Determination of malignant and invasive predictors in branch duct type intraductal papillary mucinous neoplasms of the pancreas: a suggested scoring formula.

Prediction of malignancy or invasiveness of branch duct type intraductal papillary mucinous neoplasm (Br-IPMN) is difficult, and proper treatment strategy has not been well established. The authors investigated the characteristics of Br-IPMN and explored its malignancy or invasiveness predicting factors to suggest a scoring formula for predicting pathologic results. From 1994 to 2008, 237 patients who were diagnosed as Br-IPMN at 11 tertiary referral centers in Korea were retrospectively reviewed. The patients' mean age was 63.1 ± 9.2 yr. One hundred ninty-eight (83.5%) patients had nonmalignant IPMN (81 adenoma, 117 borderline atypia), and 39 (16.5%) had malignant IPMN (13 carcinoma in situ, 26 invasive carcinoma). Cyst size and mural nodule were malignancy determining factors by multivariate analysis. Elevated CEA, cyst size and mural nodule were factors determining invasiveness by multivariate analysis. Using the regression coefficient for significant predictors on multivariate analysis, we constructed a malignancy-predicting scoring formula: 22.4 (mural nodule [0 or 1]) + 0.5 (cyst size [mm]). In invasive IPMN, the formula was expressed as invasiveness-predicting score = 36.6 (mural nodule [0 or 1]) + 32.2 (elevated serum CEA [0 or 1]) + 0.6 (cyst size [mm]). Here we present a scoring formula for prediction of malignancy or invasiveness of Br-IPMN which can be used to determine a proper treatment strategy.

Prognostic factors after early recurrence in patients who underwent curative resection for hepatocellular carcinoma.

BACKGROUND: The prognosis of the patients with early recurrence after curative hepatectomy for hepatocellular carcinoma (HCC) is usually dismal. METHODS: One hundred twenty-four patients underwent curative resection for HCC at Kyungpook National University Hospital from January 2002 to December 2006. An early recurrence was defined as a recurrence within 2 years after a curative resection. The risk factors associated with an early recurrence were analyzed as well as other risk factors correlated with survival after early recurrence. RESULTS: Early disease recurrence developed in 56 patients (45.2%). The risk factors associated with an early recurrence were a tumor size larger than 5 cm (P = 0.001) and the presence of tumor micrometastasis (P < 0.001). The 1 year/2 year overall survival, after early recurrence, was 57.0%/41.0% and the preoperative α-fetoprotein, C-reactive protein (CRP), tumor size, macroscopic vascular invasion, and number of tumors were associated with survival on the univariate analysis. The multivariate analysis showed that the independent risk factors for survival, after early disease recurrence, were a preoperative CRP >1.0 mg/dl and macroscopic vascular invasion. (P = 0.004, P < 0.001, respectively). CONCLUSION: The preoperative CRP and macroscopic vascular invasion were associated with the aggressiveness of early recurrent HCC.

Predictive factors for invasive intraductal papillary mucinous neoplasm of the pancreas.

BACKGROUNDS/AIMS: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas has malignant potential. Predicting invasive IPMN has proven difficult and controversial. We tried to identify predictive factors for invasive IPMN. METHODS: Thirty six patients underwent resection for IPMN from February 2001 to July 2011. Clinicopathological features including demographic, imaging, microscopic, and serological findings were retrospectively reviewed. Receiver operating characteristic (ROC) curve analysis was used to analyze sensitivity and specificity of all possible cut-off values for the diameter of the main pancreatic duct and mass size predicting invasive IPMN. Student t-test, chi-square test, and logistic regression were used for univariate and multivariate analysis. RESULTS: The mean age was 63.5±8.4 years. Males were more commonly affected (58.3% vs 41.7%). Pancreaticoduodenectomy was performed in 55.6% of patients, distal pancreatectomy in 36.1%, and central pancreatic resection in 8.3%. Non-invasive IPMNs were present in 80.6% (n=29), whereas invasive IPMNs were present in 19.4% (n=7). In univariate analysis, tumor location (p=0.036), Kuroda classification (p=0.048), mural nodule (p=0.016), and main duct dilatation (≥8 mm) (p=0.006) were statistically significant variables. ROC curve analysis showed that a value of 8 mm for the main duct dilatation and a value of 35 mm for the size of the mass lesion have 80% sensitivity and 75% specificity and 100% sensitivity and 82.6% specificity, respectively. However, in multivariate analysis, main ductal dilatation (≥8 mm) was identified to be the only independent factor for invasive IPMN (p=0.049). CONCLUSIONS: Main duct dilatation appears to be a useful indicator for predicting invasive IPMN.

