Toshiki Rikiyama

DNA methylation alterations of AXIN2 in serrated adenomas and colon carcinomas with microsatellite instability

BackgroundRecent work led to recognize sessile serrated adenomas (SSA) as precursor to many of the sporadic colorectal cancers with microsatellite instability (MSI). However, comprehensive analyses of DNA methylation in SSA and MSI cancer have not been conducted.MethodsWith an array-based methylation sensitive amplified fragment length polymorphism (MS-AFLP) method we analyzed 8 tubular (TA) and 19 serrated (SSA) adenomas, and 14 carcinomas with (MSI) and 12 without (MSS) microsatellite instability. MS-AFLP array can survey relative differences in methylation between normal and tumor tissues of 9,654 DNA fragments containing all NotI sequences in the human genome.ResultsUnsupervised clustering analysis of the genome-wide hypermethylation alterations revealed no major differences between or within these groups of benign and malignant tumors regardless of their location in intergenic, intragenic, promoter, or 3′ end regions. Hypomethylation was less frequent in SSAs compared with MSI or MSS carcinomas. Analysis of variance of DNA methylation between these four subgroups identified 56 probes differentially altered. The hierarchical tree of this subset of probes revealed two distinct clusters: Group 1, mostly composed by TAs and MSS cancers with KRAS mutations; and Group 2 with BRAF mutations, which consisted of cancers with MSI and MLH1 methylation (Group 2A), and SSAs without MLH1 methylation (Group 2B). AXIN2, which cooperates with APC and β-catenin in Wnt signaling, had more methylation alterations in Group 2, and its expression levels negatively correlated with methylation determined by bisulfite sequencing. Within group 2B, low and high AXIN2 expression levels correlated significantly with differences in size (P = 0.01) location (P = 0.05) and crypt architecture (P = 0.01).ConclusionsSomatic methylation alterations of AXIN2, associated with changes in its expression, stratify SSAs according to some clinico-pathological differences. We conclude that hypermethylation of MLH1, when occurs in an adenoma cell with BRAF oncogenic mutational activation, drives the pathway for MSI cancer by providing the cells with a mutator phenotype. AXIN2 inactivation may contribute to this tumorigenic pathway either by mutator phenotype driven frameshift mutations or by epigenetic deregulation contemporary with the unfolding of the mutator phenotype.

The “right” way is not always popular: comparison of surgeons’ perceptions during laparoscopic cholecystectomy for acute cholecystitis among experts from Japan, Korea and Taiwan

Generally, surgeons’ perceptions of surgical safety are based on experience and institutional policy. Our recent pilot survey demonstrated that the acceptable duration of surgery and criteria for open conversion during laparoscopic cholecystectomy (LC) vary among workplaces.

What are the appropriate indicators of surgical difficulty during laparoscopic cholecystectomy? Results from a Japan‐Korea‐Taiwan multinational survey

Serious complications continue to occur in laparoscopic cholecystectomy (LC). The commonly used indicators of surgical difficulty such as the duration of surgery are insufficient because they are surgeon and institution dependent. We aimed to identify appropriate indicators of surgical difficulty during LC.

Tokyo Guidelines 2018: initial management of acute biliary infection and flowchart for acute cholangitis

The initial management of patients with suspected acute biliary infection starts with the measurement of vital signs to assess whether or not the situation is urgent. If the case is judged to be urgent, initial medical treatment should be started immediately including respiratory/circulatory management if required, without waiting for a definitive diagnosis. The patients medical history is then taken; an abdominal examination is performed; blood tests, urinalysis, and diagnostic imaging are carried out; and a diagnosis is made using the diagnostic criteria for cholangitis/cholecystitis. Once the diagnosis has been confirmed, initial medical treatment should be started immediately, severity should be assessed according to the severity grading criteria for acute cholangitis/cholecystitis, and the patients general status should be evaluated. For mild acute cholangitis, in most cases initial treatment including antibiotics is sufficient, and most patients do not require biliary drainage. However, biliary drainage should be considered if a patient does not respond to initial treatment. For moderate acute cholangitis, early endoscopic or percutaneous transhepatic biliary drainage is indicated. If the underlying etiology requires treatment, this should be provided after the patients general condition has improved; endoscopic sphincterotomy and subsequent choledocholithotomy may be performed together with biliary drainage. For severe acute cholangitis, appropriate respiratory/circulatory management is required. Biliary drainage should be performed as soon as possible after the patients general condition has been improved by initial treatment and respiratory/circulatory management. Free full articles and mobile app of TG18 are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47. Related clinical questions and references are also included.

