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BACKGROUND: Afamitresgene autoleucel (afami-cel) showed acceptable safety and promising efficacy in a phase 1 trial (NCT03132922). The aim of this study was to further evaluate the efficacy of afami-cel for the treatment of patients with HLA-A*02 and MAGE-A4-expressing advanced synovial sarcoma or myxoid round cell liposarcoma. METHODS: SPEARHEAD-1 was an open-label, non-randomised, phase 2 trial done across 23 sites in Canada, the USA, and Europe. The trial included three cohorts, of which the main investigational cohort (cohort 1) is reported here. Cohort 1 included patients with HLA-A*02, aged 16-75 years, with metastatic or unresectable synovial sarcoma or myxoid round cell liposarcoma (confirmed by cytogenetics) expressing MAGE-A4, and who had received at least one previous line of anthracycline-containing or ifosfamide-containing chemotherapy. Patients received a single intravenous dose of afami-cel (transduced dose range 1·0 × 109-10·0 × 109 T cells) after lymphodepletion. The primary endpoint was overall response rate in cohort 1, assessed by a masked independent review committee using Response Evaluation Criteria in Solid Tumours (version 1.1) in the modified intention-to-treat population (all patients who received afami-cel). Adverse events, including those of special interest (cytokine release syndrome, prolonged cytopenia, and neurotoxicity), were monitored and are reported for the modified intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT04044768; recruitment is closed and follow-up is ongoing for cohorts 1 and 2, and recruitment is open for cohort 3. FINDINGS: Between Dec 17, 2019, and July 27, 2021, 52 patients with cytogenetically confirmed synovial sarcoma (n=44) and myxoid round cell liposarcoma (n=8) were enrolled and received afami-cel in cohort 1. Patients were heavily pre-treated (median three [IQR two to four] previous lines of systemic therapy). Median follow-up time was 32·6 months (IQR 29·4-36·1). Overall response rate was 37% (19 of 52; 95% CI 24-51) overall, 39% (17 of 44; 24-55) for patients with synovial sarcoma, and 25% (two of eight; 3-65) for patients with myxoid round cell liposarcoma. Cytokine release syndrome occurred in 37 (71%) of 52 of patients (one grade 3 event). Cytopenias were the most common grade 3 or worse adverse events (lymphopenia in 50 [96%], neutropenia 44 [85%], leukopenia 42 [81%] of 52 patients). No treatment-related deaths occurred. INTERPRETATION: Afami-cel treatment resulted in durable responses in heavily pre-treated patients with HLA-A*02 and MAGE-A4-expressing synovial sarcoma. This study shows that T-cell receptor therapy can be used to effectively target solid tumours and provides rationale to expand this approach to other solid malignancies. FUNDING: Adaptimmune.
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Anemia , Lipossarcoma Mixoide , Sarcoma Sinovial , Trombocitopenia , Adulto , Humanos , Sarcoma Sinovial/tratamento farmacológico , Sarcoma Sinovial/genética , Lipossarcoma Mixoide/etiologia , Síndrome da Liberação de Citocina/etiologia , Ifosfamida , Trombocitopenia/etiologia , Anemia/etiologia , Antígenos HLA-A , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
INTRIGUE was an open-label, phase 3 study in adult patients with advanced gastrointestinal stromal tumor who had disease progression on or intolerance to imatinib and who were randomized to once-daily ripretinib 150 mg or sunitinib 50 mg. In the primary analysis, progression-free survival (PFS) with ripretinib was not superior to sunitinib. In clinical and nonclinical studies, ripretinib and sunitinib have demonstrated differential activity based on the exon location of KIT mutations. Therefore, we hypothesized that mutational analysis using circulating tumor DNA (ctDNA) might provide further insight. In this exploratory analysis (N = 362), baseline peripheral whole blood was analyzed by a 74-gene ctDNA next-generation sequencing-based assay. ctDNA was detected in 280/362 (77%) samples with KIT mutations in 213/362 patients (59%). Imatinib-resistant mutations were found in the KIT ATP-binding pocket (exons 13/14) and activation loop (exons 17/18). Mutational subgroup assessment showed 2 mutually exclusive populations with differential treatment effects. Patients with only KIT exon 11 + 13/14 mutations (ripretinib, n = 21; sunitinib, n = 20) had better PFS with sunitinib versus ripretinib (median, 15.0 versus 4.0 months). Patients with only KIT exon 11 + 17/18 mutations (ripretinib, n = 27; sunitinib, n = 25) had better PFS with ripretinib versus sunitinib (median, 14.2 versus 1.5 months). The results of this exploratory analysis suggest ctDNA sequencing may improve the prediction of the efficacy of single-drug therapies and support further evaluation of ripretinib in patients with KIT exon 11 + 17/18 mutations. ClinicalTrials.gov identifier: NCT03673501.
