Endoscopic Removal of Premalignant Lesions Reduces Long-Term Colorectal Cancer Risk: Results From the Japan Polyp Study.

BACKGROUND & AIMS: To date, no regional evidence of long-term colorectal cancer (CRC) risk reduction after endoscopic premalignant lesion removal has been established. We aimed to analyze this over a long-term follow-up evaluation. METHODS: This was a prospective cohort study of participants from the Japan Polyp Study conducted at 11 Japanese institutions. Participants underwent scheduled follow-up colonoscopies after a 2-round baseline colonoscopy process. The primary outcome was CRC incidence after randomization. The observed/expected ratio of CRC was calculated using data from the population-based Osaka Cancer Registry. Secondary outcomes were the incidence and characteristics of advanced neoplasia (AN). RESULTS: A total of 1895 participants were analyzed. The mean number of follow-up colonoscopies and the median follow-up period were 2.8 years (range, 1-15 y) and 6.1 years (range, 0.8-11.9 y; 11,559.5 person-years), respectively. Overall, 4 patients (all males) developed CRCs during the study period. The observed/expected ratios for CRC in all participants, males, and females, were as follows: 0.14 (86% reduction), 0.18, and 0, respectively, and 77 ANs were detected in 71 patients (6.1 per 1000 person-years). Of the 77 ANs detected, 31 lesions (40.3%) were laterally spreading tumors, nongranular type. Nonpolypoid colorectal neoplasms (NP-CRNs), including flat (<10 mm), depressed, and laterally spreading, accounted for 59.7% of all detected ANs. Furthermore, 2 of the 4 CRCs corresponded to T1 NP-CRNs. CONCLUSIONS: Endoscopic removal of premalignant lesions, including NP-CRNs, effectively reduced CRC risk. More than half of metachronous ANs removed by surveillance colonoscopy were NP-CRNs. The Japan Polyp Study: University Hospital Medical Information Network Clinical Trial Registry: University Hospital Medical Information Network Clinical Trial Registry, C000000058; cohort study: UMIN000040731.

Visualization of horizontal canal benign paroxysmal positional vertigo using 3DCT imaging and its assessment.

BACKGROUND: There have been no useful imaging methods to diagnose benign paroxysmal positional vertigo (BPPV), a common cause of vertigo, depending on the characteristic symptom. OBJECTIVE: To visualize horizontal canal (HC) BPPV using 3DCT and assess its clinical usefulness. SUBJECTS AND METHODS: Ten BPPV patients were diagnosed with distinct BPPV, canalolithiasis, and cupulolithiasis of the HC (hc-BPPV, hc-BPPV-cu), which were definitely diagnosed on the basis of criteria of BPPV by the Barany Society and 10 healthy subjects without a history of dizziness were investigated using 3DCT with several different CT window values (CTWVs). RESULTS: The HCs of BPPV patients were clearly visualized and the luminal aspects showed differences among ears with cupulolithiasis, canalolithiasis and no symptoms healthy subjects. CONCLUSIONS AND SIGNIFICANCE: 3DCT images visualized the characteristic changes of the HC of patients with BPPV compared to healthy subjects. The HC images were coincident with the clinical condition of cupulolithiasis and canalolithiasis. This imaging technique is clinically useful for diagnosing, treating and assessing the prognosis of HC BPPV.

Randomised comparison of postpolypectomy surveillance intervals following a two-round baseline colonoscopy: the Japan Polyp Study Workgroup.

