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BACKGROUND: Desmoid tumors are rare, locally aggressive, highly recurrent soft-tissue tumors without approved treatments. METHODS: We conducted a phase 3, international, double-blind, randomized, placebo-controlled trial of nirogacestat in adults with progressing desmoid tumors according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were assigned in a 1:1 ratio to receive the oral γ-secretase inhibitor nirogacestat (150 mg) or placebo twice daily. The primary end point was progression-free survival. RESULTS: From May 2019 through August 2020, a total of 70 patients were assigned to receive nirogacestat and 72 to receive placebo. Nirogacestat had a significant progression-free survival benefit over placebo (hazard ratio for disease progression or death, 0.29; 95% confidence interval, 0.15 to 0.55; P<0.001); the likelihood of being event-free at 2 years was 76% with nirogacestat and 44% with placebo. Between-group differences in progression-free survival were consistent across prespecified subgroups. The percentage of patients who had an objective response was significantly higher with nirogacestat than with placebo (41% vs. 8%; P<0.001), with a median time to response of 5.6 months and 11.1 months, respectively; the percentage of patients with a complete response was 7% and 0%, respectively. Significant between-group differences in secondary patient-reported outcomes, including pain, symptom burden, physical or role functioning, and health-related quality of life, were observed (P≤0.01). Frequent adverse events with nirogacestat included diarrhea (in 84% of the patients), nausea (in 54%), fatigue (in 51%), hypophosphatemia (in 42%), and maculopapular rash (in 32%); 95% of adverse events were of grade 1 or 2. Among women of childbearing potential receiving nirogacestat, 27 of 36 (75%) had adverse events consistent with ovarian dysfunction, which resolved in 20 women (74%). CONCLUSIONS: Nirogacestat was associated with significant benefits with respect to progression-free survival, objective response, pain, symptom burden, physical functioning, role functioning, and health-related quality of life in adults with progressing desmoid tumors. Adverse events with nirogacestat were frequent but mostly low grade. (Funded by SpringWorks Therapeutics; DeFi ClinicalTrials.gov number, NCT03785964.).
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Antineoplásicos , Fibromatosis Agresiva , Inhibidores y Moduladores de Gamma Secretasa , Tetrahidronaftalenos , Adulto , Femenino , Humanos , Secretasas de la Proteína Precursora del Amiloide/uso terapéutico , Antineoplásicos/uso terapéutico , Método Doble Ciego , Fibromatosis Agresiva/tratamiento farmacológico , Inhibidores y Moduladores de Gamma Secretasa/uso terapéutico , Supervivencia sin Progresión , Calidad de Vida , Tetrahidronaftalenos/uso terapéutico , Valina/análogos & derivadosRESUMEN
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.).
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Anticuerpos Monoclonales Humanizados , Antígeno B7-H1 , Sarcoma de Parte Blanda Alveolar , Adolescente , Adulto , Niño , Humanos , Recién Nacido , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Peso Corporal , Sarcoma de Parte Blanda Alveolar/tratamiento farmacológico , Administración IntravenosaRESUMEN
Soft-tissue sarcomas represent a heterogeneous group of cancer, with more than 50 histological subtypes1,2. The clinical presentation of patients with different subtypes is often atypical, and responses to therapies such as immune checkpoint blockade vary widely3,4. To explain this clinical variability, here we study gene expression profiles in 608 tumours across subtypes of soft-tissue sarcoma. We establish an immune-based classification on the basis of the composition of the tumour microenvironment and identify five distinct phenotypes: immune-low (A and B), immune-high (D and E), and highly vascularized (C) groups. In situ analysis of an independent validation cohort shows that class E was characterized by the presence of tertiary lymphoid structures that contain T cells and follicular dendritic cells and are particularly rich in B cells. B cells are the strongest prognostic factor even in the context of high or low CD8+ T cells and cytotoxic contents. The class-E group demonstrated improved survival and a high response rate to PD1 blockade with pembrolizumab in a phase 2 clinical trial. Together, this work confirms the immune subtypes in patients with soft-tissue sarcoma, and unravels the potential of B-cell-rich tertiary lymphoid structures to guide clinical decision-making and treatments, which could have broader applications in other diseases.