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Antineoplásicos , Neoplasias Gastrointestinais , Tumores do Estroma Gastrointestinal , Naftiridinas , Ureia/análogos & derivados , Adulto , Humanos , Sunitinibe/uso terapêutico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Mesilato de Imatinib/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Biomarcadores , Mutação/genética , Antineoplásicos/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologiaRESUMO
PURPOSE: In the INTRIGUE trial, ripretinib showed no significant difference versus sunitinib in progression-free survival for patients with advanced gastrointestinal stromal tumour (GIST) previously treated with imatinib. We compared the impact of these treatments on health-related quality of life (HRQoL). PATIENTS AND METHODS: Patients were randomised 1:1 to once-daily ripretinib 150 mg or once-daily sunitinib 50 mg (4 weeks on/2 weeks off). Patient-reported outcomes were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer-30 (EORTC QLQ-C30) questionnaire at day (D)1, and D29 of all cycles until treatment discontinuation. Change from baseline was calculated. Time without symptoms or toxicity (TWiST) was estimated as the mean number of days without progression, death, or grade ≥3 treatment-emergent adverse events per patient over 1 year of follow-up. RESULTS: Questionnaire completion at baseline was 88.1% (199/226) for ripretinib and 87.7% (199/227) for sunitinib and remained high for enrolled patients throughout treatment. Patients receiving sunitinib demonstrated within-cycle variation in self-reported HRQoL, corresponding to the on/off dosing regimen. Patients receiving ripretinib reported better HRQoL at D29 assessments than patients receiving sunitinib on all scales except constipation. HRQoL was similar between treatments at D1 assessments, following 2 weeks without treatment for sunitinib patients. TWiST was greater for ripretinib patients (173 versus 126 days). CONCLUSION: Patients receiving ripretinib experienced better HRQoL than patients receiving sunitinib during the dosing period and similar HRQoL to patients who had not received sunitinib for 2 weeks for all QLQ-C30 domains except constipation. Ripretinib may provide clinically meaningful benefit to patients with advanced GIST previously treated with imatinib.
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Tumores do Estroma Gastrointestinal , Humanos , Sunitinibe/efeitos adversos , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Mesilato de Imatinib/efeitos adversos , Qualidade de Vida , Medidas de Resultados Relatados pelo Paciente , Constipação Intestinal/induzido quimicamenteRESUMO
BACKGROUND: Immune checkpoint inhibitors (ICIs) have shown modest antitumor activity in unselected advanced sarcomas. Histology driven approach to patient selection is the current standard for off-label anti-programmed cell death 1 (PD1) immunotherapy use. METHODS: We retrospectively reviewed the clinical characteristics and outcomes of patients with advanced sarcoma who were treated with off label anti-PD1 immunotherapy at our center. RESULTS: A total of 84 patients with 25 histological subtypes were included. Nineteen patients (23%) had a cutaneous primary tumor site. Eighteen patients (21%) were classified as having clinical benefit, including 1 patient with complete response, 14 with partial response, and 3 with stable disease lasting over 6 months with previously progressive disease. Cutaneous primary site location was associated with higher clinical benefit rate (58% vs. 11%, p < 0.001), longer median PFS (8.6 vs. 2.5 months, p = 0.003) and OS (19.0 vs. 9.2 months, p = 0.011), compared to non-cutaneous primary. Patients with histological subtypes that pembrolizumab is indicated per current National Comprehensive Cancer Network guidelines had modestly higher rate of clinical benefit versus other histologies, however, the difference was statistically insignificant (29% vs. 15%, p = 0.182) and no statistically significant difference in PFS or OS was observed between these groups. Immune-related adverse events were more frequently seen among patients with clinical benefit (72% vs. 35%, p = 0.007). CONCLUSIONS: Anti-PD1-based immunotherapy is highly efficacious in advanced sarcomas of cutaneous primary site. Cutaneous primary site location is a stronger predictor of ICI response than histologic subtype and should be accounted for in treatment guidelines and clinical trial design.
