RESUMO
Malnutrition and cachexia occur commonly in patients with advanced gastric cancer (AGC). This study elucidated the effect of nutritional support (NS) on survival outcomes among patients with AGC undergoing chemotherapy. We retrospectively evaluated new AGC cases at our institute between January 2015 and January 2021. Inclusion criteria were unresectable or recurrent chemotherapy-treated gastric adenocarcinoma, ECOG performance status (PS) 0-2, and adequate organ function. Time to treatment failure (TTF) and overall survival (OS) were evaluated, and univariate and multivariate analyses identified prognostic factors. A total of 103 eligible patients were separated into groups: 69 patients (67%) into NS and 34 (33%) into routine care (RC). The median follow-up time was 11.0 mo, (0.5-92). NS was offered to patients with poorer PS (p = 0.03), Glasgow prognostic score (GPS) positivity (p = 0.001), and high neutrophil-to-lymphocyte ratios (cut-off ≤ 3, p = 0.02). Median OS and TTF in the RC and NS groups were 11.6 and 10.4 mo, (p = 0.99) and 4.2 and 5.5 mo, (p = 0.07), respectively. Multivariate analyses identified NS (hazard ratio [HR] = 0.53, p = 0.01) and GPS positivity for TTF, and low body mass index (HR = 2.03, p = 0.007) and GPS positivity (HR = 2.25, p = 0.001) for OS as significant prognostic factors. Thus, NS with chemotherapy is a potentially effective intervention for AGC.
Assuntos
Adenocarcinoma , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patologia , Prognóstico , Estudos Retrospectivos , Apoio Nutricional , Adenocarcinoma/patologiaRESUMO
BACKGROUND: Bacterial contamination status may differ under different biliary drainage conditions. The purpose of this study was to determine the impact of qualitative and quantitative biliary bacterial contamination on the incidence of infection complications in patients undergoing pancreatoduodenectomy. METHODS: Patients undergoing pancreatoduodenectomy for periampullary diseases with different biliary drainage conditions, such as external drainage (ED), internal drainage (ID), and no drainage (ND), were included. Bile was collected intraoperatively, and biliary contamination status was qualified and quantified using bacterium-specific ribosomal RNA-targeted reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The impact of biliary contamination status on infection complications was analyzed. RESULTS: A total of 152 patients were included (38 with ED, 40 with ID, and 74 with ND). The positive rate of microorganisms in bile was higher in the ID group (98%) compared with the ED group (82%, p = 0.021) and the ND group (65%, p < 0.001). The number of microorganisms detected in bile samples was higher in the ID group compared with the ED group (median 489,788 vs. 5375 bacteria/mL of bile, p < 0.001). With multivariate analysis, soft pancreas, intraoperative bleeding (> 600 mL), and biliary contamination by Atopobium cluster were identified as independent risk factors for infection complications. Biliary contamination by Atopobium cluster was significantly higher in the ID group compared with the other groups. CONCLUSIONS: Biliary bacterial contamination is more frequently induced by ID than either ED or ND. In addition to the previously known risk factors, biliary contamination with Atopobium cluster may be one of the risk factors of infection complications following pancreatoduodenectomy.
Assuntos
Infecções Bacterianas , Pancreaticoduodenectomia , Infecções Bacterianas/etiologia , Infecções Bacterianas/microbiologia , Bile/microbiologia , Drenagem/efeitos adversos , Drenagem/métodos , Humanos , Incidência , Pancreaticoduodenectomia/efeitos adversos , Pancreaticoduodenectomia/métodos , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/microbiologia , Cuidados Pré-OperatóriosRESUMO
BACKGROUND: The clinical role of peritoneal lavage cytology (CY) in pancreatic ductal adenocarcinoma (PDAC) remains controversial, partly due to its low sensitivity. This study aimed to develop a new biomarker, defined as peritoneal lavage tumor DNA (ptDNA), using DNAs extracted from peritoneal lavage samples from patients with PDAC. METHODS: Samples were collected intraoperatively from 89 PDAC patients who underwent pancreatectomy between 2012 and 2017. Droplet digital polymerase chain reaction (PCR) was used to measure ptDNA for detection of KRAS mutations. The ptDNA status and clinical characteristics were retrospectively evaluated. RESULTS: Positive ptDNA was found in 41 patients, including all 9 patients positive for CY (CY+) and 32 patients negative for CY (CY-). The mutant allele frequency was significantly higher in the CY+ patients than in the CY- patients. The disease-free survival (DFS) and overall survival (OS) were significantly poorer in the high-ptDNA group than in the low-ptDNA group (median DFS, 11.0 vs. 18.8 months; p = 0.007; median OS, 28.7 vs not reached; p = 0.001). The survival curves of DFS and OS in the CY+ group were almost equal to those in the CY- and high-ptDNA group. In a multivariable analysis, ptDNA was an independent predictive factor for DFS (p = 0.025) and OS (p = 0.047). The estimated cumulative incidence of peritoneal recurrence was 45.5% in the high-ptDNA group. The ptDNA biomarker had a much higher sensitivity for peritoneal recurrence than CY, whereas CY had higher specificity. CONCLUSIONS: As a promising biomarker, ptDNA may predict poor prognosis and peritoneal recurrence in PDAC, resolving the controversy surrounding CY.
Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Neoplasias Peritoneais , Biomarcadores , Carcinoma Ductal Pancreático/genética , DNA/genética , Humanos , Recidiva Local de Neoplasia/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/cirurgia , Lavagem Peritoneal , Neoplasias Peritoneais/genética , Prognóstico , Estudos RetrospectivosRESUMO
To evaluate whether germline variants in genes encoding pancreatic secretory enzymes contribute to pancreatic cancer susceptibility, we sequenced the coding regions of CPB1 and other genes encoding pancreatic secretory enzymes and known pancreatitis susceptibility genes (PRSS1, CPA1, CTRC, and SPINK1) in a hospital series of pancreatic cancer cases and controls. Variants in CPB1, CPA1 (encoding carboxypeptidase B1 and A1), and CTRC were evaluated in a second set of cases with familial pancreatic cancer and controls. More deleterious CPB1 variants, defined as having impaired protein secretion and induction of endoplasmic reticulum (ER) stress in transfected HEK 293T cells, were found in the hospital series of pancreatic cancer cases (5/986, 0.5%) than in controls (0/1,045, P = 0.027). Among familial pancreatic cancer cases, ER stress-inducing CPB1 variants were found in 4 of 593 (0.67%) vs. 0 of 967 additional controls (P = 0.020), with a combined prevalence in pancreatic cancer cases of 9/1,579 vs. 0/2,012 controls (P < 0.01). More ER stress-inducing CPA1 variants were also found in the combined set of hospital and familial cases with pancreatic cancer than in controls [7/1,546 vs. 1/2,012; P = 0.025; odds ratio, 9.36 (95% CI, 1.15-76.02)]. Overall, 16 (1%) of 1,579 pancreatic cancer cases had an ER stress-inducing CPA1 or CPB1 variant, compared with 1 of 2,068 controls (P < 0.00001). No other candidate genes had statistically significant differences in variant prevalence between cases and controls. Our study indicates ER stress-inducing variants in CPB1 and CPA1 are associated with pancreatic cancer susceptibility and implicate ER stress in pancreatic acinar cells in pancreatic cancer development.
