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1.
J Surg Oncol ; 124(5): 801-809, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34231222

RESUMO

INTRODUCTION: Neoadjuvant therapy (NAT) is an emerging strategy for operable pancreatic ductal adenocarcinoma (PDAC). While NAT increases multimodal therapy completion, it risks functional decline and treatment dropout. We used decision analysis to determine optimal management of localized PDAC and consider risks faced by elderly patients. METHODS: A Markov cohort decision analysis model evaluated treatment options for a 60-year-old patient with resectable PDAC: (1) upfront pancreaticoduodenectomy or (2) NAT. One-way and probabilistic sensitivity analyses were performed. A subanalysis considered the scenario of a 75-year-old patient. RESULTS: For the base case, NAT offered an incremental survival gain of 4.6 months compared with SF (overall survival: 26.3 vs. 21.7 months). In one-way sensitivity analyses, findings were sensitive to recurrence-free survival for NAT patients undergoing adjuvant, probability of completing NAT, and probability of being resectable at exploration after NAT. On probabilistic analysis, NAT was favored in a majority of trials (97%) with a median survival benefit of 5.1 months. In altering the base case for the 75-year-old scenario, NAT had a survival benefit of 3.8 months. CONCLUSIONS: This analysis demonstrates a significant benefit to NAT in patients with localized PDAC. This benefit persists even in the elderly cohort.


Assuntos
Adenocarcinoma/terapia , Carcinoma Ductal Pancreático/terapia , Técnicas de Apoio para a Decisão , Cadeias de Markov , Terapia Neoadjuvante/mortalidade , Pancreatectomia/mortalidade , Neoplasias Pancreáticas/terapia , Adenocarcinoma/patologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/patologia , Terapia Combinada , Seguimentos , Humanos , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
2.
Gynecol Oncol ; 163(1): 110-116, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34304907

RESUMO

This study aimed to prospectively evaluate the impact of dose-escalated irradiation of nodal metastases on clinical outcomes compared to no boost in patients with node-positive, bulky, locally advanced cervical cancer (LACC) undergoing standard chemoradiation and MRI-based brachytherapy. METHODS: This comparative study included 161 patients with node-positive LACC treated with definitive chemoradiation and MRI-based brachytherapy. The prospective Boost arm accrued 71 patients to receive nodal boost either sequentially or simultaneously to an equivalent dose of 60 Gy. The control arm comprised 90 patients treated before this protocol period with no additional nodal boost. RESULT: Baseline patient and tumor characteristics were similar in both groups. All patients had at least one tumor dimension >5 cm at presentation, and 31% had para-aortic node involvement. With a median follow-up of 36 months (IQR:19-50.5), the overall 3-year Local control rate was 88.8%. The 3-year Regional control (93% vs. 80%, p = 0.035) was statistically better in the Boost arm. No nodal failure was observed in nodes <3 cc and < 2 cm, even in the No-boost arm. There was no significant difference in Disease-free survival (67.6% vs. 58.9%,p = 0.454) and Overall Survival (78.9% vs. 74.4%,p = 0.87) between the two arms. Incidence of acute or late toxicities did not differ significantly with nodal boost or the boost delivery technique. CONCLUSION: The addition of external radiation nodal boost to standard treatment of high-volume cervical cancer has improved pelvic control with an acceptable rate of toxicities. However, high systemic failures continue to pose a challenge in improving survival outcomes.

3.
J Surg Oncol ; 124(3): 308-316, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33893740

RESUMO

BACKGROUND AND OBJECTIVES: Neoadjuvant chemotherapy (NAT) for pancreatic adenocarcinoma (PDAC) is increasingly being utilized. However, a significant number of patients will experience early recurrence, possibly negating the benefit of surgery. We aimed to identify factors implicated in early disease recurrence. METHODS: A retrospective review of pancreaticoduodenectomies performed between 2005 and 2017 at our institution for PDAC following NAT was performed. A 6-month cut-off was used to stratify patients into early/late recurrence groups. Multivariate analysis was performed to identify predictors of recurrence. RESULTS: Of 273 patients, 64 (23%) developed early recurrence or died within 90 days of surgery. The median time to recurrence was 4 months (95% confidence interval [CI]: 2.2-4.3) in the early group versus 16 months (95% CI: 13.7-19.9) in the late group. The former had higher baseline and post-NAT Ca19-9 levels than the latter (472 vs. 153 IU/ml, p = 0.001 and 71 vs. 39 IU/ml, p = 0.005, respectively). A higher positive lymph node ratio significantly increased the risk of early recurrence (hazard ratio [HR]: 15.9, p < 0.001) while adjuvant chemotherapy was protective (HR: 0.4, p < 0.001). CONCLUSION: Our findings acknowledge the limitations of clinically measured factors used to ascertain response to NAT and underline the need for individualized molecular markers that take into consideration the specific tumor biology.


