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1.
J Immunother Cancer ; 7(1): 213, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31395100

RESUMO

BACKGROUND: Angiosarcoma is an uncommon endothelial malignancy and a highly aggressive soft tissue sarcoma. Due to its infiltrative nature, successful management of localized angiosarcoma is often challenging. Systemic chemotherapy is used in the metastatic setting and occasionally in patients with high-risk localized disease in neoadjuvant or adjuvant settings. However, responses tend to be short-lived and most patients succumb to metastatic disease. Novel therapies are needed for patients with angiosarcomas. METHODS: We performed a retrospective analysis of patients with locally advanced or metastatic angiosarcoma, who were treated with checkpoint inhibitors at our institution. We collected their clinical information and outcome measurements. In one patient with achieved complete response, we analyzed circulating and infiltrating T cells within peripheral blood and tumor tissue. RESULTS: We have treated seven angiosarcoma (AS) patients with checkpoint inhibitors either in the context of clinical trials or off label [Pembrolizumab + Axitinib (NCT02636725; n = 1), AGEN1884, a CTLA-4 inhibitor (NCT02694822; n = 2), Pembrolizumab (n = 4)]. Five patients had cutaneous angiosarcoma, one primary breast angiosarcoma and one radiation-associated breast angiosarcoma. At 12 weeks, 5/7 patients (71%) had partial response of their lesions either on imaging and/or clinical exam and two (29%) had progressive disease. 6/7 patients are alive to date and, thus far, 3/7 patients (43%) have progressed (median 3.4 months)- one achieved partial response after pembrolizumab was switched to ongoing Nivolumab/Ipilimumab, one died of progressive disease at 31 weeks (primary breast angiosarcoma) and one was placed on pazopanib. One patient had a complete response (CR) following extended treatment with monotherapy AGEN1884. No patient experienced any ≥ grade 2 toxicities. CONCLUSIONS: This case series underscores the value of targeted immunotherapy in treating angiosarcoma. It also identifies genetic heterogeneity of cutaneous angiosarcomas and discusses specific genetic findings that may explain reported benefits from immunotherapy.

2.
J Thorac Oncol ; 2019 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-31238177

RESUMO

INTRODUCTION: Presently, programmed death ligand 1 is the most commonly used biomarker to predict response to immune checkpoint inhibitors (ICIs) in NSCLC. Owing to its several limitations, there is continuous search for more precise and reliable markers. Frameshift mutations by insertion or deletion (fsindels) are suggested to induce more immunogenic tumor-specific neoantigens, conferring better response to ICIs. Positive correlation of fsindels with ICI response has been studied in melanoma and renal cell carcinoma. We investigated the implication of fsindels in the clinical outcomes and immune landscape of patients with NSCLC treated with ICIs. METHODS: We utilized The Cancer Genome Atlas data set to analyze tumor mutational burden, neoantigen burden, and immune landscape in relation to fsindel status. In addition, utilizing the clinical data from 122 patients treated with ICIs, we evaluated the influence of fsindels on disease response rates and survival outcomes. RESULTS: A positive correlation between fsindel burden and tumor mutational burden and activated CD4/CD8 T-cell infiltration was shown. Presence of fsindels was also associated with significant prolongation of progression-free survival in patients treated with ICIs (median 6.2 versus 2.7 months [p = 0.01]). In addition, significant differences in the overall response rates (26% versus 12% [p = 0.04]) and disease control rates (68% versus 48% [p = 0.02]) were observed in patients with fsindels. CONCLUSION: Our findings suggest that fsindels may have a predictive role for ICI response in NSCLC.

3.
Lancet Oncol ; 20(6): 837-848, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31078463

RESUMO

BACKGROUND: VEGF promotes an immunosuppressive microenvironment and contributes to immune checkpoint inhibitor resistance in cancer. We aimed to assess the activity of the VEGF receptor tyrosine-kinase inhibitor axitinib plus the anti-PD-1 immune checkpoint inhibitor pembrolizumab in patients with sarcoma. METHODS: This single-centre, single-arm, phase 2 trial was undertaken at a tertiary care academic medical centre in Miami, FL, USA, and participants were recruited from all over the USA and internationally. Patients were eligible if they were aged 16 years or older, and had histologically confirmed advanced or metastatic sarcomas, including alveolar soft-part sarcoma (ASPS); measurable disease with one site amenable to repeated biopsies; an ECOG performance status of 0-1; and progressive disease after previous treatment with at least one line of systemic therapy (unless no standard treatment existed or the patient declined therapy). The first five patients were enrolled in a lead-in cohort and were given axitinib 5 mg orally twice daily and pembrolizumab 200 mg intravenously for 30 min on day 8 and every 3 weeks for cycles of 6 weeks for up to 2 years. Thereafter, patients received escalating doses of axitinib (2-10 mg) plus flat dose pembrolizumab according to the schedule above. The primary endpoint was 3-month progression-free survival. All patients were evaluable for survival and safety analyses. This study is registered with ClinicalTrials.gov, number NCT02636725, and is closed to accrual. FINDINGS: Between April 19, 2016, and Feb 7, 2018, of 36 patients assessed for eligibility, 33 (92%) were enrolled and given study treatment (intention-to-treat population and safety population), 12 (36%) of whom had ASPS. With a median follow-up of 14·7 months (IQR 10·1-19·1), 3-month progression-free survival for all evaluable patients was 65·6% (95% CI 46·6-79·3). For patients with ASPS, 3-month progression-free survival was 72·7% (95% CI 37·1-90·3). The most common grade 3 or 4 treatment-related adverse events included hypertension (five [15%] of 33 patients), autoimmune toxicities (five [15%]), nausea or vomiting (two [6%]), and seizures (two [6%]). Serious treatment-related adverse events occurred in seven (21%) patients, including autoimmune colitis, transaminitis, pneumothorax, haemoptysis, seizures, and hypertriglyceridemia. There were no treatment-related deaths. INTERPRETATION: Axitinib plus pembrolizumab has manageable toxicity and preliminary activity in patients with advanced sarcomas, particularly patients with ASPS, warranting further investigation in randomised controlled trials. FUNDING: Merck, Pfizer, American Cancer Society, and Sylvester Comprehensive Cancer Center.