Assuntos
Carboxipeptidase B , Carboxipeptidases A , Estresse do Retículo Endoplasmático/genética , Predisposição Genética para Doença , Mutação , Proteínas de Neoplasias , Neoplasias Pancreáticas , Idoso , Idoso de 80 Anos ou mais , Carboxipeptidase B/genética , Carboxipeptidase B/metabolismo , Carboxipeptidases A/genética , Carboxipeptidases A/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologiaRESUMO
To obtain a better understanding of the genetic alterations of high-grade pancreatic intraepithelial neoplasia (HG-PanIN), we performed whole-genome copy number analysis by using single nucleotide polymorphism microarrays and targeted next-generation sequencing of 11 microdissected HG-PanIN and two low-grade PanIN lesions associated with HG-PanIN. HG-PanIN mutation profiles were compared with those of their associated invasive pancreatic ductal adenocarcinoma. All PanIN lesions harbored somatic KRAS mutations. The most common copy number losses in the HG-PanIN were at the CDKN2A (9p21), TP53 (17p13), and SMAD4 (18q21) loci. Chromosomal losses in HG-PanIN were also found at 6p25-p24, 6q11-q27, 12q24, and 17q23-q24. Biallelic inactivation of CDKN2A and TP53 was detected in five of eight and in three of eight evaluable PanIN lesions, respectively. None of the HG-PanIN lesions had SMAD4 mutations or homozygous deletion. Copy number gains were noted at the MYC (8q24) and CCNE1 (19q12) loci and at 1q25-q31. Four HG-PanINs and one low-grade PanIN harbored chromothripsis-like regions. Five of seven pancreatic ductal adenocarcinomas evaluated had additional mutations that were not found in their associated HG-PanIN. HG-PanIN harbors widespread copy number alterations and commonly shows evidence of biallelic inactivation of CDKN2A and TP53 but not SMAD4. Chromothripsis events contribute to the copy number alterations of HG-PanIN.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma in Situ/genética , Carcinoma Ductal Pancreático/genética , Variações do Número de Cópias de DNA , Genoma Humano , Mutação , Neoplasias Pancreáticas/genética , Idoso , Carcinoma in Situ/patologia , Carcinoma Ductal Pancreático/patologia , DNA de Neoplasias/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Pancreáticas/patologia , Neoplasias PancreáticasRESUMO
BACKGROUND: Identification of gastric cancer-related molecules is necessary to elucidate the pathological mechanisms of this heterogeneous disease. The purpose of this study was to identify novel genes associated with aggressive phenotypes of gastric cancer. METHODS: Global expression profiling was conducted using tissues from four patients with metastatic gastric cancer to identify genes overexpressed in gastric cancer. Fifteen gastric cell lines and 262 pairs of surgically resected gastric tissues were subjected to mRNA expression analysis. The contribution of the candidate gene on gastric cancer cell proliferation, invasion, adhesion, and migration were evaluated using small interfering RNA. RESULTS: DnaJ heat shock protein family (Hsp40) member C12 (DNAJC12) was identified as a candidate gene by transcriptome analysis. In clinical samples, DNAJC12 mRNA levels were higher in gastric cancer tissues compared with normal adjacent tissues. Patients with high DNAJC12 expression showed significantly shorter overall survival in our cohort and in the extra-validation cohort analyzed by a published microarray dataset. High DNAJC12 expression in gastric cancer tissues was significantly associated with lymphatic involvement, infiltrative growth type, lymph node metastasis, and advanced stage and was identified as an independent prognostic factor for overall survival in multivariable analysis. Increased expression of DNAJC12 was found in 12 of 14 examined gastric cancer cell lines. Knockdown of DNAJC12 expression significantly decreased the proliferation and invasion abilities of gastric cancer cells. CONCLUSIONS: Our findings support DNAJC12 as a candidate gene associated with aggressive phenotypes of gastric cancer.
Assuntos
Biomarcadores Tumorais/metabolismo , Movimento Celular , Proliferação de Células , Proteínas Repressoras/metabolismo , Neoplasias Gástricas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Adesão Celular , Estudos de Coortes , Feminino , Seguimentos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Proteínas Repressoras/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/cirurgia , Taxa de SobrevidaRESUMO
BACKGROUND: The detection of molecules and mechanisms affecting the malignant phenotype of gastric cancer cells may contribute to the identification of biomarkers for metastasis and recurrence, and such molecules may serve as targets of therapy. For this purpose, in this study transcriptome analysis was performed using surgically resected specimens from patients with gastric cancer with synchronous metastasis. We identified homeobox C10 (HOXC10) as the most highly expressed gene in gastric cancer tissues compared with the adjacent noncancerous gastric mucosa. METHODS: Polymerase chain reaction (PCR) array analysis was performed to identify genes coordinately expressed with HOXC10. The effects of inhibiting HOXC10 on malignant phenotype was evaluated using HOXC10 knockout gastric cancer cell lines, and antibody array analysis was performed to assess the effect of HOXC10 knockout on intracellular signaling. We used a mouse subcutaneous xenograft model to evaluate the tumorigenicity. HOXC10 expression was determined in gastric cancer tissues acquired from 300 patients with gastric cancer. RESULTS: PCR array analysis revealed that the levels of HOXC10 messenger RNA positively correlated with those of FGFBP1 and SOX10. The phosphorylation of ERK1/2 was decreased in HOXC10 knockout cells. HOXC10 knockout significantly suppressed proliferation by increasing apoptosis and reducing the migration and invasiveness of gastric cancer cells. Mouse xenograft models revealed that the tumorigenicity of HOXC10 knockout cells was attenuated compared with the parental cells. The relatively high expression levels of HOXC10 in gastric cancer tissues were significantly associated with hepatic and peritoneal recurrence, as well as worse prognosis. CONCLUSIONS: Our results indicated that HOXC10 enhances the malignant phenotype of gastric cancer cells. The expression levels of HOXC10 may therefore serve as a prognostic biomarker and the products of HOXC10 may provide targets of therapy.
Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Homeodomínio/metabolismo , Neoplasias Hepáticas/mortalidade , Recidiva Local de Neoplasia/mortalidade , Neoplasias Gástricas/mortalidade , Idoso , Apoptose , Estudos de Casos e Controles , Movimento Celular , Proliferação de Células , Feminino , Seguimentos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Metástase Linfática , Masculino , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Fenótipo , Prognóstico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Taxa de Sobrevida , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: The association between neoadjuvant therapy (NAT) and nutritional status in pancreatic cancer (PC) is unknown. OBJECTIVE: The aim of this study was to assess the impact of NAT on nutritional status. METHODS: Overall, 161 patients who underwent pancreatoduodenectomy for PC between August 2010 and March 2017 were enrolled and were divided into two groups: the neoadjuvant group (NAG; n = 67) and the control group (CG; n = 94). Based on relative dose intensity (RDI), patients in the NAG group were further divided into RDI ≥ 80% (n = 39) and RDI < 80% (n = 19). Changes in nutritional index, inflammatory index, and inflammation-based prognostic scores during NAT and the perioperative period were assessed. RESULTS: Retinol-binding protein, prealbumin, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and prognostic nutrition index significantly worsened in the NAG after NAT (p = 0.007, p = 0.03, p = 0.04, p = 0.007, and p = 0.004, respectively). The recovery of rapid turnover proteins after postoperative day 5 was significantly worse in the NAG compared with the CG (p < 0.05), but tended to be more prompt in the RDI ≥ 80% group among the NAG. There was no significant difference in the incidence of postoperative complications, length of hospital stay, and time to postoperative adjuvant therapy between the NAG and the CG. CONCLUSIONS: NAT for PC could aggravate nutritional status and hamper its postoperative recovery. Furthermore, malnutrition might decrease tolerance of NAT. These findings suggest the importance of nutritional support for patients with NAT in PC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Mediadores da Inflamação/metabolismo , Desnutrição/etiologia , Terapia Neoadjuvante/efeitos adversos , Estado Nutricional , Neoplasias Pancreáticas/tratamento farmacológico , Pancreaticoduodenectomia/efeitos adversos , Idoso , Feminino , Seguimentos , Humanos , Tempo de Internação , Masculino , Desnutrição/patologia , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , PrognósticoRESUMO
BACKGROUND: Although peritoneal metastasis is a serious concern in patients with gastric cancer, no acceptable and specific biomarker is available. We aimed to identify a candidate biomarker to predict peritoneal metastasis of gastric cancer. METHODS: Metastatic pathway-specific transcriptome analysis was conducted by comparison of patient groups with no recurrence and with peritoneal, hepatic, and nodal recurrence. Fifteen cell lines and 262 pairs of surgically resected gastric tissues were subjected to messenger RNA (mRNA) expression analysis. Polymerase chain reaction array analysis was performed to explore coordinately expressed cancer-related genes. To evaluate the in situ protein localization and expression patterns, immunohistochemical staining was performed. RESULTS: From transcriptome data, troponin I2 (TNNI2) was identified as a candidate molecule specifically overexpressed in gastric cancer prone to peritoneal metastasis. TNNI2 mRNA was expressed at differential levels, independent of differentiated phenotype of cell lines. Epithelial to mesenchymal transition-related genes, tumor inhibitor of metalloproteinase 1 (TIMP1), and vacuolar protein sorting 13 homolog A (VPS13A) were expressed with TNNI2 at correlation coefficient > 0.7. The optimal cutoff of TNNI2 expression was determined as 0.00017. High TNNI2 expression was significantly and specifically associated with peritoneal metastasis and served as an independent risk marker for peritoneal recurrence after curative gastrectomy. Prevalence of peritoneal recurrence increased in parallel with staining intensity of TNNI2. CONCLUSIONS: TNNI2 expression in gastric tissues may serve as a specific biomarker for prediction of peritoneal metastasis of gastric cancer and contribute to improvement of patient management.