Assuntos
Recidiva Local de Neoplasia/patologia , Idoso , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Recidiva Local de Neoplasia/mortalidade , Estadiamento de Neoplasias , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Estudos Retrospectivos , Taxa de Sobrevida
4.
Ann Surg Oncol ; 28(11): 6264-6272, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33748894

RESUMO

INTRODUCTION: Neoadjuvant therapy (NAT) is a growing strategy for patients with resectable pancreatic ductal adenocarcinoma (PDAC). Elderly patients are at increased risk of treatment withdrawal due to functional decline, and the benefit of NAT in this cohort remains to be studied. OBJECTIVE: The objective of this study was to compare outcomes of elderly patients with resectable head PDAC who underwent NAT or a surgery-first (SF) approach. METHODS: All patients 75 years of age and older with radiographically resectable (National Comprehensive Cancer Network criteria) PDAC who underwent pancreaticoduodenectomy at a single institution from 2008 to 2017 were analyzed. Baseline characteristics and perioperative outcomes were compared between the SF and NAT cohorts. Recurrence-free survival and overall survival (OS) were analyzed by treatment strategy. RESULTS: Overall, 158 patients were identified: SF cohort = 90 (57%) and NAT cohort = 68 (43%). Patients in the SF cohort were older (80 vs. 78 years; p = 0.01) but there were no differences in preoperative comorbidities or frailty indices. SF patients had a trend toward higher rates of major complications (38% vs. 24%; p = 0.06) with higher Comprehensive Complication Index totals (20.9 vs. 20; p = 0.03). There were similar rates of adjuvant therapy. NAT was associated with significantly longer OS (24.6 vs. 17.6 months; p = 0.01) in both the intent-to-treat and resected cohorts. On multivariable analysis (MVA), NAT remained an independent predictor of OS (hazard ratio 0.60; p = 0.02). CONCLUSION: NAT is safe and effective for elderly patients with PDAC. This study suggests NAT is associated with fewer complications after surgery, equal rates of adjuvant therapy receipt, and increased OS over a surgery-first approach.


Assuntos
Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Adenocarcinoma/cirurgia , Idoso , Carcinoma Ductal Pancreático/cirurgia , Humanos , Terapia Neoadjuvante , Pancreatectomia , Neoplasias Pancreáticas/cirurgia
5.
Brachytherapy ; 20(1): 112-117, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32928683

RESUMO

PURPOSE: Image-guided adaptive brachytherapy (IGABT) recently has shown excellent clinical outcomes with superior local control and less toxicity. For IGABT, T2W (T2-weighted) MRI is the gold standard. However, studies have shown that target delineation with the same results in uncertainties, poor interobserver variabilities, and low conformity indices for high-risk clinical target volume contours. In this study, we investigate the role of diffusion-weighted imaging-derived apparent diffusion coefficient (ADC) maps to aid in IGABT. We also evaluated ADC from the baseline to brachytherapy. METHODS AND MATERIALS: Thirty selected patients were enrolled for this study, and two MRIs were taken at diagnosis and before brachytherapy. Patients were divided into two groups, Group 1 being patients with parametrial involvement before external beam radiotherapy and no parametrial involvement before brachytherapy. Group 2 included patients with parametrial involvement before external beam radiotherapy and persistent parametrial involvement before brachytherapy. ADC was measured at the center, edge, and 1 cm from the edge. RESULTS: The measured ADC increased from diagnosis to brachytherapy, and this increase was more for the patients in Group 1 than in Group 2. The mean TDadc (diagnosis ADC, center), TEadc (tumor edge ADC diagnosis), and T1cmDadc (1 cm from edge at diagnosis) were 0.884, 1.45, and 1.9 × 10-3 mm2/s, respectively. The TBadc (ADC at brachytherapy, center), TEBadc (tumor edge ADC at brachytherapy), and TE1cmBadc (1 cm from edge brachytherapy) were 1.2, 1.8, and 2.3 × 10-3 mm2/s, respectively, p-value <0.00001. No abnormal ADC was present outside the high-risk clinical target volume contours. CONCLUSION: MRI-based IGABT using T2W imaging essentially covers all functionally abnormal zones at brachytherapy. Diffusion-weighted imaging, along with ADC maps, should only be used as a supplement for target delineation.

