RESUMO
BACKGROUND: Variation in an individual's genetic status can impact the development of pancreatic ductal adenocarcinoma; however, the majority of familial pancreatic cancers (FPC) cannot yet be attributed to a specific inherited mutation. We present data suggesting a correlation between loss-of-function single nucleotide polymorphisms (SNPs) in an immune regulator gene, indoleamine-2,3-dioxygenase-2 (IDO2), and an increased risk of FPC. STUDY DESIGN: Germline DNA from patients who underwent resection for pancreatic ductal adenocarcinoma (n = 79) was sequenced for the IDO2 SNPs R248W and Y359Stop. Genotypes resulting in inactivation of IDO2 (Y325X homozygous, R248W homozygous) were labeled as homozygous, and the other genotypes were grouped as wild-type or heterozygous. Genotype distributions of each SNP were analyzed for Hardy-Weinberg deviation. A genotype frequency set from the 1000 Genomes Project (n = 99) was used as a genetic control for genotype distribution comparisons. RESULTS: A significant 2-fold increase in the overall prevalence of the Y359Stop homozygous genotype compared with the expected Hardy-Weinberg equilibrium was noted (p < 0.05). Familial pancreatic cancer was noted in 15 cases (19%) and comparison of the FPC cohort set to the genetic control set showed a 3-fold increase in Y359Stop homozygous rates (p = 0.054). Overall in our cohort, the homozygous genotype group was associated with increased risk of FPC (odds ratio 5.4; 95% CI 1.6 to 17.6; p < 0.01). Sex, age at diagnosis, and history of tobacco use were not found to be significantly associated with FPC. CONCLUSIONS: Our preliminary data suggest a strong association between the IDO2 inactivating Y359Stop SNP and an increased risk of FPC when compared with the control group. Future studies will evaluate the value of IDO2 genotyping as a prognostic, early detection marker for pancreatic ductal adenocarcinoma and a predictive marker for novel immune checkpoint therapies.
Assuntos
Carcinoma Ductal Pancreático/genética , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Mutação com Perda de Função/genética , Neoplasias Pancreáticas/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Feminino , Humanos , MasculinoRESUMO
OBJECTIVES: We tested cytoplasmic HuR (cHuR) as a predictive marker for response to chemotherapy by examining tumor samples from the international European Study Group of Pancreatic Cancer-3 trial, in which patients with resected pancreatic ductal adenocarcinoma (PDA) received either gemcitabine (GEM) or 5-fluorouracil (5-FU) adjuvant monotherapy. BACKGROUND: Previous studies have implicated the mRNA-binding protein, HuR (ELAVL1), as a predictive marker for PDA treatment response in the adjuvant setting. These studies were, however, based on small cohorts of patients outside of a clinical trial, or a clinical trial in which patients received multimodality therapy with concomitant radiation. METHODS: Tissue samples from 379 patients with PDA enrolled in the European Study Group of Pancreatic Cancer-3 trial were immunolabeled with an anti-HuR antibody and scored for cHuR expression. Patients were dichotomized into groups of high versus low cHuR expression. RESULTS: There was no association between cHuR expression and prognosis in the overall cohort [disease-free survival (DFS), P = 0.44; overall survival, P = 0.41). Median DFS for patients with high cHuR was significantly greater for patients treated with 5-FU compared to GEM [20.1 months, confidence interval (CI): 8.3-36.4 vs 10.9 months, CI: 7.5-14.2; P = 0.04]. Median DFS was similar between the treatment arms in patients with low cHuR (5-FU, 12.8 months, CI: 10.6-14.6 vs GEM, 12.9 months, CI: 11.2-15.4). CONCLUSIONS: Patients with high cHuR-expressing tumors may benefit from 5-FU-based adjuvant therapy as compared to GEM, whereas those patients with low cHuR appear to have no survival advantage with GEM compared with 5-FU. Further studies are needed to validate HuR as a biomarker in both future monotherapy and multiagent regimens.
Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/tratamento farmacológico , Desoxicitidina/análogos & derivados , Proteína Semelhante a ELAV 1/metabolismo , Fluoruracila/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/cirurgia , Quimioterapia Adjuvante , Citoplasma/metabolismo , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Pancreatectomia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/cirurgia , Análise Serial de Tecidos , Resultado do Tratamento , GencitabinaRESUMO
BACKGROUND: Pancreatectomy is associated with a high complication rate that varies between 40-60%. Although many specific complications have been extensively studied, postoperative pneumonia has received little attention. METHODS: Patients undergoing pancreaticoduodenectomy (n = 1,090) and distal pancreatectomy (n = 436) from 2002 to 2014 at Thomas Jefferson University Hospital were retrospectively assessed for postoperative pneumonia. Incidence, predictive factors, and outcomes were determined. RESULTS: Pneumonia was diagnosed in 4.3% of patients after pancreaticoduodenectomy and 2.5% after distal pancreatectomy. The majority of the pneumonias were attributed to aspiration (87.2% and 81.8%, respectively). Pneumonias were more frequently severe (Clavien-Dindo grades 4 or 5) in the pancreaticoduodenectomy group compared to the distal pancreatectomy group (55.3% vs 9.1%, P = .006). Post-pancreaticoduodenectomy pneumonia predictors included delayed gastric emptying (odds ratio 8.2, P < .001), oxygen requirement on postoperative day 3 (odds ratio 3.2, P = .005), and chronic obstructive pulmonary disease (odds ratio 3.1, P = .049). In the post-pancreaticoduodenectomy group, pneumonia was associated with a very high 90-day mortality compared with those who did not have pneumonia (29.8% vs 2.1%, P < .001) and had the largest effect on mortality after pancreaticoduodenectomy (odds ratio 9.6, P < .001). A preoperative risk score model for pneumonia post-pancreaticoduodenectomy was developed. CONCLUSION: Pneumonia after pancreaticoduodenectomy is an uncommon but highly morbid event and is associated with a substantially increased risk of perioperative death.
