Three Molecular Developmental Pathways of Remnant Pancreatic Cancer after Resection: A Nationwide Project Study of Japan Pancreas Society.

OBJECTIVE: This study aimed to clarify the molecular mechanism of remnant pancreatic cancer (PC) development after primary PC resection. SUMMARY BACKGROUND DATA: Molecular mechanisms of the development of remnant PCs following primary PC resection are largely unknown. METHODS: Forty-three patients undergoing remnant PC resection after primary PC resection between 2001 and 2017 at 26 institutes were retrospectively analyzed. Clinicopathological features and molecular alterations detected by targeted amplicon sequencing of 36 PC-associated genes were evaluated. RESULTS: These patients showed significantly lower body mass indices and higher hemoglobin A1c values at remnant PC resection than at primary PC resection. A comparison of the molecular features between primary and remnant PCs indicated that remnant PCs were likely to develop via three different molecular pathways: successional, showing identical and accumulated alterations (n=14); phylogenic, showing identical and distinct alterations (n=26); and distinct, showing independent distinctive alterations (n=3). The similarity of gene alterations was associated with time to the remnant PC development (r=－0.384, P=0.0173). Phylogenic pathways were significantly associated with the intraductal spread of carcinoma (P=0.007). Patient survival did not differ significantly depending on these molecular pathways. CONCLUSION: Molecular profiling uncovered three pathways for the development of remnant PCs, namely, successional, phylogenic, and distinct pathways. The vast majority of remnant PCs are likely to be molecularly associated with primary PCs either in the successional or phylogenic way. This information could impact the design of a strategy for monitoring and treating remnant PCs.

Factors Affecting Nonfunctioning Small Pancreatic Neuroendocrine Neoplasms and Proposed New Treatment Strategies.

BACKGROUND & AIMS: Despite previously reported treatment strategies for nonfunctioning small (≤20 mm) pancreatic neuroendocrine neoplasms (pNENs), uncertainties persist. We aimed to evaluate the surgically resected cases of nonfunctioning small pNENs (NF-spNENs) in a large Japanese cohort to elucidate an optimal treatment strategy for NF-spNENs. METHODS: In this Japanese multicenter study, data were retrospectively collected from patients who underwent pancreatectomy between January 1996 and December 2019, were pathologically diagnosed with pNEN, and were treated according to the World Health Organization 2019 classification. Overall, 1490 patients met the eligibility criteria, and 1014 were included in the analysis cohort. RESULTS: In the analysis cohort, 606 patients (59.8%) had NF-spNENs, with 82% classified as grade 1 (NET-G1) and 18% as grade 2 (NET-G2) or higher. The incidence of lymph node metastasis (N1) by grade was significantly higher in NET-G2 (G1: 3.1% vs G2: 15.0%). Independent factors contributing to N1 were NET-G2 or higher and tumor diameter ≥15 mm. The predictive ability of tumor size for N1 was high. Independent factors contributing to recurrence included multiple lesions, NET-G2 or higher, tumor diameter ≥15 mm, and N1. However, the independent factor contributing to survival was tumor grade (NET-G2 or higher). The appropriate timing for surgical resection of NET-G1 and NET-G2 or higher was when tumors were >20 and >10 mm, respectively. For neoplasms with unknown preoperative grades, tumor size >15 mm was considered appropriate. CONCLUSIONS: NF-spNENs are heterogeneous with varying levels of malignancy. Therefore, treatment strategies based on tumor size alone can be unreliable; personalized treatment strategies that consider tumor grading are preferable.

Thick mesopancreas is a novel predictor of surgical outcomes of patients who undergo pancreaticoduodenectomy.