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Linfocitos B/inmunología , Inmunoterapia , Sarcoma/tratamiento farmacológico , Sarcoma/inmunología , Estructuras Linfoides Terciarias/inmunología , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Linfocitos T CD8-positivos/inmunología , Estudios de Cohortes , Células Dendríticas Foliculares/inmunología , Humanos , Mutación , Fenotipo , Pronóstico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Reproducibilidad de los Resultados , Sarcoma/clasificación , Sarcoma/patología , Tasa de Supervivencia , Microambiente TumoralRESUMEN
AIMS: Ossifying fibromyxoid tumor (OFMT) is a rare enigmatic tumor of uncertain differentiation that can be classified as typical, atypical, and malignant subtypes based on cellularity, nuclear grade, and mitotic activity. The majority of OFMTs, regardless of the risk of malignancy, harbor genetic translocations. We report two malignant OFMTs, including one with evidence of dedifferentiation, with novel genefusions. METHODS AND RESULTS: Case 1 was a 63-year-old male with a dedifferentiated OFMT arising in the right wrist, while case 2 was a 41-year-old male with a malignant OFMT presenting as a posterior mediastinal mass. Case 2 showed multifocal expression with EMA and synaptophysin, while desmin and S100 were absent in both tumors. NGS sequencing studies detected PHF1::FOXR1 and PHF1::FOXR2 gene fusions in cases 1 and 2, respectively. Despite aggressive regimens, both progressed with wide spread metastases resulting in death within six years of diagnosis. CONCLUSIONS: We expand the genetic spectrum of OFMTs with two novel gene fusions, PHF1::FOXR1 and PHF1::FOXR2. These cases confirm the previously reported tendencies for OFMTs with rare variant fusions to demonstrate malignant behavior, unusual morphology, and non-specific immunophenotype.
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Fibroma Osificante , Fibroma , Neoplasias de los Tejidos Blandos , Masculino , Humanos , Persona de Mediana Edad , Adulto , Fibroma Osificante/patología , Neoplasias de los Tejidos Blandos/patología , Fibroma/patología , Fusión Génica , Proteínas de Unión al ADN/genética , Proteínas del Grupo Polycomb/genética , Proteínas del Grupo Polycomb/metabolismo , Factores de Transcripción Forkhead/genéticaAsunto(s)
Coactivador 2 del Receptor Nuclear , Sarcoma , Humanos , Sarcoma/genética , Sarcoma/patología , Coactivador 2 del Receptor Nuclear/genética , Proteínas de Unión al ADN/genética , Reordenamiento Génico , Masculino , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/patología , FemeninoAsunto(s)
Leucemia Mieloide Aguda , Sarcoma , Humanos , Sarcoma/diagnóstico , Sarcoma/genética , Reordenamiento GénicoRESUMEN
Gastrointestinal stromal tumors (GISTs) represent 1% of alimentary tract neoplasms. Up to 90% of GISTs are driven by activating mutations in tyrosine kinase KIT or PDGFRα genes. Imatinib mesylate is a tyrosine kinase inhibitor that has recently been used in a neoadjuvant role for locally advanced GIST. Pathologic complete response (pCR) to imatinib, however, is rare and may be limited to patients with certain mutations. We report on a 71-year-old woman with a large advanced gastric GIST near the gastroesophageal junction initially involving the pancreas, spleen, adrenal, and aortic wall. The tumor harbored a KIT exon 11 deletion mutation in codon 558, which predicts a favorable response to imatinib. After 6 months of neoadjuvant imatinib therapy, the tumor was downstaged to allow partial gastric resection without the need for total gastrectomy reconstruction. The patient underwent partial gastrectomy, distal pancreatectomy, and splenectomy, and histologic examination showed a margin-negative resection with a near-pCR, with <5% viable tumor. Prolonged neoadjuvant therapy was undertaken based on the prognostic significance of a KIT exon 11 deletion mutation in codon 558, which facilitated an R0 resection while minimizing the surgical extent of the resection. A near-pCR of a large gastric GIST after neoadjuvant imatinib therapy remains a rare occurrence. Molecular testing should be undertaken before neoadjuvant therapy, because specific mutations can identify patients who will respond to imatinib and those likely to achieve significant downstaging and pCR.
