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2.
World Neurosurg ; 133: e804-e812, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31605839

RESUMO

BACKGROUND: Histopathological grading of meningiomas is insufficient for optimal risk stratification. The purpose of the present study was to determine the prognostic value of atypical histopathological features across all nonmalignant meningiomas (World Health Organization [WHO] grade I-II). METHODS: The data from 334 patients with WHO grade I (n = 275) and grade II (n = 59) meningiomas who had undergone surgical resection from 2001 to 2015 at 2 academic centers were pooled. Progression/recurrence (P/R) was determined radiographically and measured from the date of surgery. RESULTS: The median follow-up was 52 months. The patients were stratified by the number of atypical features: 0 (n = 151), 1 (n = 71), 2 (n = 66), 3 (n = 22), and 4 or 5 (n = 24). The risk of P/R increased with an increasing number of atypical features (log-rank test, P = 0.001). The 5-year actuarial rates of P/R stratified by the number of atypical features were as follows: 0, 16.3% (95% confidence interval [CI], 10.7-24.4); 1, 21.7% (95% CI, 12.8-35.2); 2, 28.2% (95% CI, 18.4-41.7); 3, 30.4% (95% CI, 13.8-58.7); and 4 or 5, 51.4% (95% CI, 31.7-74.5). On univariate analysis, the presence of high nuclear/cytoplasmic ratio (P = 0.007), prominent nucleoli (P = 0.007), and necrosis (P < 0.00005) were associated with an increased risk of P/R. On multivariate analysis, the number of atypical features (hazard ratio [HR], 1.30; 95% CI, 1.03-1.63; P = 0.03), ≥4 mitoses per high-power fields (HR, 2.45; 95% CI, 1.17-5.15; P = 0.02), subtotal resection (HR, 3.9; 95% CI, 2.5-6.3; P < 0.0005), and the lack of adjuvant radiotherapy (HR, 2.40; 95% CI, 1.19-4.80; P = 0.01) were associated with an increased risk of P/R. CONCLUSIONS: An increased number of atypical features, ≥4 mitoses per 10 high-power fields, subtotal resection, and the lack of adjuvant radiotherapy were independently associated with P/R of WHO grade I-II meningiomas. Patients with these features might benefit from intensified therapy.


Assuntos
Neoplasias Meníngeas/cirurgia , Meningioma/cirurgia , Progressão da Doença , Feminino , Humanos , Masculino , Neoplasias Meníngeas/patologia , Neoplasias Meníngeas/radioterapia , Meningioma/patologia , Meningioma/radioterapia , Gradação de Tumores , Prognóstico , Radioterapia Adjuvante , Estudos Retrospectivos , Fatores de Risco , Falha de Tratamento
4.
Adv Radiat Oncol ; 3(4): 534-547, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30370353

RESUMO

The intersection of immunotherapy and radiation oncology is a rapidly evolving area of preclinical and clinical investigation. The strategy of combining radiation and immunotherapy to enhance local and systemic antitumor immune responses is intriguing yet largely unproven in the clinical setting because the mechanisms of synergy and the determinants of therapeutic response remain undefined. In recent years, several noninvasive molecular imaging approaches have emerged as a platform to interrogate the tumor immune microenvironment. These tools have the potential to serve as robust biomarkers for cancer immunotherapy and may hold several advantages over conventional anatomic imaging modalities and contemporary invasive tissue acquisition techniques. Given the key and expanding role of precision imaging in radiation oncology for patient selection, target delineation, image guided treatment delivery, and response assessment, noninvasive molecular-specific imaging may be uniquely suited to evaluate radiation/immunotherapy combinations. Herein, we describe several experimental imaging-based strategies that are currently being explored to characterize in vivo immune responses, and we review a growing body of preclinical data and nascent clinical experience with immuno-positron emission tomography molecular imaging as a putative biomarker for cancer immunotherapy. Finally, we discuss practical considerations for clinical translation to implement noninvasive molecular imaging of immune checkpoint molecules, immune cells, or associated elements of the antitumor immune response with a specific emphasis on its potential application at the interface of radiation oncology and immuno-oncology.