Assuntos
Biomarcadores Tumorais/metabolismo , Gastrectomia/mortalidade , Recidiva Local de Neoplasia/patologia , Neoplasias Peritoneais/secundário , Neoplasias Gástricas/patologia , Troponina I/metabolismo , Idoso , Biomarcadores Tumorais/genética , Transição Epitelial-Mesenquimal , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Masculino , Invasividade Neoplásica , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/cirurgia , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/cirurgia , Prognóstico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/cirurgia , Taxa de Sobrevida , Troponina I/genética , Células Tumorais CultivadasRESUMO
High-grade pancreatic intraepithelial neoplasia (HG-PanIN) is the major precursor of pancreatic ductal adenocarcinoma (PDAC) and is an ideal target for early detection. To characterize pure HG-PanIN, we analysed 23 isolated HG-PanIN lesions occurring in the absence of PDAC. Whole-exome sequencing of five of these HG-PanIN lesions revealed a median of 33 somatic mutations per lesion, with a total of 318 mutated genes. Targeted next-generation sequencing of 17 HG-PanIN lesions identified KRAS mutations in 94% of the lesions. CDKN2A alterations occurred in six HG-PanIN lesions, and RNF43 alterations in five. Mutations in TP53, GNAS, ARID1A, PIK3CA, and TGFBR2 were limited to one or two HG-PanINs. No non-synonymous mutations in SMAD4 were detected. Immunohistochemistry for p53 and SMAD4 proteins in 18 HG-PanINs confirmed the paucity of alterations in these genes, with aberrant p53 labelling noted only in three lesions, two of which were found to be wild type in sequencing analyses. Sixteen adjacent LG-PanIN lesions from ten patients were also sequenced using targeted sequencing. LG-PanIN harboured KRAS mutations in 94% of the lesions; mutations in CDKN2A, TP53, and SMAD4 were not identified. These results suggest that inactivation of TP53 and SMAD4 are late genetic alterations, predominantly occurring in invasive PDAC. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Assuntos
Carcinoma in Situ/genética , Genes p53/genética , Mutação , Neoplasias Pancreáticas/genética , Proteína Smad4/genética , Carcinoma in Situ/metabolismo , Carcinoma in Situ/patologia , Genoma Humano/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Gradação de Tumores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Proteína Smad4/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
BACKGROUND: Surgical resection is the mainstay of treatment for patients with gastric cancer (GC). Development of a simple, high-performance, integrated scoring system is needed to provide appropriate management. This study aimed to evaluate predictive values of the systemic inflammation score (SIS) for short- and long-term outcomes of patients who underwent surgery for GC. METHODS: A total of 187 patients who underwent gastrectomy for pT2-4 GC without preoperative treatment were analyzed. SIS was formulated based on serum albumin level and lymphocyte-monocyte ratio, and graded into SIS 0, 1, and 2. RESULTS: Preoperative SIS was significantly associated with incidence of postoperative complications, showing a stepwise increased incidence in proportion to SIS in the entire cohort and all subgroups according to operative procedure and disease stage. Overall and disease-free survival times of patients in SIS 0, 1, and 2 shortened in a stepwise fashion. SIS was linked to prevalence of hematogenous metastasis as initial recurrence site. Survival differences between patients with SIS 2 and the others were particularly large in patients who underwent adjuvant chemotherapy. The continuation rate of adjuvant S-1 was lower in the SIS 2 group. CONCLUSION: SIS represents a simple predictor for incidence of postoperative complications and survival in patients with pT2-4 GC.