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Biomarcadores de Tumor/genética , Tumores del Estroma Gastrointestinal/terapia , Mesilato de Imatinib/uso terapéutico , Proteínas Proto-Oncogénicas c-kit/genética , Neoplasias Gástricas/terapia , Anciano , Biopsia , Femenino , Gastrectomía , Tumores del Estroma Gastrointestinal/diagnóstico por imagen , Tumores del Estroma Gastrointestinal/genética , Tumores del Estroma Gastrointestinal/patología , Humanos , Mesilato de Imatinib/farmacología , Mutación , Terapia Neoadyuvante/métodos , Tomografía Computarizada por Tomografía de Emisión de Positrones , Pronóstico , Estómago/diagnóstico por imagen , Estómago/patología , Estómago/cirugía , Neoplasias Gástricas/diagnóstico por imagen , Neoplasias Gástricas/genética , Resultado del TratamientoRESUMEN
BACKGROUND: Patients with advanced sarcomas have a poor prognosis and few treatment options that improve overall survival. Chemotherapy and targeted therapies offer short-lived disease control. We assessed pembrolizumab, an anti-PD-1 antibody, for safety and activity in patients with advanced soft-tissue sarcoma or bone sarcoma. METHODS: In this two-cohort, single-arm, open-label, phase 2 study, we enrolled patients with soft-tissue sarcoma or bone sarcoma from 12 academic centres in the USA that were members of the Sarcoma Alliance for Research through Collaboration (SARC). Patients with soft-tissue sarcoma had to be aged 18 years or older to enrol; patients with bone sarcoma could enrol if they were aged 12 years or older. Patients had histological evidence of metastatic or surgically unresectable locally advanced sarcoma, had received up to three previous lines of systemic anticancer therapy, had at least one measurable lesion according to the Response Evaluation Criteria In Solid Tumors version 1.1, and had at least one lesion accessible for biopsy. All patients were treated with 200 mg intravenous pembrolizumab every 3 weeks. The primary endpoint was investigator-assessed objective response. Patients who received at least one dose of pembrolizumab were included in the safety analysis and patients who progressed or reached at least one scan assessment were included in the activity analysis. Accrual is ongoing in some disease cohorts. This trial is registered with ClinicalTrials.gov, number NCT02301039. FINDINGS: Between March 13, 2015, and Feb 18, 2016, we enrolled 86 patients, 84 of whom received pembrolizumab (42 in each disease cohort) and 80 of whom were evaluable for response (40 in each disease cohort). Median follow-up was 17·8 months (IQR 12·3-19·3). Seven (18%) of 40 patients with soft-tissue sarcoma had an objective response, including four (40%) of ten patients with undifferentiated pleomorphic sarcoma, two (20%) of ten patients with liposarcoma, and one (10%) of ten patients with synovial sarcoma. No patients with leiomyosarcoma (n=10) had an objective response. Two (5%) of 40 patients with bone sarcoma had an objective response, including one (5%) of 22 patients with osteosarcoma and one (20%) of five patients with chondrosarcoma. None of the 13 patients with Ewing's sarcoma had an objective response. The most frequent grade 3 or worse adverse events were anaemia (six [14%]), decreased lymphocyte count (five [12%]), prolonged activated partial thromboplastin time (four [10%]), and decreased platelet count (three [7%]) in the bone sarcoma group, and anaemia, decreased lymphocyte count, and prolonged activated partial thromboplastin time in the soft-tissue sarcoma group (three [7%] each). Nine (11%) patients (five [12%] in the bone sarcoma group and four [10%] in the soft-tissue sarcoma group) had treatment-emergent serious adverse events (SAEs), five of whom had immune-related SAEs, including two with adrenal insufficiency, two with pneumonitis, and one with nephritis. INTERPRETATION: The primary endpoint of overall response was not met for either cohort. However, pembrolizumab showed encouraging activity in patients with undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma. Enrolment to expanded cohorts of those subtypes is ongoing to confirm and characterise the activity of pembrolizumab. FUNDING: Merck, SARC, Sarcoma Foundation of America, QuadW Foundation, Pittsburgh Cure Sarcoma, and Ewan McGregor.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Sarcoma/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Centros Médicos Académicos , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Neoplasias Óseas/mortalidad , Neoplasias Óseas/patología , Intervalos de Confianza , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Estimación de Kaplan-Meier , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Seguridad del Paciente/estadística & datos numéricos , Pronóstico , Sarcoma/mortalidad , Sarcoma/patología , Neoplasias de los Tejidos Blandos/mortalidad , Neoplasias de los Tejidos Blandos/patología , Análisis de Supervivencia , Resultado del Tratamiento , Estados UnidosAsunto(s)
