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Background: The conventional H category-based classification for colorectal liver metastases (CRLM) was created by equal weighting of tumor number and tumor size; however, our previous nomogram to predict postoperative disease-free survival demonstrated that CRLM =5 as a parameter provided 4.5 times greater impact compared with a largest CRLM size >5 cm. Methods: A total of 3815 patients newly diagnosed with CRLM between 2005 and 2007, including 2220 resectable cases, were investigated. Six groups were created based on largest lesion size (= 5 vs >5 cm) and lesion number (1, 2-4, and =5). Results: The novel (n) H1, nH2, and nH3 categories were defined as solitary lesions with a size =5 cm; lesions other than nH1 or nH3; and =5 lesions with any lesion size, respectively. In the resectable cohort, the 5-year cumulative overall survival rates were 64.0%, 53.5%, and 42.6% in the nH1, nH2, and nH3 groups, respectively (P < .001), and no significant differences were observed between the conventional H2 and H3 categories. In the overall cohort, the discrimination ability of the two classifications were comparable. Conclusion: The novel H category-based classification might be beneficial in predicting overall survival in patients with CRLM independent of their resectability. [ABSTRACT FROM AUTHOR]

Background: The high operative mortality rate after hepatopancreatoduodenectomy (HPD) is still a major issue. The present study explored why operative mortality differs significantly due to hospital volume. Method: Surgical case data were extracted from the National Clinical Database (NCD) in Japan from 2011 to 2014. Surgical procedures were categorized as major (=2 sections) and minor (<2 sections) hepatectomy. Hospitals were categorized according to the certification system by the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS) based on the number of major hepato-biliary-pancreatic surgeries performed per year. The FTR rate was defined as death in a patient with at least one postoperative complication. Results: A total of 422 patients who underwent HPD were analyzed. The operative mortality rates in board-certified A training institutions, board-certified B training institutions, and non-certified institution were 7.2%, 11.6%, and 21.4%, respectively. Multiple logistic regression showed that certified A institutions, major hepatectomy, and blood transfusion were the predictors of operative mortality. Failure to rescue rates were lowest in certified A institutions (9.3%, 17.0%, and 33.3% in certified A, certified B, and non-certified, respectively). Conclusions: To reduce operative mortality after HPD, further centralization of this procedure is desirable. Future studies should clarify specific ways to improve the failure-to-rescue rates in certified institutions. [ABSTRACT FROM AUTHOR]

Background/Aim: The aim of the study was to compare the outcomes of anatomical resection (AR) versus non-anatomical resection (NAR) for Japanese and Taiwanese patients with single, resectable hepatocellular carcinoma (HCC). Patients and Methods: A propensity score matched (PSM) analysis was performed to compare the outcomes of the AR group to those of the NAR group. Tumor size <5 cm, T1 or T2 grade, without evidence of extrahepatic metastasis, invasion of portal or hepatic veins, or direct invasion of adjacent organs, were included in the study. Results: A total of 385 cases (Taiwanese 105, Japanese 280) were analyzed. After PSM, a total of 152 cases remain (Taiwan and Japan both 76 cases). Disease-free survival (DFS) and overall survival (OS) data were not significantly different between the two groups at 5 years follow-up. Conclusion: AR of HCC in Japanese patients has a similar 5-year DFS and OS as NAR of HCC in Taiwanese patients. [ABSTRACT FROM AUTHOR]

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant disorder characterized by progressive and profoundly disabling heterotopic ossification (HO). Here we show that fibro/adipogenic progenitors (FAPs) are a major cell-of-origin of HO in an accurate genetic mouse model of FOP (Acvr1tnR206H). Targeted expression of the disease-causing type I bone morphogenetic protein (BMP) receptor, ACVR1(R206H), to FAPs recapitulates the full spectrum of HO observed in FOP patients. ACVR1(R206H)-expressing FAPs, but not wildtype FAPs, activate osteogenic signaling in response to activin ligands. Conditional loss of the wild-type Acvr1 allele dramatically exacerbates FAP-directed HO, suggesting that mutant and wild-type ACVR1 receptor complexes compete for activin ligands or type II BMP receptor binding partners. Finally, systemic inhibition of activin A completely blocks HO and restores wild-type-like behavior to transplanted Acvr1R206H/+ FAPs. Understanding the cells that drive HO may facilitate the development of cell-specific therapeutic approaches to inhibit catastrophic bone formation in FOP. [ABSTRACT FROM AUTHOR]