OBJECTIVE: To assess whether follow-up colonoscopy after polypectomy at 3 years only, or at 1 and 3 years would effectively detect advanced neoplasia (AN), including nonpolypoid colorectal neoplasms (NP-CRNs). DESIGN: A prospective multicentre randomised controlled trial was conducted in 11 Japanese institutions. The enrolled participants underwent a two-round baseline colonoscopy (interval: 1 year) to remove all neoplastic lesions. Subsequently, they were randomly assigned to undergo follow-up colonoscopy at 1 and 3 years (2-examination group) or at 3 years only (1-examination group). The incidence of AN, defined as lesions with low-grade dysplasia ≥10 mm, high-grade dysplasia or invasive cancer, at follow-up colonoscopy was evaluated. RESULTS: A total of 3926 patients were enrolled in this study. The mean age was 57.3 (range: 40-69) years, and 2440 (62%) were male. Of these, 2166 patients were assigned to two groups (2-examination: 1087, 1-examination: 1079). Overall, we detected 29 AN in 28 patients at follow-up colonoscopy in both groups. On per-protocol analysis (701 in 2-examination vs 763 in 1-examination group), the incidence of AN was similar between the two groups (1.7% vs 2.1%, p=0.599). The results of the non-inferiority test were significant (p=0.017 in per-protocol, p=0.001 in intention-to-treat analysis). NP-CRNs composed of dominantly of the detected AN (62%, 18/29), and most of them were classified into laterally spreading tumour non-granular type (83%, 15/18). CONCLUSION: After a two-round baseline colonoscopy, follow-up colonoscopy at 3 years detected AN, including NP-CRNs, as effectively as follow-up colonoscopies performed after 1 and 3 years.

Increased risk of recurrence in resected EGFR-positive pN0M0 invasive lung adenocarcinoma.

BACKGROUND: This study was conducted to evaluate the prognostic and recurrent impact of EGFR mutation status in resected pN0M0 lung adenocarcinoma with consideration of the histological subtype. METHODS: Following retrospective analysis of whole 474 consecutive pathological N0M0 lung adenocarcinoma patients, the prognostic significance of EGFR mutation status was evaluated in limited 394 subjects. Overall survival and recurrence-free interval (RFI) were estimated using the Kaplan-Meier method and compared using a log-rank test. Univariate and multivariate analyses were performed using Cox proportional hazard models. RESULTS: The five-year RFI was 85.7% and 93.3% for EGFR positive (n = 176) and negative (n = 218) cases, respectively (hazard ratio [HR] 1.992, 95% confidence interval [CI] 1.005-3.982; P = 0.048). Following the exclusion of specific subtypes free from recurrence or EGFR mutation (adenocarcinoma in situ, minimally invasive adenocarcinoma, and invasive mucinous adenocarcinoma), the five-year RFI was obviously poorer in EGFR positive compared to negative cases (80.7% and 92.1%, respectively; HR 2.163, 95% CI 1.055-4.341; P = 0.035). Multivariate analysis excluding the specific subtypes confirmed that male sex, age, current or Ex-smoking status, pleural invasion, and EGFR-positive status were independently associated with shorter RFI. No significant differences in five-year overall survival were found between the EGFR mutation positive and negative groups (88.7% and 93.7%, respectively; HR 1.630, 95% CI 0.787-3.432; P = 0.2). CONCLUSION: EGFR mutations are associated with recurrence in pN0M0 lung adenocarcinoma. EGFR mutation status and histological subtype should be considered when evaluating the risk of recurrence in resected lung adenocarcinoma patients.

Alcohol abstinence and risk assessment for second esophageal cancer in Japanese men after mucosectomy for early esophageal cancer.

BACKGROUND: Alcohol consumption combined with inactive aldehyde dehydrogenase-2 (ALDH2) and the presence of multiple esophageal Lugol-voiding lesions (LVLs; dysplasia) are strong predictors for multiple development of esophageal squamous cell carcinoma (ESCC) in East Asians. We invented a health risk appraisal (HRA) model for predicting the risk of ESCC based on drinking, smoking, dietary habits, and alcohol flushing, i.e., past or present facial flushing after drinking a glass of beer, a surrogate marker for inactive ALDH2. METHODS: Prospective follow-up examinations (median follow-up time, 50.3 months) were performed in 278 Japanese men after endoscopic mucosectomy for early ESCC (UMIN Clinical Trials Registry ID: UMIN000001676). RESULTS: Sixty-four subjects developed metachronous ESCC. A receiver operating characteristic curve showed that HRA scores ≥12 best predicted the development of metachronous ESCC. The ESCC detection rate per 100 person-years was 9.8 in the high-HRA-score group (n = 104) and 4.5 in the low-HRA-score group (n = 174), and the risk of development of metachronous ESCC was higher in the high-HRA-score group than in the low-HRA-score group (adjusted hazard ratio: 2.00 [95% CI: 1.12-3.30]). Multiple LVLs was a very strong predictor of the development of metachronous SCC, but high HRA scores predicted it independently. The cumulative incidences of metachronous ESCC decreased after drinking cessation in the high-HRA-score drinker group (adjusted hazard ratio: 0.37 [0.14-0.97]). CONCLUSIONS: Both the HRA model that included alcohol flushing and the multiple LVL grade predicted the development of metachronous ESCC in Japanese men after endoscopic mucosectomy for ESCC. Drinking cessation in the high-HRA-score drinker group reduced the rate of metachronous ESCC.