5.
Am Soc Clin Oncol Educ Book ; 38: 382-390, 2018 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-30231379

RESUMO

The last decade has seen substantial advances in androgen receptor targeting in prostate cancer. In addition, advances have been made in immunotherapy and radiopharmaceutical-based therapy, although their optimal use in the clinic remains unclear. Recent understanding of the relevance and actionability of DNA damage repair mutations in a considerable minority of patients with prostate cancer is likely to open up a new frontier in prostate cancer therapeutics. As androgen receptor-directed therapy moves earlier in the disease process for prostate cancer, advances in these nonandrogen receptor-based therapeutics may take on greater significance in the years to come.


Assuntos
Neoplasias da Próstata/terapia , Ensaios Clínicos como Assunto , Terapia Combinada/métodos , Reparo do DNA/efeitos dos fármacos , Gerenciamento Clínico , Humanos , Imunoterapia , Masculino , Mutação , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/mortalidade , Compostos Radiofarmacêuticos/farmacologia , Compostos Radiofarmacêuticos/uso terapêutico , Resultado do Tratamento
6.
J Immunother Cancer ; 6(1): 78, 2018 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-30081947

RESUMO

In this White Paper, we discuss the current state of microbial cancer therapy. This paper resulted from a meeting ('Microbial Based Cancer Therapy') at the US National Cancer Institute in the summer of 2017. Here, we define 'Microbial Therapy' to include both oncolytic viral therapy and bacterial anticancer therapy. Both of these fields exploit tumor-specific infectious microbes to treat cancer, have similar mechanisms of action, and are facing similar challenges to commercialization. We designed this paper to nucleate this growing field of microbial therapeutics and increase interactions between researchers in it and related fields. The authors of this paper include many primary researchers in this field. In this paper, we discuss the potential, status and opportunities for microbial therapy as well as strategies attempted to date and important questions that need to be addressed. The main areas that we think will have the greatest impact are immune stimulation, control of efficacy, control of delivery, and safety. There is much excitement about the potential of this field to treat currently intractable cancer. Much of the potential exists because these therapies utilize unique mechanisms of action, difficult to achieve with other biological or small molecule drugs. By better understanding and controlling these mechanisms, we will create new therapies that will become integral components of cancer care.


Assuntos
Bactérias , Terapia Biológica/métodos , Vetores Genéticos , Neoplasias/prevenção & controle , Neoplasias/terapia , Vírus , Animais , Bactérias/genética , Terapia Biológica/normas , Terapia Biológica/tendências , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Estudos Clínicos como Assunto , Terapia Combinada , Avaliação Pré-Clínica de Medicamentos , Engenharia Genética , Vetores Genéticos/genética , Humanos , Neoplasias/etiologia , Terapia Viral Oncolítica , Resultado do Tratamento , Vírus/genética
8.
Clin Cancer Res ; 24(20): 5058-5071, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-29898992

RESUMO

Purpose: In the proper context, radiotherapy can promote antitumor immunity. It is unknown if elective nodal irradiation (ENI), a strategy that irradiates tumor-associated draining lymph nodes (DLN), affects adaptive immune responses and combinatorial efficacy of radiotherapy with immune checkpoint blockade (ICB).Experimental Design: We developed a preclinical model to compare stereotactic radiotherapy (Tumor RT) with or without ENI to examine immunologic differences between radiotherapy techniques that spare or irradiate the DLN.Results: Tumor RT was associated with upregulation of an intratumoral T-cell chemoattractant chemokine signature (CXCR3, CCR5-related) that resulted in robust infiltration of antigen-specific CD8+ effector T cells as well as FoxP3+ regulatory T cells (Tregs). The addition of ENI attenuated chemokine expression, restrained immune infiltration, and adversely affected survival when combined with ICB, especially with anti-CLTA4 therapy. The combination of stereotactic radiotherapy and ICB led to long-term survival in a subset of mice and was associated with favorable CD8 effector-to-Treg ratios and increased intratumoral density of antigen-specific CD8+ T cells. Although radiotherapy technique (Tumor RT vs. ENI) affected initial tumor control and survival, the ability to reject tumor upon rechallenge was partially dependent upon the mechanism of action of ICB; as radiotherapy/anti-CTLA4 was superior to radiotherapy/anti-PD-1.Conclusions: Our results highlight that irradiation of the DLN restrains adaptive immune responses through altered chemokine expression and CD8+ T-cell trafficking. These data have implications for combining radiotherapy and ICB, long-term survival, and induction of immunologic memory. Clinically, the immunomodulatory effect of the radiotherapy strategy should be considered when combining stereotactic radiotherapy with immunotherapy. Clin Cancer Res; 24(20); 5058-71. ©2018 AACR.