Comprehensive genetic analysis of colorectal malignant tumors by microarrays has identified translocase of the outer mitochondrial membrane 34 (TOMM34) and ring finger protein 43 (RNF43) as highly expressed oncogenes in malignant colorectal tumors. Vaccine therapy using cancer peptides synthesized using the amino acid sequences of tumor antigens is currently undergoing clinical trials. Since it is important to perform vaccine therapy based on the oncogene expression levels in individual tumors, analysis of tumor antigen expression is necessary for this therapy. However, the quality of the messenger RNA extracted from formalin-fixed and paraffin-embedded specimens is generally considered insufficient for gene quantification. The present study examined whether it could be possible to quantify the expression of TOMM34 and RNF43 in colorectal cancer and liver metastasis samples prepared from paraffin blocks. The formalin-fixed and paraffin-embedded specimens were sliced for slides and the colorectal cancer and normal mucosal tissues were obtained from the slides. Total RNA was extracted from the tissue samples, and quantitative polymerase chain reaction (qPCR) was performed using the Universal ProbeLibrary as a PCR probe. Quantification of TOMM34 and RNF43 gene expression in several-year-old paraffin-embedded colorectal cancer specimens was possible by qPCR using the Universal ProbeLibrary. qPCR revealed that TOMM34 expression was elevated in 78.9% (15 of 19 cases) of the primary tumors and in 73.7% (14 of 19 cases) of the liver metastasis samples. RNF43 expression was elevated in 63.2% (12 of 19 cases) of the primary tumors and in 73.7% (14 of 19 cases) of the liver metastasis samples. [ABSTRACT FROM AUTHOR]

Thymidylate synthase (TYMS) and dihydropyrimidine dehydrogenase (DPYD) are associated with the response of tumors to fluoropyrimidines. The aim of the present study was to investigate the association between the levels of TYMS and DPYD mRNAs and the efficacy of S‑1 for treating patients with HCC. A total of 35 patients with HCC who received S‑1 upon recurrence (S‑1 group) and 20 patients who never received a fluoropyrimidine (control group) were studied. The levels of TYMS and DPYD mRNA in surgically resected specimens were determined using reverse transcription‑polymerase chain reaction assays. Overall survival (OS) time of S‑1 group patients with high levels of DPYD mRNA was significantly longer compared with that of patients with low levels (median 501 days vs. 225 days; P=0.016). Similarly, the OS time of those patients with high levels of TYMS mRNA was significantly longer compared with those with low levels (median 503 days vs. 239 days; P=0.0076). By contrast, there was no difference in OS time of the control group between patients with high and low levels of DPYD and TYMS mRNAs. The levels of TYMS and DPYD mRNAs may serve as predictive markers for patients with HCC who receive S-1 chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Various types of preoperative chemoradiotherapy (CRT) have been established for rectal cancer; thus, Physicians will need to refine the selection of appropriate preoperative CRT for different patients since there are various treatment regimens. Oral tegafur-uracil (UFT) plus leucovorin (LV) is commonly used to treat rectal cancer in Japan. Oral chemotherapy offers patients many potential advantages. Since 2008, we have been performing preoperative CRT with intermittent oral UFT plus LV in locally advanced rectal cancer patients to prevent postoperative local recurrence. Here, in a retrospective analysis, we evaluated the efficacy and short-term outcomes of preoperative CRT with intermittent oral UFT plus LV. Methods: We analyzed data from 62 patients with locally advanced rectal cancer, including 31 patients who underwent preoperative CRT between 2009 and 2013 (the CRT group) and 31 patients who were treated with surgery alone between 2001 and 2008 (the non-CRT group). Clinicopathologically, both groups included patients with rectal cancer at clinical tumor stages III-IV or clinical node stages 0-III. In the CRT group, curative operations were performed ≥8 weeks after CRT. Patients were concomitantly treated with 2 cycles of oral UFT (300 mg/m2/day, days 1-14 and 29- 42) plus LV (75 mg/day, days 1-14 and 29-42) and 45 Gy of radiotherapy. Chemotherapy was repeated every 28 days, followed by a 2-week break. Results: The completion rate of CRT was high at 94% (n = 29/31). The downstaging rate of CRT was 61% (n = 19/31). The pathological complete response rate was 6.5% (n = 2/31). Significant differences were observed in the 3-year local recurrence rate between the two groups (P < 0.05). Conclusions: Preoperative CRT with intermittent oral UFT plus LV appears to be a tolerable and effective treatment for Japanese patients with rectal cancer. A further investigation of a diversification of preoperative CRT for Japanese rectal cancer patients is required. [ABSTRACT FROM AUTHOR]