Assuntos
Gastrectomia , Inflamação/complicações , Complicações Pós-Operatórias/etiologia , Neoplasias Gástricas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Gastrectomia/efeitos adversos , Humanos , Incidência , Inflamação/diagnóstico , Contagem de Leucócitos , Linfócitos , Masculino , Pessoa de Meia-Idade , Monócitos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/terapia , Período Pré-Operatório , Albumina Sérica/análise , Neoplasias Gástricas/complicações , Neoplasias Gástricas/mortalidade , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: Secretin-stimulated pancreatic juice contains DNA shed from cells lining the pancreatic ducts. Genetic analysis of this fluid may form a test to detect pancreatic ductal neoplasia. DESIGN: We employed digital next-generation sequencing ('digital NGS') to detect low-abundance mutations in secretin-stimulated juice samples collected from the duodenum of subjects enrolled in Cancer of the Pancreas Screening studies at Johns Hopkins Hospital. For each juice sample, digital NGS necessitated 96 NGS reactions sequencing nine genes. The study population included 115 subjects (53 discovery, 62 validation) (1) with pancreatic ductal adenocarcinoma (PDAC), (2) intraductal papillary mucinous neoplasm (IPMN), (3) controls with non-suspicious pancreata. RESULTS: Cases with PDAC and IPMN were more likely to have mutant DNA detected in pancreatic juice than controls (both p<0.0001); mutant DNA concentrations were higher in patients with PDAC than IPMN (p=0.003) or controls (p<0.001). TP53 and/or SMAD4 mutations were commonly detected in juice samples from patients with PDAC and were not detected in controls (p<0.0001); mutant TP53/SMAD4 concentrations could distinguish PDAC from IPMN cases with 32.4% sensitivity, 100% specificity (area under the curve, AUC 0.73, p=0.0002) and controls (AUC 0.82, p<0.0001). Two of four patients who developed pancreatic cancer despite close surveillance had SMAD4/TP53 mutations from their cancer detected in juice samples collected over 1â year prior to their pancreatic cancer diagnosis when no suspicious pancreatic lesions were detected by imaging. CONCLUSIONS: The detection in pancreatic juice of mutations important for the progression of low-grade dysplasia to high-grade dysplasia and invasive pancreatic cancer may improve the management of patients undergoing pancreatic screening and surveillance.
Assuntos
Adenocarcinoma Mucinoso , Carcinoma Ductal Pancreático , Carcinoma Papilar , Suco Pancreático/metabolismo , Neoplasias Pancreáticas , Proteína Smad4/genética , Proteína Supressora de Tumor p53/genética , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Carcinoma Papilar/genética , Carcinoma Papilar/patologia , Feminino , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Pâncreas/metabolismo , Pâncreas/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Análise de Sequência de DNA/métodos , Proteína Smad4/análise , Proteína Supressora de Tumor p53/análiseRESUMO
BACKGROUND AND AIMS: Duodenal collections of pancreatic fluid can be used as a source of mutations and other markers of pancreatic ductal neoplasia, but admixing pancreatic juice with duodenal contents lowers the concentrations of mutations. Collecting pancreatic fluid directly from the ampulla could yield a purer sample of pancreatic fluid. METHODS: We used an endoscopic distal cap attachment to "cap" the ampulla and collect secretin-stimulated pancreatic fluid samples for 5 minutes from 81 patients undergoing pancreatic evaluation as part of the Cancer of the Pancreas Screening studies. We compared mutation concentrations (K-ras and GNAS) measured by droplet-digital PCR (ddPCR) in "cap-collected juice" samples to those found in juice samples obtained from 77 patients collected by aspiration from the duodenal lumen without capping the ampulla. RESULTS: Among all subjects, mutation concentrations were higher in pancreatic juice samples collected using the endoscopic cap method (median, .028%; IQR, 0-.077) compared with the noncap-collected (median, .019%; IQR, 0-.044; P = .055). Among pancreatic juice samples with detectable mutations, mutation concentrations were higher in the cap-collected juice samples than in those collected without the cap (.055%; IQR, .026-.092 vs .032%; IQR, .020-.066; P = .031). CONCLUSIONS: Collecting pancreatic juice directly from the ampulla using an endoscopic distal cap yields higher concentrations of pancreatic fluid mutations.
