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1.
Cancer Gene Ther ; 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31155611

RESUMO

Effective chimeric antigen receptor-modified T-cell (CAR-T) therapy for liver metastases (LM) will require innovative solutions to ensure efficient delivery and minimization of systemic toxicity. We previously demonstrated the safety of CAR-T hepatic artery infusions (HAI). We subsequently conducted the phase 1b HITM-SIR trial, in which six patients (pts) with CEA+ LM received anti-CEA CAR-T HAIs and selective internal radiation therapy (SIRT). The primary endpoint was safety with secondary assessments of biologic activity. Enrolled pts had a mean LM size of 6.4 cm, 4 pts had >10 LM, and pts received an average of two lines of prior systemic therapy. No grade 4 or 5 toxicities were observed, and there were no instances of severe cytokine-release syndrome (CRS) or neurotoxicity. The mean transduction efficiency was 60.4%. Following CAR-T HAI, reduced levels of GM-CSF-R, IDO, and PD-L1 were detected in LM, and serum CEA levels were stable or decreased in all subjects. Median survival time was 8 months (mean 11, range 4-31). Anti-CEA CAR-T HAI with subsequent SIRT was well tolerated, and biologic responses were demonstrated following failure of conventional therapy. HAI of CAR-T was once again confirmed not to be associated with severe CRS or neurotoxicity.

2.
JAMA Oncol ; : e184060, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30383140

RESUMO

Importance: Three years of adjuvant imatinib mesylate therapy is associated with reduced recurrence rates and improved overall survival in patients with high-risk primary gastrointestinal stromal tumor (GIST) compared with patients who receive 1 year of treatment. The impact of a longer duration of therapy is unknown. Objective: To determine whether adjuvant treatment for primary GIST with imatinib for 5 years is tolerable and efficacious. Design, Setting, and Participants: This prospective, single-arm, phase 2 clinical trial (Postresection Evaluation of Recurrence-free Survival for Gastrointestinal Stromal Tumors With 5 Years of Adjuvant Imatinib [PERSIST-5]) included adult patients with primary GIST (expressing KIT) at 21 US institutions who underwent a macroscopically complete resection and were at intermediate or high risk of recurrence, defined as primary GIST at any site measuring 2 cm or larger with 5 or more mitoses per 50 high-power field or nongastric primary GIST measuring 5 cm or larger. Data were collected from August 5, 2009, through December 20, 2016. Interventions: Imatinib, 400 mg once daily, orally for 5 years or until discontinuation of therapy because of progression or intolerance. Main Outcomes and Measures: The primary end point was recurrence-free survival (RFS). The secondary end point was overall survival. Results: Of the 91 patients enrolled, 48 (53%) were men with a median age of 60 years (range, 30-90 years). Median tumor size was 6.5 cm (range, 2.3-30.0 cm). Median treatment duration was 55.1 months (range, 0.5-60.6 months); 46 patients (51%) completed 5 years of imatinib therapy. Estimated 5-year RFS was 90% (95% CI, 80%-95%), and overall survival was 95% (95% CI, 86%-99%). Recurrence was noted in 7 patients: 1 had disease recur while receiving imatinib (PDGFRA D842V mutation) and died; 6 had disease recur after discontinuation of imatinib therapy. Two additional deaths were unrelated to treatment or tumor progression. Forty-five patients (49%) stopped treatment early because of patient choice (10 [21%]), adverse events (15 [16%]), or other (11 [12%]). All 91 patients experienced at least 1 adverse event, and 17 (19%) experienced grade 3 or 4 adverse events. Conclusions and Relevance: In this first adjuvant trial, to our knowledge, of patients with resected primary GIST who received 5 years of imatinib therapy, no patient with imatinib-sensitive mutations had disease recur during therapy. For patients in whom disease recurred, recurrence was within 2 years of discontinuation of imatinib therapy. Approximately half of the patients discontinued treatment early, most commonly because of patient choice, thus emphasizing the importance of close clinical monitoring to continue imatinib treatment for patients at appropriate risk. Trial Registration: ClinicalTrials.gov identifier: NCT00867113.