Background: The molecular profiles of tumors may inform the selection of appropriate targeted therapies. Circulating tumor cells (CTCs) reflect the real-time status of tumor genotypes. CTCs exhibit high genetic heterogeneity within a patient; accordingly, the analysis of individual CTCs, including their heterogeneity, may enable more precise treatments. We analyzed KRAS mutations in single CTCs from patients with metastatic colorectal cancer (mCRC) using a new single-cell picking system.Methods: Blood samples were obtained from 61 patients with mCRC. CTCs were enriched and fluorescently labeled using the CellSearch® System. They were recovered using the single-cell picking system based on the fluorescence intensity of marker dyes. Single CTCs and tumor tissue samples were examined for mutations in codons 12 and 13 of the KRAS gene.Results: CTCs were detected in 27 of 61 patients with mCRC. We isolated at least two CTCs from 15 of 27 patients. KRAS genotype was evaluated in a total of 284 CTCs from 11 patients, and 15 cells with mutations were identified in four patients. In 10 of 11 patients, the KRAS status was the same in the primary tumor and CTCs. In one patient, the KRAS status was discordant between the primary tumor and CTCs. In two patients, different KRAS mutations were found among individual CTCs.Conclusions: We successfully isolated single CTCs and detected KRAS mutations in individual cells from clinical samples using a novel application of single-cell isolation system. Using the system, we detected CTC heterozygosity and heterogeneity in KRAS status among CTCs within a patient and between CTCs and tumor tissues. [ABSTRACT FROM AUTHOR]

Background: Several recent studies have reported that patients with metastatic colorectal cancer (CRC) whose primary tumor is located in left side of the colon have more favorable responses to anti-epidermal growth factor receptor (EGFR) antibody therapy than those with right-sided tumors. However, the mechanism for this phenomenon is unknown.Methods: Fifty-two cases of primary CRC with liver metastases were analyzed in this retrospective study. The mRNA levels of 19 signal transduction genes in both primary tumor and liver metastases were measured by real-time reverse transcription polymerase chain reaction. The purposes of this study were (1) to determine the correspondence between signal transduction gene expressions in primary tumors and corresponding liver metastases, and (2) to determine whether expression levels of these genes differ by primary tumor location.Results: mRNA expression levels of 14 of 19 signal transduction genes, including PTEN, ERBB2, MET, HGF, AREG, and EREG, showed significant correlations between the primary tumor and corresponding liver metastases. When the mRNA levels of the primary tumors were compared by tumor location, only PTEN mRNA expression differed significantly between left and right-sided CRC (median PTEN expression: left 1.00 vs. right 1.68; p = 0.017). When rectal cancers were separated from left-sided colon cancers, PTEN mRNA levels increased progressively from rectum to right-sided colon (median; rectum 0.84, left colon 1.23, right colon 1.68, p = 0.013). PTEN mRNA expression in liver metastases also differed significantly according to primary tumor location (median; left 0.92 vs. right 1.27, p = 0.048). There was no difference in overall survival between patients with high versus low levels of PTEN mRNA (p = 0.59).Conclusions: Our data suggest that the PIK3/AKT/mTOR pathway is more active in left- than right-sided CRC, which provides a possible explanation for the fact that efficacy of anti-EGFR therapy differs by location of primary tumor. [ABSTRACT FROM AUTHOR]