Fusión Génica , Neoplasias Renales/genética , Neoplasias Renales/patología , Proteína 1 del Sitio de Integración Viral Ecotrópica Mieloide/genética , Metástasis de la Neoplasia , Coactivador 2 del Receptor Nuclear/genética , Sarcoma/genética , Sarcoma/patología , Femenino , Humanos , Neoplasias Renales/diagnóstico por imagen , Neoplasias Renales/terapia , Persona de Mediana Edad , Metástasis de la Neoplasia/genética , Sarcoma/diagnóstico por imagen , Sarcoma/terapiaRESUMEN
Immunologic approaches to cancer are over a century old. Over the years, the strategy has been fine-tuned from inciting infections in subjects to inhibiting negative regulatory signals from the innate immune system. Sarcomas are among the first tumors to be considered for immune interventions. From Coley's toxin to cytokine-based therapies to adoptive cell therapy, there have been numerous immunotherapeutic investigations in this patient population. A promising strategy includes adoptive T cell therapy which has been studied in small cohorts of synovial sarcoma, a subtype that is known to widely express the cancer testis antigen, NY-ESO-1. Additionally, recent data in metastatic melanoma and renal cell carcinoma demonstrate the utility and tremendous efficacy of immune checkpoint blockade with increased rates of durable responses compared to standard therapies. Responses in traditionally "non-immunogenic" tumors, such as lung and bladder cancers, provide ample rationale for the study of immune checkpoint inhibitors in sarcoma. While immunotherapy has induced some responses in sarcomas, further research will help clarify optimal patient selection for future clinical trials and new combinatorial immunotherapeutic strategies.
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Inmunoterapia Adoptiva/métodos , Terapia Molecular Dirigida/tendencias , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Sarcoma/terapia , Antígenos de Neoplasias/inmunología , Humanos , Inmunoterapia Adoptiva/tendencias , Recurrencia Local de Neoplasia/prevención & control , Selección de Paciente , Guías de Práctica Clínica como Asunto , Sarcoma/inmunología , Sarcoma/patologíaRESUMEN
OPINION STATEMENT: Current therapies in advanced sarcomas are primarily based on cytotoxic chemotherapy and have modest efficacy coupled with significant toxicity. Little progress has been made in the field since imatinib was approved for the treatment of gastrointestinal stromal tumor (GIST) in 2002 despite the recent FDA approval of the multi-tyrosine kinase inhibitor pazopanib. Novel therapies are clearly needed. Immunotherapy utilizing checkpoint inhibitors has yielded significant clinical benefit in multiple solid tumors manifesting as durable responses in melanoma, kidney, lung, and bladder cancers, as well as hematologic malignancies. Given the success in several "non-immunogenic" tumors and recent preclinical data, there is sufficient evidence to support the use of immunotherapy in sarcoma. Cytokine-based therapies have shown no benefit in the advanced setting. Two large randomized trials of muramyl tripeptide or of interferon maintenance in resected osteosarcoma patients did not provide unequivocal statistically significant benefit. More promising results have been reported in small studies evaluating vaccines and adoptive T cell therapy in specific subtypes of sarcoma such as synovial sarcoma, which widely expresses the immunogenic cancer testis antigen NY-ESO-1. Emerging approaches with chimeric antigen receptor (CAR)-engineered T cells are hypothesis-generating and thought-provoking. However, the unprecedented clinical activity and excellent safety profile of checkpoint inhibitors targeting programmed death-1 receptor and its ligand (PD-1/PD-L1) have galvanized the field and generated much enthusiasm to harness the power of immunotherapy in pursuit of cures in patients with advanced sarcomas. An ongoing phase II study (SARC028) will hopefully usher an era of investigation of this exciting approach in sarcoma. However, it is unlikely that one agent will carry a universal cure and future approaches need to focus on patient selection as well as on identifying the optimal combination of checkpoint inhibitors with targeted therapy, chemotherapy, or radiation therapy.
