Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 549
Filtrar
1.
Gan To Kagaku Ryoho ; 51(6): 585-590, 2024 Jun.
Artigo em Japonês | MEDLINE | ID: mdl-39009511

RESUMO

Alveolar soft part sarcoma(ASPS)is a rare malignant tumor whose origin is unidentified, arising from deep soft tissue and affecting adolescents and young adults. ASPS is characterized by its abundant vascular network forming alveolar structures, and demonstrates frequent hematogenous metastasis. An ASPSCR1-TFE3 fusion gene derived from t(X;17)chromosome translocation is detected as a disease gene in all cases, and the ASPSCR1-TFE3 protein causes abnormal transcriptional regulation. We generated a mouse model for ASPS by introducing ASPSCR1-TFE3 into mouse embryonic mesenchymal cells. In the model, tumor angiogenesis and alveolar structures of human ASPS were reproduced, revealing pericyte-rich blood vessels and metastatic processes with pericytic encapsulation of tumor cell nests. ASPSCR1-TFE3 is frequently associated with active enhancers and super-enhancers, and angiogenesis-related enhancers were significantly diminished by the loss of ASPSCR1- TFE3. Angiogenesis-associated enhancers and important target genes, Rab27a, Sytl2, Pdgfb and Vwf were identified by epigenetic CRISPR screening. Rab27a and Sytl2 facilitates trafficking of cytoplasmic vesicles containing angiogenic factors such as Pdgfb and Vwf, resulting in pericyte-rich vascular structures in ASPS. These studies highlight the importance of the Rab27/Sytl axis as a novel drug target in cancer.


Assuntos
Neovascularização Patológica , Sarcoma Alveolar de Partes Moles , Sarcoma Alveolar de Partes Moles/genética , Sarcoma Alveolar de Partes Moles/patologia , Humanos , Animais , Neovascularização Patológica/genética , Proteínas de Fusão Oncogênica/genética , Camundongos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos
2.
BMC Oral Health ; 24(1): 689, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38872175

RESUMO

BACKGROUND: Alveolar soft part sarcoma (ASPS) occurs most often in the deep muscles or fascia of the extremities in adults, with only 3.4% of these tumours originating from the head, face and neck. To date, only 17 cases of buccal ASPS have been reported, including the case presented here. Only one case of ASPS recurrence at the primary site, similar to our case, has been reported thus far. Immune checkpoint inhibitors (ICPis)-associated diabetes, with an estimated incidence of 0.43%, is usually seen in older cancer patients and has not been reported in younger people or in patients with ASPS. CASE PRESENTATION: A 24-year-old male patient presented with a slowly progressing right cheek mass with a clinical history of approximately 28 months. Sonographic imaging revealed a hypoechoic mass, which was considered a benign tumour. However, a pathological diagnosis of ASPS was made after excision of the mass. Five days later, functional right cervical lymph node dissection was performed. No other adjuvant therapy was administered after surgery. In a periodic follow-up of the patient six months later, blood-rich tumour growth was noted at the primary site, and Positron emission tomography-computedtomography (PET-CT) ruled out distant metastasis in other areas. The patient was referred to the Ninth People's Hospital of Shanghai Jiaotong University. Due to the large extent of the mass, the patient received a combination of a Programmed Cell Death Ligand 1(PD-L1) inhibitor and a targeted drug. Unfortunately, the patient developed three episodes of severe diabetic ketoacidosis after the administration of the drugs. A confirmed diagnosis of ICPis-associated diabetes was confirmed. After the second operation, the postoperative pathological diagnosis was ASPS, and the margins were all negative. Therefore, we made a final clinical diagnosis of ASPS recurrence at the primary site. Currently in the follow-up, the patient is alive, has no distant metastases, and undergoes multiple imaging examinations every 3 months for the monitoring of their condition. CONCLUSIONS: In analysing the characteristics of all previously reported cases of buccal ASPS, it was found that the clinical history ranged from 1 to 24 months, with a mean of approximately 3 to 9 months. Tumour recurrence at the primary site has been reported in only one patient with buccal ASPS, and the short-term recurrence in our patient may be related to the extraordinarily long 28-month history. ICPis-associated diabetes may be noted in young patients with rare tumours, and regular insulin level monitoring after use is necessary.