6.
Rep Pract Oncol Radiother ; 25(6): 1011-1016, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33299382

RESUMO

Aim: To evaluate the difference between GTVBT (Gross Tumor Volume at Brachytherapy) and HR CTV (High Risk Clinical Tumor Volume) delineated with DWI and T2W MRI. To evaluate doses to organs at risk and targets from plans generated using T2W and DWI. Background: Functional imaging with DWI can improve cervical tumor distinction as it is more sensitive than T2W MRI even in detecting parametrial invasion. This study does a dosimetric comparison between a T2W and DWI based plan. Methods: Fifty carcinoma cervix patients were subjected to MRI based brachytherapy. T2W and a diffusion weighted sequence were acquired. Target delineation and brachytherapy planning was done on both T2W and DWI. Standard DVH parameters were recorded and the treatment was given using the plan generated from T2W images. Results: GTVBT and HRCTV contours on DWI were different when compared with T2W. Mean GTVBT volume on T2W and DWI was 5.25 and 5.23, respectively (p value 0.8). Mean HRCTV on T2W and DWI was 28.3 and 27 cc, respectively (p value 0.003). Planning on the above volumes resulted in a superior coverage in terms of HRCTV D90 and D100 for DWI based plan, HRCTV D90 - 735.1 and 741 cGy for T2W and DWI, respectively (p value 0.006), HRCTV D100 - 441.05 and 444.5 for T2W and DWI plans, respectively (p value = 0.006). Doses to the OAR were not significantly increased. Conclusion: GEC ESTRO based contouring guidelines cover all the functionally abnormal areas on DWI. DWI should only be used as a supplement to T2W for contouring target volumes.

7.
Brachytherapy ; 19(1): 73-80, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31813739

RESUMO

PURPOSE: The aim of the study was to evaluate the impact of image-based combined intracavitary-interstitial brachytherapy (IC-ISBT) using a transperineal template in locally advanced cervical cancer treatment. METHODS AND MATERIALS: A total of 94 patients of cervical cancer stage IIB-IVA underwent image-based transperineal interstitial brachytherapy without tandem (ISBT) or with tandem (IC-ISBT) between June 2008 and June 2018 at our institution. After pelvic chemoradiation, 42 patients underwent ISBT and 52 IC-ISBT. Dosimetric data, clinical response, and toxicity records of these patients were reviewed. RESULTS: Clinical stage distribution was as follows: IIB: 22.4% (21), IIIA: 10.6% (10), IIIB: 56.4% (53), and IVA: 10.6% (10). Mean high-risk clinical target volume was 75.72 cc, and mean cumulative equivalent of 2 Gy per fraction for high-risk clinical target volume was 81 Gy. The median followup was 35.5 months. Overall 3- and 5-year local control, disease-free survival (DFS), and overall survival (OS) were 84% and 84%, 69.1% and 62.9%, and 80.9% and 71.5%, respectively. Local control (90.4% vs. 76.2%; p = 0.048) and DFS (78.8% vs. 57.1%; p = 0.04) were significantly better in the patients of IC-ISBT arm. IC-ISBT (hazard ratio: 0.763; 95% confidence interval 0.217, 1.38; p = 0.046) and D90 dose >85 Gy (hazard ratio: 0.957; 95% confidence interval 0.927, 1.07; p = 0.037) were predictors of better DFS on univariate analysis. Overall survival was not affected significantly by any of the factors. Grade 3 and 4 late complications were recorded in 3.2% (3) of patients and were similar in both arms (p = 0.86). However, the mean rectum 2 cc dose was significantly lower in the IC-ISBT arm (p = 0.038). CONCLUSIONS: Combined IC-ISBT is a safe and effective approach to treat ICBT unsuitable cases. It integrates the benefits of ICBT to the adaptability of ISBT around various targets and should be practiced whenever feasible to provide superior outcomes in locally advanced cervical cancer.