4.
Am Soc Clin Oncol Educ Book ; (38): 916-924, 2018 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-30231406

RESUMO

Sarcomas, rare and heterogenous malignancies that comprise less than 1% of all cancers, have poor outcomes in the metastatic and refractory setting. Their management requires a multidisciplinary approach that consists of medical and surgical oncologists, radiation oncologists, and pathologists as well as ancillary support. In addition to systemic treatments, most patients will require surgical resection and radiation therapy, which mandates the use of the latest technologies and specialized expertise. Management guidelines have been developed in high-income countries, but their applicability in low-income countries, where resources may be limited, remains a challenge. In this article, we propose the best possible evidence-based practices specifically for income-constrained settings to overcome this challenge. In addition, we review the different methods that can be used in low-income countries to access new and expensive treatments, which often times carry prohibitive costs for these areas.


Assuntos
Doenças Raras/epidemiologia , Sarcoma/epidemiologia , Países em Desenvolvimento , Saúde Global , Recursos em Saúde , Acesso aos Serviços de Saúde , Humanos , Vigilância em Saúde Pública , Doenças Raras/diagnóstico , Doenças Raras/terapia , Sarcoma/diagnóstico , Sarcoma/terapia , Fatores Socioeconômicos
6.
J Dermatolog Treat ; : 1-5, 2018 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-29726735

RESUMO

BACKGROUND: Pigmented purpuric dermatoses (PPDs) is a group of diseases with distinguishing clinical characteristics, characterized mainly by purpuric skin lesions. The course of PPDs is chronic and recurrences are common. Although PPDs are considered to be benign, the associated symptoms, such as pruritus, and their cosmetic effect can be extremely distressing to patients. So far no evidence-based treatment has been found to be drastically effective in a large scale of patients. MATERIALS AND METHODS: This paper is a systematic overview of all the reported successful treatments described in the literature. Articles derived from the databases PubMed and SCOPUS and published between 1990 and 2018, were analyzed for this review. The study was conducted according to the PRISMA Guidelines. RESULTS: In the literature there are several case series and case reports, demonstrating encouraging results with the use of various agents, such as local calcineurin-inhibitors, colchicine, pentoxifylline, immunosuppresants, UV- and Laser-therapy. CONCLUSION: To our knowledge, this is the first review focusing on the therapeutic strategies for pigmented purpuric dermatoses. This paper aims to raise awareness for the need to conduct larger systematic studies in order to adequately evaluate the effectiveness of the above mentioned therapeutic strategies.

7.
Discov Med ; 25(137): 131-144, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29641974

RESUMO

Soft tissue sarcomas (STS) are a heterogeneous group of over 100 histologically and genetically distinct mesenchymal tumors. Standard of care for metastatic STS has historically relied on anthracycline-based chemotherapy regimens. Although effective for some patients, conventional chemotherapeutic agents used in STS are associated with substantial toxicity and also are not equally effective in all histologic subtypes of sarcoma. Pazopanib is an orally active antiangiogenic drug that is approved for non-adipogenic sarcomas after failure of at least one line of previous chemotherapy, and has a relatively favorable toxicity profile. Earlier use of pazopanib may be a better choice for patients with subtypes of sarcoma that do not respond well to conventional chemotherapy or those who are unlikely to tolerate chemotherapy. Here we review the evidence for the activity and toxicity profile of pazopanib and consider potential histologic, clinical, and genetic predictive factors that can help to guide treatment choices. Further prospective studies validating these observations may lead to refinement of a precision medicine approach to match ideal sarcoma patients to earlier treatment with pazopanib over traditional chemotherapy.