Hypermethylation of the Ras association domain family 1A (RASSF1A) gene in gallbladder cancer.

The tumor suppressor gene Ras association domain family 1A (RASSF1A) is highly methylated in a wide range of human sporadic tumors. The current study investigated the hypermethylation of RASSF1A, the expression of RASSF1A protein, and the correlation between these and the clinicopathological features of gallbladder (GB) cancer in Korean patients. Formalin-fixed, paraffin-embedded tumors and non-neoplastic GB tissues (22 carcinomas, 8 adenomas, 26 normal epithelia) were collected from patients who had undergone surgical resection. The methylation status of two regions of the RASSF1A CpG island was determined by methylation-specific PCR (MSP), and the expression of RASSF1A protein was examined by immunohistochemistry using tissue microarrays. The K-RAS mutation was analyzed by direct sequencing. Methylation of the RASSF1A promoter (region 1) was detected in 22.7% (5/22) of carcinomas, 12.5% (1/8) of adenomas, and 0% (0/26) of normal gallbladder epithelia (P = 0.025). Methylation of the first exon (region 2) was found in 36.4% (8/22) of carcinomas, 25.0% (2/8) of adenomas, and 8.0% (2/26) of normal gallbladder epithelia (P = 0.038). K-RAS mutations were present in 4.5% (1/22) of carcinomas and 25% (2/8) of adenomas. RASSF1A methylaton was not associated with clinicopathological factors or K-ras mutation. Reduction or loss of RASSF1A expression was observed in most methylated adenocarcinomas. Three RASSF1A-expressing human biliary tract cancer cell lines examined contained unmethylated promoters and exons 1. These results suggest that downregulation of RASSF1A expression by DNA hypermethylation may be involved in GB carcinogenesis.

The surgeon's expertise-outcome relationship in gastric cancer surgery.

PURPOSE: The surgical caseload or duration of practice of a surgeon may influence the outcomes of gastric cancer surgery. This study aimed to clarify the surgical quality provided by specialized gastric cancer surgeons. MATERIALS AND METHODS: The postoperative courses of 1,877 patients who underwent surgery for gastric cancer were retrospectively reviewed. For classification of the surgeon's expertise, the number of yearly resections performed by, and consecutive years of practice of, the surgeons were used. The outcome measures used were the 30-day mortality and long-term survival. RESULTS: Surgical mortalities of patients who underwent surgery by a specialized surgeon and those by a general surgeon revealed no statistically significant difference. A significant difference in the five-year survival rates was found with surgeons with at least two consecutive years of practice compared to those with less than two years, when 50 or more cases had been conducted per year (63.9% and 59.7%; p=0.0380). In cases of four-years of consecutive practice, the five-year survival rate was significantly improved, even if only 10 cases were performed annually (64.9% and 58.3%; p=0.0023), although the best survival rate was found with surgeons that had performed 50 or more surgeries per year. CONCLUSION: Improved survival rates, with acceptable surgical mortality, can be achieved for gastric cancer when the surgery is performed by a specialized surgeon. A specialized gastric cancer surgeon can be defined as one who has operated on more than 50 new cases per year, with 2 or more consecutive years of surgical practice.

Comparison of epigenetic and genetic alterations in mucinous cystic neoplasm and serous microcystic adenoma of pancreas.

Mucinous cystic neoplasms and serous microcystic adenomas account for the majority of cystic tumors of pancreas. Mucinous cystic neoplasms and serous microcystic adenomas have different frequencies of progression to malignancy. The genetic and epigenetic alterations of these tumors have not been studied in detail. In this study, we compared methylation status of p16, p14, VHL, and ppENK genes by methylation-specific PCR (MSP), and genetic alterations including K-ras and beta-catenin gene mutations, chromosome 3p loss, and microsatellite instability in 15 mucinous cystic neoplasms (10 benign and 5 borderline) and 16 serous microcystic adenomas. There were no significant differences between mucinous cystic neoplasms and serous microcystic adenomas in methylation of p16 (14%, 2/14 and 12%, 2/16), p14 (15%, 2/13 and 37%, 6/16), VHL (0/14 and 7%, 1/14), and ppENK (0/14 and 0/13), respectively. K-ras mutation was present only in mucinous cystic neoplasms but not in serous microcystic adenomas (33%, 5/15 versus 0/16; P =.004). In addition, LOH at 3p25, the chromosomal location of VHL gene, was present in 57% (8/14) of serous microcystic adenomas compared with in 17% (2/12) of mucinous cystic neoplasms (P =.03). No beta-catenin mutation, microsatellite instability, or mutation of transforming growth factor beta type II receptor was present in either type of tumors. In conclusion, K-ras mutations and allelic loss of VHL locus at 3p25, but not methylation, distinguished mucinous cystic neoplasms and serous microcystic adenomas. The differences in genetic alterations but not epigenetic alterations may explain the pathogenesis and progression to malignancy of these cystic tumors of pancreas.