Assuntos
Bochecha , Recidiva Local de Neoplasia , Sarcoma Alveolar de Partes Moles , Humanos , Masculino , Sarcoma Alveolar de Partes Moles/patologia , Sarcoma Alveolar de Partes Moles/diagnóstico por imagem , Sarcoma Alveolar de Partes Moles/cirurgia , Bochecha/patologia , Adulto Jovem , Recidiva Local de Neoplasia/patologia , Neoplasias Bucais/patologia , Neoplasias Bucais/diagnóstico por imagem , Neoplasias Bucais/cirurgia
4.
J Stomatol Oral Maxillofac Surg ; 125(3S): 101852, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38570254

RESUMO

PURPOSE: Alveolar Soft Part Sarcoma (ASPS) is an exceedingly rare and aggressive cancer in children. Our objective was to conduct a population-based cohort study to forecast overall survival (OS) in pediatric ASPS patients. METHODS: We utilized the Surveillance, Epidemiology, and End Results (SEER) database to identify all pediatric ASPS patients diagnosed between 1975 and 2019. Kaplan-Meier estimations were employed to construct survival curves based on various criteria. Survival curves were compared using the log-rank test. Cox proportional-hazards regression was utilized to determine variables associated with OS. Additionally, we constructed a nomogram to predict overall survival in pediatric ASPS patients. RESULTS: A total of 103 pediatric ASPS patients were identified. Predominantly, the tumors affected females (62.2 %), and most of them located in the extremities (53.4 %). The majority of patients underwent surgery (83.5 %). Survival rates declined with increasing tumor size, and patients with localized tumors exhibited significantly better prognoses than those with distant tumors. Surgery conferred superior survival outcomes compared to no surgery. Cox proportional hazard regression analysis identified SEER stage and surgery as important independent predictors of survival. CONCLUSIONS: Our study highlights SEER stage and surgery as key predictors of OS in pediatric ASPS, offering crucial epidemiological insights for clinical management.


Assuntos
Programa de SEER , Sarcoma Alveolar de Partes Moles , Humanos , Feminino , Masculino , Criança , Adolescente , Programa de SEER/estatística & dados numéricos , Sarcoma Alveolar de Partes Moles/epidemiologia , Sarcoma Alveolar de Partes Moles/diagnóstico , Sarcoma Alveolar de Partes Moles/patologia , Sarcoma Alveolar de Partes Moles/terapia , Sarcoma Alveolar de Partes Moles/mortalidade , Prognóstico , Pré-Escolar , Taxa de Sobrevida , Estimativa de Kaplan-Meier , Lactente , Nomogramas , Modelos de Riscos Proporcionais , Estados Unidos/epidemiologia , Estudos de Coortes
5.
Diagn Pathol ; 19(1): 62, 2024 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-38643139

RESUMO

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.


Assuntos
Sarcoma Alveolar de Partes Moles , Masculino , Humanos , Pessoa de Meia-Idade , Sarcoma Alveolar de Partes Moles/diagnóstico , Sarcoma Alveolar de Partes Moles/genética , Sarcoma Alveolar de Partes Moles/patologia , Proteínas de Fusão Oncogênica/genética , Fatores de Transcrição , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Éxons
6.
Cancer Res ; 84(14): 2247-2264, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38657118