Immediate discontinuation of ablation during pulmonary vein isolation remarkably decreases the incidence of esophageal thermal lesions even when using steerable sheaths.

BACKGROUND: Left atrial-esophageal fistulas (LAEFs) are serious complications with high mortality after atrial fibrillation radiofrequency ablation (AFRA). Decreasing the incidence of esophageal thermal lesions (EsoTLs) that may lead to LAEFs is important. The aim of this study was to suppress EsoTL development and determine the appropriate alarm setting for a temperature-monitoring probe by using steerable sheath (STS) methods. METHODS: We enrolled 82 consecutive patients (mean, 61.9±11.7 years; 75.6% men) who underwent AFRA, including pulmonary vein isolation for symptomatic, drug-refractory atrial fibrillation with esophageal temperature monitoring by using STS between January 2011 and April 2014. All patients underwent upper gastrointestinal endoscopy (UGE) 1-3 days after AFRA. The timing of ablation discontinuation in the first 17 patients was determined by each physician during AFRA (only monitoring group, OM). In the next 65 patients, physicians were to immediately discontinue ablation when an alarm set at 39 °C went off (instruction group, INS). We compared two groups with respect to the incidence of EsoTLs. RESULTS: Among the 82 patients, 5 (6.1%) had EsoTLs after AFRA. EsoTLs occurred in 3 of 17 patients (17.6%) and 2 of 65 patients (3.1%) in the OM and INS groups, respectively. The incidence of EsoTLs in the INS group was significantly lower than that in the OM group (p=0.0254). EsoTL did not occur at maximal temperature less than 39 °C, measured by using esophageal temperature-monitoring probe. CONCLUSIONS: Immediate discontinuation of ablation during pulmonary vein isolation remarkably decreased the incidence of EsoTLs, even when using STS.

Alcohol Consumption and Multiple Dysplastic Lesions Increase Risk of Squamous Cell Carcinoma in the Esophagus, Head, and Neck.

BACKGROUND & AIMS: Some patients develop multiple squamous cell carcinomas (SCCs) in the upper aerodigestive tract, attributed to field cancerization; alcohol consumption has been associated with this process. We examined the association between multiple areas of dysplastic squamous epithelium with the development of SCC of the esophagus or head and neck cancer, as well as alcohol consumption and smoking. METHODS: We examined 331 patients with early stage esophageal SCC using Lugol chromoendoscopy to evaluate the dysplastic squamous epithelium in the esophagus. Patients then were assigned to 3 groups, based on the number of Lugol-voiding lesions: A, no lesion; B, 1-9 lesions; or C, 10 or more lesions. Participants completed lifestyle surveys on their history of drinking, smoking, and diet. All participants were evaluated by laryngopharyngoscopy before registration; only those without head and neck cancer were included, except for patients with superficial SCC limited to the subepithelial layer. Lesions detected in the esophagus and head and neck by surveillance were considered to be metachronous. The study end point was the cumulative incidence of metachronous SCCs in the esophagus and head and neck after endoscopic resection of esophageal SCC, according to the grade of Lugol-voiding lesions. At study entry, all patients were instructed to abstain from alcohol and smoking. RESULTS: Over the 2-year study period, metachronous SCCs of the esophagus were detected in 4% of patients in group A, in 9.4% of patients in group B, and in 24.7% of patients in group C (P < .0001 for patients in group A vs B or B vs C). Head and neck SCCs were detected in none of the patients in group A, in 1.7% of the patients in group B, and in 8.6% of the patients in group C (P = .016 for patients in group A vs C and P = .008 for patients in group B vs C). SCC of the esophagus or head and neck developed in 4.0% of patients in group A, in 10.0% of patients in group B, and in 31.4% of patients in group C (P < .0001 for group A vs B or A vs C). Alcohol abstinence decreased the risk of multiple SCCs of the esophagus (adjusted hazard ratio, 0.47, 95% confidence interval, 0.25-0.91; P = .025), whereas smoking abstinence did not. CONCLUSIONS: Multiple dysplastic lesions in the esophagus increase the risk of multiple SCCs. Alcohol abstinence reduces the risk of metachronous SCCs. Clinical Trials registry: UMIN000001676 and UMIN000005466.