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Antineoplásicos Imunológicos , Neoplasias Pulmonares , Sarcoma , Humanos , Estudos Retrospectivos , Antineoplásicos Imunológicos/farmacologia , Sarcoma/tratamento farmacológico , Imunoterapia , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
A 73-year-old man with a history of atrial myxoma and basal cell carcinoma presented with unexplained fever. Contrast-enhanced CT abdomen showed a large left hepatic lobe mass with early enhancement and delayed venous washout, concerning for hepatocellular carcinoma. Fine needle aspiration showed numerous spindle cells with malignant nuclear features, suggestive of malignant spindle cell neoplasm. The patient underwent left hepatectomy. The surgical specimen showed a well-circumscribe solid mass (14.6 × 13.0 × 10.0 cm) with necrosis. Histopathological examination revealed a proliferation of spindle tumor cells with characteristic staghorn-shaped blood vessels, frequent mitoses, and necrosis. The tumor cells showed strong and diffuse expression of CD34 and STAT6, confirming the diagnosis of malignant solitary fibrous tumor. Solitary fibrous tumor is a rare fibroblastic tumor characterized by a staghorn vasculature and NAB2-STAT6 gene rearrangement. Solitary fibrous tumor of the liver is a rare occurrence. Although most solitary fibrous tumors behave in a benign fashion, solitary fibrous tumors might act aggressively. This case is unique in that it demonstrates an excellent correlation between radiologic, macroscopic, and microscopic features which can contribute to the improvement of radiologic and pathologic diagnostic accuracy.
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Affinity-optimized T cell receptors can enhance the potency of adoptive T cell therapy. Afamitresgene autoleucel (afami-cel) is a human leukocyte antigen-restricted autologous T cell therapy targeting melanoma-associated antigen A4 (MAGE-A4), a cancer/testis antigen expressed at varying levels in multiple solid tumors. We conducted a multicenter, dose-escalation, phase 1 trial in patients with relapsed/refractory metastatic solid tumors expressing MAGE-A4, including synovial sarcoma (SS), ovarian cancer and head and neck cancer ( NCT03132922 ). The primary endpoint was safety, and the secondary efficacy endpoints included overall response rate (ORR) and duration of response. All patients (N = 38, nine tumor types) experienced Grade ≥3 hematologic toxicities; 55% of patients (90% Grade ≤2) experienced cytokine release syndrome. ORR (all partial response) was 24% (9/38), 7/16 (44%) for SS and 2/22 (9%) for all other cancers. Median duration of response was 25.6 weeks (95% confidence interval (CI): 12.286, not reached) and 28.1 weeks (95% CI: 12.286, not reached) overall and for SS, respectively. Exploratory analyses showed that afami-cel infiltrates tumors, has an interferon-γ-driven mechanism of action and triggers adaptive immune responses. In addition, afami-cel has an acceptable benefit-risk profile, with early and durable responses, especially in patients with metastatic SS. Although the small trial size limits conclusions that can be drawn, the results warrant further testing in larger studies.
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Antígenos de Neoplasias , Neoplasias de Cabeça e Pescoço , Masculino , Humanos , Proteínas de Neoplasias , Antígenos HLA-A , Terapia Baseada em Transplante de Células e Tecidos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodosRESUMO
Autologous T cells transduced to express a high affinity T-cell receptor specific to NY-ESO-1 (letetresgene autoleucel, lete-cel) show promise in the treatment of metastatic synovial sarcoma, with 50% overall response rate. The efficacy of lete-cel treatment in 45 synovial sarcoma patients (NCT01343043) has been previously reported, however, biomarkers predictive of response and resistance remain to be better defined. This post-hoc analysis identifies associations of response to lete-cel with lymphodepleting chemotherapy regimen (LDR), product attributes, cell expansion, cytokines, and tumor gene expression. Responders have higher IL-15 levels pre-infusion (p = 0.011) and receive a higher number of transduced effector memory (CD45RA- CCR7-) CD8 + cells per kg (p = 0.039). Post-infusion, responders have increased IFNγ, IL-6, and peak cell expansion (p < 0.01, p < 0.01, and p = 0.016, respectively). Analysis of tumor samples post-treatment illustrates lete-cel infiltration and a decrease in expression of macrophage genes, suggesting remodeling of the tumor microenvironment. Here we report potential predictive and pharmacodynamic markers of lete-cel response that may inform LDR, cell dose, and strategies to enhance anticancer efficacy.