3.
Oncogene ; 2018 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-30158673

RESUMO

Immunosuppressive myeloid-derived suppressor cells (MDSC) subvert antitumor immunity and limit the efficacy of chimeric antigen receptor T cells (CAR-T). Previously, we reported that the GM-CSF/JAK2/STAT3 axis drives liver-associated MDSC (L-MDSC) proliferation and blockade of this axis rescued antitumor immunity. We extended these findings in our murine liver metastasis (LM) model, by treating tumor-bearing mice with STAT3 inhibitors (STATTIC or BBI608) to further our understanding of how STAT3 drives L-MDSC suppressive function. STAT3 inhibition caused significant reduction of tumor burden as well as L-MDSC frequencies due to decrease in pSTAT3 levels. L-MDSC isolated from STATTIC or BBI608-treated mice had significantly reduced suppressive function. STAT3 inhibition of L-MDSC was associated with enhanced antitumor activity of CAR-T. Further investigation demonstrated activation of apoptotic signaling pathways in L-MDSC following STAT3 inhibition as evidenced by an upregulation of the pro-apoptotic proteins Bax, cleaved caspase-3, and downregulation of the anti-apoptotic protein Bcl-2. Accordingly, there was also a decrease of pro-survival markers, pErk and pAkt, and an increase in pro-death marker, Fas, with activation of downstream JNK and p38 MAPK. These findings represent a previously unrecognized link between STAT3 inhibition and Fas-induced apoptosis of MDSCs. Our findings suggest that inhibiting STAT3 has potential clinical application for enhancing the efficacy of CAR-T cells in LM through modulation of L-MDSC.

4.
Hepatobiliary Surg Nutr ; 6(3): 154-161, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28652998

RESUMO

BACKGROUND: The primary objective of our study was to assess the association of primary tumor lymph node ratio (LNR) in stage IV colorectal adenocarcinomas (CRC) with overall survival (OS) and the extent of metastatic disease in the liver. METHODS: We analyzed data on 53 stage IV CRC patients who underwent surgical resection of the primary tumor. The median LNR of 0.25 was used to stratify patients into high LNR (H-LNR) and low LNR (L-LNR) groups. Statistical comparison was performed using chi square test and multiple regression models. OS was calculated using the Kaplan-Meier (KM) method while cox regression was used for multivariate analysis. RESULTS: H-LNR status was associated with the presence of >3 liver metastases (LM) [odds ratio (OR): 2.43, P=0.047] and bilobar LM (OR: 3.94, P=0.039). The OS in H-LNR patients was significantly worse in the entire cohort compared to L-LNR (9% vs. 34% at 3 years, P=0.027). The 5-year OS in patients undergoing liver resection for LM was also significantly worse in the H-LNR group (0% vs. 37%, P=0.013). LNR was independently associated with survival on multivariate analysis [HR: 2.63; 95% confidence intervals (CI), 1.13-6.14; P=0.025]. CONCLUSIONS: In stage IV CRC, LNR is associated with the extent of hepatic tumor burden and was an independent predictor of survival in patients undergoing liver resection.

5.
J Leukoc Biol ; 102(2): 201-208, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28546503

RESUMO

Chimeric antigen receptor expressing T cells (CAR-T) are a promising form of immunotherapy, but the influence of age-related immune changes on CAR-T production remains poorly understood. We showed that CAR-T cells from geriatric donors (gCAR-T) are functionally impaired relative to CAR-T from younger donors (yCAR-T). Higher transduction efficiencies and improved cell expansion were observed in yCAR-T cells compared with gCAR-T. yCAR-T demonstrated significantly increased levels of proliferation and signaling activation of phosphorylated (p)Erk, pAkt, pStat3, and pStat5. Furthermore, yCAR-T contained higher proportions of CD4 and CD8 effector memory (EM) cells, which are known to have enhanced cytolytic capabilities. Accordingly, yCAR-T demonstrated higher levels of tumor antigen-specific cytotoxicity compared with gCAR-T. Enhanced tumor killing by yCAR-T correlated with increased levels of perforin and granzyme B. yCAR-T had increased α5ß1 integrin expression, a known mediator of retroviral transduction. We found that treatment with M-CSF or TGF-ß1 rescued the impaired transduction efficiency of the gCAR-T by increasing the α5ß1 integrin expression. Neutralization of α5ß1 confirmed that this integrin was indispensable for CAR expression. Our study suggests that the increase of α5ß1 integrin expression levels enhances CAR expression and thereby improves tumor killing by gCAR-T.