A phase II study of bevacizumab with modified OPTIMOX1 as first-line therapy for metastatic colorectal cancer: the TCOG-GI 0802 study.

BACKGROUND: Although bevacizumab plus FOLFOX is a standard treatment for metastatic colorectal cancer, oxaliplatin must be withdrawn in many patients because of cumulative neurotoxicity. We postulated that a reduced dose of oxaliplatin and modified treatment schedule would prolong the time to treatment failure and evaluated bevacizumab combined with a modified OPTIMOX1 regimen (mOPTIMOX1, oxaliplatin dose: 85 mg/m(2)). METHODS: Eligible patients had a histologically confirmed diagnosis of metastatic colorectal cancer and a performance status of 0-1. Patients were excluded if they had grade 1 or higher peripheral sensory neuropathy or had previously received chemotherapy for metastatic colorectal cancer. Patients received bevacizumab plus mFOLFOX6 every 2 weeks for 6 cycles, followed by 12 cycles of a simplified biweekly regimen of leucovorin and fluorouracil (sLV5FU2) plus bevacizumab. Oxaliplatin was then reintroduced, and bevacizumab plus mFOLFOX6 was continued until progressive disease. RESULTS: The median duration of disease control was 11.7 months (95 % confidence interval [CI], 9.7-13.5 months). The median overall survival was 23.1 months (95 % CI, 18.8-27.9 months). The overall response rate according to both the RECIST and WHO criteria was 51.3 %. The most common grade 3 or 4 toxicities were neutropaenia (32.5 %), hypertension (17.5 %), leukocytopaenia, sensory neuropathy, and diarrhoea (10.0 %). There were no treatment-related deaths. CONCLUSIONS: Bevacizumab plus mFOLFOX6 was well tolerated, and patients could continue chemotherapy for longer than with conventional FOLFOX regimens. This regimen might be an effective treatment option for patients with metastatic colorectal cancer.

Practical 3DCT imaging of the vestibular aqueduct for Meniere's disease.

CONCLUSION: Radiographic visualization of the vestibular aqueduct (VA) from a lateral inside view was effective in assessing patients with Meniere's disease (MD). There were no VA shapes specific to MD on radiography, except for an obliterated VA. This technique could yield more accurate images and functional assessment of the VA for MD evaluation in a clinically useful and convenient manner, without requiring morphologic measurement. OBJECTIVE: To visualize the detailed images of the VA using three-dimensional (3D) computed tomography (CT) and discuss its clinical utility in assessing MD. SUBJECTS AND METHODS: The VAs in 13 healthy subjects and 25 MD patients, who were definitely diagnosed according to criteria described by the Committee on Hearing and Equilibrium of the American Academy of Otolaryngology, Head and Neck Surgery (AAO-HNS), were imaged from the medial and lateral sides using 3DCT and compared to conventional CT images. RESULTS: Examination of the VA from both the lateral outside and inside views on 3DCT yielded more precise images than generated by conventional CT and could be useful to estimate the VA function. The estimated VA function in the MD ears was significantly abnormal compared to the function in healthy ears. An obliterated VA was characteristic of affected MD ears.

Three-dimensional cone beam computed tomography imaging of the membranous labyrinth in patients with Meniere's disease.

