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Background Some patients with inflammatory bowel disease (IBD) who were under mesalamine treatment develop adverse reactions called “mesalamine allergy,” which includes high fever and worsening diarrhea. Currently, there is no method to predict mesalamine allergy. Pharmacogenomic approaches may help identify these patients. Here we analyzed the genetic background of mesalamine intolerance in the first genome-wide association study of Japanese patients with IBD. Methods Two independent pharmacogenetic IBD cohorts were analyzed: the MENDEL (n = 1523; as a discovery set) and the Tohoku (n = 788; as a replication set) cohorts. Genome-wide association studies were performed in each population, followed by a meta-analysis. In addition, we constructed a polygenic risk score model and combined genetic and clinical factors to model mesalamine intolerance. Results In the combined cohort, mesalamine-induced fever and/or diarrhea was significantly more frequent in ulcerative colitis vs Crohn’s disease. The genome-wide association studies and meta-analysis identified one significant association between rs144384547 (upstream of RGS17) and mesalamine-induced fever and diarrhea (P = 7.21e-09; odds ratio = 11.2). The estimated heritability of mesalamine allergy was 25.4%, suggesting a significant correlation with the genetic background. Furthermore, a polygenic risk score model was built to predict mesalamine allergy (P = 2.95e-2). The combined genetic/clinical prediction model yielded a higher area under the curve than did the polygenic risk score or clinical model alone (area under the curve, 0.89; sensitivity, 71.4%; specificity, 90.8%). Conclusions Mesalamine allergy was more common in ulcerative colitis than in Crohn’s disease. We identified a novel genetic association with and developed a combined clinical/genetic model for this adverse event.

Most patients with Crohn’s disease (CD) experience surgical recurrence. In this era of novel therapies, we conducted this study to clarify which treatments effectively decrease the risk of surgical recurrence in patients with CD. The subjects of this retrospective study were 37 patients with CD. We created cumulative surgery rate curves and performed univariate and multivariate analyses. Univariate analysis revealed that patients who consumed an elemental diet (ED; ≥ 900 kcal/day), anti-tumor necrosis factor-alpha, and thiopurines had a significantly better prognosis than those who did not (p = 0.011, p = 0.025, and p = 0.0080, respectively). Multivariate analysis revealed that ED therapy and thiopurines were independent significant factors for controlling surgical recurrence (p = 0.046 and p = 0.032, respectively). Additional analyses showed that the most promising ED therapeutic dose was ≥ 1200 kcal/day, while an ED therapeutic dose of ≥ 900 kcal/day was acceptable. Although univariate analyses revealed that all three treatment strategies had significant effects on surgical recurrence in patients with CD, multivariate analysis revealed that only ED therapy was significantly associated with surgical recurrence rates. Thus, ED therapy plays an important role in the management of CD, even in the era of biological therapies.

Impaired Wnt signaling pathway plays a crucial role in the development of colorectal cancer through activation of the β-catenin/TCF7L2 complex. Although genes upregulated by Wnt/β-catenin signaling have been intensively studied, the roles of downregulated genes are poorly understood. Previously, we reported that interferon-induced proteins with tetratricopeptide repeats 2 (IFIT2) was downregulated by the Wnt/β-catenin signaling, and that the suppressed expression of IFIT2 conferred antiapoptotic property to colorectal cancer (CRC) cells. However, the mechanisms underlying how Wnt/β-catenin signaling regulates IFIT2 remain to be elucidated. In this study, we have uncovered that the expression of IFIT2 is induced by IRF1, which is negatively regulated by the Wnt/β-catenin signaling. In addition, we found that downregulation of IRF1 is mediated by its degradation through the ubiquitination-proteasome pathway, and that decreased activity of a deubiquitinase complex containing USP1 and UAF1 is involved in the degradation of IRF1 by Wnt/β-catenin signaling. These data should provide better understanding of the Wnt signaling pathway and human carcinogenesis.

We previously performed a randomized controlled trial (RCT) comparing targeted and random biopsy in neoplasia detection in patients with ulcerative colitis (UC), which showed the short-term effectiveness of targeted biopsy with one-time colonoscopy. In this retrospective cohort study, we investigated the long-term effectiveness of targeted biopsy in tertiary care hospitals, using the follow-up data from patients with UC for &ge, 8 years who had enrolled in the initial RCT. The primary outcome was death from colorectal cancer (CRC). Secondary outcomes were advanced neoplasia (CRC or high-grade dysplasia) and colectomy due to neoplasia after the RCT. We compared these outcomes between target and random groups. Data on 195 of the 221 patients (88.2%) enrolled in the previous RCT were collected from 28 institutions between 2008 and 2019. No patients died of CRC in either group, with a median 8.8-year follow-up demonstrating a robustness for targeted biopsy in terms of CRC death prevention. Advanced neoplasia was detected in four and three patients in the target and random groups, respectively. Colectomy was required due to neoplasia in three patients in each group. The chance of developing CRC in patients with a negative colonoscopy was low, and the targeted biopsy appeared effective in this population. Conversely, patients found with low-grade dysplasia at initial RCT have 10-fold higher risk of progression to high-grade dysplasia and/or CRC. Ten extracolonic malignancies were observed during the follow-up, resulting in four deaths. Panchromoendoscopy was used only in 4.6% and targeted biopsy was only performed in 59.1% of colonoscopies. We recommend targeted biopsy rather than &gt, 33 random biopsies in real-world settings under adequate observation by specialists.