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Inmunoterapia/métodos , Sarcoma/terapia , Animales , Terapia Combinada , Humanos , Sarcoma/genética , Sarcoma/metabolismo , Sarcoma/mortalidad , Sarcoma/patología , Resultado del TratamientoRESUMEN
Previous research has not adequately assessed the independent contributions of component attentional processes to anxiety-linked biases. MacLeod and Sadler developed a novel, lexical decision task using negative and neutral word stimuli, to enable the independent measurement of attentional engagement and disengagement. Their results suggest that anxiety-linked attentional biases are associated with facilitated attentional engagement with negative information. The present study aimed to determine the replicability of these findings, with two important extensions. First, this study included positive word stimuli in the lexical decision task, to determine whether anxiety-linked attentional biases exist only towards negative information, or toward emotionally arousing information in general. Second, this study explored age-related differences in anxiety-linked attentional biases. Younger (N=32) and older adults (N=32) with both high and low trait anxiety completed the lexical decision task. The results suggest that heightened anxiety may be associated with a deficit in engaging with positive words. No age-related differences in anxiety-linked attentional biases were apparent.
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Envejecimiento/psicología , Ansiedad/psicología , Atención/fisiología , Adolescente , Anciano , Anciano de 80 o más Años , Nivel de Alerta , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: In 2021, the HIV prevalence among South African adults was 18% and more than 2 million people had uncontrolled HIV and, therefore, had increased risk of poor outcomes with SARS-CoV-2 infection. We investigated trends in COVID-19 admissions and factors associated with in-hospital COVID-19 mortality among people living with HIV and people without HIV. METHODS: In this analysis of national surveillance data, we linked and analysed data collected between March 5, 2020, and May 28, 2022, from the DATCOV South African national COVID-19 hospital surveillance system, the SARS-CoV-2 case line list, and the Electronic Vaccination Data System. All analyses included patients hospitalised with SARS-CoV-2 with known in-hospital outcomes (ie, who were discharged alive or had died) at the time of data extraction. We used descriptive statistics for admissions and mortality trends. Using post-imputation random-effect multivariable logistic regression models, we compared characteristics and the case fatality ratio of people with HIV and people without HIV. Using modified Poisson regression models, we compared factors associated with mortality among all people with COVID-19 admitted to hospital and factors associated with mortality among people with HIV. FINDINGS: Among 397â082 people with COVID-19 admitted to hospital, 301â407 (75·9%) were discharged alive, 89â565 (22·6%) died, and 6110 (1·5%) had no recorded outcome. 270â737 (68·2%) people with COVID-19 had documented HIV status (22â858 with HIV and 247â879 without). Comparing characteristics of people without HIV and people with HIV in each COVID-19 wave, people with HIV had increased odds of mortality in the D614G (adjusted odds ratio 1·19, 95% CI 1·09-1·29), beta (1·08, 1·01-1·16), delta (1·10, 1·03-1·18), omicron BA.1 and BA.2 (1·71, 1·54-1·90), and omicron BA.4 and BA.5 (1·81, 1·41-2·33) waves. Among all COVID-19 admissions, mortality was lower among people with previous SARS-CoV-2 infection (adjusted incident rate ratio 0·32, 95% CI 0·29-0·34) and with partial (0·93, 0·90-0·96), full (0·70, 0·67-0·73), or boosted (0·50, 0·41-0·62) COVID-19 vaccination. Compared with people without HIV who were unvaccinated, people without HIV who were vaccinated had lower risk of mortality (0·68, 0·65-0·71) but people with HIV who were vaccinated did not have any difference in mortality risk (1·08, 0·96-1·23). In-hospital mortality was higher for people with HIV with CD4 counts less than 200 cells per µL, irrespective of viral load and vaccination status. INTERPRETATION: HIV and immunosuppression might be important risk factors for mortality as COVID-19 becomes endemic. FUNDING: South African National Institute for Communicable Diseases, the South African National Government, and the United States Agency for International Development.