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Sarcoma Sinovial , Antígenos de Neoplasias/metabolismo , Biomarcadores/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Sarcoma Sinovial/genética , Sarcoma Sinovial/patologia , Sarcoma Sinovial/terapia , Microambiente TumoralRESUMO
OBJECTIVE: Primary pulmonary sarcomas (PPS) and pulmonary carcinosarcomas (PCS) are rare aggressive lung malignancies. We reviewed our 21-year experience with the surgical and nonsurgical treatment of both tumors, comparing their clinical, histopathologic, and treatment results. METHODS: All patients with PPS or PCS who underwent surgical and nonsurgical treatment between 1998 and 2019 at our cancer center were retrospectively reviewed. Multivariable Cox proportional hazards model was constructed. RESULTS: In total, 100 patients were analyzed: 45 with PPS and 55 with PCS. Among patients with PPS, 31 of 45 (69%) underwent surgery with 1 (3%) operative mortality. For patients with PCS, 29 of 55 (53%) underwent surgery with no operative mortality. Patients with PPS were younger than PCS (P < .01). Fewer patients were smokers among PPS (58%) versus PCS (93%) (P < .01). For resected PPS, mean tumor size was 8.2 ± 4.1 cm (range 2.2-18.0) compared with 10.1 ± 5.0 cm (range 3.9-17.0) for unresected PPS. Tumor size for resected PCS was 6.2 ± 2.6 cm (range 2.0-10.5) versus 6.8 ± 3.5 cm (range 1.2-13.5) for unresected PCS. Of resected patients, 5 of 31 (16%) with PPS and 9 of 29 (31%) with PCS were node positive. Overall survival estimates were as follows: for PPS, median survival and 5-year overall survival for resected versus unresected cases were 39.6 months/28.7% versus 4.9 months/7.8%. For PCS, survival estimates were 23.6 months/31.0% versus 14.9 months/28.2%, respectively. In multivariable analyses (N = 100), age, smoking history, histology, and surgery were risk factors of survival. CONCLUSIONS: At initial evaluation, PPS and PCS presented with large-sized tumors and usually were not stage I. Surgery had a positive impact on survival among patients with PPS. Whenever feasible, surgical resection, even in locally advanced disease, may yield long-term survival in these aggressive lung tumors, although the level of evidence is low.
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Carcinossarcoma , Neoplasias Pulmonares , Sarcoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinossarcoma/epidemiologia , Carcinossarcoma/mortalidade , Carcinossarcoma/patologia , Carcinossarcoma/terapia , Feminino , Humanos , Pulmão/cirurgia , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Pneumonectomia/mortalidade , Estudos Retrospectivos , Fatores de Risco , Sarcoma/epidemiologia , Sarcoma/mortalidade , Sarcoma/patologia , Sarcoma/terapia , Resultado do TratamentoRESUMO
Adrenal crisis is a life-threatening complication of adrenal insufficiency which is triggered by physiological stressors such as injury, infection or a surgical procedure when the plasma concentration of adrenal corticosteroids is insufficient for physiological requirements. It is associated with a high mortality rate unless early diagnosis and treatment is initiated. We report a case of a patient with metastatic sarcoma and adrenal insufficiency who underwent right hepatic artery chemoembolization to control his intrahepatic metastases. He did not receive stress dose glucocorticoid and his glucocorticoid supplement medication was accidentally discontinued after embolization. He died due to an unrecognized adrenal crisis 2 days after embolization. This case suggests that embolization should be recognized as a stressor to prompt the need to continue chronic replacement of corticosteroids and to consider supplemental stress-dose corticosteroids. There is a growing population of patients on chronic corticosteroids for various conditions who may require tumor embolization. Therefore, it is important to consider adrenal crisis in post-embolization settings since the symptoms are non-specific and mortality can be avoided only if the diagnosis of adrenal crisis is considered and parenteral glucocorticoids administered.
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Insuficiência Adrenal , Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Sarcoma , Insuficiência Adrenal/induzido quimicamente , Quimioembolização Terapêutica/efeitos adversos , Evolução Fatal , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/terapia , MasculinoRESUMO
BACKGROUND: Pexidartinib is approved in the U.S. for tenosynovial giant cell tumors (TGCTs). Herein, we assessed the hepatic safety profile of pexidartinib across patients with TGCTs receiving pexidartinib. MATERIALS, AND METHODS: Hepatic adverse reactions (ARs) were assessed by type and magnitude of liver test abnormalities, classified as (a) isolated aminotransferase elevations (alanine [ALT] or aspartate [AST], without significant alkaline phosphatase [ALP] or bilirubin elevations), or (b) mixed or cholestatic hepatotoxicity (increase in ALP with or without ALT/AST and bilirubin elevations, based on adjudication). Median follow-up from initial pexidartinib treatment was 39 months (range, 32-82) in 140 patients with TGCTs across clinical studies NCT01004861, NCT02371369, NCT02734433, and NCT03291288. RESULTS: In total, 95% of patients with TGCTs (133/140) treated with pexidartinib (median duration of exposure, 19 months [range, 1-76]), experienced a hepatic AR. A total of 128 patients (91%) had reversible, low-grade dose-dependent isolated AST/ALT elevations without significant ALP elevations. Five patients (4%) experienced serious mixed or cholestatic injury. No case met Hy's law criteria. Onset of hepatic ARs was predominantly in the first 2 months. All five serious hepatic AR cases recovered 1-7 months following pexidartinib discontinuation. Five patients from the non-TGCT population (N = 658) experienced serious hepatic ARs, two irreversible cases. CONCLUSION: This pooled analysis provides information to help form the basis for the treating physician's risk assessment for patients with TCGTs, a locally aggressive but typically nonmetastatic tumor. In particular, long-term treatment with pexidartinib has a predictable effect on hepatic aminotransferases and unpredictable risk of serious cholestatic or mixed liver injury. IMPLICATIONS FOR PRACTICE: This is the first long-term pooled analysis to report on the long-term hepatic safety of pexidartinib in patients with tenosynovial giant cell tumors associated with severe morbidity or functional limitations and not amenable to improvement with surgery. These findings extend beyond what has been previously published, describing the observed instances of hepatic toxicity following pexidartinib treatment across the clinical development program. This information is highly relevant for medical oncologists and orthopedic oncologists and provides guidance for its proper use for appropriate patients within the Pexidartinib Risk Evaluation and Mitigation Safety program.