Enhanced inflammatory cytokine production at ischemia/reperfusion in human liver resection.

BACKGROUND/AIMS: Clinical implications of acute reactant cytokine responses remain to be clarified in the setting of ischemia/reperfusion of human liver during liver resection and transplantation. METHODOLOGY: In serial samples of portal and systemic venous blood we examined acute inflammatory cytokine activities at the time points--before i), at the end of clamping ii), and one hour iii) and day 1 iv) after continuous hepatic inflow occlusion in 25 patients undergoing elective hepatectomy (15 major and 10 minor). Responses of tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6 and interleukin-8 were compared with intraoperative parameters such as the duration of hepatic inflow occlusion and portal venous pressure during the occlusion, postoperative hepatocyte injury markers such as serum transaminases and bilirubin and also related complications. RESULTS: Portal interleukin-6 levels were significantly elevated during hepatic inflow occlusion, as compared with the systemic events (P < 0.02, at time point ii), but there were no differences in the interleukin-8 levels between the portal and systemic circulation. The increase in portal interleukin-6 levels during liver resection (time points, ii and iii) significantly correlated with the duration of hepatic inflow occlusion (48 +/- 9 min, mean +/- SD), portal venous pressure (500 +/- 127 mmH2O), and postoperative serum levels of transaminases (day 1; S-ALT, 705 +/- 1023 U/L; S-AST 892 +/- 1255 U/L) and maximum bilirubin (2.6 +/- 2.5 mg/dL). Interleukin-8 levels in the portal circulation showed no such correlation, but the levels in systemic blood showed significant positive relationships with the intra- and postoperative parameters. One patient who died had an enhanced generation of the cytokines in the presence of an elevated portal venous pressure. CONCLUSIONS: These observations suggest that overproduction of acute reactant cytokines (interleukin-6 from the portal system and interleukin-8 from the systemic circulation) in hepatic ischemia/reperfusion relates positively with postoperative hepatocyte injury in humans. We propose that hepatectomy done under a prolonged continuous inflow occlusion should be reconsidered when an enhanced generation of acute cytokines is anticipated, especially in case of a markedly high portal pressure during hepatic pedicle clamping.

Hepatocyte protection by a protease inhibitor against ischemia/reperfusion injury of human liver.

BACKGROUND: Total clamping of the hepatic pedicle can induce profound hepatic ischemia/reperfusion (I/R) injury, which remains a potentially lethal problem after hepatectomy. STUDY DESIGN: The purpose of this study was to evaluate the efficacy of a protease inhibitor in ameliorating I/R injury of the human liver. In a prospective, randomized, clinical study, 66 patients who underwent liver resection under conditions of continuous inflow occlusion were randomly assigned to three groups: 25 patients were given a synthetic protease inhibitor (gabexate mesilate [GM], 2.0 mg/kg/hr) intravenously starting 24 hours before surgery until postoperative day 3 (preop GM group); 16 were similarly given GM at the beginning of surgery (intraop GM group); and 25 served as controls (without GM group). Laboratory data and intraoperative and postoperative variables were analyzed and plasma levels of cytokines--tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6)--were measured to determine the relationship between surgical stress and hepatic I/R injury. RESULTS: The three groups of patients were similar in terms of age, gender, preoperative assessments, hepatic inflow occlusion time (approximately 50 minutes), extent of resection (proportion of major and minor hepatectomy), and background liver conditions. Preoperative administration of gabexate mesilate (preop GM group) substantially ameliorated hepatic I/R injury as compared with the other patients (intraop and without GM groups); postoperative serum transaminase levels were notably decreased in association with marked suppression of IL-6 levels in blood circulation during liver surgery. This was accompanied by a lower rate of postoperative complications and no mortality. Gabexate mesilate pretreatment abrogated the positive correlation between postreperfusion hepatocyte injury and hepatic ischemia time. CONCLUSIONS: Preoperative administration of GM is useful for preventing I/R injury of the human liver, accompanied by suppression of the plasma proinflammatory cytokine IL-6.