Assuntos
Imunoterapia , Linfonodos/patologia , Linfonodos/efeitos da radiação , Neoplasias/patologia , Neoplasias/terapia , Radiocirurgia , Transferência Adotiva , Animais , Linhagem Celular Tumoral , Terapia Combinada , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Imunoterapia/métodos , Linfonodos/imunologia , Linfonodos/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Melanoma Experimental , Camundongos , Neoplasias/imunologia , Neoplasias/metabolismo , Prognóstico , Radiocirurgia/métodos , Especificidade do Receptor de Antígeno de Linfócitos T , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Urol Oncol ; 36(6): 309.e7-309.e14, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29551548

RESUMO

OBJECTIVES: Perineural invasion (PNI) has not yet gained universal acceptance as an independent predictor of adverse outcomes for prostate cancer treated with external beam radiotherapy (EBRT). We analyzed the prognostic influence of PNI for a large institutional cohort of prostate cancer patients who underwent EBRT with and without androgen deprivation therapy (ADT). MATERIAL AND METHODS: We, retrospectively, reviewed prostate cancer patients treated with EBRT from 1993 to 2007 at our institution. The primary endpoint was biochemical failure-free survival (BFFS), with secondary endpoints of metastasis-free survival (MFS), prostate cancer-specific survival (PCSS), and overall survival (OS). Univariate and multivariable Cox proportional hazards models were constructed for all survival endpoints. Hazard ratios for PNI were analyzed for the entire cohort and for subsets defined by NCCN risk level. Additionally, Kaplan-Meier survival curves were generated for all survival endpoints after stratification by PNI status, with significant differences computed using the log-rank test. RESULTS: Of 888 men included for analysis, PNI was present on biopsy specimens in 187 (21.1%). PNI was associated with clinical stage, pretreatment PSA level, biopsy Gleason score, and use of ADT (all P<0.01). Men with PNI experienced significantly inferior 10-year BFFS (40.0% vs. 57.8%, P = 0.002), 10-year MFS (79.7% vs. 89.0%, P = 0.001), and 10-year PCSS (90.9% vs. 95.9%, P = 0.009), but not 10-year OS (67.5% vs. 77.5%, P = 0.07). On multivariate analysis, PNI was independently associated with inferior BFFS (P<0.001), but not MFS, PCSS, or OS. In subset analysis, PNI was associated with inferior BFFS (P = 0.04) for high-risk patients and with both inferior BFFS (P = 0.01) and PCSS (P = 0.05) for low-risk patients. Biochemical failure occurred in 33% of low-risk men with PNI who did not receive ADT compared to 8% for low-risk men with PNI treated with ADT (P = 0.01). CONCLUSION: PNI was an independently significant predictor of adverse survival outcomes in this large institutional cohort, particularly for patients with NCCN low-risk disease. PNI should be carefully considered along with other standard prognostic factors when treating these patients with EBRT. Supplementing EBRT with ADT may be beneficial for select low-risk patients with PNI though independent validation with prospective studies is recommended.