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Doença Hepática Induzida por Substâncias e Drogas , Tumor de Células Gigantes de Bainha Tendinosa , Aminopiridinas , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Humanos , Fígado , PirróisRESUMO
Preclinical data suggest that a "prime-boost" vaccine regimen using a target-expressing lentiviral vector for priming, followed by a recombinant protein boost, may be effective against cancer; however, this strategy has not been evaluated in a clinical setting. CMB305 is a prime-boost vaccine designed to induce a broad anti-NY-ESO-1 immune response. It is composed of LV305, which is an NY-ESO-1 expressing lentiviral vector, and G305, a recombinant adjuvanted NY-ESO-1 protein. This multicenter phase 1b, first-in-human trial evaluated CMB305 in patients with NY-ESO-1 expressing solid tumors. Safety was examined in a 3 + 3 dose-escalation design, followed by an expansion with CMB305 alone or in a combination with either oral metronomic cyclophosphamide or intratumoral injections of a toll-like receptor agonist (glucopyranosyl lipid A). Of the 79 patients who enrolled, 81.0% had sarcomas, 86.1% had metastatic disease, and 57.0% had progressive disease at study entry. The most common adverse events were fatigue (34.2%), nausea (26.6%), and injection-site pain (24.1%). In patients with soft tissue sarcomas, a disease control rate of 61.9% and an overall survival of 26.2 months (95% CI, 22.1-NA) were observed. CMB305 induced anti-NY-ESO-1 antibody and T-cell responses in 62.9% and 47.4% of patients, respectively. This is the first trial to test a prime-boost vaccine regimen in patients with advanced cancer. This approach is feasible, can be delivered safely, and with evidence of immune response as well as suggestion of clinical benefit.
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Vacinas Anticâncer , Sarcoma , Adjuvantes Imunológicos , Antígenos de Neoplasias/genética , Vacinas Anticâncer/efeitos adversos , Humanos , Proteínas de Membrana/genéticaRESUMO
BACKGROUND: Soft tissue sarcomas (STS) are rare and heterogeneous tumors making chemotherapy use controversial. Our goal was to identify a subset of patients with primary STS that benefit with the addition of chemotherapy. METHODS: A retrospective chart review included intermediate to high-grade localized primary STS of the extremity/trunk, and tumor size > 5 cm. The effect of chemotherapy was evaluated for local control (LC), distant control (DC), progression free survival (PFS), and overall survival (OS). RESULTS: In this cohort (n = 273), patients were treated with surgery (98%), radiation (81%), and chemotherapy (24.5%). With a median follow-up of 51 months, the entire cohort's 5-year LC, DC, PFS, and OS are 79.1%, 59.9%, 43.8%, and 68.7%, respectively. The addition of chemotherapy did not provide a DC benefit (p = 0.238) for the entire cohort. High-grade disease (n = 210) experienced a 5-year benefit in DC (68% vs. 54.4%, p = 0.04), which was more pronounced with MAI (Mesna, Adriamycin, Ifosfamide) based regimens (74.2%, p = 0.016), and a 5-year PFS (50.8% vs 45%, p = 0.025) and OS benefit (76.2% vs 70%, p = 0.067) vs. no chemotherapy. On multivariate analysis of the high-grade subset, chemotherapy independently predicted for a DC benefit (HR 0.48 95% CI 0.26-89, p = 0.019). The benefit of chemotherapy was more pronounced with MAI, showing a significant benefit in DC (HR 0.333 95% CI 0.145-0.767, p = 0.01) and PFS (HR 0.52 95% CI 0.28-0.99, p = 0.047). CONCLUSION: In patients with localized STS > 5 cm, the high-grade subset had a distant control benefit with the addition of chemotherapy, leading to improved progression free survival. This is more pronounced with the use of MAI and should be considered in patients eligible for this regimen.