PURPOSE: Mesopancreas resection is a crucial but difficult procedure when performing pancreaticoduodenectomy. This study evaluated the influence of mesopancreas thickness on surgical outcomes in patients undergoing pancreaticoduodenectomy. METHODS: We measured the thickness of the fat tissue on the right side of the superior mesenteric artery from the dorsal margin of the confluence of the superior mesenteric vein and portal vein to the ventral margin of the left renal vein on preoperative contrast-enhanced computed tomography and defined it as the mesopancreas thickness. We evaluated the correlation between mesopancreas thickness and intraoperative and postoperative variables in 357 patients who underwent pancreaticoduodenectomy. RESULTS: Multivariate analysis revealed that a thick mesopancreas was significantly associated with a long operative time (ß = 10.361; 95% confidence interval, 0.370-20.353, p = 0.042), high estimated blood loss (ß = 36.038; 95% confidence interval, -27.192-99.268, p = 0.013), and a low number of resected lymph nodes (ß = -1.551; 95% confidence interval, -2.662--0.439, p = 0.006). This analysis further revealed that thick mesopancreas was a significant risk factor for overall morbidity (odds ratio 2.170; 95% confidence interval 1.340-3.520, p = 0.002), major morbidity (odds ratio 2.430; 95% confidence interval 1.360-4.340, p = 0.003), and a longer hospital stay (ß = 2.386; 95% confidence interval 0.299-4.474, p = 0.025). CONCLUSION: A thick mesopancreas could predict a longer operation time, higher estimated blood loss, fewer resected lymph nodes, more frequent overall and major morbidities, and a longer hospital stay in patients who underwent pancreaticoduodenectomy more precisely than the body mass index.

Aqueous Povidone-Iodine Versus Normal Saline For Intraoperative Wound Irrigation on The Incidence of Surgical Site Infection in Clean-Contaminated Wounds After Gastroenterological Surgery: A Single-Institute, Prospective, Blinded-Endpoint, Randomized Controlled Trial.

OBJECTIVE: This trial evaluated the superiority of intraoperative wound irrigation (IOWI) with aqueous povidone-iodine (PVP-I) compared with that with saline for reducing the incidence of surgical site infection (SSI). BACKGROUND: IOWI with aqueous PVP-I is recommended for the prevention of SSI by the World Health Organization and the Centers for Disease Control and Prevention, although the evidence level is low. METHODS: This single institute in Japan, prospective, randomized, blinded-endpoint trial was conducted to assess the superiority of IOWI with aqueous PVP-I in comparison with IOWI with saline for reducing the incidence of SSI in clean-contaminated wounds after gastroenterological surgery. Patients 20 years or older were assessed for eligibility, and the eligible participants were randomized at a 1:1 ratio using a computer-generated block randomization. In the study group, IOWI was performed for 1 minute with 40 mL of aqueous 10% PVP-I before skin closure. In the control group, the procedure was performed with 100 mL of saline. Participants, assessors, and analysts were masked to the treatment allocation. The primary outcome was the incidence of incisional SSI in the intention-to-treat set. RESULTS: Between June 2019 and March 2022, 941 patients were randomized to the study group (473 patients) or the control group (468 patients). The incidence of incisional SSI was 7.6% in the study group and 5.1% in the control group (risk difference 0.025, 95% CI -0.006 to 0.056; risk ratio 1.484, 95% CI 0.9 to 2.448; P =0.154). CONCLUSION: The current recommendation of IOWI with aqueous PVP-I should be reconsidered.

A postoperative body weight increase is a novel risk factor for incisional hernia of midline abdominal incision after elective gastroenterological surgery.

PURPOSE: Midline abdominal incisions (MAIs) are widely used in both open and minimally invasive surgery. Incisional hernia (IH) accounts for most long-term postoperative wound complications. This study explored the risk factors for IH due to MAI in patients with clean-contaminated wounds after elective gastroenterological surgery. METHODS: The present study targeted patients enrolled in 2 randomized controlled trials to evaluate the efficacy of intraoperative interventions for incisional SSI prevention after gastroenterological surgery for clean-contaminated wounds. The patients were reassessed, and pre- and intraoperative variables and postoperative outcomes were collected. IH was defined as any abdominal wall gap, regardless of bulge, in the area of a postoperative scar that was perceptible or palpable on clinical examination or computed tomography according to the European Hernia Society guidelines. The risk factors for IH were identified using univariate and multivariate analyses. RESULTS: The study population included 1,281 patients, of whom 273 (21.3%) developed IH. Seventy-four (5.8%) patients developed incisional SSI. Multivariate logistic regression analysis revealed that female sex (odds ratio [OR], 1.39; 95% confidence interval [CI] 1.03-1.86, p = 0.031), high preoperative body mass index (OR, 1.81; 95% CI 1.19-2.77, p = 0.006), incisional SSI (OR, 2.29; 95% CI 1.34-3.93, p = 0.003), and postoperative body weight increase (OR, 1.49; 95% CI 1.09-2.04, p = 0.012) were independent risk factors for IH due to MAI in patients who underwent elective gastroenterological surgery. CONCLUSION: We identified postoperative body weight increase at one year as a novel risk factor for IH in patients with MAI after elective gastroenterological surgery.