We describe a 64-year-old man diagnosed as having gastric cancer with a patent right gastroepiploic artery (RGEA) used for coronary artery bypass grafting (CABG). Before gastrectomy, the native coronary artery was revascularized to safely dissect the infrapyloric lymphatic tissue along the layer recently identified as an appropriate layer for radical lymphadenectomy, in anticipation of preserving the radically skeletonized RGEA. The perioperative strategy was feasible. Postoperatively, hemorrhage extended the stopping period of antiplatelet therapy. However, since the RGEA was preserved, an alternative route was available for coronary flow. After a 41-month postoperative follow-up, the patient remained in good health, with no recurrence or cardiac ischemia. In this case, the alternative route of coronary flow could be constantly maintained, although radical infrapyloric lymphadenectomy had been performed. Preoperative revascularization and preserving the RGEA with radical skeletonization can be a safe yet permissibly radical strategy for gastric cancer treatment following CABG involving the RGEA. [ABSTRACT FROM AUTHOR]

Angiogenesis is an important mechanism of tumor development, growth and metastasis in hepatocellular carcinoma (HCC). The poor prognosis of HCC patients has been associated with a failure to detect recurrences following surgery. In the present study, we investigated the association between the patient characteristics and the expression of angiogenic genes to identify early biomarkers of HCC. A comprehensive angiogenic gene expression profile was obtained by paired TaqMan gene array analysis of primary HCC nodules and adjacent non-HCC liver tissue from 12 patients. A total of 14 genes were found to be differentially expressed in HCC liver nodules (>2-fold change); the genes encoding collagen type XVα1, IVα1 and IVα2 were upregulated and the genes associated with vessel growth, neuropilin 2 (NRP2) and lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) were downregulated. The histopathological analysis revealed that the evolution of HCC nodules from well to poorly differentiated was associated with a 5-fold decrease in LYVE-1 expression, reaching its lowest level early during the transition. The significance of this gene as a biomarker of postoperative survival was demonstrated by a 2-fold decrease in overall survival (OS) rates in the low expression group compared to the high expression group. The multivariate and univariate Cox regression analyses identified LYVE-1 expression as a significant independent prognostic parameter of OS [hazard ratio (HR)=3.067; 95% confidence interval (CI): 1.507-6.273; P=0.0021]. Thus, the results of this study suggested that LYVE-1 expression may constitute a novel early biomarker of postoperative survival in HCC patients. [ABSTRACT FROM AUTHOR]

A 69-year-old man, who had undergone pylorus-preserving pancreaticoduodenectomy (PD) (Imanaga procedure) for duodenum papilla cancer 13 years prior, had a history of repeated hospitalization due to cholangitis since the third year after surgery and liver abscess at the 10th year after surgery. Gastrointestinal series indicated no stenosis after the cholangiojejunostomy. However, reflux of contrast media into the bile duct and persistence of food residues were observed. We considered the cholangitis to be caused by reflux and persistence of food residues into the bile duct. So, we performed the tract conversion surgery, Imanaga procedure to Child method. The postoperative course was good even after re-initiating dietary intake. He was discharged on the 19th day after surgery. He has not experienced recurrent cholangitis for 18 months. For patients with post-PD recurrent cholangitis caused by reflux of food residues like ours, surgical treatment should be considered because tract conversion may be an effective solution. [ABSTRACT FROM AUTHOR]

Abstract Purpose  We assessed the significance of an extra bile duct resection by comparing the survival of patients with advanced gallbladder carcinoma who had resected bile ducts with those who had preserved bile ducts. A radical cholecystectomy that includes extra bile duct resections has been performed without any clear evidence of whether an extra bile duct resection is preventive or curative. Methods  We conducted a questionnaire survey among clinicians who belonged to the 114 member institutions of the Japanese Society of Biliary Surgery. The questionnaires included questions on the preoperative diagnosis, complications, treatment, and surgical treatment, resection procedures, surgical results, pathological and histological findings, mode and site of recurrence, and the need for additional postoperative treatment. A total of 4243 patients who had gallbladder carcinoma and were treated from January 1, 1994 to December 31, 2003 were identified. The 838 R0 patients with pT2, pT3, and pT4 advanced carcinoma of the gallbladder for which there was no cancer invasion to the hepatoduodenal ligament or cystic duct in the final analysis. Results  The 5-year cumulative survival, postoperative complications, postoperative lymph node metastasis, and local recurrence along the hepatoduodenal ligament were not substantially different between the resected bile duct and the preserved bile duct groups. Conclusions  Our retrospective questionnaire survey showed that an extrahepatic bile duct resection had no preventive value in some patients with advanced gallbladder carcinoma in comparison to similar patients who had no such bile duct resection. An extrahepatic bile duct resection may therefore be unnecessary in advanced gallbladder carcinoma without a direct infiltration of the hepatoduodenal ligament and the cystic duct. [ABSTRACT FROM AUTHOR]