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PURPOSE: The purpose of this study was to determine the safety and efficacy of liver-directed therapies in patients with unresectable metastatic leiomyosarcoma to the liver. Liver-directed therapies included in this study were transarterial chemoembolization with doxorubicin eluting beads (DEB-TACE), yttrium-90 (Y90) radioembolization, and percutaneous microwave ablation. METHODS: This is a single institution retrospective study of unresectable metastatic leiomyosarcoma to the liver treated with DEB-TACE, radioembolization, or microwave ablation. DEB-TACE was performed using 70-150 or 100-300 µ doxorubicin-loaded drug-eluting LC beads. Radioembolization was performed using Y90 glass microspheres. Electronic medical records were retrospectively reviewed to evaluate clinical and biochemical toxicities, tumor response on imaging, overall survival (OS), and liver progression-free survival (PFS). RESULTS: A total of 24 patients with metastatic leiomyosarcoma to the liver who underwent liver-directed treatment were identified (8 males, 16 females; average age, 62.8±11.4 years). Of these patients, 13 underwent DEB-TACE, 6 underwent Y90, and 5 underwent ablation. Three patients received a combination of treatments: one received Y90 followed by DEB-TACE, one received ablation followed by DEB-TACE, and one received ablation followed by Y90. Of the 24 patients, 19 received prior chemotherapy. At 3-month follow-up, grade 1 or 2 lab toxicities were found in 20 patients; 3 patients had grade 3 toxicities. A grade 3 clinical toxicity was reported in one patient. MELD score was 7.5±1.89 at baseline and 8.8±4.2 at 3 months. Median OS was 59 months (95% CI, 39.8-78.2) from diagnosis, 27 months (95% CI, 22.9-31.0) from development of liver metastasis, and 9 months (95% CI, 0-21.4) from first liver-directed treatment. Median liver PFS was 9 months (95% CI, 1.4-16.6). CONCLUSION: Treatment with liver-directed therapies for patients with unresectable metastatic leiomyosarcoma to the liver is safe and can improve overall survival, with OS after liver-directed therapy being similar to patients who underwent surgical resection.
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Carcinoma Hepatocelular , Quimioembolização Terapêutica , Leiomiossarcoma , Neoplasias Hepáticas , Preparações Farmacêuticas , Carcinoma Hepatocelular/terapia , Doxorrubicina , Feminino , Humanos , Leiomiossarcoma/terapia , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Outcomes data regarding advanced synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are limited, consisting primarily of retrospective series and post hoc analyses of clinical trials. METHODS: In this multi-center retrospective study, data were abstracted from the medical records of 350 patients from nine sarcoma centers throughout the United States and combined into a registry. Patients with advanced/unresectable or metastatic SS (n = 249) or MRCL (n = 101) who received first-line systemic anticancer therapy and had records of tumor imaging were included. Overall survival (OS), time to next treatment, time to distant metastasis, and progression-free survival (PFS) were evaluated using the Kaplan-Meier method and Cox regression. RESULTS: At start of first-line systemic anticancer therapy, 92.4% of patients with SS and 91.1% of patients with MRCL had metastatic lesions. However, 74.7% of patients with SS and 72.3% of patients with MRCL had ≥2 lines of systemic therapy. Median OS and median PFS from first-line therapy for SS was 24.7 months (95% CI, 20.9-29.4) and 7.5 months, respectively (95% CI, 6.4-8.4). Median OS and median PFS from start of first-line therapy for MRCL was 29.9 months (95% CI, 27-44.6) and 8.9 months (95% CI 4.5-12.0). CONCLUSIONS: To the best of our knowledge, this is the largest retrospective study of patients with SS and MRCL. It provides an analysis of real-world clinical outcomes among patients treated at major sarcoma cancer centers and could inform treatment decisions and design of clinical trials. In general, the survival outcomes for this selected population appear more favorable than in published literature.
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Antineoplásicos/uso terapêutico , Institutos de Câncer , Lipossarcoma Mixoide/tratamento farmacológico , Sarcoma Sinovial/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Estimativa de Kaplan-Meier , Lipossarcoma Mixoide/mortalidade , Lipossarcoma Mixoide/patologia , Lipossarcoma Mixoide/secundário , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Análise de Regressão , Estudos Retrospectivos , Sarcoma Sinovial/mortalidade , Sarcoma Sinovial/patologia , Sarcoma Sinovial/secundário , Resultado do Tratamento , Estados Unidos , Adulto JovemRESUMO
INTRODUCTION: Pembrolizumab is an immune checkpoint inhibitor targeting the programmed death receptor with clinical effect on multiple malignancies including sarcoma. Associated cardio-toxicities include myocarditis, cardiomyopathy, heart failure, and arrhythmias. Although in most cases of immune checkpoint inhibitor cardiotoxicity the offending agent is discontinued, we report a case of successful and safe re-challenge with a checkpoint inhibitor in a patient with mild myocarditis. CASE REPORT: We describe a 37-year-old female with alveolar soft part sarcoma, metastatic to the lungs on cycle 13 of pembrolizumab who presented with dyspnea, cough, and vague chest discomfort. Telemetry showed bigeminal bradycardia that transitioned to self-terminating torsades de pointes. Cardiac MRI showed subtle patchy T2 signal increase within the left ventricular septum without late gadolinium uptake, suggesting mild focal myocarditis.Management and outcome: The patient was started on a steroid taper without additional arrhythmias. We have re-challenged the patient who safely tolerated re-challenge with pembrolizumab despite an episode of torsades de pointes and documented myocarditis. She continues to receive pembrolizumab at seven months after the initial event without further cardiovascular events. DISCUSSION: To the best of our knowledge, this is the first reported case of successful re-challenge of pembrolizumab after an episode of myocarditis. In patients with mild myocarditis and no evidence of left ventricular dysfunction, re-challenge may be a viable option. However, close monitoring for the development of heart failure, cardiomyopathy, or serious arrhythmias is necessary to ensure patient safety.