CONCLUSION: Three-dimensional cone beam computed tomography (3DCT) images revealed characteristic malformations of the membranous labyrinth of the inner ear in Meniere's disease (MD). The morphology of the membranous region between the vestibular cecum of the cochlea and the saccule of ears with MD was compared to that of healthy ears. The present study supports the hypothesis proposed earlier that reuniting duct blockade is a result of the dislodgement of saccular otoconia. OBJECTIVE: To visualize the membranous labyrinth using 3DCT and to investigate the pathology of MD. METHODS: A preparatory study was conducted to determine the optimal 3DCT window settings for the detection of water, muscle, calcium carbonate (CaCO3), and bone. Based on this preparatory study, the ears of 13 healthy volunteers and 25 MD patients definitely diagnosed according to the criteria issued by the Committee on Hearing and Equilibrium of the American Academy of Otolaryngology, Head and Neck Surgery (AAO-HNS), were visualized. RESULTS: The differences in the membranous labyrinth between MD ears and healthy ears could be visualized using 3DCT. The images were classified into three types based on their morphological pattern. The ears of patients with MD were different from normal ears in terms of this classification.

Distinct molecular features of different macroscopic subtypes of colorectal neoplasms.

BACKGROUND: Colorectal adenoma develops into cancer with the accumulation of genetic and epigenetic changes. We studied the underlying molecular and clinicopathological features to better understand the heterogeneity of colorectal neoplasms (CRNs). METHODS: We evaluated both genetic (mutations of KRAS, BRAF, TP53, and PIK3CA, and microsatellite instability [MSI]) and epigenetic (methylation status of nine genes or sequences, including the CpG island methylator phenotype [CIMP] markers) alterations in 158 CRNs including 56 polypoid neoplasms (PNs), 25 granular type laterally spreading tumors (LST-Gs), 48 non-granular type LSTs (LST-NGs), 19 depressed neoplasms (DNs) and 10 small flat-elevated neoplasms (S-FNs) on the basis of macroscopic appearance. RESULTS: S-FNs showed few molecular changes except SFRP1 methylation. Significant differences in the frequency of KRAS mutations were observed among subtypes (68% for LST-Gs, 36% for PNs, 16% for DNs and 6% for LST-NGs) (P<0.001). By contrast, the frequency of TP53 mutation was higher in DNs than PNs or LST-Gs (32% vs. 5% or 0%, respectively) (P<0.007). We also observed significant differences in the frequency of CIMP between LST-Gs and LST-NGs or PNs (32% vs. 6% or 5%, respectively) (P<0.005). Moreover, the methylation level of LINE-1 was significantly lower in DNs or LST-Gs than in PNs (58.3% or 60.5% vs. 63.2%, P<0.05). PIK3CA mutations were detected only in LSTs. Finally, multivariate analyses showed that macroscopic morphologies were significantly associated with an increased risk of molecular changes (PN or LST-G for KRAS mutation, odds ratio [OR] 9.11; LST-NG or DN for TP53 mutation, OR 5.30; LST-G for PIK3CA mutation, OR 26.53; LST-G or DN for LINE-1 hypomethylation, OR 3.41). CONCLUSION: We demonstrated that CRNs could be classified into five macroscopic subtypes according to clinicopathological and molecular differences, suggesting that different mechanisms are involved in the pathogenesis of colorectal tumorigenesis.

Molecular features of colorectal polyps presenting Kudo's type II mucosal crypt pattern: are they based on the same mechanism of tumorigenesis?

BACKGROUND AND STUDY AIMS: The molecular features of serrated polyps (SPs) with hyperplastic crypt pattern, also called Kudo's type II observed by chromoendoscopy, were evaluated. METHODS: The clinicopathological and molecular features of 114 SPs with a hyperplastic pit pattern detected under chromoendoscopy (five dysplastic SPs, 63 sessile serrated adenoma/polyps (SSA/Ps), 36 microvesicular hyperplastic polyps (MVHPs), and 10 goblet cell-rich hyperplastic polyps (GCHPs)) were examined. The frequency of KRAS and BRAF mutations and CpG island methylator phenotype (CIMP) were investigated. RESULTS: Dysplastic SPs and SSA/Ps were frequently located in the proximal colon compared to others (SSA/Ps vs. MVHPs or GCHPs, P < 0.0001). No significant difference was found in the frequency of BRAF mutation among SPs apart from GCHP (60 % for dysplastic SPs, 44 % for SSA/Ps, 47 % for MVHPs, and 0 % for GCHPs). The frequency of CIMP was higher in dysplastic SPs or SSA/Ps than in MVHPs or GCHPs (60 % for dysplastic SPs, 56 % for SSA/Ps, 32 % for MVHPs, and 10 % for GCHPs) (SSA/Ps vs. GCHP, P = 0.0068). When serrated neoplasias (SNs) and MVHPs were classified into proximal and distal lesions, the frequency of CIMP was significantly higher in the proximal compared to the distal SNs (64 % vs. 11 %, P = 0.0032). Finally, multivariate analysis showed that proximal location and BRAF mutation were significantly associated with an increased risk of CIMP. CONCLUSIONS: Distinct molecular features were observed between proximal and distal SPs with hyperplastic crypt pattern. Proximal MVHPs may develop more frequently through SSA/Ps to CIMP cancers than distal MVHPs.