Assuntos
Braquiterapia/métodos , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/radioterapia , Adulto , Idoso , Braquiterapia/efeitos adversos , Quimiorradioterapia , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Órgãos em Risco , Períneo , Modelos de Riscos Proporcionais , Doses de Radiação , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador , Radioterapia Guiada por Imagem , Reto , Taxa de Sobrevida , Fatores de Tempo , Neoplasias do Colo do Útero/tratamento farmacológico
8.
J Surg Res ; 231: 304-308, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30278945

RESUMO

BACKGROUND: Safety of pancreaticoduodenectomy has improved significantly in the past 3 decades. Current inpatient and 30-d mortality rates are low. However, incidence and causes of 90-d and 1-y mortality are poorly defined and largely unexplored. METHODS: All patients who had pancreaticoduodenectomy between 2007 and 2016 were included in this single institution, retrospective cohort study. Distributions of pancreaticoduodenectomy-specific morbidity and cause-specific mortality were compared between early (within 90 d) and late (91-365 d) postoperative recovery periods. RESULTS: A total of 551 pancreaticoduodenectomies were performed during the study period. Of these, 6 (1.1%), 20 (3.6%), and 91 (16.5%) patients died within 30, 90, and 365 d after pancreaticoduodenectomy, respectively. Causes of early and late mortality varied significantly (all P ≤ 0.032). The most common cause of death within 90 d was due to multisystem organ failure from sepsis or aspiration in 9 (45%) patients, followed by post-pancreatectomy hemorrhage in 5 (25%) patients, and cardiopulmonary arrest from myocardial infarction or pulmonary embolus in 3 (15%) patients. In contrast, recurrent cancer was the most common cause of death in 46 (65%) patients during the late postoperative period between 91 and 365 d. Mortality from failure to thrive and debility was similar between early and late postoperative periods (15% versus 19.7%, P = 0.76). CONCLUSIONS: Most quality improvement initiatives in patients selected for pancreaticoduodenectomy have focused on reduction of technical complications and improvement of early postoperative mortality. Further reduction in postoperative mortality after pancreaticoduodenectomy can be achieved by improving patient selection, mitigating postoperative malnutrition, and optimizing preoperative cancer staging and management strategies.


Assuntos
Causas de Morte , Pancreaticoduodenectomia/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Pancreaticoduodenectomia/métodos , Seleção de Pacientes , Assistência Perioperatória/métodos , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
9.
PLoS One ; 13(9): e0203841, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30212577

RESUMO

BACKGROUND: Pancreatic fistula remains a morbid complication after pancreatectomy. Since the proposed mechanism of pancreatic fistula is different between pancreaticoduodenectomy and distal pancreatectomy, we hypothesized that pancreatic gland texture and duct size are not associated with pancreatic fistula after distal pancreatectomy. METHODS: All patients ≥18 years in the 2014-15 American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) targeted pancreatectomy dataset were linked with the ACS NSQIP Public Use File (PUF). Pancreatic duct size (<3 mm, 3-6 mm, >6 mm) and pancreatic gland texture (hard, intermediate, soft) were categorized. Separate multivariable analyses were performed to evaluate associations between pancreatic duct size and gland texture after pancreaticoduodenectomy and distal pancreatectomy. RESULTS: A total of 9366 patients underwent pancreaticoduodenectomy or distal pancreatectomy during the study period. Proportion of pancreatic fistula was similar after distal pancreatectomy (606 of 3132, 19.4%) and pancreaticoduodenectomy (1163 of 6335, 18.4%, p = 0.245). Both pancreatic gland texture and duct size were significantly associated with pancreatic fistula after pancreaticoduodenectomy (p<0.001). However, there was no association between pancreatic fistula and gland texture or duct size (all p≥0.169) after distal pancreatectomy. Operative approach (minimally invasive versus open) was not associated with pancreatic fistula after distal pancreatectomy (p = 0.626). Patients with pancreatic fistula after distal pancreatectomy had increased rate of postoperative complications including longer length of stay, higher rates of readmission and reoperation compared to patients who did not have a pancreatic fistula (all p<0.001). CONCLUSIONS: Unlike among patients who had pancreaticoduodenectomy, pancreatic gland texture and duct size are not associated with development of pancreatic fistula following distal pancreatectomy. Other clinical factors should be considered in this patient population.


