prognostically unfavorable chemoresistant neoplasm. Children have a better prognosis compared to adults. Early detection of tumor in a localized stage with complete surgical removal remains a mainstay therapeutic option. Due to its tendency to late metastases, a long-term thorough follow-up of the patient is necessary.

Exploratory study of an anti-PD-L1/TGF-ß antibody, TQB2858, in patients with refractory or recurrent osteosarcoma and alveolar soft part sarcoma: a report from Chinese sarcoma study group (TQB2858-Ib-02).

BACKGROUND: Novel and effective immunotherapies are required for refractory or recurrent sarcomas. Transforming growth factor-beta (TGF-ß) is a diverse regulatory and fibrogenic protein expressed in multiple sarcoma tumors that promotes epithelial-mesenchymal transition and excessive deposition of extracellular matrix. This study evaluated the efficacy and safety of the anti-PD-L1/TGF-ß antibody TQB2858 in patients with refractory osteosarcoma and alveolar soft part sarcoma (ASPS). METHODS: This single-arm phase 1b exploratory study included patients with refractory osteosarcoma or ASPS who had previously undergone at least two lines of systemic therapy. Patients were administered 1200 mg of TQB2858 once every 3 weeks. The primary endpoint was objective response rate (ORR), with null and alternative hypotheses of ORR ≤5% and ≥20%, respectively. Exploratory biomarker analyses using immunohistochemistry (IHC) staining (for PD-L1 and TGF-ß) were performed on pre-treatment tumor samples. RESULTS: Eleven eligible patients were included in this study. TQB2858 did not demonstrate evidence of efficacy as 0/5 osteosarcomas had any objective response, while 2/6 ASPS showed a partial response. The median progression-free survivals were 1.51 (1.38, Not Evaluable) and 2.86 (1.38, Not Evaluable) months for the osteosarcoma and ASPS groups, respectively. None of the administered cycles met the criteria for unacceptable toxicity. Other Grade 3 toxicities included abnormal liver function and elevation of γ-glutamyl transferase. IHC analysis revealed that functional enrichment in the TGF-ß pathway or PD-L1 was not associated with treatment outcomes. CONCLUSIONS: The combination of PD-L1 and TQB2858 did not significantly improve the ORR in patients with recurrent osteosarcoma. However, it improved immunogenic responses in ASPS, even after progression upon anti-PD-1/PD-L1 therapy, with an acceptable safety profile. IHC profiling with pathway enrichment analysis may not have any predictive value for survival outcomes. TRIAL REGISTRATION: Prospectively registered in the Ethical Review Committee of Peking University People's Hospital. The trial registration number is 2021PHA105-001 and 2021PHA140-001 and the registration date was March 2, 2022. CLINICALTRIALS: gov Identifier CTR20213001 and CTR20220390.

Alveolar soft part sarcoma of the uterine corpus: A 13-year follow-up case report and review of the literature.

OBJECTIVE: Female genital alveolar soft part sarcoma (ASPS) is rare and has a favourable prognosis compared to ASPS from other sites. We reported our experience to manage a case with uterine corpus ASPS (UC ASPS) and conducted a literature review on prognosis of ASPS from different sites of female genital tract. CASE REPORT: This report represented a 33-year-old woman who had UC ASPS. She received tumor excision with uterine preservation and had the longest follow-up time (155 months) without recurrence in the literature. CONCLUSION: UC ASPS has better prognosis than ASPS from the uterine cervix, the low uterine segment, vulvovaginal area and perineum. We recommended conservative treatment for young women with UC ASPS.

Atezolizumab for Advanced Alveolar Soft Part Sarcoma.