Drain output volume after pancreaticoduodenectomy is a useful warning sign for postoperative complications.

INTRODUCTION: The drain output volume (DOV) after pancreaticoduodenectomy (PD) is an easily assessable indicator in clinical settings. We explored the utility of the DOV as a possible warning sign of complications after PD. METHODS: A total of 404 patients undergoing PD were considered for inclusion. The predictability of the DOV for overall morbidity, major complications, intraabdominal infection (IAI), clinically relevant (CR) postoperative pancreatic fistula (POPF), CR delayed gastric emptying (DGE), CR chyle leak (CL), and CR post-pancreatectomy hemorrhaging (PPH) was evaluated. RESULTS: One hundred (24.8%) patients developed major complications, and 131 (32.4%) developed IAI. Regarding CR post-pancreatectomy complications, 75 (18.6%) patients developed CR-POPF, 23 (5.7%) developed CR-DGE, 20 (5.0%) developed CR-CL, and 28 (6.9%) developed CR-PPH. The median DOV on postoperative day (POD) 1 and POD 3 was 266 and 234.5 ml, respectively. A low DOV on POD 1 was an independent predictor of CR-POPF, and a high DOV on POD 3 was an independent predictor of CR-CL. A receiver operating characteristics (ROC) analysis revealed that the DOV on POD 1 had a negative predictive value (area under the curve [AUC] 0.655, sensitivity 65.0%, specificity 65.3%, 95% confidence interval [CI]: 0.587-0.724), with a calculated optimal cut-off value of 227 ml. An ROC analysis also revealed that the DOV on POD 3 had a positive predictive value (AUC 0.753, sensitivity 70.1%, specificity 75.0%, 95% CI: 0.651-0.856), with a calculated optimal cut-off value of 332 ml. CONCLUSION: A low DOV on POD 1 might be a postoperative warning sign for CR-POPF, similar to high drain amylase (DA) on POD 1, high DA on POD 3, and high CRP on POD 3. When the DOV on POD 1 after PD was low, surgeons should evaluate the reasons of a low DOV. A high DOV on POD 3 was a postoperative warning sign CR-CL, and might require an appropriate management of protein loss.

Bridge of preoperative biliary drainage is a useful management for patients undergoing pancreaticoduodenectomy.

BACKGROUND/OBJECTIVES: The aims of this study were to clarify the effect of preoperative biliary drainage (PBD) on postoperative outcomes and the role of preoperative intentional exchange from endoscopic nasobiliary drainage (ENBD) to endoscopic retrograde biliary drainage (ERBD) for patients waiting to undergo pancreaticoduodenectomy (PD). METHODS: We evaluated the effect of PBD and intentional exchange of PBD on the perioperative variables in 292 patients. RESULTS: A total of 179 (61.3%) of 292 patients received PBD. There was no marked difference in the postoperative outcomes between the patients who did and did not receive PBD. Among the 160 patients who initially received endoscopic PBD, 10 (6.3%) underwent stent exchange for stent dysfunction, 59 (36.9%) who did not develop stent dysfunction underwent intentional stent exchange from ENBD to ERBD (bridge PBD group), and 91 (56.9%) did not receive any stent exchange (unchanged PBD group). The bridge PBD group had a longer duration of PBD (37 days) (p < 0.001) and a shorter preoperative hospital stay after PBD (32 days) (p < 0.001) than the unchanged PBD group (25 and 46 days, respectively); however, there were no significant differences in the postoperative variables. The incidence of stent exchange due to stent dysfunction in the bridge PBD group (11.9%) was lower than that in patients who initially received ERBD (36.0%) (p = 0.015). CONCLUSIONS: Bridge PBD worked well for extending the duration of PBD without worsening the postoperative outcomes after PD.

A lack of postoperative complications after pancreatectomy contributes to the long-term survival of patients with pancreatic cancer.