Assuntos
Pâncreas/patologia , Pâncreas/cirurgia , Pancreatectomia , Fístula Pancreática/cirurgia , Pancreaticoduodenectomia , Complicações Pós-Operatórias/patologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão
10.
Gynecol Oncol ; 150(3): 420-425, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30017538

RESUMO

PURPOSE: The purpose of this series is to study the effectiveness of MRI based image-guided brachytherapy (IGBT) in Indian patients with cervical cancer who mostly present in later stages with bulky diseases. PATIENTS AND METHODS: 151 cervical cancer patients treated at our institution in last four years, with definitive chemoradiation followed by MRI-based brachytherapy were reviewed. With median follow up of 26 months, Kaplan Meier estimates at two years were calculated for local control (LC), pelvic control (PC), disease-free survival (DFS) and overall survival (OS). Also, severe late sequelae were reported. RESULTS: The patients predominantly presented with locally advanced cervical cancer in FIGO stages IIB (53.6%) and IIIB (23.2%). Tumour dimensions at diagnosis were ≥5 cm in 56.3% and pelvic nodal involvement was found in 38.4% of the patients. 94% of the patients received curative chemoradiation. Mean HRCTV volume at the time of brachytherapy was 42.2 ±â€¯19 cm3 and mean cumulative dose to HRCTV was 78.9 ±â€¯5.6 Gy. Overall LC, PC, DFS and OS at 2 years were 88.7%, 88.1%, 82.2% and 94% respectively. The predictors for local failure were FIGO stage (p = 0.002) and tumour size at diagnosis (p = 0.009). Late grade 3-4 bladder and bowel toxicities were observed in 3.8% of the patients. CONCLUSION: Our review demonstrates that IGBT is an effective strategy to improve locoregional control with limited long-term sequelae in patients with locally advanced extensive cervical cancer in the setting of a developing country.


Assuntos
Adenocarcinoma/terapia , Braquiterapia/métodos , Carcinoma de Células Escamosas/terapia , Neoplasias do Colo do Útero/terapia , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/secundário , Adulto , Idoso , Braquiterapia/efeitos adversos , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/secundário , Quimiorradioterapia , Intervalo Livre de Doença , Fracionamento da Dose de Radiação , Feminino , Seguimentos , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Radiografia Intervencionista , Taxa de Sobrevida , Tomografia Computadorizada por Raios X , Carga Tumoral , Neoplasias do Colo do Útero/diagnóstico por imagem , Neoplasias do Colo do Útero/patologia
11.
J Gastrointest Surg ; 22(4): 661-667, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29247421

RESUMO

BACKGROUND: Despite technical advances, bile leak remains a significant complication after hepatectomy. The current study uses a targeted multi-institutional dataset to characterize perioperative factors that are associated with bile leakage after hepatectomy to better understand the impact of bile leak on morbidity and mortality. METHODS: Adult patients in the 2014-2015 ACS NSQIP targeted hepatectomy dataset were linked to the ACS NSQIP PUF dataset. Bivariable and multivariable regression analyses were used to assess the associations between clinical factors and post-hepatectomy bile leak. RESULTS: Of 6859 patients, 530 (7.7%) had a postoperative bile leak. Proportion of bile leaks was significantly greater in patients after major compared to minor hepatectomy (12.6 vs. 5.1%, p < 0.001). The proportion of patients with bile leak was significantly greater in patients after major hepatectomy who had concomitant enterohepatic reconstruction (31.8 vs. 10.1%, p < 0.001). Postoperative mortality was significantly greater in patients with bile leaks (6.0 vs. 1.7%, p < 0.001). After adjusting for significant covariates, bile leak was independently associated with increased risk of postoperative morbidity (OR = 4.55; 95% CI 3.72-5.56; p < 0.001). After adjusting for significant effects of postoperative complications, liver failure, and reoperation (all p<0.001), bile leak was not independently associated with increased risk of postoperative mortality (p = 0.262). CONCLUSION: Major hepatectomy and enterohepatic biliary reconstruction are associated with significantly greater rates of bile leak after liver resection. Bile leak is independently associated with significant postoperative morbidity. Mitigation of bile leak is critical in reducing morbidity and mortality after liver resection.