Successful perioperative management for a breast cancer patient with Bernard-Soulier syndrome.

We herein report the first case of a Bernard-Soulier syndrome (BSS) patient undergoing a surgical procedure for breast cancer. BSS is a rare hereditary thrombocytopathy associated with defects of the platelet glycoprotein complex glycoprotein Ib/V/IX and characterized by large platelets, thrombocytopenia, and severe bleeding symptoms. Because of the rarity of BSS, there are as yet no defined protocols for the perioperative management, which can be very complex and challenging in patients with coagulopathies, in particular BSS. In this case we successfully performed both an interventional examination as well as mastectomy with axillary lymph node dissection, under the preventive and intermittent transfusion of platelets. No intra- or postoperative bleeding complications occurred. Unfortunately, the patient was diagnosed as having metastatic disease involving liver, lungs, and bones 10 months after the surgery. She had received 1st, 2nd, and 3rd line chemotherapy without severe adverse events. However, gastrointestinal bleeding appeared after she was treated with 4th line chemotherapy. Finally, she succumbed 22 months after the breast surgery.

DNA methylation profiles of primary colorectal carcinoma and matched liver metastasis.

BACKGROUND: The contribution of DNA methylation to the metastatic process in colorectal cancers (CRCs) is unclear. METHODS: We evaluated the methylation status of 13 genes (MINT1, MINT2, MINT31, MLH1, p16, p14, TIMP3, CDH1, CDH13, THBS1, MGMT, HPP1 and ERα) by bisulfite-pyrosequencing in 79 CRCs comprising 36 CRCs without liver metastasis and 43 CRCs with liver metastasis, including 16 paired primary CRCs and liver metastasis. We also performed methylated CpG island amplification microarrays (MCAM) in three paired primary and metastatic cancers. RESULTS: Methylation of p14, TIMP3 and HPP1 in primary CRCs progressively decreased from absence to presence of liver metastasis (13.1% vs. 4.3%; 14.8% vs. 3.7%; 43.9% vs. 35.8%, respectively) (P<.05). When paired primary and metastatic tumors were compared, only MGMT methylation was significantly higher in metastatic cancers (27.4% vs. 13.4%, P = .013), and this difference was due to an increase in methylation density rather than frequency in the majority of cases. MCAM showed an average 7.4% increase in DNA methylated genes in the metastatic samples. The numbers of differentially hypermethylated genes in the liver metastases increased with increasing time between resection of the primary and resection of the liver metastasis. Bisulfite-pyrosequencing validation in 12 paired samples showed that most of these increases were not conserved, and could be explained by differences in methylation density rather than frequency. CONCLUSIONS: Most DNA methylation differences between primary CRCs and matched liver metastasis are due to random variation and an increase in DNA methylation density rather than de-novo inactivation and silencing. Thus, DNA methylation changes occur for the most part before progression to liver metastasis.

Right colon cancer presenting as hemorrhagic shock.