Assuntos
Endoscopia Gastrointestinal/instrumentação , Suco Pancreático , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Idoso , Ampola Hepatopancreática , Cromograninas/genética , Feminino , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Humanos , Biópsia Líquida/instrumentação , Masculino , Pessoa de Meia-Idade , Mutação , Pâncreas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Secretina/administração & dosagemRESUMO
OBJECTIVES: The aim of this study was to investigate the efficacy and mechanism of action of combined S-1 and nab-paclitaxel in pancreatic cancer. METHODS: Three human pancreatic cancer cell lines were treated with S-1, nab-paclitaxel, alone or in combination. Mice bearing subcutaneous xenograft of the cell line, PANC-1, were treated with the same drugs. RESULTS: The growth-inhibitory effect of combined S-1 and nab-paclitaxel was greater than that of the individual drugs, and the combination index value indicated that S-1 and nab-paclitaxel had a synergistic effect in vitro. The combination of S-1 and nab-paclitaxel showed greater efficacy in vivo than monotherapy, and the growth-inhibitory effect was significantly greater when compared with the controls (P = 0.009), although no significant reduction in body weight was observed. Fractional tumor volume analysis indicated that the combination had a synergistic effect. Tumor stroma staining with α-smooth muscle actin was significantly decreased by nab-paclitaxel (P < 0.001) while the number of CD31-stained microvessel lumina was significantly increased by the combination therapy when compared with the control (P = 0.046). CONCLUSIONS: S-1 and nab-paclitaxel had a synergetic effect in preclinical studies with good tolerability, and may play a role in stromal depletion and tumor angiogenesis. J. Surg. Oncol. 2016;113:413-419. © 2016 Wiley Periodicals, Inc.
Assuntos
Albuminas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Ácido Oxônico/farmacologia , Paclitaxel/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Tegafur/farmacologia , Albuminas/administração & dosagem , Animais , Linhagem Celular Tumoral , Combinação de Medicamentos , Sinergismo Farmacológico , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ácido Oxônico/administração & dosagem , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/patologia , Distribuição Aleatória , Células Estromais/efeitos dos fármacos , Células Estromais/patologia , Tegafur/administração & dosagem , Ensaios Antitumorais Modelo de XenoenxertoAssuntos
Carcinoma Ductal Pancreático , Neoplasias Primárias Desconhecidas , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/epidemiologia , Carcinoma Ductal Pancreático/terapia , Humanos , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/terapia , Lavagem Peritoneal , PrevalênciaRESUMO
BACKGROUND AND OBJECTIVES: The clinical implications of single nucleotide polymorphisms (SNPs) in CD44 remain unclear. This study examined the relationships of CD44 SNPs with clinicopathological parameters and prognosis in Japanese gastric cancer patients. METHODS: The CD44 SNPs were analyzed in 11 gastric cancer cell lines and 517 clinical specimens. The expression of CD44 standard (CD44s) and CD44 variant 9 isoform (CD44v9) transcripts were measured by quantitative real-time polymerase chain reaction. RESULTS: The CD44 rs187116 A/A, A/G, and G/G genotypes were present in 10.3%, 45.1%, and 44.7% of patients, respectively. The presence of CD44 rs187116 A/G or G/G genotypes was significantly associated with positive peritoneal washing cytology (P = 0.012). Disease-free survival of patients with these genotypes was significantly worse than in those with the A/A genotype (P = 0.039). Multivariate analysis showed that the CD44 rs187116 was independently prognostic of disease-free survival (P = 0.047). The CD44s/CD44v9 ratio was significantly lower in patients with the CD44 rs187116 A/A genotype than in those with the A/G (P = 0.046) and G/G (P = 0.047) genotypes. CONCLUSIONS: The CD44 rs187116 genotype could predict disease recurrence in Japanese gastric cancer patients, and the SNP was associated with CD44 isoform switching.