Abstract Background/purpose  Graft survival is affected by various factors, such as preoperative state and the ages of the recipient and donor, as well as graft size. The objective of this study was to analyze the risk factors for graft survival. Methods  From September 1997 to July 2005, 24 patients who had undergone living-donor liver transplantation (LDLT) were retrospectively analyzed. Sixteen patients survived and the eight graft-loss cases were classified into two groups according to the cause of graft loss: graft dysfunction without major post-transplantation complications (graft dysfunction group; n = 3), and graft dysfunction with such complications (secondary graft dysfunction group; n = 5). Various factors were compared between these groups and the survival group. Results  Mean donor age was 31.9 years in the survival group and 49.2 years in the secondary graft dysfunction group (P = 0.024). Graft weight/recipient standard liver volume ratios (G/SLVs) were 36.7% in the survival group, and 26.2% in the graft dysfunction group (P = 0.037). The postoperative mean PT% for 1 week was 48.6% in the survival group and 38.1% in the secondary graft dysfunction group (P = 0.05). Conclusions  Our surgical results demonstrated that G/SLV and donor age were independent factors that affected graft survival rates. [ABSTRACT FROM AUTHOR]

Abstract Purpose  We conducted this study to evaluate the optimal hepatic resection for pT2 and pT3 advanced carcinoma of the gallbladder without invasion of the hepatoduodenal ligament. Methods  We conducted a questionnaire survey regarding 4,243 cases of carcinoma of the gallbladder treated during the recent 10-year period at 112 institutions belonging to the Japanese Society of Biliary Surgery. The questionnaires included questions on preoperative-diagnosis, complications, treatment, and surgical treatment, procedures of resection, surgical result, path histological findings, mode, and site of recurrence, additional post-operative treatment. They included 293 pT2 and 192 pT3 R0 cases, which were negative for hepatoduodenal ligament invasion, and the cumulative survival rates and sites of postoperative recurrence in the form of liver metastasis, were retrospectively analyzed in these 485 cases. Result  There were no significant differences in survival rate or recurrence rates in the form of liver metastasis between the groups that underwent resection of the gallbladder bed, the group that underwent segmentectomy 4a+5, and the group that underwent hepatectomy in patients with of both pT2 or pT3 gallbladder cancers. Our results also did not show that liver metastasis to segment 4a5 alone was particularly common. Conclusion  For gallbladder cancer, neither with hepatoduodenal ligament invasion nor hepatic invasion, resection of the gallbladder bed is more preferable for surgical hepatic procedure. For gallbladder cancer that invades any hepatic sites, a hepatic surgical procedure that could eliminate surgical margins would be desirable. [ABSTRACT FROM AUTHOR]