Assuntos
Envelhecimento/imunologia , Imunoterapia/métodos , Integrina alfa5beta1/biossíntese , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Adulto , Idoso , Western Blotting , Quimera , Citotoxicidade Imunológica/imunologia , Feminino , Citometria de Fluxo , Humanos , Integrina alfa5beta1/imunologia , Ativação Linfocitária/imunologia , Masculino , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T/metabolismo , Adulto Jovem
6.
J Surg Res ; 205(1): 198-203, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27621019

RESUMO

BACKGROUND: Surgical resection is the only curative option for patients with colorectal liver metastases (CRLM). The objective of our study was to identify factors associated with failure to refer patients with CRLM to a surgeon with oncologic and hepatobiliary expertise. MATERIALS AND METHODS: Data were retrospectively reviewed on 75 patients with CRLM treated at our institution. Patients were divided into referred and nonreferred groups for comparison. Quantitative assessment of association was tabulated using the odds ratio (OR). Statistical comparison was performed using the chi-square test and multiple regression models. Overall survival (OS) was calculated using the Kaplan-Meier method. Multivariate analysis was done using Cox regression. RESULTS: Factors independently associated with lower surgical referral rates included age ≥ 65 y (OR 0.29, 95% confidence interval [CI] 0.09-0.89, P = 0.032), bilobar CRLM (OR 0.35, 95% CI 0.09-0.97, P = 0.048), and presence of >3 CRLM (OR 0.33, 95% CI 0.11-0.94, P = 0.044). The 5-y OS for referred patients was 33% compared with only 8% in patients who were not referred (P < 0.001). Factors independently associated with worse OS included age ≥ 65 y (hazard ratio [HR] 2.01, 95% CI 1.12-3.59, P = 0.019), bilobar hepatic metastases (HR 3.04, 95% CI 1.62-5.70, P < 0.001), and the presence of extrahepatic metastases (HR 2.11, 95% CI 1.02-4.16, P = 0.011). Referral to a surgeon was associated with improved OS (HR 0.42, 95% CI 0.24-0.74, P = 0.003). CONCLUSIONS: Failure to refer CRLM patients for surgical evaluation is associated with aggressive biologic features that do not necessarily preclude resection. Determination of resectability should be made with input from appropriately trained surgical experts.


Assuntos
Adenocarcinoma/secundário , Neoplasias Colorretais/patologia , Cirurgia Geral , Neoplasias Hepáticas/secundário , Encaminhamento e Consulta/estatística & dados numéricos , Adenocarcinoma/mortalidade , Adenocarcinoma/cirurgia , Idoso , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Rhode Island/epidemiologia
7.
Clin Cancer Res ; 21(14): 3149-59, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-25850950

RESUMO

PURPOSE: Chimeric antigen receptor-modified T cells (CAR-T) have demonstrated encouraging results in early-phase clinical trials. Successful adaptation of CAR-T technology for CEA-expressing adenocarcinoma liver metastases, a major cause of death in patients with gastrointestinal cancers, has yet to be achieved. We sought to test intrahepatic delivery of anti-CEA CAR-T through percutaneous hepatic artery infusions (HAIs). EXPERIMENTAL DESIGN: We conducted a phase I trial to test HAI of CAR-T in patients with CEA(+) liver metastases. Six patients completed the protocol, and 3 received anti-CEA CAR-T HAIs alone in dose-escalation fashion (10(8), 10(9), and 10(10) cells). We treated an additional 3 patients with the maximum planned CAR-T HAI dose (10(10) cells × 3) along with systemic IL2 support. RESULTS: Four patients had more than 10 liver metastases, and patients received a mean of 2.5 lines of conventional systemic therapy before enrollment. No patient suffered a grade 3 or 4 adverse event related to the CAR-T HAIs. One patient remains alive with stable disease at 23 months following CAR-T HAI, and 5 patients died of progressive disease. Among the patients in the cohort that received systemic IL2 support, CEA levels decreased 37% (range, 19%-48%) from baseline. Biopsies demonstrated an increase in liver metastasis necrosis or fibrosis in 4 of 6 patients. Elevated serum IFNγ levels correlated with IL2 administration and CEA decreases. CONCLUSIONS: We have demonstrated the safety of anti-CEA CAR-T HAIs with encouraging signals of clinical activity in a heavily pretreated population with large tumor burdens. Further clinical testing of CAR-T HAIs for liver metastases is warranted.