Assuntos
Fístula Anastomótica/etiologia , Fístula Anastomótica/mortalidade , Hepatectomia/efeitos adversos , Hepatectomia/mortalidade , Idoso , Bile , Feminino , Hepatectomia/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Reconstrutivos/estatística & dados numéricos , Fatores de Risco , Estados Unidos/epidemiologia
12.
J Leukoc Biol ; 101(1): 329-338, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27493244

RESUMO

The liver contains 2 transcriptionally distinct group 1 ILC subsets: CD49a+ ILC1s and CD49b+ NK cells. However, little is known about how group 1 ILCs contribute to hepatic immune responses. Therefore, we characterized murine liver-resident group 1 ILCs and found that CD49a+ ILC1s express high levels of the inhibitory receptor NKG2A and localize near DCs in perivascular spaces surrounding the portal triads. Upon hepatic viral infection, NKG2A signaling in group 1 ILCs, especially in CD49a+ ILC1s, inhibits CXCL9 expression required for robust accumulation of IFN-γ+CD49b+ NK cells. As a consequence, NKG2A-/- mice showed increased numbers of IFN-γ-producing NK cells that preferentially activate liver CD103+ DCs, leading to the sustained proliferation of adoptively transferred, virus-specific CD8+ T cells. Collectively, these data suggest that group 1 ILCs play a role in maintaining the liver as a tolerogenic site by limiting the recruitment of peripheral NK cells during the early phase of viral infection. Furthermore, our findings implicate that the inhibition of NKG2A signaling on group 1 ILCs may be a novel vaccine strategy to induce robust CD8+ T cell responses against persistent liver pathogens.


Assuntos
Antivirais/imunologia , Linfócitos T CD8-Positivos/imunologia , Apresentação Cruzada/imunologia , Imunidade Inata , Fígado/citologia , Linfócitos/citologia , Adenoviridae/metabolismo , Animais , Antígenos CD/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Contagem de Células , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Quimiocina CXCL9/biossíntese , Fatores Quimiotáticos/farmacologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Epitopos/imunologia , Feminino , Imunidade Inata/efeitos dos fármacos , Cadeias alfa de Integrinas/metabolismo , Integrina alfa1/metabolismo , Interferon gama/metabolismo , Células Matadoras Naturais/imunologia , Linfócitos/efeitos dos fármacos , Masculino , Camundongos , Subfamília C de Receptores Semelhantes a Lectina de Células NK/deficiência , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo
13.
PLoS One ; 11(6): e0156996, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27280294

RESUMO

Hepatitis C is a chronic liver disease that contributes to progressive metabolic dysfunction. Infection of hepatocytes by hepatitis C virus (HCV) results in reprogramming of hepatic and serum lipids. However, the specific contribution of these distinct pools of lipids to HCV infection remains ill defined. In this study, we investigated the role of hepatic lipogenesis in HCV infection by targeting the rate-limiting step in this pathway, which is catalyzed by the acetyl-CoA carboxylase (ACC) enzymes. Using two structurally unrelated ACC inhibitors, we determined that blockade of lipogenesis resulted in reduced viral replication, assembly, and release. Supplementing exogenous lipids to cells treated with ACC inhibitors rescued HCV assembly with no effect on viral replication and release. Intriguingly, loss of viral RNA was not recapitulated at the protein level and addition of 2-bromopalmitate, a competitive inhibitor of protein palmitoylation, mirrored the effects of ACC inhibitors on reduced viral RNA without a concurrent loss in protein expression. These correlative results suggest that newly synthesized lipids may have a role in protein palmitoylation during HCV infection.