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COVID-19 , Infecciones por VIH , Adulto , Humanos , Sudáfrica/epidemiología , SARS-CoV-2 , Vacunas contra la COVID-19 , Infecciones por VIH/complicaciones , Infecciones por VIH/epidemiologíaRESUMEN
PURPOSE: Epithelioid hemangioendothelioma (EHE) is a rare vascular cancer with pathogenic TAZ-CAMTA1 operating as an oncogenic driver through activation of MAPK pathway. Trametinib is an inhibitor of MEK, a critical kinase in the MAPK pathway. We sought to evaluate the effect of trametinib in patients with EHE. PATIENTS AND METHODS: A phase 2 trial of trametinib was conducted in patients with locally advanced or metastatic EHE. Eligibility requirements included evidence of tumor progression or presence of EHE-related pain requiring opiates for management prior to enrollment. The primary endpoint was objective response rate (ORR) per RECIST1.1 in cases with TAZ-CAMTA1 confirmed by fusion-FISH. Secondary objectives were to estimate ORR for all patients, median PFS, 2-year OS rate, patient safety, and change in patient-reported global health and pain scores per PROMIS questionnaires. RESULTS: 44 patients enrolled and 42 started trametinib. TAZ-CAMTA1 was detected in 27 tumor samples. The ORR was 3.7% (95% CI: 0.094, 19.0), median PFS was 10.4 months (95% CI: 7.1, NA), and 2-year OS rate was 33.3% (95% CI: 19.1, 58.2) in the target population. Median pain intensity and interference scores improved significantly after 4 weeks of trametinib in patients using opiates. Common AEs related to trametinib were rash, fatigue, nausea/vomiting, diarrhea/constipation, alopecia and edema; one Grade 5 ARDS/pneumonitis was related to trametinib. CONCLUSIONS: Trametinib was associated with reduction in EHE-related pain and median PFS of more than 6 months providing palliative benefit in patients with advanced EHE, but the trial did not meet the ORR goal.
RESUMEN
OBJECTIVES: Integrative models of psychopathology suggest that quality of interpersonal relationships is a key determinant of psychological well-being. However, there is a relative paucity of research evaluating the association between interpersonal problems and psychopathology within cognitive behavioural therapy. Partly, this may be due to lack of brief, well-validated, and easily interpretable measures of interpersonal problems that can be used within clinical settings. The aim of the present study was to evaluate the psychometric properties, factor invariance, and external validity of the Inventory of Interpersonal Problems 32 (IIP-32) across anxiety, depression, and eating disorders. METHODS: Two treatment-seeking samples with principal anxiety and depressive disorders (AD sample, n = 504) and eating disorders (ED sample, n = 339) completed the IIP-32 along with measures of anxiety, depression, and eating disorder symptoms, as well as quality of life (QoL). RESULTS: The previously established eight-factor structure of the IIP-32 provided the best fit for both the AD and ED groups, and was robustly invariant across the two samples. The IIP-32 also demonstrated excellent external validity against well-validated measures of anxiety, depression, and eating disorder symptoms, as well as QoL. CONCLUSION: The IIP-32 provides a clinically useful measure of interpersonal problems across emotional and ED.