Assuntos
Adenocarcinoma/terapia , Quimioterapia do Câncer por Perfusão Regional/métodos , Imunoterapia/métodos , Neoplasias Hepáticas/terapia , Receptores de Antígenos de Linfócitos T/administração & dosagem , Linfócitos T/transplante , Adenocarcinoma/secundário , Idoso , Feminino , Neoplasias Gastrointestinais/patologia , Neoplasias Gastrointestinais/terapia , Humanos , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade
8.
J Leukoc Biol ; 94(4): 813-23, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23883516

RESUMO

Biliary obstruction is a common clinical problem that is associated with intrahepatic inflammation and impaired immunity. PD-1 is well known to mediate T cell dysfunction but has been reported to promote and attenuate acute inflammation in various injury models. With the use of a well-established murine model of BDL, we studied the effects of intrahepatic PD-1 expression on LTC function, inflammation, and cholestasis. Following BDL, PD-1 expression increased significantly among LTCs. Increased PD-1 expression following BDL was associated with decreased LTC proliferation and less IFN-γ production. Elimination of PD-1 expression resulted in significantly improved proliferative capacity among LTC following BDL, in addition to a more immunostimulatory cytokine profile. Not only was LTC function rescued in PD-1(-/-) mice, but also, the degrees of biliary cell injury, cholestasis, and inflammation were diminished significantly compared with WT animals following BDL. PD-1-mediated acute inflammation following BDL was associated with expansions of intrahepatic neutrophil and Th17 cell populations, with the latter dependent on IL-6. PD-1 blockade represents an attractive strategy for reversing intrahepatic immunosuppression while limiting inflammatory liver damage.


Assuntos
Colestase/imunologia , Colestase/fisiopatologia , Inflamação/imunologia , Fígado/patologia , Neutrófilos/patologia , Receptor de Morte Celular Programada 1/metabolismo , Células Th17/patologia , Animais , Ductos Biliares/metabolismo , Ductos Biliares/patologia , Proliferação de Células , Colestase/complicações , Colestase/patologia , Inflamação/complicações , Inflamação/patologia , Interleucina-6/metabolismo , Icterícia/complicações , Icterícia/imunologia , Icterícia/patologia , Icterícia/fisiopatologia , Ligadura , Fígado/imunologia , Fígado/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/imunologia , Transdução de Sinais , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Regulação para Cima
9.
J Transl Med ; 11: 46, 2013 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-23433424

RESUMO

BACKGROUND: Imatinib mesylate is an effective treatment for metastatic gastrointestinal stromal tumor (GIST). However, most patients eventually develop resistance and there are few other treatment options. Immunotherapy using genetically modified or designer T cells (dTc) has gained increased attention for several malignancies in recent years. The aims of this study were to develop and test novel anti-KIT dTc engineered to target GIST cells. METHODS: Human anti-KIT dTc were created by retroviral transduction with novel chimeric immune receptors (CIR). The gene for stem cell factor (SCF), the natural ligand for KIT, was cloned into 1st generation (SCF-CD3ζ, 1st gen) and 2nd generation (SCF-CD28-CD3ζ, 2nd gen) CIR constructs. In vitro dTc proliferation and tumoricidal capacity in the presence of KIT+ tumor cells were measured. In vivo assessment of dTc anti-tumor efficacy was performed by treating immunodeficient mice harboring subcutaneous GIST xenografts with dTc tail vein infusions. RESULTS: We successfully produced the 1st and 2nd gen anti-KIT CIR and transduced murine and human T cells. Average transduction efficiencies for human 1st and 2nd gen dTc were 50% and 42%. When co-cultured with KIT+ tumor cells, both 1st and 2nd gen dTc proliferated and produced IFNγ. Human anti-KIT dTc were efficient at lysing GIST in vitro compared to untransduced T cells. In mice with established GIST xenografts, treatment with either 1st or 2nd gen human anti-KIT dTc led to significant reductions in tumor growth rates. CONCLUSIONS: We have constructed a novel anti-KIT CIR for production of dTc that possess specific activity against KIT+ GIST in vitro and in vivo. Further studies are warranted to evaluate the therapeutic potential and safety of anti-KIT dTc.


Assuntos
Tumores do Estroma Gastrointestinal/terapia , Proteínas Proto-Oncogênicas c-kit/imunologia , Linfócitos T/citologia , Animais , Sequência de Bases , Proliferação de Células , Primers do DNA , Tumores do Estroma Gastrointestinal/patologia , Masculino , Camundongos , Camundongos Nus , Reação em Cadeia da Polimerase , Linfócitos T/imunologia
10.
Hepatobiliary Surg Nutr ; 2(2): 97-107, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24570923

RESUMO

The treatment of colorectal cancer liver metastases (CRLM) has evolved significantly in the last 15 years. Currently, complete surgical resection remains the only potentially curative option; unfortunately, approximately 80% of patients with CRLM are not candidates for complete tumor resection. For patients with unresectable CRLM the available treatment options were historically limited; however, the development of regional hepatic therapies (RHT) and improvement of systemic chemotherapeutic regimens have emerged as viable options to improve overall survival and quality of life for this group of patients. The selection, sequence and integration of interventions into a multi-modal approach is a complex and evolving discipline. In this article, the currently available RHT modalities for CRLM are presented as a guide to the options for clinical treatment decisions.