Assuntos
Antagonistas de Androgênios/administração & dosagem , Quimiorradioterapia/mortalidade , Recidiva Local de Neoplasia/mortalidade , Nervos Periféricos/patologia , Neoplasias da Próstata/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Dosagem Radioterapêutica , Estudos Retrospectivos , Taxa de Sobrevida
10.
Curr Treat Options Oncol ; 19(3): 16, 2018 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-29520448

RESUMO

OPINION STATEMENT: Bacillus Calmette-Guérin in urothelial carcinoma, high-dose interleukin-2 in renal cell carcinoma, and sipuleucel-T in prostate cancer serve as enduring examples that the host immune response can be harnessed to promote effective anti-tumor immunity in genitourinary malignancies. Recently, cancer immunotherapy with immune checkpoint inhibitors has transformed the prognostic landscape leading to durable responses in a subset of urothelial carcinoma and renal cell carcinoma patients with traditionally poor prognosis. Despite this success, many patients fail to respond to immune checkpoint inhibitors and progression/relapse remains common. Furthermore, modest clinical activity has been observed with ICIs as a monotherapy in advanced PCa. As such, novel treatment approaches are warranted and improved biomarkers for patient selection and treatment response are desperately needed. Future efforts should focus on exploring synergistic and rational combinations that safely and effectively boost response rates and survival in genitourinary malignancies. Specific areas of interest include (1) evaluating the optimal sequencing, disease burden, and timing of immuno-oncology agents with other anti-cancer therapeutics and (2) validating novel biomarkers of response to immunotherapy to optimize patient selection and to identify individuals most likely to benefit from immunotherapy across the heterogenous spectrum of genitourinary malignancies.


Assuntos
Imunidade Inata/imunologia , Recidiva Local de Neoplasia/economia , Microambiente Tumoral/genética , Neoplasias Urogenitais/tratamento farmacológico , Humanos , Imunidade Inata/efeitos dos fármacos , Imunoterapia/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/imunologia , Microambiente Tumoral/imunologia , Neoplasias Urogenitais/imunologia
11.
Cancer Immunol Res ; 6(4): 422-433, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29472271

RESUMO

The cGAS-STING cytosolic DNA sensing pathway may play an integral role in the initiation of antitumor immune responses. Studies evaluating the immunogenicity of various cyclic dinucleotide (CDN) STING agonists administered by intratumoral (i.t.) injection showed potent induction of inflammation, tumor necrosis, and, in some cases, durable tumor-specific adaptive immunity. However, the specific immune mechanisms underlying these responses remain incompletely defined. The majority of these studies have focused on the effect of CDNs on immune cells but have not conclusively interrogated the role of stromal cells in the acute rejection of the CDN-injected tumor. Here, we revealed a mechanism of STING agonist-mediated tumor response that relied on both stromal and immune cells to achieve tumor regression and clearance. Using knockout and bone marrow chimeric mice, we showed that although bone marrow-derived TNFα was necessary for CDN-induced necrosis, STING signaling in radioresistant stromal cells was also essential for CDN-mediated tumor rejection. These results provide evidence for crosstalk between stromal and hematopoietic cells during CDN-mediated tumor collapse after i.t. administration. These mechanistic insights may prove critical in the clinical development of STING agonists. Cancer Immunol Res; 6(4); 422-33. ©2018 AACR.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Membrana/agonistas , Neoplasias/etiologia , Neoplasias/metabolismo , Nucleotídeos Cíclicos/farmacologia , Tolerância a Radiação , Células Estromais/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Medula Óssea/metabolismo , Linhagem Celular Tumoral , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Imunidade Inata , Interferon beta/metabolismo , Melanoma Experimental , Camundongos , Camundongos Knockout , Necrose/metabolismo , Necrose/patologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Tolerância a Radiação/efeitos dos fármacos , Tolerância a Radiação/genética , Transdução de Sinais/efeitos dos fármacos , Células Estromais/patologia , Células Estromais/efeitos da radiação , Carga Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
12.
Int J Radiat Oncol Biol Phys ; 100(4): 916-925, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29485071