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Anticorpos Monoclonais Humanizados/efeitos adversos , Miocardite/induzido quimicamente , Torsades de Pointes/diagnóstico , Adulto , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Cardiotoxicidade/etiologia , Feminino , Humanos , Torsades de Pointes/induzido quimicamenteRESUMO
BACKGROUND: Gene-modified autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T-cell receptor (TCR) reactive against the NY-ESO-1-specific HLA-A*02-restricted peptide SLLMWITQC (NY-ESO-1 SPEAR T-cells; GSK 794), have demonstrated clinical activity in patients with advanced synovial sarcoma (SS). The factors contributing to gene-modified T-cell expansion and the changes within the tumor microenvironment (TME) following T-cell infusion remain unclear. These studies address the immunological mechanisms of response and resistance in patients with SS treated with NY-ESO-1 SPEAR T-cells. METHODS: Four cohorts were included to evaluate antigen expression and preconditioning on efficacy. Clinical responses were assessed by RECIST v1.1. Engineered T-cell persistence was determined by qPCR. Serum cytokines were evaluated by immunoassay. Transcriptomic analyses and immunohistochemistry were performed on tumor biopsies from patients before and after T-cell infusion. Gene-modified T-cells were detected within the TME via an RNAish assay. RESULTS: Responses across cohorts were affected by preconditioning and intra-tumoral NY-ESO-1 expression. Of the 42 patients reported (data cut-off 4June2018), 1 patient had a complete response, 14 patients had partial responses, 24 patients had stable disease, and 3 patients had progressive disease. The magnitude of gene-modified T-cell expansion shortly after infusion was associated with response in patients with high intra-tumoral NY-ESO-1 expression. Patients receiving a fludarabine-containing conditioning regimen experienced increases in serum IL-7 and IL-15. Prior to infusion, the TME exhibited minimal leukocyte infiltration; CD163+ tumor-associated macrophages (TAMs) were the dominant population. Modest increases in intra-tumoral leukocytes (≤5%) were observed in a subset of subjects at approximately 8 weeks. Beyond 8 weeks post infusion, the TME was minimally infiltrated with a TAM-dominant leukocyte infiltrate. Tumor-associated antigens and antigen presentation did not significantly change within the tumor post-T-cell infusion. Finally, NY-ESO-1 SPEAR T cells trafficked to the TME and maintained cytotoxicity in a subset of patients. CONCLUSIONS: Our studies elucidate some factors that underpin response and resistance to NY-ESO-1 SPEAR T-cell therapy. From these data, we conclude that a lymphodepletion regimen containing high doses of fludarabine and cyclophosphamide is necessary for SPEAR T-cell persistence and efficacy. Furthermore, these data demonstrate that non-T-cell inflamed tumors, which are resistant to PD-1/PD-L1 inhibitors, can be treated with adoptive T-cell based immunotherapy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01343043 , Registered 27 April 2011.
Assuntos
Antígenos de Neoplasias/imunologia , Imunoterapia Adotiva , Proteínas de Membrana/imunologia , Sarcoma Sinovial/imunologia , Sarcoma Sinovial/terapia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Biomarcadores , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Citocinas/metabolismo , Citotoxicidade Imunológica , Antígenos HLA-A/imunologia , Humanos , Imuno-Histoquímica , Imunoterapia Adotiva/métodos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Sarcoma Sinovial/patologia , Especificidade do Receptor de Antígeno de Linfócitos T , Resultado do Tratamento , Microambiente Tumoral/imunologiaRESUMO
Molecular diagnostics of sarcoma subtypes commonly involve the identification of characteristic oncogenic fusions. EWSR1-PATZ1 is a rare fusion partnering in sarcoma, with few cases reported in the literature. In the current study, a series of 11 cases of EWSR1-PATZ1 fusion positive malignancies are described. EWSR1-PATZ1-related sarcomas occur across a wide age range and have a strong predilection for chest wall primary site. Secondary driver mutations in cell-cycle genes, and in particular CDKN2A (71%), are common in EWSR1-PATZ1 sarcomas in this series. In a subset of cases, an extended clinical and histopathological review was performed, as was confirmation and characterization of the fusion breakpoint revealing a novel intronic pseudoexon sequence insertion. Unified by a shared gene fusion, EWSR1-PATZ1 sarcomas otherwise appear to exhibit divergent morphology, a polyphenotypic immunoprofile, and variable clinical behavior posing challenges for precise classification.