Assuntos
Medicina de Precisão/métodos , Pirimidinas/uso terapêutico , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Sulfonamidas/uso terapêutico , Humanos , Sarcoma/diagnóstico , Sarcoma/metabolismo , Sarcoma/patologia , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/metabolismo , Neoplasias de Tecidos Moles/patologia
8.
Curr Treat Options Oncol ; 19(3): 14, 2018 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-29520447

RESUMO

OPINION STATEMENT: Angiosarcomas are rare vascular neoplasms that are among the most aggressive subtypes of soft tissue sarcomas. Surgical resection is often challenging even in localized disease, as the infiltrative nature of these cancers leads to frequent local and metastatic recurrences. Cytotoxic chemotherapy, including anthracycline-based regimens and taxanes can produce significant responses in a subset of patients but durability is limited with most patients ultimately succumbing to metastatic disease. Targeted therapy with tyrosine kinase inhibitors is usually well-tolerated but prone to development of resistance. Few head-to-head trials have addressed the optimal sequence of therapies, or demonstrated conclusive benefits of one therapy over another based on clinical and etiologic factors. Novel therapies in clinical trials, including antibodies to endoglin and checkpoint inhibitors have demonstrated exciting early activity in patients with angiosarcoma. Improved understanding of the genetic heterogeneity within various angiosarcoma subtypes may identify predictive biomarkers to match patients to effective existing and future therapies. Overall, angiosarcoma patients with optimal performance status are best served in clinical trials that incorporate novel combinations of cytotoxic chemotherapy, targeted therapies, and immunotherapies.

9.
BMJ Case Rep ; 20172017 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-29183892

RESUMO

A 32-year-old female with stage IV colorectal cancer and metastasis to the liver experienced cardiotoxic reactions after treatment with 5-fluorouracil and its oral prodrug capecitabine even at two-thirds the recommended dose. After careful considerations, the decision was made to attempt capecitabine retrial at a further suboptimal dose with combination chemotherapy where she no longer experienced cardiac events. As a result, the liver tumour shrank and rectal mass stabilised, tumour markers dropped and she underwent surgical resection of both masses. Later there was local recurrence of disease near the previous liver tumour, so the suboptimal capecitabine therapy was restarted without complaint. The patient became a candidate for a NanoKnife procedure, offering a potentially curative therapy. This case report summarises a novel treatment strategy for those patients with advanced colorectal cancer who experience cardiotoxic reactions to fluoropyrimidines, the active agent of gold standard treatment.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Capecitabina/administração & dosagem , Cardiotoxicidade , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/administração & dosagem , Adulto , Antimetabólitos Antineoplásicos/efeitos adversos , Capecitabina/efeitos adversos , Cardiotoxicidade/etiologia , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Feminino , Fluoruracila/efeitos adversos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário
10.
Future Oncol ; 13(24): 2183-2193, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28984483

RESUMO

Gastrointestinal stromal tumors (GISTs) are the most common GI tract mesenchymal tumors. GIST patients are optimally managed by a precision medicine approach. Herein, we discuss the latest advances in precision medicine and ongoing clinical trials relevant to GIST. Circulating tumor DNA for detection of mutational changes could replace tissue biopsies and radiographic imaging once validated. Most GISTs are KIT/PDGFRα mutated, and despite the good clinical response to imatinib, treatment is generally not curative, more often due to secondary mutations. New mechanisms to bypass this resistance by inhibiting KIT downstream pathways and by targeting multiple KIT or PDGFRα mutations are being investigated. Immunotherapy for GIST patients is in its infancy. These approaches may lead to more effective, less toxic therapies.


Assuntos
Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/etiologia , Tumores do Estroma Gastrointestinal/terapia , Adulto , Animais , Biomarcadores Tumorais , DNA Tumoral Circulante , Terapia Combinada , Humanos , Imunoterapia , Biópsia Líquida , Terapia de Alvo Molecular , Mutação , Metástase Neoplásica , Estadiamento de Neoplasias
11.
Crit Rev Oncol Hematol ; 88(3): 680-95, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23972664

RESUMO

Mature T-cell lymphomas/leukemias (MTCL) have been understudied lymphoid neoplasms that currently receive growing attention. Our historically rudimentary molecular understanding and dissatisfactory interventional success in this complex and for the most part poor-prognostic group of tumors is only slightly improving. A major limiting aspect in further progress in these rare neoplasms is the lack of suitable model systems that would substantially facilitate pathogenic studies and pre-clinical drug evaluations. Such representations of MTCL have thus far not been systematically appraised. We therefore provide an overview on existing models and point out their particular advantages and limitations in the context of the specific scientific questions. After addressing issues of species-specific differences and classifications, we summarize data on MTCL cell lines of human as well as murine origin, on murine strain predispositions to MTCL, on available models of genetically engineered mice, and on transplant systems. From an in-silico meta-analysis of available primary data of gene expression profiles on human MTCL we cross-reference genes reported to transform T-cells in mice and reflect on their general vs entity-restricted relevance and on target-promoter influences. Overall, we identify the urgent need for new models of higher fidelity to human MTCL with respect to their increasingly recognized diversity and to predictions of drug response.


Assuntos
Linfoma de Células T/etiologia , Linfoma de Células T/patologia , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Modelos Animais de Doenças , Humanos , Camundongos , Gradação de Tumores
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