Assuntos
Ácidos Graxos/metabolismo , Hepacivirus/fisiologia , Hepatite C/virologia , Hepatócitos/metabolismo , Lipogênese/fisiologia , Acetil-CoA Carboxilase/antagonistas & inibidores , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Hepatite C/metabolismo , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Humanos , RNA Viral/genética , Replicação Viral/efeitos dos fármacos
14.
Immune Netw ; 16(3): 147-58, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27340383

RESUMO

The liver lies at the intersection of multiple metabolic pathways and consequently plays a central role in lipid metabolism. Pathological disturbances in hepatic lipid metabolism are characteristic of chronic metabolic diseases, such as obesity-mediated insulin resistance, which can result in nonalcoholic fatty liver disease (NAFLD). Tissue damage induced in NAFLD activates and recruits liver-resident and non-resident immune cells, resulting in nonalcoholic steatohepatitis (NASH). Importantly, NASH is associated with an increased risk of significant clinical sequelae such as cirrhosis, cardiovascular diseases, and malignancies. In this review, we describe the immunopathogenesis of NASH by defining the known functions of immune cells in the progression and resolution of disease.

15.
Hepatology ; 63(3): 799-812, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26662852

RESUMO

UNLABELLED: Nonalcoholic steatohepatitis (NASH) affects 3%-5% of the U.S. population, having severe clinical complications to the development of fibrosis and end-stage liver diseases, such as cirrhosis and hepatocellular carcinoma. A critical cause of NASH is chronic systemic inflammation promoted by innate immune cells, such as liver macrophages (Mϕ) and natural killer (NK) cells. However, little is known about how the crosstalk between Mϕ and NK cells contributes to regulate NASH progression to fibrosis. In this report, we demonstrate that NKp46(+) cells play an important role in preventing NASH progression to fibrosis by regulating M1/M2 polarization of liver Mϕ. Using a murine model of NASH, we demonstrate that DX5(+)NKp46(+) NK cells are increased during disease and play a role in polarizing Mϕ toward M1-like phenotypes. This NK's immunoregulatory function depends on the production of interferon-gamma (IFN-γ), but not by granzyme-mediated cytolytic activity. Notably, depletion of NKp46(+) cells promotes the development of fibrosis with increased expression of profibrogenic genes as well as skewed M2 Mϕ phenotypes in hepatic tissues. CONCLUSIONS: NK cell-derived IFN-γ may be essential for maintaining a balanced inflammatory environment that promotes tissue integrity and limiting NASH progression to fibrosis.


Assuntos
Células Matadoras Naturais/fisiologia , Fígado/imunologia , Macrófagos/fisiologia , Hepatopatia Gordurosa não Alcoólica/imunologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Morte Celular , Colágeno/metabolismo , Progressão da Doença , Feminino , Fibrose , Células Estreladas do Fígado/metabolismo , Imunidade Inata , Interferon gama/metabolismo , Fígado/patologia , Ativação de Macrófagos , Camundongos Endogâmicos C57BL , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Fenótipo , Receptor Cross-Talk , Linfócitos T Reguladores
16.
J Biol Chem ; 289(8): 5310-9, 2014 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-24385435

RESUMO

Hepatitis C virus (HCV) infection in hepatocytes stimulates innate antiviral responses including the production of type III interferons (IFN-λ), including IL-28A, IL-28B, and IL-29. However, the molecular mechanism(s) regulating the expression of IFN-λ genes in HCV-infected hepatocytes remains undefined. In this study, we examined regulatory elements involved in the induction of IFN-λ genes following HCV infection in hepatocytes and further determined the binding of specific transcription factor(s) to promoter regions of IFN-λ genes. Our studies reveal that the regulatory portion for IL-28A, IL-28B, and IL-29 genes is localized to a 1-kb region in their respective promoters. Notably, interferon regulatory factor (IRF)-3 and -7 are the key transcriptional factors for the induction of IL-28A and IL-28B genes, whereas NF-κB is an additional requirement for the induction of the IL-29 gene. Ligation of Toll-like receptors (TLR) 3, 7, 8, and 9, which also activate IRFs and NF-κB, resulted in more robust production of IFN-λ than that observed with HCV infection, verifying the importance of TLR pathways in IFN-λ production. Furthermore, the addition of IFN-λ to HCV-infected hepatocytes decreased viral replication and produced a concurrent reduction in microRNA-122 (miR-122). The decrease in viral replication was enhanced by the co-administration of IFN-λ and miR-122 inhibitor (miRIDIAN), suggesting that such combinatorial therapies may be beneficial for the treatment of chronic HCV infection.