RESUMO

Alveolar soft part sarcoma (ASPS) is a rare mesenchymal malignancy driven by the ASPSCR1::TFE3 fusion. A better understanding of the mechanisms by which this oncogenic transcriptional regulator drives cancer growth is needed to help identify potential therapeutic targets. In this study, we characterized the transcriptional and chromatin landscapes of ASPS tumors and preclinical models, identifying the essential role of ASPSCR1::TFE3 in tumor cell viability by regulating core transcriptional programs involved in cell proliferation, angiogenesis, and mitochondrial biology. ASPSCR1::TFE3 directly interacted with key epigenetic regulators at enhancers and promoters to support ASPS-associated transcription. Among the effector programs driven by ASPSCR1::TFE3, cell proliferation was driven by high levels of cyclin D1 expression. Disruption of cyclin D1/CDK4 signaling led to a loss of ASPS proliferative capacity, and combined inhibition of CDK4/6 and angiogenesis halted tumor growth in xenografts. These results define the ASPS oncogenic program, reveal mechanisms by which ASPSCR1::TFE3 controls tumor biology, and identify a strategy for therapeutically targeting tumor cell-intrinsic vulnerabilities. Significance: The ASPSCR1::TFE3 fusion propels the growth of alveolar soft part sarcoma  by activating transcriptional programs that regulate proliferation, angiogenesis, mitochondrial biogenesis, and differentiation and can be therapeutically targeted to improve treatment.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Proliferação de Células , Proteínas de Fusão Oncogênica , Sarcoma Alveolar de Partes Moles , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Sarcoma Alveolar de Partes Moles/genética , Sarcoma Alveolar de Partes Moles/patologia , Sarcoma Alveolar de Partes Moles/metabolismo , Humanos , Animais , Camundongos , Proliferação de Células/genética , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Feminino , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Neovascularização Patológica/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular
7.
Eur J Cancer ; 202: 114003, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38479120

RESUMO

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.


Assuntos
Sarcoma Alveolar de Partes Moles , Neoplasias de Tecidos Moles , Humanos , Sarcoma Alveolar de Partes Moles/tratamento farmacológico , Sarcoma Alveolar de Partes Moles/patologia , Neoplasias de Tecidos Moles/patologia , União Europeia , Incidência , Desenvolvimento de Medicamentos
8.
Hum Cell ; 37(3): 865-873, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38478355

RESUMO

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.


Assuntos
Antineoplásicos , Sarcoma Alveolar de Partes Moles , Neoplasias de Tecidos Moles , Humanos , Sarcoma Alveolar de Partes Moles/genética , Sarcoma Alveolar de Partes Moles/patologia , Linhagem Celular Tumoral , Neoplasias de Tecidos Moles/patologia , Fatores de Transcrição , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Antineoplásicos/farmacologia
9.
Proc Natl Acad Sci U S A ; 121(13): e2312472121, 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38502703

RESUMO

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.


Assuntos
Sarcoma Alveolar de Partes Moles , Animais , Camundongos , Sarcoma Alveolar de Partes Moles/tratamento farmacológico , Sarcoma Alveolar de Partes Moles/metabolismo , Sarcoma Alveolar de Partes Moles/patologia , Células Endoteliais/metabolismo , Técnicas de Cocultura , Microfluídica , Microambiente Tumoral
10.
Med Oncol ; 41(3): 76, 2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38393424

RESUMO

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.


Assuntos
Carcinoma de Células Renais , RNA , Sarcoma Alveolar de Partes Moles , Proteínas com Motivo Tripartido , Humanos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Hibridização In Situ , Proteínas Musculares/genética , Sarcoma Alveolar de Partes Moles/diagnóstico , Sarcoma Alveolar de Partes Moles/genética , Sarcoma Alveolar de Partes Moles/patologia , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases
11.
Zhonghua Yi Xue Za Zhi ; 104(8): 608-613, 2024 Feb 27.
Artigo em Chinês | MEDLINE | ID: mdl-38389238

RESUMO

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.


Assuntos
Hemangioma , Sarcoma Alveolar de Partes Moles , Masculino , Feminino , Humanos , Sarcoma Alveolar de Partes Moles/diagnóstico por imagem , Sarcoma Alveolar de Partes Moles/patologia , Estudos Retrospectivos , Estudos Transversais , Ultrassonografia
12.
Diagn Pathol ; 19(1): 23, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38291475

RESUMO

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.


Assuntos
Sarcoma Alveolar de Partes Moles , Humanos , Masculino , Feminino , Adolescente , Adulto , Estudos Retrospectivos , Sarcoma Alveolar de Partes Moles/diagnóstico , Sarcoma Alveolar de Partes Moles/genética , Sarcoma Alveolar de Partes Moles/patologia , Prognóstico , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Risco
13.
Ann Pharmacother ; 58(4): 407-415, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37466080

RESUMO

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.