Assuntos
Biomarcadores Tumorais/genética , Receptores de Hialuronatos/genética , Recidiva Local de Neoplasia/genética , Polimorfismo de Nucleotídeo Único/genética , Neoplasias Gástricas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Isoformas de Proteínas , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Células Tumorais Cultivadas , Adulto JovemRESUMO
BACKGROUND: Patients with advanced gastric cancer (GC) have an adverse prognosis even after curative resection. Development of novel diagnostic and therapeutic approaches for GC is urgently required. METHODS: The expression and methylation status of DENN/MADD domain-containing protein 2D (DENND2D), a member of the membrane trafficking proteins, were evaluated in 12 GC cell lines and 112 pairs of surgical specimens. Subgroup analysis based on tumor differentiation, location, and morphology was also performed. Expression and distribution of DENND2D protein were determined by immunohistochemistry. RESULTS: The majority of GC cell lines (75%) and tissues (79%) showed reduced expression of DENND2D mRNA compared with noncancerous gastric tissues. GC tissues showed a significantly lower mean expression level of mRNA and a higher frequency of promoter hypermethylation of DENND2D than corresponding noncancerous tissues. No significant differences in DENND2D mRNA expression and methylation status were found between GC subtypes categorized by tumor differentiation, location, and morphology. The expression patterns of DENND2D protein were confirmed to be consistent with those of DENND2D mRNA. Downregulation of DENND2D mRNA in GC tissues was significantly associated with factors related to more advanced GC and subsequent adverse prognosis. Among 72 patients who underwent R0 resection, downregulation of DENND2D mRNA in GC tissues was an independent prognostic factor and associated with early recurrence. CONCLUSIONS: Our results suggested that DENND2D is a putative tumor suppressor gene regulated by promoter hypermethylation in GC. Downregulation of DENND2D can serve as a novel tumor biomarker to predict progression and early recurrence of all types of GC.
Assuntos
Biomarcadores Tumorais/genética , Metilação de DNA , Mucosa Gástrica/metabolismo , Regulação Neoplásica da Expressão Gênica , Fatores de Troca do Nucleotídeo Guanina/genética , Regiões Promotoras Genéticas/genética , Neoplasias Gástricas/genética , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Ilhas de CpG/genética , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estômago/patologia , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Taxa de Sobrevida , Células Tumorais Cultivadas , Adulto JovemRESUMO
BACKGROUND/AIMS: Pancreatic head carcinoma frequently invades the superior mesenteric vein (SMV) and/or portal vein (PV). We aimed to evaluate the outcome of transection of the splenic vein (SV) and inferior mesenteric vein (IMV) in pancreatoduodenectomy (PD) with SMV and/or PV resection. METHODS: We retrospectively analyzed the records of 660 patients who had undergone pancreatectomy at our institution from January 2004 to October 2013, and selected 141 consecutive patients who had undergone PD with concurrent SMV/PV resection. Postoperative hypersplenism and the presence of remnant branches were evaluated. RESULTS: The SV had been transected in 81 patients and preserved in 60. Postoperative complications and white blood cell counts were similar between the groups. The postoperative splenic volume was not significantly associated with the status of the SV or IMV on the transected SV. The platelet count was significantly lower, and the incidence of collateral veins was higher after SV transection than after SV preservation until 6 months after surgery; these variables were similar in the long term. CONCLUSION: SV reconstruction might be unnecessary when SV transection is required. Preservation of the IMV on the remnant SV might not prevent sinistral portal hypertension.
Assuntos
Veias Mesentéricas/cirurgia , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia/métodos , Veia Esplênica/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: The clinical significance of preservation of the pyloric ring in total pancreatectomy (TP) has not been elucidated. METHODS: A total of 48 consecutive patients underwent TP and were categorized into two groups based on the absence or presence of pylorus resection: the TP (N = 33) and pylorus-preserving TP (PPTP) (N = 15) groups. Preoperative patient background, intraoperative conditions, postoperative complications, and long-term nutritional status were retrospectively compared between the two groups. RESULTS: Patient background was similar between the groups, with the exception of the prevalence of preoperative diabetes mellitus (55 and 20 %, respectively; p = 0.021). There were no differences between groups with respect to operative times, blood loss, or blood transfusion. The PPTP group was more likely to have postoperative delayed gastric emptying than was the TP group (53 and 21 %, respectively; p = 0.029), and it tended to become increasingly severe. The length of the postoperative fasting period was significantly longer in the PPTP group than in the TP group (mean 15 ± standard deviation [SD] 10.8 and 9 ± 9.7 days, respectively; p = 0.023). The body weights in the TP group started to recover by 1 year postoperatively, whereas those in the PPTP group continued to decrease. Serum hemoglobin levels tended to be higher in the TP group than in the PPTP group at 1 year postoperatively. CONCLUSIONS: Preservation of the pyloric ring provided little or no benefit to short-term outcome or long-term nutritional status among patients who underwent TP.