RESUMO

PURPOSE: To characterize the effect of concurrent stereotactic radiosurgery-stereotactic radiation therapy (SRS-SRT) and immune checkpoint inhibitors on patient outcomes and safety in patients with brain metastases (BMs). METHODS AND MATERIALS: We retrospectively identified metastatic non-small cell lung cancer, melanoma, and renal cell carcinoma patients who had BMs treated with SRS-SRT from 2010 to 2016 without prior whole-brain radiation therapy. We included SRS-SRT patients who were treated with anti-cytotoxic T-lymphocyte-associated protein 4 (ipilimumab) and anti-programmed cell death protein 1 receptor (nivolumab, pembrolizumab). Patients who were given immune checkpoint inhibitors on active or unreported clinical trials were excluded, and concurrent immune checkpoint inhibition (ICI) was defined as ICI given within 2 weeks of SRS-SRT. Patients were managed with SRS-SRT, SRS-SRT with nonconcurrent ICI, or SRS-SRT with concurrent ICI. Progression-free survival and overall survival (OS) were estimated using Kaplan-Meier survival curves, and Cox proportional hazards models were used for multivariate analysis. Logistic regression was used to identify predictors of acute neurologic toxicity, immune-related adverse events, and new BMs. RESULTS: A total of 260 patients were treated with SRS-SRT to 623 BMs. Of these patients, 181 were treated with SRS-SRT alone, whereas 79 received SRS-SRT and ICI, 35% of whom were treated with concurrent SRS-SRT and ICI. Concurrent ICI was not associated with increased rates of immune-related adverse events or acute neurologic toxicity and predicted for a decreased likelihood of the development of ≥3 new BMs after SRS-SRT (P=.045; odds ratio, 0.337). Median OS for patients treated with SRS-SRT, SRS-SRT with nonconcurrent ICI, and SRS-SRT with concurrent ICI was 12.9 months, 14.5 months, and 24.7 months, respectively. SRS-SRT with concurrent ICI was associated with improved OS compared with SRS-SRT alone (P=.002; hazard ratio [HR], 2.69) and compared with nonconcurrent SRS-SRT and ICI (P=.006; HR, 2.40) on multivariate analysis. The OS benefit of concurrent SRS-SRT and ICI was significant in comparison with patients treated with SRS-SRT before ICI (P=.002; HR, 3.82) or after ICI (P=.021; HR, 2.64). CONCLUSIONS: Delivering SRS-SRT with concurrent ICI may be associated with a decreased incidence of new BMs and favorable survival outcomes without increased rates of adverse events.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma de Células Renais/terapia , Imunoterapia/métodos , Neoplasias Renais/patologia , Neoplasias Pulmonares/patologia , Melanoma/terapia , Radiocirurgia/métodos , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias Encefálicas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma de Células Renais/secundário , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/mortalidade , Ipilimumab/uso terapêutico , Melanoma/mortalidade , Melanoma/secundário , Pessoa de Meia-Idade , Nivolumabe/uso terapêutico , Intervalo Livre de Progressão , Radiocirurgia/efeitos adversos , Radiocirurgia/mortalidade , Estudos Retrospectivos , Análise de Sobrevida
13.
J Immunother Cancer ; 6(1): 6, 2018 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-29375032

RESUMO

Radiotherapy (RT) has been a fundamental component of the anti-cancer armamentarium for over a century. Approximately half of all cancer patients are treated with radiotherapy during their disease course. Over the two past decades, there has been a growing body of preclinical evidence supporting the immunomodulatory effects of radiotherapy, particularly when combined with immunotherapy, but only anecdotal clinical examples existed until recently. The renaissance of immunotherapy and the recent U.S. Food and Drug Administration (FDA) approval of several immune checkpoint inhibitors (ICIs) and other immuno-oncology (IO) agents in multiple cancers provides the opportunity to investigate how localized radiotherapy can induce systemic immune responses. Early clinical experiences have demonstrated feasibility of this approach but additional preclinical and clinical investigation is needed to understand how RT and immunotherapy can be optimally combined.To address questions that are critical to successful incorporation of radiation oncology into immunotherapy, the American Society for Radiation Oncology (ASTRO), the Society for Immunotherapy of Cancer (SITC) and the National Cancer Institute (NCI) organized a collaborative scientific workshop, Incorporating Radiation Oncology into Immunotherapy, that convened on June 15 and 16 of 2017 at the Natcher Building, NIH Campus in Bethesda, Maryland. This report summarizes key data and highlights from each session.