BACKGROUND: Alveolar soft part sarcoma (ASPS) is a rare soft-tissue sarcoma with a poor prognosis and no established therapy. Recently, encouraging responses to immune checkpoint inhibitors have been reported. METHODS: We conducted an investigator-initiated, multicenter, single-group, phase 2 study of the anti-programmed death ligand 1 (PD-L1) agent atezolizumab in adult and pediatric patients with advanced ASPS. Atezolizumab was administered intravenously at a dose of 1200 mg (in patients ≥18 years of age) or 15 mg per kilogram of body weight with a 1200-mg cap (in patients <18 years of age) once every 21 days. Study end points included objective response, duration of response, and progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, as well as pharmacodynamic biomarkers of multistep drug action. RESULTS: A total of 52 patients were evaluated. An objective response was observed in 19 of 52 patients (37%), with 1 complete response and 18 partial responses. The median time to response was 3.6 months (range, 2.1 to 19.1), the median duration of response was 24.7 months (range, 4.1 to 55.8), and the median progression-free survival was 20.8 months. Seven patients took a treatment break after 2 years of treatment, and their responses were maintained through the data-cutoff date. No treatment-related grade 4 or 5 adverse events were recorded. Responses were noted despite variable baseline expression of programmed death 1 and PD-L1. CONCLUSIONS: Atezolizumab was effective at inducing sustained responses in approximately one third of patients with advanced ASPS. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03141684.).

Advances in treatment of alveolar soft part sarcoma: an updated review.

Alveolar soft part sarcoma is a rare neoplasm of uncertain histogenesis that belongs to a newly defined category of ultra-rare sarcomas. The neoplasm is characterized by a specific chromosomal translocation, der (17) t(X; 17)(p11.2;q25), that results in ASPSCR1-TFE3 gene fusion. The natural history of alveolar soft part sarcoma describes indolent behaviour with slow progression in deep soft tissues of the extremities, trunk and head/neck in adolescents and young adults. A high rate of detection of distant metastasis at presentation has been reported, and the most common metastatic sites in decreasing order of frequency are the lung, bone and brain. Complete surgical resection remains the standard treatment strategy, whereas radiotherapy is indicated for patients with inadequate surgical margins or unresectable tumours. Although alveolar soft part sarcoma is refractory to conventional doxorubicin-based chemotherapy, monotherapy or combination therapy using tyrosine kinase inhibitors and immune checkpoint inhibitors have provided antitumor activity and emerged as new treatment strategies. This article provides an overview of the current understanding of this ultra-rare sarcoma and recent advancements in treatments according to the clinical stage of alveolar soft part sarcoma.

Pembrolizumab in patients with rare and ultra-rare sarcomas (AcSé Pembrolizumab): analysis of a subgroup from a non-randomised, open-label, phase 2, basket trial.

BACKGROUND: Sarcoma is a heterogeneous group of diseases with few treatment options. Immunotherapy has shown little activity in studies including unselected sarcomas, but immune checkpoint blockers have shown activity in specific histotypes. We evaluated the activity of pembrolizumab in rare and ultra-rare sarcomas. METHODS: AcSé Pembrolizumab is an ongoing phase 2, basket, multitumour study investigating the activity of pembrolizumab monotherapy in rare cancers. Here, we report the results obtained in patients with selected histotypes of rare sarcomas (incidence of less than one case per 1 000 000 people per year) recruited at 24 French hospitals. Key inclusion criteria were age 15 years or older, Eastern Cooperative Oncology Group performance status of 0-1, and advanced disease that was untreated and resistant to treatment. Patients were given pembrolizumab 200 mg intravenously on day 1 of every 21-day cycle for a maximum of 24 months. The primary endpoint was objective response rate at week 12 using Response Evaluation Criteria in Solid Tumours version 1.1, assessed by local investigators. The primary endpoint and safety were analysed in the intention-to-treat population. The AcSé Pembrolizumab study is registered with ClinicalTrials.gov, NCT03012620. FINDINGS: Between Sept 4, 2017, and Dec 29, 2020, 98 patients were enrolled, of whom 97 received treatment and were included in analyses (median age 51 years [IQR 35-65]; 53 [55%] were male; 44 [45%] were female; no data were collected on race or ethnicity). 34 (35%) patients had chordomas, 14 (14%) had alveolar soft part sarcomas, 12 (12%) had SMARCA4-deficient sarcomas or malignant rhabdoid tumours, eight (8%) had desmoplastic small round cell tumours, six (6%) had epithelioid sarcomas, four (4%) had dendritic cell sarcomas, three (3%) each had clear cell sarcomas, solitary fibrous tumours, and myxoid liposarcomas, and ten (10%) had other ultra-rare histotypes. As of data cutoff (April 11, 2022), median follow-up was 13·1 months (range 0·1-52·8; IQR 4·3-19·7). At week 12, objective response rate was 6·2% (95% CI 2·3-13·0), with no complete responses and six partial responses in the 97 patients. The most common grade 3-4 adverse events were anaemia (eight [8%] of 97), alanine aminotransferase and aspartate aminotransferase increase (six [6%]), and dyspnoea (five [5%]). 86 serious adverse events were reported in 37 patients. Five deaths due to adverse events were reported, none of which were determined to be related to treatment (two due to disease progression, two due to cancer, and one due to unknown cause). INTERPRETATION: Our data show the activity and manageable toxicity of pembrolizumab in some rare and ultra-rare sarcoma histotypes, and support the PD-1/PD-L1 pathway as a potential therapeutic target in selected histotypes. The completion of the basket study will provide further evidence regarding the activity and toxicity of pembrolizumab in identified rare types of cancer. FUNDING: The Ligue contre le cancer, INCa, MSD. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Vascular Expression of Prostate-specific Membrane Antigen (PSMA) in MiTF Family Translocation Renal Cell Carcinoma and Related Neoplasms.