BACKGROUND: /Objectives: The objectives of this study were to identify the factors affecting patients' survival and the characteristics of five-year survivors of pancreatic ductal adenocarcinoma (PDAC) after pancreatectomy as well as to clarify the correlation between the development of postoperative complications and a five-year survival. METHODS: A total of 104 patients underwent pancreatectomy for PDAC between April 2005 and March 2013 with curative intent. Patients who survived for more than five years after pancreatectomy were classified as long-term survivors. Sixteen demographic and clinical variables and 10 pathological variables were comprehensively assessed for their associations with the patients' survival time and long-term survival. RESULTS: The presence of preoperative comorbidity (OR: 1.65, 95% CI 1.02-2.67, p = 0.042), postoperative overall complications (OR: 1.78, 95% CI 1.03-3.10, p = 0.041), a lymph node positivity ratio of ≥0.2 (OR: 3.04, 95% CI 1.51-6.11, p = 0.002), and portal invasion (OR: 2.58, 95% CI 1.48-4.49, p = 0.001) were identified as independent factors affecting the patients' survival. The absence of postoperative overall complications was identified as an independent factor related to long-term survival in the multivariate analysis (OR: 0.08, 95% CI 0.01-0.82, p = 0.034). CONCLUSIONS: The presence of preoperative comorbidity, postoperative overall complications, LNR ≥0.2, and portal invasion were prognostic factors affecting the patients' survival, and avoiding postoperative complications after pancreatectomy might contribute to the long-term survival of PDAC patients after pancreatectomy. The further improvement of surgical procedures and perioperative care in order to reduce the rate of postoperative complications should be attempted.

Extracellular Spermine Activates DNA Methyltransferase 3A and 3B.

We first demonstrated that long-term increased polyamine (spermine, spermidine, putrescine) intake elevated blood spermine levels in mice and humans, and lifelong consumption of polyamine-rich chow inhibited aging-associated increase in aberrant DNA methylation, inhibited aging-associated pathological changes, and extend lifespan of mouse. Because gene methylation status is closely associated with aging-associated conditions and polyamine metabolism is closely associated with regulation of gene methylation, we investigated the effects of extracellular spermine supplementation on substrate concentrations and enzyme activities involved in gene methylation. Jurkat cells and human mammary epithelial cells were cultured with spermine and/or D,L-alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase. Spermine supplementation inhibited enzymatic activities of adenosylmethionine decarboxylase in both cells. The ratio of decarboxylated S-adenosylmethionine to S-adenosyl-L-methionine increased by DFMO and decreased by spermine. In Jurkat cells cultured with DFMO, the protein levels of DNA methyltransferases (DNMTs) 1, 3A and 3B were not changed, however the activity of the three enzymes markedly decreased. The protein levels of these enzymes were not changed by addition of spermine, DNMT 3A and especially 3B were activated. We show that changes in polyamine metabolism dramatically affect substrate concentrations and activities of enzymes involved in gene methylation.

A High Abdominal Aortic Calcification Score on CT is a Risk Factor for Postoperative Pancreatic Fistula in Elderly Patients Undergoing Pancreaticoduodenectomy.

BACKGROUND: To evaluate the clinical significance of a CT-based evaluation of abdominal aortic calcification (AAC) in the postoperative outcomes after pancreaticoduodenectomy (PD) in elderly patients. METHODS: Patients 70 years of age and older who were randomly assigned to Group A were compared with those younger than 70 who were assigned to Group B in terms of preoperative and intraoperative variables and postoperative outcomes. We compared the patients with clinically relevant postoperative pancreatic fistula (CR-POPF) (Group C) to those without CR-POPF (Group D), and especially Group A. We also compared the patients with CR-POPF (Group E) to those without CR-POPF (Group E) to clarify the risk factors for POPF, in each of the analyses. The AAC score was determined using the methods of Agatston et al. RESULTS: Group A more often had frequent atherosclerosis-related comorbidities (62.2%), low serum albumin (55.9%), and a high AAC score (66.1%). There were no significant differences in the postoperative variables. The comparisons between Groups C and D identified four independent risk factors for CR-POPF: BMI ≥ 25 (OR 8.54, 95% CI 3.15-23.1), male gender (OR 3.17, 95% CI 1.28-7.85), soft pancreatic parenchyma (OR 3.43, 95% CI 1.34-8.81), and the absence of MPD dilatation (OR 5.70, 95% CI 2.13-15.3). Comparisons between Groups E and F identified two independent risk factors for CR-POPF: BMI ≥ 25 (OR 29.4, 95% CI 5.77-150) and a high ACC score (OR 10.8, 95% CI 2.08-56.6). CONCLUSIONS: We demonstrated, for the first time, that a high AAC score is a risk factor of CR-POPF in elderly patients who underwent PD.