Assuntos
Causas de Morte , Mortalidade Hospitalar/tendências , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia/efeitos adversos , Pneumonia/mortalidade , Adulto , Fatores Etários , Idoso , Estudos de Coortes , Feminino , Seguimentos , Hospitais Universitários , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatectomia/efeitos adversos , Pancreatectomia/métodos , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Pancreaticoduodenectomia/métodos , Pneumonia/fisiopatologia , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/mortalidade , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores Sexuais , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Pancreatic fistula (PF) is a significant cause of morbidity in patients undergoing distal pancreatectomy (DP), with an incidence of 15-40%. It remains unclear if the location of pancreatic transection affects the rate of PF occurrence. This study examines the correlation between the transection site of the pancreas during DP and the incidence of PF. METHODS: All cases of DP from October 2005 to January 2012 were reviewed retrospectively from an institutional review board-approved database at the Thomas Jefferson University Hospital. Patient demographics and perioperative outcomes were analyzed. The pancreatic transection location was determined by review of operative reports, and then dichotomized into 2 groups: neck/body or tail. PF were graded following the International Study Group on Pancreatic Fistula guidelines. RESULTS: During the study period, 294 DP were performed with 244 pancreas transections at the neck/body and 50 at the tail. Of the 294 patients, 52 (17.7%) developed a postoperative PF. The incidence of PF after transection at the tail of the pancreas was higher (28%) when compared with transection at the neck/body (15.6%; P = .04). When stratified by PF grade, grade A PF occurred more commonly when transection of the gland was at the tail (22% tail vs 8.2% neck/body; P = .007); however, no difference was found for grade B/C PF (6% tail vs 7.4% neck/body; P = 1). CONCLUSION: Our data suggest that PF occurs more often when the tail is transected during DP, although the majority are low grade and of minimal clinical significance. More severe PF occurred equally between the transection sites.
Assuntos
Pâncreas/cirurgia , Pancreatectomia/efeitos adversos , Fístula Pancreática/etiologia , Neoplasias Pancreáticas/cirurgia , Centros Médicos Acadêmicos , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Seguimentos , Humanos , Incidência , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Pâncreas/anatomia & histologia , Pancreatectomia/métodos , Fístula Pancreática/epidemiologia , Fístula Pancreática/cirurgia , Neoplasias Pancreáticas/patologia , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/cirurgia , Reoperação , Estudos Retrospectivos , Medição de Risco , Distribuição por Sexo , Taxa de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
Pancreatic ductal adenocarcinoma (PDA) frequently presents at an advanced and incurable stage of the disease. Common signs and symptoms of PDA include abdominal or back pain, jaundice, weight loss, pruritus, and nausea/vomiting. Diagnostic workup includes serum chemistries and CA19-9, primarily to monitor disease status and response to treatment. Imaging studies are performed to assess resectability and stage disease, and pancreatic protocol computed tomography (CT) scan or magnetic resonance imaging (MRI) are the preferred imaging studies for this purpose. Conventional staging is based on the American Joint Cancer Committee (AJCC) Staging System, 7th Edition and informs prognosis, while surgical staging systems focus specifically on assessing the likelihood of a complete (negative margins) resection with operative management. Herein, we review the presenting signs and symptoms, the diagnostic evaluation, and staging of PDA.
Assuntos
Carcinoma Ductal Pancreático/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Carcinoma Ductal Pancreático/secundário , Carcinoma Ductal Pancreático/cirurgia , Humanos , Metástase Linfática , Estadiamento de Neoplasias , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgiaRESUMO
OBJECTIVE: This study was designed to determine whether the volume and type of fluid administered for pancreaticoduodenectomy impacts postoperative outcomes. BACKGROUND: Three percent hypertonic saline (HYS) has been suggested as a means of reducing the volume of fluid required to sustain tissue perfusion in the perioperative period. METHODS: Between May 2011 and November 2013, patients undergoing pancreaticoduodenectomy were enrolled in an institutional review board-approved, single-center, prospective, parallel, randomized controlled trial (NCT 01428050), comparing lactated Ringers (LAR) (15 mL/kg/hr LAR intraoperation, 2 mL/kg/hr LAR postoperation) with HYS (9 mL/kg/hr LAR and 1 mL/kg/hr HYS intraoperation, 1 mL/kg/hr HYS postoperation). RESULTS: A total of 264 patients were randomized. Demographic variables between groups were similar. The HYS patients had a significantly reduced net fluid balance (65 vs 91 mL/kg, P = 0.02). The overall complication rate was reduced in the HYS group (43% vs 54%), with a relative risk of 0.79 [95% confidence interval (CI), 0.62-1.02; P = 0.073], factoring stratification for pancreas texture. After adjustment for age and weight, the relative risk was 0.75 [95% CI (0.58-0.96); P = 0.023]. The total number of complications was significantly reduced in the HYS group (93 vs 123), with an incidence rate ratio of 0.74 [95% CI (0.56-0.97); P = 0.027]. After adjustment for age and weight, the incidence rate ratio was 0.69 [95% CI (0.52-0.90); P = 0.0068]. Reoperations, length of stay, readmissions, and 90-day mortality were similar between groups. CONCLUSIONS: A moderately restrictive fluid regimen with HYS resulted in a statistically significant 25% reduction in complications when adjusted for age, weight, and pancreatic texture.