Assuntos
Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Animais , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais , Terapia Combinada , Humanos , Imunoterapia , Radioterapia (Especialidade)
14.
Oncotarget ; 8(61): 102767-102768, 2017 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-29262522
15.
Cancer Immunol Res ; 5(11): 992-1004, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28970196

RESUMO

Radiotherapy (RT) enhances innate and adaptive antitumor immunity; however, the effects of radiation on suppressive immune cells, such as regulatory T cells (Treg), in the tumor microenvironment (TME) are not fully elucidated. Although previous reports suggest an increased Treg infiltration after radiation, whether these Tregs are functionally suppressive remains undetermined. To test the hypothesis that RT enhances the suppressive function of Treg in the TME, we selectively irradiated implanted tumors using the small animal radiation research platform (SARRP), which models stereotactic radiotherapy in human patients. We then analyzed tumor-infiltrating lymphocytes (TIL) with flow-cytometry and functional assays. Our data showed that RT significantly increased tumor-infiltrating Tregs (TIL-Treg), which had higher expression of CTLA-4, 4-1BB, and Helios compared with Tregs in nonirradiated tumors. This observation held true across several tumor models (B16/F10, RENCA, and MC38). We found that TIL-Tregs from irradiated tumors had equal or improved suppressive capacity compared with nonirradiated tumors. Our data also indicated that after RT, Tregs proliferated more robustly than other T-cell subsets in the TME. In addition, after RT, expansion of Tregs occurred when T-cell migration was inhibited using Fingolimod, suggesting that the increased Treg frequency was likely due to preferential proliferation of intratumoral Treg after radiation. Our data also suggested that Treg expansion after irradiation was independent of TGFß and IL33 signaling. These data demonstrate that RT increased phenotypically and functionally suppressive Tregs in the TME. Our results suggest that RT might be combined effectively with Treg-targeting agents to maximize antitumor efficacy. Cancer Immunol Res; 5(11); 992-1004. ©2017 AACR.


Assuntos
Linfócitos do Interstício Tumoral/imunologia , Neoplasias/radioterapia , Radiocirurgia , Linfócitos T Reguladores/imunologia , Microambiente Tumoral/efeitos da radiação , Animais , Linhagem Celular Tumoral , Feminino , Cloridrato de Fingolimode/farmacologia , Imunossupressores/farmacologia , Interleucina-33/imunologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias/imunologia , Neoplasias/patologia , Fator de Crescimento Transformador beta/imunologia , Carga Tumoral , Microambiente Tumoral/imunologia
16.
Front Oncol ; 7: 200, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28929084

RESUMO

PURPOSE: The aim of this study is to evaluate long-term treatment outcome and toxicities among vestibular schwannoma (VS) patients treated with hypofractionated stereotactic radiotherapy (HSRT). METHODS: 383 patients with unilateral VS treated with HSRT (25 Gy, five fractions) between 1995 and 2007 were retrospectively reviewed. Treatment failure was defined as requiring salvage microsurgery. Posttreatment new/progressive clinical symptoms or increases in baseline tumor volume (BTV) due to treatment effect or progression were noted. Symptom outcomes were reported as baseline and posttreatment ± improvement, respectively. Symptoms were grouped by cranial nerve (CN) VII or CNVIII. Audiometry was assessed baseline and posttreatment hearing. Patients were grouped as having greater than serviceable hearing [Gardner Robertson (GR) score 1-2] or less than non-serviceable hearing (GR score 3-5) by audiometry. RESULTS: Median follow-up was 72.0 months. Nine (2.3%) experienced treatment failure. At last follow-up, 74 (19.3%) had new/progressive symptoms and were categorized as radiologic non-responders, whereas 300 (78.3%) had no tumor progression and were grouped as radiologic responders. Average pretreatment BTV for treatment failures, radiologic non-responders, and radiologic responders was 2.11, 0.44, and 1.87 cm3, respectively. Pretreatment CNVII and CNVIII symptoms were present in 9.4 and 93.4% of patients, respectively. Eight (24%) with pre-HSRT CNVII and 37 (10%) with pre-HSRT CNVIII symptoms recovered CN function post-HSRT. Thirty-five (9%) and 36 (9.4%) experienced new CNVII and CNVIII deficit, respectively, after HSRT. Of these, 20 (57%) and 18 (50%) recovered CNVII and CNVIII function, respectively, after HSRT. Evaluable audiograms were available in 199 patients. At baseline and at last follow-up, 65.8 and 36.2% had serviceable hearing, respectively. Fifty-one percent had preservation of serviceable hearing at last follow-up. CONCLUSION: Treatment of VS with HSRT is effective with treatment success in 97.7% and an acceptable toxicity profile. Less than one-third of patients experience any new CNVII or CNVIII deficit posttreatment. Greater than 50% of patients with serviceable hearing at baseline maintained hearing function. Improved methods to differentiate treatment effect and tumor progression are needed.