[An Elderly Patient with Metastatic Colon Cancer Achieved Long-Term Survival Following Single-Agent Chemotherapy with S-1].

Colorectal cancer is a common malignancy and a major health issue in geriatrics. Systemic chemotherapy should be considered for elderly patients. We report an 85-year-old man with metastatic cecal cancer who has achieved long-term survival following single-agent chemotherapy with S-1. His fecal occult blood test results were positive; he then underwent colonoscopy and was diagnosed with cecal cancer. Chest CT revealed multiple metastases in both lungs. Since radical excision was infeasible, we performed right hemicolectomy to prevent bowel obstruction. Histological examination revealed a T3, N0, M1a (PUL2), Stage IV tumor. After discharge from the hospital, the patient preferred receiving chemotherapy that would have fewer side effects. S-1 monotherapy was administered. Despite increased progression of the pulmonary metastases, he experienced no subjective symptoms, his QOL remained consistent, and he completed 42 cycles of chemotherapy in total. The patient is currently being managed on an outpatient basis. In conclusion, elderly patients with cancer should be carefully evaluated according to both disease control and individual circumstances, such as patient's tolerability, QOL, and preference.

Herpes simplex virus-1 encephalitis induced by chemoradiotherapy and steroids in an esophageal cancer patient: a case report.

BACKGROUND: Systemic chemotherapy combined with steroids used as prophylactic antiemetics have been reported to induce immunosuppression. Further, herpes simplex virus-1 (HSV-1) infection has been reported to occur in patients with small cell carcinomas after chemoradiotherapy that includes brain irradiation. Here, we report a case of HSV-1 encephalitis that occurred in a patient undergoing chemoradiotherapy for advanced esophageal cancer. CASE PRESENTATION: A 77-year-old woman received chemoradiotherapy (5-fluorouracil, 700 mg/m(2); cisplatin, 70 mg/m(2); and radiotherapy, 60 Gy in total) for stage III esophageal cancer. The total radiation dose was administered concurrently with the first two courses of chemotherapy, together with dexamethasone as a prophylactic antiemetic. Two days before completion of the fourth course of chemotherapy, the patient developed acute neurological symptoms of disorientation, clouding of consciousness, and fever. T2-weighted magnetic resonance imaging showed a high intensity area in the bilateral temporal lobes and insular cortex. Furthermore, DNA PCR testing of cerebrospinal fluid showed clear positivity for HSV-1 DNA, and the patient was diagnosed with herpetic encephalitis. Intravenous administration of acyclovir for 3 weeks led to gradual improvement of consciousness, and the patient was able to respond to verbal cues. CONCLUSION: In advanced esophageal cancer patients, standard treatment involves chemoradiotherapy and surgery. However, primary infection with or reactivation of endogenous latent HSV-1 in the brain cortex during chemoradiotherapy combined with administration of a steroid may compromise the benefits of treatment.

Clinical characteristics of synchronous colorectal cancers in Japan.

BACKGROUND: Incidence and clinical characteristics of synchronous colorectal cancer (sCRC) patients significantly vary among studies, likely due to differences in surveillance methodology. If remain undetected, sCRC can progress to more advanced stages seriously aggravating patient prognosis. We studied the incidence and clinicopathological characteristics of Japanese patients with sCRCs who underwent surgery for primary CRC and received exhaustive perioperative surveillance. METHODS: We recruited 1005 patients with surgically resected CRCs between January 2007 and December 2011. The associations of clinical and pathological factors with sCRC development were assessed by univariate and multivariate logistic regression. RESULTS: Eighty-four patients (8.4 %) developed sCRCs, 16 of them (19.0 %) harboring three or more cancers. Companion sCRCs were smaller and earlier stage than the index lesion (P < 0.0001). In multivariate analysis, advanced age (odds ratio (OR) 1.03 per year; P = 0.009) and left colon tumor location (OR 1.78; P = 0.013) are associated with higher risk of sCRCs, particularly in females. Overall survival did not differ between solitary CRC and sCRC (P = 0.62). CONCLUSIONS: Our results highlight the importance of perioperative colonoscopy examination to ensure the absence of sCRCs that, being small and early staged, are more difficult to detect. The incidence of sCRC, and notably of triple or more sCRCs, was higher than previously recognized. Because they are also significantly higher than expected by merely stochastic accumulation of individual cancerous lesions, we suggest that the occurrence of many sCRC reflects a hitherto uncharacterized predisposition condition.