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Trastornos de Ansiedad/psicología , Ansiedad/psicología , Depresión/psicología , Trastorno Depresivo/psicología , Trastornos de Alimentación y de la Ingestión de Alimentos/psicología , Relaciones Interpersonales , Personalidad , Adolescente , Adulto , Anciano , Trastornos de Ansiedad/diagnóstico , Depresión/diagnóstico , Trastorno Depresivo/diagnóstico , Análisis Factorial , Trastornos de Alimentación y de la Ingestión de Alimentos/diagnóstico , Femenino , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Satisfacción Personal , Valor Predictivo de las Pruebas , Escalas de Valoración Psiquiátrica , Psicopatología , Calidad de Vida , Encuestas y CuestionariosRESUMEN
INTRODUCTION: Renal sarcomas are exceedingly rare and lack a prognostic stage classification. We thus aimed to investigate the contemporary clinicopathologic characteristics and outcomes of renal sarcomas at a national level. PATIENTS AND METHODS: We utilized the Surveillance, Epidemiology, and End Results database to extract data on patients with renal sarcoma diagnosed between 2004 and 2015. We estimated median, 1-, 3-, and 5-year overall survival (OS) probabilities via Kaplan-Meier curves and used multivariable regression to compare OS between different patient groups. RESULTS: We identified 365 patients; at diagnosis, 104 patients (28.5%) had stage I disease (T1N0M0), 133 patients (36.4%) patients had stage II disease (T2-4N0M0), and 117 patients (32.1%) patients had stage III disease (any T, N1, or M1). Median survival was 105 months (interquartile range [IQR], 29 - not reached) for stage I disease, 46 months (IQR 14-118 months) for stage II disease, 8 months (IQR 3-28 months) for stage III disease, and 32 months (IQR, 8-116 months) for the entire cohort. Patient age (hazard ratio [HR] for death [per year] 1.02, 95% confidence interval [95% CI] 1.00-1.04), stage (II vs. I: HR 1.71, 95% CI 1.00-2.92; III vs. I: HR 4.93, 95% CI 2.68-9.05), grade (grade 3 vs. grade 1: 3.07, 95% CI 1.18-8.00; grade 4 vs. grade 1: HR 3.66, 95% CI 1.41-9.49), and possessing medical insurance (HR 0.40, 95% CI 0.16-0.94) were independently and significantly associated with OS. Performance of nephrectomy also trended towards independently improving OS (HR 0.23, 95% CI 0.05-1.09). CONCLUSION: A novel staging classification for renal sarcomas into a 3-stage system based on Tumor Node Metastasis (TNM) criteria produces distinct survival curves, although further studies are needed to robustly assess its validity.
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Neoplasias Renales , Sarcoma , Humanos , Estadificación de Neoplasias , Estudios Retrospectivos , Neoplasias Renales/epidemiología , Neoplasias Renales/cirugía , Pronóstico , Sarcoma/epidemiología , Sarcoma/terapia , Programa de VERFRESUMEN
PURPOSE: The study evaluated safety and efficacy of olaratumab + pembrolizumab in patients with unresectable locally advanced/metastatic soft-tissue sarcoma (STS) with disease progression on standard treatment. PATIENTS AND METHODS: This was open-label, multicenter, nonrandomized, phase Ia/Ib dose-escalation study followed by cohort expansion (olaratumab + pembrolizumab intravenous infusion). Primary objectives were safety and tolerability. RESULTS: The majority of patients enrolled (n = 41) were female [phase Ia: 9 of 13, phase Ib/dose-expansion cohort (DEC), 17 of 28], aged < 65 years. In phases Ia and Ib, 13 and 26 patients received prior systemic therapy, respectively. Patients received olaratumab 15 mg/kg (phase Ia; cohort 1) or 20 mg/kg (phase Ia; cohort 2 and phase Ib) and pembrolizumab 200 mg (phase Ia/Ib). The median (Q1-Q3) duration of therapy (olaratumab) was 6.0 (3.0-11.9; cohort 1), 14.4 (12.4-20.9; cohort 2), and 14.0 (6.0-21.8) weeks (DEC). No dose-limiting toxicities and few grade ≥ 3 treatment-emergent adverse events [TEAE; 15 mg/kg: 2 (increased lipase); 20 mg/kg: 1 (increased lipase), 1 (colitis), 2 (diarrhea), 3 (anemia)] were reported. Two TEAEs (increased lipase) were related to study discontinuations. Twenty-one patients reported mild (grade ≤ 2) TEAEs [phase Ia, disease control rate (DCR):14.3% (1/7, cohort 1); 66.7% (4/6, cohort 2); no responses were reported; phase Ib, DCR: 53.6% (15/28); objective response rate: 21.4% (6/28; RECIST and irRECIST criteria)]. No response was observed in patients with programmed death ligand-1-positive tumors. CONCLUSIONS: Antitumor activity was observed in some patients in DEC, and combination was well tolerated with manageable safety profile. Further studies are warranted to evaluate the efficacy and mechanistic impact of platelet-derived growth factor receptor inhibitors with immune checkpoint modulator coadministration.