Abstract  The only curative treatment in biliary tract cancer is surgical treatment. Therefore, the suitability of curative resection should be investigated in the first place. In the presence of metastasis to the liver, lung, peritoneum, or distant lymph nodes, curative resection is not suitable. No definite consensus has been reached on local extension factors and curability. Measures of hepatic functional reserve in the jaundiced liver include future liver remnant volume and the indocyanine green (ICG) clearance test. Preoperative portal vein embolization may be considered in patients in whom right hepatectomy or more, or hepatectomy with a resection rate exceeding 50%–60% is planned. Postoperative complications and surgery-related mortality may be reduced with the use of portal vein embolization. Although hepatectomy and/or pancreaticoduodenectomy are preferable for the curative resection of bile duct cancer, extrahepatic bile duct resection alone is also considered in patients for whom it is judged that curative resection would be achieved after a strict diagnosis of its local extension. Also, combined caudate lobe resection is recommended for hilar cholangiocarcinoma. Because the prognosis of patients treated with combined portal vein resection is significantly better than that of unresected patients, combined portal vein resection may be carried out. Prognostic factors after resection for bile duct cancer include positive surgical margins, especially in the ductal stump; lymph node metastasis; perineural invasion; and combined vascular resection due to portal vein and/or hepatic artery invasion. For patients with suspected gallbladder cancer, laparoscopic cholecystectomy is not recommended, and open cholecystectomy should be performed as a rule. When gallbladder cancer invading the subserosal layer or deeper has been detected after simple cholecystectomy, additional resection should be considered. Prognostic factors after resection for gallbladder cancer include the depth of mural invasion; lymph node metastasis; extramural extension, especially into the hepatoduodenal ligament; perineural invasion; and the degree of curability. Pancreaticoduodenectomy is indicated for ampullary carcinoma, and limited operation is also indicated for carcinoma in adenoma. The prognostic factors after resection for ampullary carcinoma include lymph node metastasis, pancreatic invasion, and perineural invasion. [ABSTRACT FROM AUTHOR]

A high rate of sleep apnea syndrome (SAS) complicated by atrial fibrillation (AF) has been reported. We reviewed the frequency of SAS complications in AF patients, and reported on the patients for whom SAS was considered to be a cause of the AF. We studied 28 patients with AF who were able to receive a sleep apnea examination. All patients had oxygen saturation measured by an ambulatory percutaneus monitor (PULSOX) during sleep. A sleep apnea examination was performed by polysomnograph (Morpheus) in 19 of the patients. There were 18 patients (64%) with moderate to severe SAS whose apnea hypoxia index (AHI) or 3% oxygen disaturation index was more than 20. In this study, AF was stopped by treating SAS with continuous positive airway pressure (CPAP) or noninvasive positive pressure ventilation (NPPV) in 2 cases. Our study shows a high rate of SAS complications with AF, which is in accord with previous studies. We experienced cases in which AF was stopped by treating SAS with CPAP or NPPV, suggesting it is a cause of AF. [Copyright &y& Elsevier]

Abstract  From 1979 to 1996, 32 patients underwent at least right hepatic lobectomy with pancreatoduodenectomy (right HPD) for advanced carcinoma of the biliary tract at our institute. Twelve of the 32 patients underwent hepatoligamentopancreatoduodenectomy (HLPD). Curative resection was achieved in 20 (63%) of the 32 patients, but the operative outcomes were not satisfactory. Operative deaths occurred in 15 (47%) of the 32 patients, and postoperative complications in 29 (91%). The overall cumulative 1-, 3-, and 5-year survival rates were 12%, 6%, and 3%, respectively. These results suggested that simultaneous hepatectomy of the right lobe and pancreatoduodenectomy is undesirable, especially when accompanied by vascular resection and reconstruction. Since 1997, we have used partial pancreatectomy and partial duodenectomy instead of pancreatoduodenectomy for access to peripancreatic lesions, and this has markedly improved the operative outcome. From 1997 to 2004, 42 patients underwent resection of the right hepatic lobe, extrahepatic bile duct, and other related organs for advanced carcinoma of the biliary tract. There were postoperative complications in 13 (31%), but no operative death occurred. Recent advances in operative procedures and perioperative management may offer greater safety for right HPD, but the appropriate applications of and the necessity for right HPD are still matters of controversy and require further discussion. [ABSTRACT FROM AUTHOR]

The initial value problem for the two-dimensional dissipative quasi-geostrophic equation derived from geophysical fluid dynamics is studied. The dissipation of this equation is given by the fractional Laplacian. It is known that the half Laplacian is a critical dissipation for the quasi-geostrophic equation. The global existence of solutions upon the suitable condition is also well known, and that solutions of a fractional dissipative equation decay with a polynomial order as the spatial variable tends to infinity. In this paper, far field asymptotics of solutions to the quasi-geostrophic equation are given in the critical and the supercritical cases. Those estimates are derived from the energy methods for the difference between the solution and its asymptotic profile. [ABSTRACT FROM AUTHOR]