Multiple primary malignancies involving primary sporadic colorectal cancer in Japan: incidence of gastric cancer with colorectal cancer patients may be higher than previously recognized.

BACKGROUND: Improvement in the prognosis of colorectal cancer (CRC) patients has led to increasing occurrences of multiple primary malignancies (MPMs) alongside CRC but little is known about their characteristics. This study was undertaken to clarify the clinical and pathological features of MPMs, especially those at extra colonic sites, in patients with CRC. METHODS: We reviewed 1,111 patients who underwent operations for primary sporadic CRC in Saitama Medical Center, Jichi Medical University between April 2007 and March 2012. Two patients with familial adenomatous polyposis, one with hereditary non-polyposis colorectal cancer, two with colitic cancer, and any patients with metastasis from CRC were excluded. We compared the clinicopathological features of CRC patients with and without MPMs. As a control, we used a database compiled of patients with gastric cancer (GC) detected by mass screening performed in the Saitama Prefecture in Japan 2010 and compared these with CRC patients with synchronous GC. RESULTS: Multiple primary malignancies at extracolonic sites were identified in 117 of 1,111 CRC patients (10.5%). The median age was 68 (range, 29 to 96) versus 71 (50 to 92) (P < 0.001). The incidence of GC (44.4% (52 of 117)) was the highest of all MPMs. All CRC patients with GC were older than 57 years. Synchronous GC was detected in 26 patients. By contrast, out of 200,007 screened people, 225 people were diagnosed as having GC in the Saitama Prefecture. The age-standardized incidence of synchronous GC in CRC patients was significantly higher (0.53%) than in the control group (0.03%) (odds ratio, 18.8; 95% confidence interval, 18.6 to 19.0; P < 0.001). CONCLUSION: Patients with CRC who were older than 50 years preferentially developed GC synchronously and metachronously. Thus, this patient group should undergo careful perioperative screening for GC.

Feasibility Assessment of Modified FOLFOX-6 as adjuvant treatment after resection of liver metastases from colorectal cancer: analyses of a multicenter phase II clinical trial (Miyagi-HBPCOG Trial-001).

BACKGROUND/AIMS: This multicenter and single arm phase II clinical trial was performed to examine the safety and efficacy of modified FOLFOX6 (mFOLFOX6) as adjuvant treatment after resection of liver metastases from colorectal cancer. METHODOLOGY: Patients who had undergone R0-1 resection of liver metastases were assigned to 12 cycles of mFOLFOX6. The primary end point was disease-free survival (DFS). RESULTS: We enrolled 49 cases and analyzed adverse events in 48 cases, since in one patient cancer recurred before starting treatment. As to the relative dose intensity, 5-FU was 78.8%, and oxaliplatin was 75.9%. Adverse events of Grade 3 and above includ- ed 18 cases of neutropenia (37.5%), 4 cases of sensory neuropathy (8.3%), 4 cases of thrombocytopenia (8.3%) and 4 cases of allergy (8.3%), and there were no cases of fatality caused by adverse events. The most difference of adverse event compared with MOSAIC trial (Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer) was thrombocytopenia. The 2-year DFS was 59.2% (95% CI: 36.7-78.4) in the 49 enrolled cases. CONCLUSION: mFOLFOX6 after hepatectomy was tolerable. And mFOLFOX6 also seemed to improve DFS. mFOLFOX is one of the options for such patients and appears promising as an adjuvant treatment.

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

BACKGROUND: Recent 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. METHODS: With 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. RESULTS: Unsupervised 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 ß-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). CONCLUSIONS: Somatic 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.

Laparoscopic wedge resection of the stomach for gastrointestinal stromal tumor (GIST): non-touch lesion lifting method.