Assuntos
Regulação da Expressão Gênica , Hepacivirus/fisiologia , Hepatócitos/virologia , Fator Regulador 3 de Interferon/metabolismo , Fator Regulador 7 de Interferon/metabolismo , Interleucinas/genética , NF-kappa B/metabolismo , Células Cultivadas , Hepatite C/genética , Hepatite C/virologia , Hepatócitos/metabolismo , Humanos , Interferons , Interleucinas/metabolismo , Ligantes , Fígado/metabolismo , Fígado/patologia , Fígado/virologia , MicroRNAs/metabolismo , Regiões Promotoras Genéticas/genética , Ligação Proteica , Transcrição Genética , Ativação Transcricional/genética
17.
Immunol Rev ; 255(1): 210-21, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23947357

RESUMO

Myeloid derived suppressor cells (MDSCs) are immature cells of myeloid origin, frequently found in tumor microenvironments and in the blood of cancer patients. In recent years, MDSCs have also been found in non-cancer settings, including a number of viral infections. The evasion of host immunity employed by viruses to establish viral persistence strikingly parallels mechanisms of tumor escape, prompting investigations into the generation and function of MDSCs in chronic viral infections. Importantly, analogous to the tumor microenvironment, MDSCs effectively suppress antiviral host immunity by limiting the function of several immune cells including T cells, natural killer cells, and antigen-presenting cells. In this article, we review studies on the mechanisms of MDSC generation, accumulation, and survival in an effort to understand their emergent importance in viral infections. We include a growing list of viral infections in which MDSCs have been reported. Finally, we discuss how MDSCs might play a role in establishing chronic viral infections and identify potential therapeutics that target MDSCs.


Assuntos
Células Mieloides/imunologia , Viroses/imunologia , Vírus/imunologia , Animais , Epigênese Genética , Humanos , Tolerância Imunológica , Imunoterapia , Células Mieloides/citologia , Células Mieloides/metabolismo , Viroses/genética , Viroses/metabolismo , Viroses/terapia
18.
Cancer Prev Res (Phila) ; 3(4): 438-46, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20332301

RESUMO

Association of chronic inflammation with an increased risk of cancer is well established, but the contributions of innate versus adaptive immunity are not fully delineated. There has furthermore been little consideration of the role played by chronic inflammation-associated antigens, including cancer antigens, and the possibility of using them as vaccines to lower the cancer risk. We studied the human tumor antigen MUC1 which is abnormally expressed in colon cancers and also in inflammatory bowel disease (IBD) that gives rise to colitis-associated colon cancer (CACC). Using our new mouse model of MUC1(+) IBD that progresses to CACC, interleukin-10 knockout mice crossed with MUC1 transgenic mice, we show that vaccination against MUC1 delays IBD and prevents progression to CACC. One mechanism is the induction of MUC1-specific adaptive immunity (anti-MUC1 IgG and anti-MUC1 CTL), which seems to eliminate abnormal MUC1(+) cells in IBD colons. The other mechanism is the change in the local and the systemic microenvironments. Compared with IBD in vaccinated mice, IBD in control mice is dominated by larger numbers of neutrophils in the colon and myeloid-derived suppressor cells in the spleen, which can compromise adaptive immunity and facilitate tumor growth. This suggests that the tumor-promoting microenvironment of chronic inflammation can be converted to a tumor-inhibiting environment by increasing adaptive immunity against a disease-associated antigen.


Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/uso terapêutico , Neoplasias do Colo/prevenção & controle , Doenças Inflamatórias Intestinais/imunologia , Mucina-1/imunologia , Animais , Vacinas Anticâncer/imunologia , Separação Celular , Neoplasias do Colo/imunologia , Modelos Animais de Doenças , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Doenças Inflamatórias Intestinais/complicações , Interleucina-10/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Mucina-1/genética , Mucina-1/metabolismo , Lesões Pré-Cancerosas/imunologia
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