A 67-year-old man visited our hospital with a history of continuous hematochezia leading to hemorrhagic shock. An abdominal computed tomography scan revealed a large mass in the ascending colon invading the duodenum and pancreatic head as well as extravasation of blood from the gastroduodenal artery (GDA) into the colon. Colonoscopy revealed an irregular ulcerative lesion and stenosis in the ascending colon. Therefore, right hemicolectomy combined with pylorus-preserving pancreaticoduodenectomy was performed. Histologically, the tumor was classified as a moderately differentiated adenocarcinoma. Moreover, cancer cells were mainly located in the colon but had also invaded the duodenum and pancreas and involved the GDA. Immunohistochemically, the tumor cells were positive for cytokeratin (CK)20 and carcinoembryonic antigen (CEA) but not for CK7 and carbohydrate antigen (CA)19-9. The patient died 23 d after the surgery because he had another episode of arterial bleeding from the anastomosis site. Although En bloc resection of the tumor with pancreaticoduodenectomy and colectomy performed for locally advanced colon cancer can ensure long-term survival, patients undergoing these procedures should be carefully monitored, particularly when the tumor involves the main artery.

Clinicopathological and molecular features of colorectal serrated neoplasias with different mucosal crypt patterns.

OBJECTIVES: Endoscopic examination shows that serrated neoplasias (SNs), such as serrated adenomas and sessile serrated adenomas, exhibit different mucosal crypt patterns. However, it remains unclear whether advanced serrated polyps with different mucosal crypt patterns have different clinicopathological or molecular features. METHODS: We classified the mucosal crypt patterns of 86 SNs into three types (hyperplastic, adenomatous, and mixed pattern) and evaluated their clinicopathological and molecular features. RESULTS: We found significant differences in the proliferative activity status between SNs with mixed/adenomatous patterns and those with the hyperplastic patterns. SNs with the hyperplastic pattern were frequently located in the proximal colon and had a macroscopically superficial appearance, whereas SNs with the adenomatous pattern were often located in the distal colon and had a protruding appearance. Furthermore, a significant difference was observed in the frequency of the CpG island methylator phenotype (CIMP), involving the methylation of two or more CIMP-related genes (MINT1, MINT2, MINT31, p16, and MLH1), between SNs with the hyperplastic pattern and those with the mixed/adenomatous patterns (18/32 (56%) vs. 8/28 (29%) or 7/26 (27%); P=0.0309 or P=0.0249, respectively). Moreover, the prevalence of KRAS mutations was significantly higher in SNs with the adenomatous pattern than in those with the hyperplastic pattern (7/26 (27%) vs. 1/32 (3%); P=0.0173). In comparison with other patterns, the mixed pattern was detected more frequently in mixed serrated polyps (MSPs), which contain separate histological components. Some MSPs exhibited concordant molecular alterations among the different histological components. CONCLUSIONS: The clinicopathological and molecular features of SNs correlated strongly with their mucosal crypt patterns, which were observed using chromoendoscopy.

Primary micropapillary carcinoma of the colon: a case report and literature review.

We report a case of micropapillary carcinoma (MPC) of the transverse colon. A 56-year-old woman was admitted to our hospital with hematochezia. A lower gastrointestinal examination revealed an irregular ulcerative tumor of approximately 60 mm diameter with marginal elevation in the transverse colon. Abdominal computed tomography showed multiple swollen lymph nodes. A histological examination of the resected specimen revealed that cancer cells had invaded the subserosa. Microscopically, small papillary cells proliferated with lacuna spaces and the cribriform glandular configuration was observed. Immunohistochemically, the basal surface of the neoplastic cell clusters was diffusely positive for MUC1. No primary tumor was observed except for the colon. Therefore, this tumor was diagnosed as a primary MPC of the colon. Since a colorectal MPC was first reported in 2005, seven case reports and three pathological reviews have been presented in the English literature. MPC has an aggressive behavior with a high incidence of lymphovascular invasion and nodal metastases. We should take intensive chemotherapy for colorectal MPC into account, even if surgical resection is curative.

[Cost-effectiveness analysis of chemotherapy with GEM or S-1 for patients with non-resectable pancreatic cancer].