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Neoplasias Primarias Secundarias , Sarcoma , Neoplasias de los Tejidos Blandos , Femenino , Humanos , Masculino , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Primarias Secundarias/tratamiento farmacológico , Sarcoma/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Introduction: Sarcomas are comprised of diverse bone and connective tissue tumors with few effective therapeutic options for locally advanced unresectable and/or metastatic disease. Recent advances in immunotherapy, in particular immune checkpoint inhibition (ICI), have shown promising outcomes in several cancer indications. Unfortunately, ICI therapy has provided only modest clinical responses and seems moderately effective in a subset of the diverse subtypes. Methods: To explore the immune parameters governing ICI therapy resistance or immune escape, we performed whole exome sequencing (WES) on tumors and their matched normal blood, in addition to RNA-seq from tumors of 31 sarcoma patients treated with pembrolizumab. We used advanced computational methods to investigate key immune properties, such as neoantigens and immune cell composition in the tumor microenvironment (TME). Results: A multifactorial analysis suggested that expression of high quality neoantigens in the context of specific immune cells in the TME are key prognostic markers of progression-free survival (PFS). The presence of several types of immune cells, including T cells, B cells and macrophages, in the TME were associated with improved PFS. Importantly, we also found the presence of both CD8+ T cells and neoantigens together was associated with improved survival compared to the presence of CD8+ T cells or neoantigens alone. Interestingly, this trend was not identified with the combined presence of CD8+ T cells and TMB; suggesting that a combined CD8+ T cell and neoantigen effect on PFS was important. Discussion: The outcome of this study may inform future trials that may lead to improved outcomes for sarcoma patients treated with ICI.
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Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Sarcoma/tratamiento farmacológico , Antígenos de Neoplasias , Linfocitos T CD8-positivos , RNA-Seq , Microambiente TumoralRESUMEN
PURPOSE: Uterine leiomyosarcoma (uLMS) is an aggressive subtype of soft-tissue sarcoma with frequent metastatic relapse after curative surgery. Chemotherapy provides limited benefit for advanced disease. Multiomics profiling studies have identified homologous recombination deficiency in uLMS. In preclinical studies where olaparib and temozolomide provided modest activity, the combination was highly effective for inhibiting uLMS tumor growth. PATIENTS AND METHODS: NCI Protocol 10250 is a single-arm, open-label, multicenter, phase II study evaluating olaparib and temozolomide in advanced uLMS. Patients with progression on ≥1 prior line received temozolomide 75 mg/m2 orally once daily with olaparib 200 mg orally twice a day both on days 1-7 in 21-day cycles. The primary end point was the best objective response rate (ORR) within 6 months. A one-stage binomial design was used. If ≥5 of 22 responded, the treatment would be considered promising (93% power; α = .06). All patients underwent paired biopsies that were evaluated with whole-exome sequencing (WES)/RNAseq and a RAD51 foci formation assay. RESULTS: Twenty-two patients were evaluable. The median age was 55 years, and 59% had received three or more prior lines. Best ORR within 6 months was 23% (5 of 22). The overall ORR was 27% (6 of 22). The median progression-free survival (mPFS) was 6.9 months (95% CI, 5.4 months to not estimable). Hematologic toxicity was common (grade 3/4 neutropenia: 75%; thrombocytopenia: 32%) but manageable with dose modification. Five of 16 (31%) of tumors contained a deleterious homologous recombination gene alteration by WES, and 9 of 18 (50%) were homologous recombination-deficient by the RAD51 assay. In an exploratory analysis, mPFS was prolonged for patients with homologous recombination-deficient versus homologous recombination-proficient tumors (11.2 v 5.4 months, P = .05) by RAD51. CONCLUSION: Olaparib and temozolomide met the prespecified primary end point and provided meaningful clinical benefit in patients with advanced, pretreated uLMS.