11.
J Gastrointest Oncol ; 3(1): 69-77, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22811871

RESUMO

Surgical resection for colorectal hepatic metastases (CRHM) is the preferred treatment for suitable candidates, and the only potentially curative modality. However, due to various limitations, the majority of patients with CRHM are not candidates for liver resection. In recent years, there has been an increasing interest in the role of thermal tumor ablation (TTA) as a component of combined resection-ablation strategies, staged hepatic resections, or as standalone adjunct treatment for patients with CRHM. Thus, ablative approaches have expanded the group of patients with CRHM that may benefit from liver-directed treatment strategies.

12.
World J Surg Oncol ; 10: 147, 2012 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-22799628

RESUMO

BACKGROUND: Totally laparoscopic (without hand-assist) resection for rectal cancer continues to evolve, and both obesity and locally advanced disease are perceived to add to the complexity of these procedures. There is a paucity of data on the impact of obesity on perioperative and oncologic outcomes for totally-laparoscopic rectal cancer resection (TLRR) for locally advanced disease. METHODS: In order to identify potential limitations of TLRR, a single-institution database was queried and identified 26 patients that underwent TLRR for locally advanced rectal cancers (T3/T4) over a three-year period. Patients were classified as normal-weight (NW, body mass index (BMI)=18.5 to 24.9 kg/m2), overweight (OW, BMI=25 to 29.9 kg/m2) and obese (OB, BMI >/= 30 kg/m2). Perioperative outcomes, lymph node harvest and margin status were assessed. RESULTS: Seven patients were classified as NW (26.9%), 12 as OW (46.2%) and 7 as OB (26.9%). Age, tumor stage, gender and American Society of Anesthesiologists (ASA) scores were similar. OB had more co-morbidities (median 3.0, range 0.0 to 5.0 vs. 2.0, range 0.0 to 3.0 for NW and 1.0, range 0.0 to 3.0 for OW). Five patients had tumors <5 cm from anal verge (NW=2; OW=1; OB=2). A median of 19.0, range 9.0 to 32.0; 20.0, range 9.0 to 46.0 and 19.0, range 15.0 to 31.0 lymph nodes were retrieved in the NW, OW and OB, respectively (Not Significant (NS)). Median node ratios for NW, OW and OB were 0.32, 0.13 and 0.00, respectively. All groups had negative proximal and distal margins. Radial margins were negative for 100% of NW, 83.3% of OW and 85.7% of OB (NS). Conversion rates were 14.3% for NW, 16.7% for OW & 0% for OB (NS). NW, OW and OB had complication rates of 28.3%, 33.3% and 14.3%, respectively. Median operative time, median estimated blood loss and median length of hospital stay were similar for all groups. CONCLUSION: The perceived limitation that obesity would have on TLRR was not demonstrated by the analyzed data. Although our findings are limited by the modest sized cohort, the results suggest that it is reasonable to offer TLRR to obese patients with rectal cancer.


Assuntos
Laparoscopia , Obesidade/fisiopatologia , Neoplasias Retais/mortalidade , Neoplasias Retais/cirurgia , Idoso , Índice de Massa Corporal , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Linfonodos/patologia , Linfonodos/cirurgia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Duração da Cirurgia , Prognóstico , Estudos Prospectivos , Neoplasias Retais/patologia , Fatores de Risco
13.
J Surg Res ; 178(1): 242-7, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22482755