OBJECTIVE: To assess the cost-effectiveness of chemotherapy for patients with non-resectable pancreatic cancer, we compared two regimens containing either gemcitabine (GEM) or S-1. METHODS: We developed a decision tree that showed the clinical processes of non-resectable pancreatic cancer patients. We calculated the probabilities of endpoint and life months gained (LMG) based on previously reported articles. To estimate the costs, we analyzed medical records of 44 inpatients with non-resectable pancreatic cancer treated with GEM(n=34)or S-1(n=10). Sensitivity analysis was used to check the robustness of the results. RESULTS: In the GEM group and S-1 group, costs were 1,636,393 and 985,042 yen, and LMG was 6. 0 and 9. 0 months, respectively. Thus, the cost-effectiveness ratio(CER)was calculated to be 272,732 and 109,449 yen/LMG, respectively, and the incremental cost effectiveness ratio (ICER) was -217,117 yen/LMG. The sensitivity analysis showed that the result was definitely robust. CONCLUSION: Our findings suggest that the markedly cost-effective S-1 regimen could prolong LMG with less cost than the GEM regimen.

Does daily alcohol and/or cigarette consumption cause low-grade dysplasia, a precursor of esophageal squamous cell carcinoma?

BACKGROUND: Cigarette smoking and alcohol consumption are well-known risk factors for esophageal squamous cell carcinoma (ESCC), which has a very poor prognosis. Successful screening strategies for precursor lesions that can be targets for early detection and treatment are required to prevent ESCC. METHODS: This is a prospectively cross-sectional study. To clarify whether daily smoking and/or alcohol consumption are risk factors for dysplasia, which is the initial lesion leading to ESCC. Lugol chromoendoscopy was performed in 1,345 eligible individuals. Six hundred ninety individuals had daily smoking and/or alcohol consumption; 655 individuals did not smoke and drink alcohol. The effects of smoking and alcohol consumption among high-grade dysplasia (HGD), low-grade dysplasia (LGD), and controls without dysplasia were evaluated using multiple logistic regression analysis. RESULTS: Among 1,345 individuals, 17 HGD and 23 LGD lesions were confirmed histologically. The prevalence of both smoking and drinking consumption was significantly higher in HGD than in LGD individuals (age and sex adjusted odds ratio; 113.0, 95% confidence interval; 6.26), whereas no significant difference was seen in both consumption between LGD individuals and controls (odds ratio; 1.29, 95% confidence interval; 0.33-6.37). Approximately 70% of HGD individuals, but only 13% of LGD individuals, both smoked and consumed alcohol. CONCLUSIONS: Daily cigarette and alcohol consumption were not the risk factors for LGD, however, consumption of both were high-risk factors for HGD. We suggest that documenting the difference of risk factors for LGD and HGD can assist in the development of effective screening, early detection, and prevention strategies for ESCC.

Rapamycin enhances chemotherapy-induced cytotoxicity by inhibiting the expressions of TS and ERK in gastric cancer cells.

We have previously reported the synergistic cytotoxic effects of Docetaxel (TXT) and S-1 in gastric cancer in vitro and in vivo, and the combination regimen is now under phase III clinical trail. In this study, to elucidate whether the rapamycin, the inhibitor of the mTOR (mammalian target of rapamaycin), can enhance the potentiation of TXT and 5-fluorouracil (5-Fu) in gastric carcinoma cells. Rapamycin inhibited the growth of TMK-1, MKN-28, MKN-45 and MKN-74 cell lines by MTT assay, and it demonstrated the cytostatic effects as G1 arrest shown by flowcytometry. However, the cytotoxic effects of 5-Fu, TXT and cisplatin were enhanced by 2 to 4 times with the concomitant administration of rapamycin. To clarify the mechanism of the potentiation, the expression changes of the enzymes relating DNA metabolism and cell growth signal transduction pathways were examined by western blot analysis. Interestingly, the expression of thymidilate synthase was markedly decreased by the administration of rapamycin in TMK-1 cells in a time- and dose-dependent manner. Moreover, rapamycin decreased the phosphorylation of 4E-BP1, the phosphorylation of ERK1/2 and enhanced the phosphorylation of c-Jun NH2-terminal kinase, and the activation of caspase of apoptotic pathways in combination with TXT. These results strongly indicate that the mTOR inhibitor can enhance the potentiation of TXT and 5-Fu or S-1 and can serve as a new therapeutic tool for advanced and recurrent gastric cancer patients.