BACKGROUND: Laparoscopic surgery for GIST carries a risk of intraoperative tumor dissemination. To avoid tumor dissemination, we have utilized a "non-touch" method for surgical resection of GIST since 2000. METHODS: Forty-two patients with gastric GIST were treated at our institution between 2000 and 2012. Laparoscopic wedge resection of the stomach was used as the standard procedure for tumors that were 2-5 cm in size. Tumors larger than 5 cm were treated with open surgery. Our non-touch procedure included a lesion-lifting method using traction sutures at the normal stomach wall around the tumor. Intraoperative gastroscopy was utilized to confirm the location of the tumor with laparoscopy. After lifting of the tumor, tumors with a clear operative margin were resected using a linear stapler. Tumors located at the posterior wall of the stomach or located near the esophagogastric junction were resected using traction sutures. RESULTS: Median operative time was 140 min and median blood loss was 0 ml. Postoperative course was uneventful excepting one patient who experienced postoperative bleeding. The median postoperative stay was 7 days. One patient developed liver metastasis after surgery. None of the patients had local recurrence or peritoneal recurrence case. CONCLUSION: This non-touch lesion-lifting method was useful for the surgical management of gastric GIST.

Treatment of stage IV gastric cancer with induction chemotherapy using S-1 and cisplatin followed by curative resection in selected patients.

BACKGROUND: The standard treatment for stage IV gastric cancer is chemotherapy, but outcomes remain poor. The effectiveness of induction chemotherapy followed by surgery in selected patients who had a good response to chemotherapy is unclear. METHODS: A total of 59 patients with stage IV gastric cancer received induction chemotherapy with S-1 and cisplatin. In each cycle, oral S-1 (80 mg/m2) was administered for 3 weeks, followed by a 2-week drug holiday. Intravenous cisplatin (60 mg/m2) was administered on day 8 after adequate premedication and hydration. If unresectable features resolved after chemotherapy, patients underwent curative (R0) resection. The safety and outcomes of this treatment combination were evaluated, and predictive factors for survival were determined. RESULTS: Thirteen of 59 patients (22%) were eligible for R0 resection after induction chemotherapy. Kaplan-Meier analysis showed an overall median survival time of 13 months and a 3-year survival rate of 18.2%. Among patients who underwent R0 resection, the median survival time was 53 months and the 3-year survival rate was 53.8%. Multivariate analyses showed that negative para-aortic lymph nodes and undergoing R0 resection were independent predictors of survival. CONCLUSIONS: Treatment of stage IV gastric cancer with S-1 and cisplatin induction chemotherapy followed by R0 resection is safe and may improve survival compared with chemotherapy alone. Further study of this dual-modality therapy is warranted.

Instruction of expert surgeon secures favorable outcomes after standard pancreaticoduodenectomy performed by less experienced surgeons.

BACKGROUND/AIMS: We investigated the factors associated with a favorable outcome after standard pancreaticoduodenectomy (PD) performed by the less experienced surgeon under expert supervision in a high-volume hospital of PD. METHODOLOGY: Between April 2009 and March 2013, 139 PDs were performed in our hospital, and among them 99 PDs were standard fashion. Two expert surgeons performed 57 of 99 PDs, and the cases were assigned as Group A. Forty-two of 99 PDs were performed by 5 less experienced surgeons under the instruction of expert surgeons, and the cases were assigned as Group B. We compared the intraoperative outcomes and postoperative major complications and mortality between two groups. RESULTS: There was no hospital death in Group B, but one in Group A (1.8%), and the overall mortality rate of 99 patients in this series was 1.0%. In comparison of postoperative major complications, there was no significant difference in the frequencies of patients with all postoperative major complications (Group A; 43.9% vs. Group B 33.3%). CONCLUSIONS: Outcomes after standard PD performed by less experienced surgeons were favorable. The instruction of expert surgeon in a high volume hospital may secure a favorable outcome after standard PD.

[Systemic chemotherapy and surgery for recurrent metachronous liver metastases with peritoneal dissemination from triple colon cancers-a case report].

Although the first-line treatment for liver metastases arising from colorectal cancer is surgery, it is unknown whether this treatment is equally effective for liver metastases with peritoneal dissemination. We report a case of long-term survival after oxaliplatin-based chemotherapy and surgery for metachronous liver metastases with peritoneal dissemination from triple colon cancer. A 76-year-old man with a history of stage III descending colon cancer developed recurrent localized peritoneal dissemination and multiple liver metastases 30 months after surgery. He underwent partial liver resection, partial peritoneal resection, and 8 courses of capecitabine plus oxalitlatin (XELOX). There has been no disease recurrence 75 months after the initial surgery. While though there is no consensus for treatment of liver metastasis with peritoneal dissemination, surgery combined with systemic chemotherapy may be beneficial.