An opportunity in difficulty: Japan–Korea–Taiwan expert Delphi consensus on surgical difficulty during laparoscopic cholecystectomy

We previously identified 25 intraoperative findings during laparoscopic cholecystectomy (LC) as potential indicators of surgical difficulty per nominal group technique. This study aimed to build a consensus among expert LC surgeons on the impact of each item on surgical difficulty.

Molecular biomarkers for the detection of metastatic colorectal cancer cells

Approximately half of all patients with colorectal cancer develop local recurrence or distant metastasis during the course of their illness. Recently, the molecular detection of metastatic cancer cells in various types of clinical samples, such as lymph nodes, bone marrow, peripheral blood, and peritoneal lavage fluid, has been investigated as a potential prognostic marker. The prognostic value of molecular tumor cell detection was independent of the type of detection method used. As assays become more sensitive and quantitative, a more thorough assessment of the cancer status of patients will be based on molecular markers alone. At present, it is difficult to conclude that one specific molecular marker is superior to others. Comparative analyses are recommended to assess the prognostic impact of molecular analyses in the same patient and determine the biomarkers that provide the most accurate prognostic information.

Delphi consensus on bile duct injuries during laparoscopic cholecystectomy: an evolutionary cul‐de‐sac or the birth pangs of a new technical framework?

Bile duct injury (BDI) during laparoscopic cholecystectomy remains a serious iatrogenic surgical complication. BDI most often occurs as a result of misidentification of the anatomy; however, clinical evidence on its precise mechanism and surgeons’ perceptions is scarce. Surgeons from Japan, Korea, Taiwan, and the USA, etc. (n = 614) participated in a questionnaire regarding their BDI experience and near‐misses; and perceptions on landmarks, intraoperative findings, and surgical techniques. Respondents voted for a Delphi process and graded each item on a five‐point scale. The consensus was built when ≥80% of overall responses were 4 or 5. Response rates for the first‐ and second‐round Delphi were 60.6% and 74.9%, respectively. Misidentification of local anatomy accounted for 76.2% of BDI. Final consensus was reached on: (1) Effective retraction of the gallbladder, (2) Always obtaining critical view of safety, and (3) Avoiding excessive use of electrocautery/clipping as vital procedures; and (4) Calots triangle area and (5) Critical view of safety as important landmarks. For (6) Impacted gallstone and (7) Severe fibrosis/scarring in Calots triangle, bail‐out procedures may be indicated. A consensus was reached among expert surgeons on relevant landmarks and intraoperative findings and appropriate surgical techniques to avoid BDI.

The importance of tissue environment surrounding the tumor on the development of cancer cachexia

The relationship between host factors and cancer cachexia was investigated. A single cell clone (clone 5 tumor) established from colon 26 adenocarcinoma by limiting dilution cell cloning methods was employed to eliminate the inoculation site-dependent differences in the composition of cell clones. Clone 5 tumor did not provoke manifestations of cancer cachexia when inoculated in subcutaneous tissue. However, when inoculated in the gastrocnemius muscle, the peritoneal cavity or the thoracic cavity of CD2F1 male mice, typical manifestations of cancer cachexia were observed in all groups of mice with intergroup variations. The blood levels of various cytokines, chemokines and hormones were increased but with wide intergroup variations. Analyses by stepwise multiple regression models revealed that serum interleukin-10 was the most significant factor associated with manifestations of cancer cachexia, suggesting the possible involvement of mechanisms similar to cancer patients suffering cancer cachexia. White blood cells, especially neutrophils, seemed to have some roles on the induction of cancer cachexia, because massive infiltrations and an increase in peripheral blood were observed in cachectic mice bearing clone 5 tumors. The amount of malonyl-CoA in liver correlated with manifestations of cancer cachexia, however the mRNA levels of spermidine/spermine N-1 acetyl transferase (SSAT) (of which overexpression has been shown to provoke manifestations similar to cancer cachexia) were not necessarily associated with cancer cachexia. These data suggest that the induction of cancer cachexia depends on the environment in which the tumor grows and that the infiltration of host immune cells into the tumor and the resultant increase in inflammation result in the production of cachectic factors, such as cytokines, leading to SSAT activation. Further, multiple factors likely mediate the mechanisms of cancer cachexia. Finally, this animal model was suitable for the investigation of the mechanisms involved in cachexia of cancer patients.