RESUMO

BACKGROUND: Sorafenib is currently approved for advanced hepatocellular carcinoma (HCC) and is presently being studied as an adjuvant treatment for HCC following resection. The effects of sorafenib on liver regeneration have not been clearly defined. Our objective was to identify the effects of sorafenib on liver regeneration in a murine partial hepatectomy (PH) model. MATERIALS AND METHODS: We performed PH in C57Bl/6 mice treated with a range of sorafenib doses with assessments at several time points. Liver sinusoidal endothelial cells (LSEC) and hepatocyte DNA synthesis and proliferation were assessed with 5-bromo-2'-deoxyuridine (BrdU) and Ki67 by flow cytometry and immunohistochemistry. RESULTS: Treatment with sorafenib did not result in any deaths following PH. When we measured BrdU uptake to assess DNA synthesis, there was a statistically significant increase at 48 h post-PH for nonfibrotic LSEC following treatment with 60 mg/kg of sorafenib. However, BrdU and Ki67 staining among LSEC and hepatocytes was not significantly affected by sorafenib at any of the other doses or time points. BrdU and Ki67 flow cytometry data correlated with immunohistochemistry findings and postoperative liver weights. CONCLUSION: In a murine PH model, sorafenib did not alter the repair response of normal or fibrotic livers following PH as measured by changes in liver weight, DNA synthesis, and cellular proliferation. These findings suggest sorafenib administered following hepatic resection does not impair liver regeneration.


Assuntos
Benzenossulfonatos/farmacologia , Hepatectomia/métodos , Regeneração Hepática/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/cirurgia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Hepatócitos/efeitos dos fármacos , Hepatócitos/fisiologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/cirurgia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/cirurgia , Regeneração Hepática/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Niacinamida/análogos & derivados , Compostos de Fenilureia , Sorafenibe
14.
Am Surg ; 77(11): 1526-30, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22196669

RESUMO

Laparoscopic distal pancreatectomy (LDP) has emerged as the procedure of choice for selected patients. This study is to evaluate the feasibility of LDP and procedural outcomes in a series of consecutive nonselected patients. All patients undergoing distal pancreatectomy over 18 months were identified from a prospectively maintained database, under institutional review board approval. A completely laparoscopic (non hand-assisted) procedure was performed using a 4-trocar technique. Conversion to an open procedure, operative time (OR), estimated blood loss (EBL), transfusion requirements, postoperative length of stay (LOS), and complications were assessed. Sixteen patients were identified; 2/16 patients had undergone distal pancreatectomy as a component of another multiorgan open procedure, and were thus excluded. The remaining 14 patients had consented for LDP. Conversion occurred in 4/14 cases. Converted patients trended towards increased OR, EBL, and LOS (P = not significant). No mortalities occurred, and overall morbidities included: pancreatic fistula (n = 2), splenic abscess (n = 1), and pneumonia (n = 1). LDP-splenectomy (n = 3/14) was associated with both increased EBL (683 mL ± 388 vs 168 ± 141, P < 0.002) and increased transfusion rate (3/3 vs 3/11, P = 0.05), as compared with LDP-splenic preservation. LDP with splenic artery preservation (LDP-SAP) was completed in 7 of 14 patients, with less OR (2 hours 29 minutes ± 53 minutes vs 3 hours 40 minutes ± 1 hour, P < 0.05), a decreased transfusion rate (14% vs 71%, P = 0.05), and decreased LOS (2.8 days vs 6.8 days, P = 0.002) compared with LDP without SAP. Pathology was intraductal papillary mucinous neoplasm (IPMN) (n = 5), ductal carcinoma (n = 3), high grade dysphasia (n = 2), neuroendocrine tumor (n = 2), and pancreatitis (n = 2). Patients undergoing LDP-SAP demonstrated superior peri-procedural outcomes. This series of nonselected consecutive patients supports that LDP is technically feasible with a comparable procedural outcome to the selected-patient literature, suggesting potentially expanded indications for LDP.


Assuntos
Laparoscopia , Pancreatectomia/métodos , Pancreatopatias/cirurgia , Seleção de Pacientes , Idoso , Perda Sanguínea Cirúrgica/estatística & dados numéricos , Feminino , Seguimentos , Humanos , Incidência , Tempo de Internação/tendências , Masculino , Complicações Pós-Operatórias/epidemiologia , Estudos Prospectivos , Resultado do Tratamento , Estados Unidos/epidemiologia
15.
HPB (Oxford) ; 13(9): 621-5, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21843262