Assuntos
Fatores de Transcrição Kruppel-Like/genética , Proteína EWS de Ligação a RNA/genética , Proteínas Repressoras/genética , Sarcoma/genética , Sarcoma/patologia , Adolescente , Adulto , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Sarcoma/classificação , Neoplasias de Tecidos Moles/classificação , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Adulto JovemRESUMO
PURPOSE: Sarcomas are a diverse group of malignant tumors that arise from soft tissues or bone. For most advanced cases, there is a substantial need for improved therapeutic options and, therefore, a desire to more precisely tailor therapy in individual cases. In this study, we review our institutional experience with next-generation sequencing (NGS)-based molecular profiling for non-GI stromal tumors sarcomas, with a focus on the clinical utility of the results. PATIENTS AND METHODS: We retrospectively analyzed results of NGS performed on tumors from 114 patients with a diagnosis of sarcoma. A chart review was conducted to review the clinical impact of NGS findings. RESULTS: A median of three putatively oncogenic gene alterations were identified per tumor sample (range, 0 to 19) and at least one mutation was detected in 96.7% of tumors. Fifty-six patients (49.1%) harbored a finding that was felt to be actionable after review by a molecular tumor board. Five patients (4.4%) had a diagnosis change as a result of NGS findings. In 15 patients (13.2%), therapeutic selection was influenced by NGS findings. Four of 15 (26.7%) of the NGS-influenced systemic therapies resulted in clinical benefit. CONCLUSION: Putatively oncogenic mutations are readily detected in the majority of sarcomas. Genetic profiling affected the diagnosis and/or treatment approach in a sizeable minority of patients with sarcoma treated at our center. Additional study is required to determine if genetic profiling leads to improved clinical outcomes.
RESUMO
BACKGROUND: Retroperitoneal sarcoma is rare. Using initial specimens on biopsy, a definitive diagnosis of histological subtypes is ideal but not always achievable. METHODS: A retrospective institutional review was performed for all cases of adult retroperitoneal sarcoma from 1996 to 2015. A review of the literature was also performed related to the distribution of retroperitoneal sarcoma subtypes. A meta-analysis was performed. RESULTS: Liposarcoma is the most common subtype (45%), followed by leiomyosarcoma (21%), not otherwise specified (8%), and undifferentiated pleomorphic sarcoma (6%) by literature review. Data from Moffitt Cancer Center demonstrate the same general distribution for subtypes of retroperitoneal sarcoma. A pathology-based algorithm for the diagnosis of retroperitoneal sarcoma is illustrated, and common pitfalls in the pathology of retroperitoneal sarcoma are discussed. CONCLUSIONS: An informative diagnosis of retroperitoneal sarcoma via specimens on biopsy is achievable and meaningful to guide effective therapy. A practical and multidisciplinary algorithm focused on the histopathology is helpful for the management of retroperitoneal sarcoma.
Assuntos
Neoplasias Retroperitoneais/terapia , Sarcoma/terapia , Feminino , Humanos , Masculino , Neoplasias Retroperitoneais/patologia , Estudos Retrospectivos , Sarcoma/patologiaRESUMO
BACKGROUND: Pulmonary metastasectomy (PM) for metastatic sarcoma can result in long-term survival. The purpose of this study was to describe factors associated with survival in a series of patients undergoing PM for metastatic sarcoma. METHODS: We reviewed all patients undergoing PM for metastatic sarcoma over a 12-year period (2000-2012). Multivariate analyses were used to identify factors associated with outcomes. Survival was calculated with Kaplan-Meier and Cox proportional hazard models. RESULTS: A total of 120 patients underwent PM with a median follow-up was 48 months. Among 81 (85%) patients who presented with local disease, the median disease free interval (DFI) was 13 months and median overall survival (OS) was 48 months. Fourteen patients (15%) had synchronous metastasis with a median OS of 21 months. On multivariate analysis, synchronous metastasis (P = 0.005), older age (P = 0.02), and number of lung lesions (P = 0.003) were associated with poor survival. The median OS of patients with a DFI ≥12 versus <12 months following primary resection was 93 and 43 months (P = 0.004). CONCLUSION: While patients with a DFI >12 months have the best OS following PM, patients with a DFI <12 months also have excellent outcomes as compared to systemic therapy and should be considered for PM.