En bloc pancreaticoduodenectomy and right hemicolectomy for locally advanced right-sided colon cancer

AIM To assess the usefulness of en bloc right hemicolectomy with pancreaticoduodenectomy (RHCPD) for locally advanced right-sided colon cancer (LARCC). METHODS We retrospectively reviewed the database of Saitama Medical Center, Jichi Medical University, between January 2009 and December 2016. During this time, 299 patients underwent radical right hemicolectomy for right-sided colon cancer. Among them, 5 underwent RHCPD for LARCC with tumor infiltration to adjacent organs. Preoperative computed tomography (CT) was routinely performed to evaluate local tumor infiltration into adjacent organs. During the operation, we evaluated the resectability and the amount of infiltration into the adjacent organs without dissecting the adherent organs from the cancer. When we confirmed that radical resection was feasible and could lead to R0 resection, we performed RHCPD. The clinical data were carefully reviewed, and the demographic variables, intraoperative data, and postoperative parameters were recorded. RESULTS The median age of the 5 patients who underwent RHCPD for LARCC was 70 years. The tumors were located in the ascending colon (three patients) and transverse colon (two patients). Preoperative CT revealed infiltration of the tumor into the duodenum in all patients, the pancreas in four patients, the superior mesenteric vein (SMV) in two patients, and tumor thrombosis in the SMV in one patient. We performed RHCPD plus SMV resection in three patients. Major postoperative complications occurred in 3 patients (60%) as pancreatic fistula (grade B and grade C, according to International Study Group on Pancreatic Fistula Definition) and delayed gastric empty. None of the patients died during their hospital stay. A histological examination confirmed malignant infiltration into the duodenum and/or pancreas in 4 patients (80%), and no patients showed any malignant infiltration into the SMV. Two patients were histologically confirmed to have tumor thrombosis in the SMV. All of the tumors had clear resection margins (R0). The median follow-up time was 77 mo. During this period, two patients with tumor thrombosis died from liver metastasis. The overall survival rates were 80% at 1 year and 60% at 5 years. All patients with node-negative status (n = 2) survived for more than seven years. CONCLUSION This study showed that the long-term survival is possible for patients with LARCC if RHCPD is performed successfully, particularly in those with node-negative status.

Complete Resection of a Complicated Huge Mesenteric Lymphangioma Guided by Mesenteric Computed Tomography Angiography With Three-Dimensional Reconstruction: Report of a Case

We herein describe the case of an adult with a complicated huge lymphangioma of the small bowel mesentery. Computed tomography (CT) confirmed a 45 × 30 × 14 cm multiple and separate, mixed and solid cystic tumor without enhancement by contrast medium in the abdominal cavity. Mesenteric CT angiography with three-dimensional (3D) reconstruction showed that the tumor did not involve the first jejunal artery, although the tumor did involve the subsequent jejunal and ileal arteries and the corresponding segment of the small bowel. Under anatomic guidance based on mesenteric CT angiography with 3D reconstruction, we were able to successfully excise the tumor. Mesenteric lymphangioma should be excised even when the tumor is asymptomatic. Mesenteric CT angiography with 3D reconstruction is useful for the surgical treatment of huge mesenteric tumors.