RESUMO

BACKGROUND: Laparoscopic spleen-preserving distal pancreatectomy has gained popularity in recent years. Splenic preservation can be achieved with or without splenic vessel preservation (SVP). The potential morbidity of this approach in patients aged >70 years has not been well defined. METHODS: Ten patients aged >70 years underwent attempted laparoscopic spleen-preserving distal pancreatectomy within a 2-year period. Multiple patient parameters were examined and chi-squared analysis was used to evaluate the association between the operative technique (SVP or splenic vessel division [SVD]) and splenic infarction. The Mann-Whitney test was used to compare the SVP and SVD groups with regard to age, estimated blood loss (EBL), operating time, splenic volume and length of stay (LoS). RESULTS: Median age was 81 years (range: 71-92 years). Operating room time, LoS, EBL and complication rates were similar to those reported in published series of younger patients. In four patients, the splenic vessels were divided in a manner relying on short gastric collateral flow; SVP was achieved in all other patients. All four patients who underwent SVD developed splenic infarcts and three required splenectomy to manage this (P=0.002). Median LoS was increased in the SVD group (9.3 days vs. 4.3 days; P=0.053). Estimated blood loss was higher in the SVP group (200 ml vs. 100 ml; P=0.091). One pancreatic leak occurred. There were no mortalities. CONCLUSIONS: Spleen-preserving laparoscopic distal pancreatectomy can be performed safely in elderly patients, with results comparable with those achieved in younger subjects. However, elderly patients undergoing division of the splenic artery and vein may be at higher risk for splenic infarct and the aetiology of this is unclear.


Assuntos
Laparoscopia/efeitos adversos , Pancreatectomia/efeitos adversos , Baço/irrigação sanguínea , Infarto do Baço/etiologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Estudos de Viabilidade , Humanos , Pancreatectomia/métodos , Reoperação , Rhode Island , Medição de Risco , Fatores de Risco , Esplenectomia , Artéria Esplênica/cirurgia , Infarto do Baço/cirurgia , Veia Esplênica/cirurgia , Fatores de Tempo , Resultado do Tratamento
16.
J Immunol ; 187(3): 1150-6, 2011 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21697460

RESUMO

Although obstructive jaundice has been associated with a predisposition toward infections, the effects of bile duct ligation (BDL) on bulk intrahepatic T cells have not been clearly defined. The aim of this study was to determine the consequences of BDL on liver T cell phenotype and function. After BDL in mice, we found that bulk liver T cells were less responsive to allogeneic or syngeneic Ag-loaded dendritic cells. Spleen T cell function was not affected, and the viability of liver T cells was preserved. BDL expanded the number of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg), which were anergic to direct CD3 stimulation and mediated T cell suppression in vitro. Adoptively transferred CD4(+)CD25(-) T cells were converted into Treg within the liver after BDL. In vivo depletion of Treg after BDL restored bulk liver T cell function but exacerbated the degrees of inflammatory cytokine production, cholestasis, and hepatic fibrosis. Thus, BDL expands liver Treg, which reduce the function of bulk intrahepatic T cells yet limit liver injury.


Assuntos
Colestase Intra-Hepática/imunologia , Colestase Intra-Hepática/prevenção & controle , Icterícia Obstrutiva/imunologia , Cirrose Hepática Biliar/imunologia , Cirrose Hepática Biliar/prevenção & controle , Fígado/imunologia , Ativação Linfocitária/imunologia , Linfócitos T Reguladores/imunologia , Animais , Antígenos CD4/biossíntese , Diferenciação Celular/imunologia , Células Cultivadas , Colestase Intra-Hepática/patologia , Subunidade alfa de Receptor de Interleucina-2/biossíntese , Icterícia Obstrutiva/complicações , Icterícia Obstrutiva/patologia , Ligadura/efeitos adversos , Fígado/patologia , Cirrose Hepática Biliar/patologia , Testes de Função Hepática , Depleção Linfocítica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia
18.
HPB (Oxford) ; 12(10): 674-83, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21083792

RESUMO

BACKGROUND: Tumour-infiltrating lymphocytes (TILs) have been shown to predict survival in numerous malignancies. The importance of TILs in primary pancreatic neuroendocrine tumours (NETs) and NET liver metastases (NETLMs) has not been defined. METHODS: We identified 87 patients with NETs and 39 with NETLMs who had undergone resection. Immunohistochemistry was performed to determine TIL counts. Recurrence-free survival (RFS) and overall survival (OS) were determined using the log-rank test. RESULTS: The median follow-up time was 62 months in NET patients and 48 months in NETLM patients. Vascular invasion and histologic grade were the only independent predictors of outcome for NETs and NETLMs, respectively. Analysis of intermediate-grade NETs indicated that a dense T cell (CD3+) infiltrate was associated with a median RFS of 128 months compared with 61 months for those with low levels of intratumoral T cells (P= 0.05, univariate analysis). Examination of NETLMs revealed that a low level of infiltrating regulatory T cells (Treg, FoxP3+) was a predictor of prolonged survival (P < 0.01, univariate analysis). CONCLUSIONS: A robust T cell infiltrate is associated with improved RFS following resection of intermediate-grade NETs, whereas the presence of more Treg correlated with shorter OS after treatment of NETLMs. Further study of the immune response to intermediate-grade NETs and NETLMs is warranted.