17.
Front Oncol ; 7: 124, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28660173

RESUMO

OBJECTIVE: Dysphonia is common among patients with early stage glottic cancer. Laryngeal videostroboscopy (LVS) has not been routinely used to assess post-radiotherapy (RT) voice changes. We hypothesized that LVS would demonstrate improvement in laryngeal function after definitive RT for early-stage glottic cancer. STUDY DESIGN: Blinded retrospective review of perceptual voice and stroboscopic parameters for patients with early glottic cancer and controls. SETTING: High-volume, single-institution academic medical center. SUBJECTS AND METHODS: Fifteen patients underwent RT for Tis-T2N0M0 glottic cancer and were evaluated with serial LVS exams pre- and post-RT. Stroboscopic assessment included six parameters: vocal fold (VF) vibration, VF mobility, erythema/edema, supraglottic compression, glottic closure, and secretions. Grade, roughness, breathiness, asthenia, strain (GRBAS) voice perceptual scale was graded in tandem with LVS score. Assessments were grouped by time interval from RT: pre-RT, 0-4, 4-12, and >12 months post-RT. RESULTS: 60 LVS exams and corresponding GRBAS assessments were reviewed. There were significant improvements in ipsilateral VF motion (P = 0.03) and vibration (P = 0.001) and significant worsening in contralateral VF motion (P < 0.001) and vibration (P = 0.008) at >12 months post-RT. Glottic closure significantly worsened, most prominent >12 months post-RT (P = 0.01). Composite GRBAS scores were significantly improved across all post-RT intervals. CONCLUSION: LVS proved to be a robust tool for assessing pre- and post-RT laryngeal function. We observed post-RT improvement in ipsilateral VF function, a decline in contralateral VF function, and decreased glottic closure. These results demonstrate that LVS can detect meaningful changes in VF and glottic function and support its use for post-RT evaluation of glottic cancer patients.

18.
Immunol Rev ; 276(1): 80-96, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28258692

RESUMO

Despite the impressive impact of CTLA4 and PD1-PDL1-targeted cancer immunotherapy, a large proportion of patients with many tumor types fail to respond. Consequently, the focus has shifted to targeting alternative inhibitory receptors (IRs) and suppressive mechanisms within the tumor microenvironment. Lymphocyte activation gene-3 (LAG3) (CD223) is the third IR to be targeted in the clinic, consequently garnering considerable interest and scrutiny. LAG3 upregulation is required to control overt activation and prevent the onset of autoimmunity. However, persistent antigen exposure in the tumor microenvironment results in sustained LAG3 expression, contributing to a state of exhaustion manifest in impaired proliferation and cytokine production. The exact signaling mechanisms downstream of LAG3 and interplay with other IRs remain largely unknown. However, the striking synergy between LAG3 and PD1 observed in multiple settings, coupled with the contrasting intracellular cytoplasmic domain of LAG3 as compared with other IRs, highlights the potential uniqueness of LAG3. There are now four LAG3-targeted therapies in the clinic with many more in preclinical development, emphasizing the broad interest in this IR. Given the translational relevance of LAG3 and the heightened interest in the impact of dual LAG3/PD1 targeting in the clinic, the outcome of these trials could serve as a nexus; significantly increasing or dampening enthusiasm for subsequent targets in the cancer immunotherapeutic pipeline.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígenos CD/metabolismo , Imunoterapia/métodos , Neoplasias/terapia , Linfócitos T/imunologia , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Humanos , Ativação Linfocitária , Camundongos , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais , Evasão Tumoral , Microambiente Tumoral
19.
Neurosurgery ; 81(1): 136-146, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28201783