Multiple studies have demonstrated prostate-specific membrane antigen (PSMA) expression in the neo-vasculature of non-prostate tumors including clear cell renal cell carcinoma (ccRCC). However, PSMA expression in rare renal tumors including MiTF family translocation renal cell carcinoma has not been previously characterized. We examined PSMA expression by immunohistochemistry in a series of MiTF family translocation renal cell carcinomas as well as in several genetically related tumors including alveolar soft part sarcoma and PEComas with TFE3 rearrangements. PSMA expression was also studied in several cases of ccRCC and papillary RCC. Overall, PSMA immunohistochemistry was performed in 61 samples from 58 patients. Vascular PSMA expression was seen with the highest frequency in ccRCC [88% (14/16)] (38% focal, 50% diffuse). Translocation RCC (tRCC) demonstrated the second highest frequency of PSMA expression [71% (22/28)] (57% focal, 14% diffuse), followed by alveolar soft part sarcoma [50% (4/8)] (38% focal, 12% diffuse). No PSMA expression was seen in PEComas with TFE3 rearrangement (0/3) or papillary RCC (0/6). PSMA expression was only present in tumor-associated neo-vasculature. A patient with oligometastatic tRCC underwent 68 Ga-PSMA-11 PET imaging which detected multiple putative metastatic lesions not detected on conventional computed tomography imaging performed 2 weeks prior, supporting the potential utility of PSMA imaging in tRCC. These findings have potential implications for the utility of PSMA guided diagnostic and therapeutic agents in both common and uncommon renal cell carcinoma subtypes as well as genetically related mesenchymal neoplasms.

Treatment of a case of primary alveolar soft part sarcoma of the lung: Case report and literature review.

Alveolar soft part sarcoma (ASPS) is an extremely rare type of soft tissue sarcoma. The primary sites of ASPS are mostly located in the extremities and trunk. Primary pulmonary ASPS is extremely rare. A search of the PubMed® database identified only five cases of primary pulmonary ASPS. This current case report describes the sixth case of ASPS in a 15-year-old male that presented with recurrent headaches. Head computed tomography showed space-occupying lesions in the left parietal lobe. Positron emission tomography-computed tomography confirmed the space-occupying lesions in the left parietal lobe and showed multiple nodules and masses in the two lungs and pleura, which were considered to be low-grade malignant mesenchymal tumours. The case report presents the clinical characteristics, diagnosis and treatment process. Programmed cell death protein 1 monoclonal antibody (sintilimab) combined with a tyrosine kinase inhibitor (anlotinib hydrochloride) achieved a good therapeutic effect, indicating that this combination therapy is worth exploring further. Large-scale prospective studies are needed to explore and develop standardized treatments for ASPS.