Assuntos
Neoplasias Hepáticas/cirurgia , Linfócitos do Interstício Tumoral/imunologia , Tumores Neuroendócrinos/cirurgia , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Bases de Dados como Assunto , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tumores Neuroendócrinos/imunologia , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/secundário , Cidade de Nova Iorque , Modelos de Riscos Proporcionais , Medição de Risco , Fatores de Risco , Linfócitos T Reguladores/imunologia , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
19.
World J Surg Oncol ; 8: 72, 2010 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-20727181

RESUMO

BACKGROUND: Hyperthermic chemotherapy applies thermal energy to both abdominal wall as well as the intra-abdominal viscera. The combination of the hyperthemia, chemotherapy and cytoreductive surgery (CRS) is associated with a defined risk of abdominal wall and intestinal morbidity reported to be as high as 15%, respectively to date, no studies have evaluated the use of biomaterial mesh as adjuvant to abdominal wall closure in this group of patients. In the present report, we hypothesized that post HIPEC closure with a biomaterial can reduce abdominal wall morbidity after CRS and hyperthermic intraperitoneal chemotherapy. MATERIALS AND METHODS: All patients treated with HIPEC in a tertiary care center over 12 months (2008-2009) period were included. Eight patients received cytoreductive surgery followed by HIPEC for 90 minutes using Mitomycin C (15 mg q 45 minutes x 2). Abdominal wall closure was performed using Surgisis (Cook Biotech.) mesh in an underlay position with 3 cm fascial overlap-closure. Operative time, hospital length of stay (LOS) as well as postoperative outcome with special attention to abdominal wall and bowel morbidity were assessed. RESULTS: Eight patients, mean age 59.7 ys (36-80) were treated according to the above protocol. The primary pathology was appendiceal mucinous adenocarcinoma (n = 3) colorectal cancer (n = 3), and ovarian cancer (n = 2). Four patients (50%) presented initially with abdominal wall morbidity including incisional ventral hernia (n = 3) and excessive abdominal wall metastatic implants (n = 1). The mean peritoneal cancer index (PCI) was 8.75. Twenty eight CRS were performed (3.5 CRS/patient). The mean operating time was 6 hours. Seven patients had no abdominal wall or bowel morbidity, the mean LOS for these patients was 8 days. During the follow up period (mean 6.3 months), one patient required exploratory laparotomy 2 weeks after surgery and subsequently developed an incisional hernia and enterocutaneous fistula. CONCLUSION: The use of biomaterial mesh in concert with HIPEC enables the repair of concomitant abdominal wall hernia and facilitates abdominal wall closure following the liberal resection of abdominal wall tumors. Biomaterial mesh prevents evisceration on repeat laparotomy and resists infection in immunocompromised patients even when associated with bowel resection.


Assuntos
Traumatismos Abdominais/terapia , Parede Abdominal/cirurgia , Materiais Biocompatíveis/uso terapêutico , Quimioterapia do Câncer por Perfusão Regional , Hipertermia Induzida , Complicações Pós-Operatórias/terapia , Traumatismos Abdominais/etiologia , Traumatismos Abdominais/patologia , Parede Abdominal/patologia , Adenocarcinoma Mucinoso/patologia , Adenocarcinoma Mucinoso/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Apêndice/patologia , Neoplasias do Apêndice/terapia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Feminino , Hérnia Ventral/patologia , Hérnia Ventral/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Complicações Pós-Operatórias/patologia , Resultado do Tratamento
20.
Surg Clin North Am ; 90(4): 699-718, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20637942

RESUMO

The increased use of sensitive imaging modalities has led to increased identification of the incidental liver mass (ILM). A combination of careful consideration of patient factors and imaging characteristics of the ILM enables clinicians to recommend a safe and efficient course of action. Using an algorithmic approach, this article includes pertinent clinical factors and the specific radiologic criteria of ILMs and discusses the indications for potential procedures. It is the aim of this article to assist with the development of an individualized strategy for each patient with an ILM.


Assuntos
Achados Incidentais , Neoplasias Hepáticas , Biópsia , Diagnóstico Diferencial , Diagnóstico por Imagem , Humanos , Incidência , Neoplasias Hepáticas/classificação , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/epidemiologia , Fatores de Risco
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