RESUMO

BACKGROUND: There is no consensus regarding the optimal management of inoperable high-grade arteriovenous malformations (AVMs). This long-term study of 42 patients with high-grade AVMs reports obliteration and adverse event (AE) rates using planned multistage repeat stereotactic radiosurgery (SRS). OBJECTIVE: To evaluate the efficacy and safety of multistage SRS with treatment of the entire AVM nidus at each treatment session to achieve complete obliteration of high-grade AVMs. METHODS: Patients with high-grade Spetzler-Martin (S-M) III-V AVMs treated with at least 2 multistage SRS treatments from 1989 to 2013. Clinical outcomes of obliteration rate, minor/major AEs, and treatment characteristics were collected. RESULTS: Forty-two patients met inclusion criteria (n = 26, S-M III; n = 13, S-M IV; n = 3, S-M V) with a median follow-up was 9.5 yr after first SRS. Median number of SRS treatment stages was 2, and median interval between stages was 3.5 yr. Twenty-two patients underwent pre-SRS embolization. Complete AVM obliteration rate was 38%, and the median time to obliteration was 9.7 yr. On multivariate analysis, higher S-M grade was significantly associated ( P = .04) failure to achieve obliteration. Twenty-seven post-SRS AEs were observed, and the post-SRS intracranial hemorrhage rate was 0.027 events per patient year. CONCLUSION: Treatment of high-grade AVMs with multistage SRS achieves AVM obliteration in a meaningful proportion of patients with acceptable AE rates. Lower obliteration rates were associated with higher S-M grade and pre-SRS embolization. This approach should be considered with caution, as partial obliteration does not protect from hemorrhage.


Assuntos
Malformações Arteriovenosas Intracranianas/radioterapia , Radiocirurgia , Adolescente , Adulto , Idoso , Criança , Protocolos Clínicos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Doses de Radiação , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
20.
J Neurosurg ; 124(1): 106-14, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26274991

RESUMO

OBJECT World Health Organization (WHO) Grade I (benign) meningiomas with atypical features may behave more aggressively than similarly graded tumors without atypical features. Here, the prognostic significance of atypical features in benign meningiomas was determined. METHODS Data from patients diagnosed with WHO Grade I benign meningiomas per the 2007 WHO criteria and who underwent surgery between 2002 and 2012 were retrospectively reviewed. Patients were stratified by the absence or presence of 1 to 2 atypical features with review of the clinical and histological factors. RESULTS A total of 148 patients met the inclusion criteria (n = 77 with atypia; n = 71 without atypia). The median follow-up duration after pathological diagnosis was 37.5 months. Thirty patients had progression/recurrence (P/R) after initial treatment, and 22 (73%) of 30 patients with P/R had 1-2 atypical features. The presence of atypical features was significantly associated with P/R (p = 0.03) and independent of the MIB-1 labeling index. The 1-year and 5-year actuarial rates of P/R were 9.6% versus 1.4% and 30.8% versus 13.8% fortumors with and without atypical features, respectively. Higher Simpson grade resection (II-IV vs I) was associated with the increased risk of P/R (p < 0.001). Stratification of patients into low-risk (Simpson Grade I), intermediate-risk (Simpson Grade II-IV with no atypical features), and high-risk groups (Simpson Grade II-IV with atypical features) was significantly correlated with increased risk of P/R (p < 0.001). CONCLUSIONS Patients with benign meningiomas with atypical features and those undergoing Simpson Grade II-IV resection are at significantly increased risk of P/R. Patients with these features may benefit from the consideration of additional surgery and/or radiation therapy.


Assuntos
Meningioma/patologia , Meningioma/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Progressão da Doença , Feminino , Seguimentos , Humanos , Antígeno Ki-67 , Masculino , Meningioma/cirurgia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Procedimentos Neurocirúrgicos , Prognóstico , Radioterapia Adjuvante , Estudos Retrospectivos , Medição de Risco , Resultado do Tratamento , Organização Mundial da Saúde , Adulto Jovem
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