Assuntos
Antígeno B7-H1 , Sarcoma Alveolar de Partes Moles , Adulto , Humanos , Criança , Receptor de Morte Celular Programada 1 , Sarcoma Alveolar de Partes Moles/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos
14.
Histopathology ; 84(3): 482-491, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37936565

RESUMO

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.


Assuntos
Neoplasias de Células Epitelioides Perivasculares , Sarcoma Alveolar de Partes Moles , Feminino , Humanos , Masculino , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Sarcoma Alveolar de Partes Moles/genética , Sarcoma Alveolar de Partes Moles/metabolismo , Sarcoma Alveolar de Partes Moles/patologia , Fusão Gênica , Neoplasias de Células Epitelioides Perivasculares/genética , Neoplasias de Células Epitelioides Perivasculares/patologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Biologia Molecular , Peptídeos e Proteínas de Sinalização Intracelular/genética
15.
PLoS Negl Trop Dis ; 17(11): e0011727, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37948465

RESUMO

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.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Clonorquíase , Clonorchis sinensis , Fasciola hepatica , Sarcoma Alveolar de Partes Moles , Animais , Humanos , Fasciola hepatica/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sarcoma Alveolar de Partes Moles/metabolismo , Clonorchis sinensis/genética , Estresse Oxidativo , Proteínas de Transporte/metabolismo , Proliferação de Células , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia
16.
ESMO Open ; 8(6): 102045, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38016251

RESUMO

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.


Assuntos
Antineoplásicos , Sarcoma Alveolar de Partes Moles , Adulto , Humanos , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Estudos Retrospectivos , Sarcoma Alveolar de Partes Moles/tratamento farmacológico , Sarcoma Alveolar de Partes Moles/patologia , Antineoplásicos/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico
17.
Medicine (Baltimore) ; 102(46): e36092, 2023 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-37986295

RESUMO

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.


Assuntos
Hipersensibilidade Imediata , Sarcoma Alveolar de Partes Moles , Feminino , Humanos , Adulto , Meios de Contraste/efeitos adversos , Gadolínio/efeitos adversos , Sarcoma Alveolar de Partes Moles/diagnóstico por imagem , Sarcoma Alveolar de Partes Moles/tratamento farmacológico , Gadolínio DTPA , Imageamento por Ressonância Magnética/métodos
18.
Klin Onkol ; 36(4): 396-400, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37877532

RESUMO

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.


Assuntos
Sarcoma Alveolar de Partes Moles , Adulto , Feminino , Humanos , Criança , Adolescente , Sarcoma Alveolar de Partes Moles/diagnóstico , Sarcoma Alveolar de Partes Moles/genética , Sarcoma Alveolar de Partes Moles/cirurgia , Proteínas de Fusão Oncogênica , Fusão Gênica , Prognóstico , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética
19.
N Engl J Med ; 389(10): 911-921, 2023 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-37672694

RESUMO

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.).


Assuntos
Anticorpos Monoclonais Humanizados , Antígeno B7-H1 , Sarcoma Alveolar de Partes Moles , Adolescente , Adulto , Criança , Humanos , Recém-Nascido , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Peso Corporal , Sarcoma Alveolar de Partes Moles/tratamento farmacológico , Administração Intravenosa
20.
BMC Cancer ; 23(1): 868, 2023 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-37715133

RESUMO

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.


Assuntos
Antineoplásicos Imunológicos , Neoplasias Ósseas , Osteossarcoma , Sarcoma Alveolar de Partes Moles , Neoplasias de Tecidos Moles , Humanos , Povo Asiático , Neoplasias Ósseas/tratamento farmacológico , População do Leste Asiático , Osteossarcoma/tratamento farmacológico , Sarcoma Alveolar de Partes Moles/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Fator de Crescimento Transformador beta/antagonistas & inibidores , Antígeno B7-H1/antagonistas & inibidores , Antineoplásicos Imunológicos/uso terapêutico , Anticorpos/uso terapêutico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...