Background Despite NUDT15 variants showing significant association with thiopurine-induced adverse events (AEs) in Asians, it remains unclear which variants of NUDT15 or whether additional genetic variants should be tested to predict AEs. To clarify the best pharmacogenetic test to be used clinically, we performed association studies of NUDT15 variants and haplotypes with AEs, genome-wide association study (GWAS) to discover additional variants, and ROC analysis to select the model to predict severe AEs. Methods Overall, 2630 patients with inflammatory bowel disease (IBD) were enrolled and genotyped for NUDT15 codon 139; 1291 patients were treated with thiopurines. diplotypes were analyzed in 970 patients, and GWASs of AEs were performed with 1221 patients using population-optimized genotyping array and imputation. Results We confirmed the association of NUDT15 p.Arg139Cys with leukopenia and alopecia (p = 2.20E−63, 1.32E−69, OR = 6.59, 12.1, respectively), and found a novel association with digestive symptoms (p = 6.39E−04, OR = 1.89). Time to leukopenia was significantly shorter, and when leukopenia was diagnosed, thiopurine doses were significantly lower in Arg/Cys and Cys/Cys than in Arg/Arg. In GWASs, no additional variants were found to be associated with thiopurine-induced AEs. Despite strong correlation of leukopenia frequency with estimated enzyme activities based on the diplotypes (r2 = 0.926, p = 0.0087), there were no significant differences in the AUCs of diplotypes from those of codon 139 to predict severe AEs (AUC = 0.916, 0.921, for acute severe leukopenia, AUC = 0.990, 0.991, for severe alopecia, respectively). Conclusions Genotyping of NUDT15 codon 139 was sufficient to predict acute severe leukopenia and alopecia in Japanese patients with IBD. Electronic supplementary material The online version of this article (10.1007/s00535-018-1486-7) contains supplementary material, which is available to authorized users.

Pouchitis is the most common long-term complication of restorative proctocolectomy with ileal pouch-anal anastomosis. We investigated alterations in the expression of microRNAs, noncoding RNAs that act as potent negative regulators of gene expression, in pouchitis. The subjects of this study were 16 patients with diagnosed pouchitis and 48 patients without pouchitis after restorative proctocolectomy, performed for ulcerative colitis. Total RNA was extracted from biopsies and microRNAs were quantified using a real-time polymerase chain reaction. The expression of microRNA 21 and 223 was higher, whereas that of microRNA 192 and 196a was lower, in the inflamed mucosa from the pouchitis patients than in the mucosa from the non-pouchitis patients. The levels of 14 microRNAs were significantly lower in the mucosa from the pouchitis patients, than in the non-inflamed proximal ileal mucosal samples. The expression of microRNA 192 was remarkably reduced in pouchitis. A significant negative correlation was found between microRNA 192 and interleukin 17 receptor A mRNA levels. Significant alteration in miRNA expression in line with inflammatory bowel disease was evident in the mucosa from the pouchitis patients. Interleukin 17 receptor A may be involved in the pathogenesis of pouchitis through the downregulation of microRNA 192.

Highlights • Secondary perineal hernia can develop after abdominoperineal resection of the rectum. • An incarcerated secondary perineal hernia caused strangulated bowel obstruction. • Wound-healing-delaying factors are the risk factors for perineal hernia development. • The pelvic floor and peritoneum should be repaired via laparoscopic rectum surgery., Introduciton We report a recent case of strangulated bowel obstruction due to an incarcerated secondary perineal hernia that developed after laparoscopic rectal resection. Presentation of case A 75-year-old man undergoing treatment for alcoholic cirrhosis underwent laparoscopic abdominoperineal resection of the rectum (APR) for lower rectal cancer after preoperative chemoradiotherapy. Lung metastases were diagnosed 2 months postoperatively. Ten days after chemotherapy initiation, the patient was hospitalized on an emergency basis due to hepatic encephalopathy. Ten days thereafter, we observed perineal skin protrusion. Moreover, the skin disintegrated spontaneously, resulting in ascetic fluid outflow. Pain and fever developed, with inflammatory reactions. Contrast-enhanced computed tomography showed strangulated small bowel obstruction due to perineal hernia. We performed an emergency surgery, during which we found small intestine wall incarcerated in the pelvic dead space, with thickening and edema; no necrosis or perforation was observed. We performed internal fixation by introducing an ileus tube into the ileocecum and fixing its balloon at the cecal terminus. Discussion Secondary perineal hernia is rare and can develop after APR. Its prevalence is likely to increase in future because of the increasing ubiquity of laparoscopic APR, in which no repair of peritoneal stretching to the pelvic floor is performed. However, only two case of secondary perineal hernia causing strangulated bowel obstruction has been reported in the literature. The follow-up evaluation of our procedures and future accumulation of cases will be important in raising awareness of this clinical entity. Conclusion We suggest that the pelvic floor and the peritoneum should be repaired.

Highlights • A mobile cecum is not an uncommon congenital anomaly. • Acute appendicitis in the presence of mobile caecum may present with atypical abdominal findings. • The presence of mobile cecum should be considered in the differential diagnosis of acute abdomen. • CT examination may be helpful in establishing the diagnosis in atypical presentation of acute appendicitis. • Abdominal computed tomography (CT) should be done in diagnosing acute abdomen., Introduction A mobile cecum is a frequently encountered congenital anomaly. It is important to recognize this atypical position of the cecum as it may interfere with an accurate diagnosis of acute appendicitis. Presentation of case A 48-year-old man presented with abdominal pain, anorexia, and fever. He had mild lower abdominal discomfort, and rebound tenderness in the suprapubic region, but no guarding or right lower quadrant findings. Laboratory tests identified an elevated white blood cell count (12350 cells/mL) and C-reactive protein level (4.56 mg/dL). In view of the clinical picture suggestive of localized peritonitis, an abdominal computed tomography (CT) was performed, which revealed a caudally located cecum, lying in the pelvis, along with evidence of an acutely inflamed appendix. An urgent surgical procedure was performed, which confirmed the diagnosis of acute appendicitis accompanying a mobile cecum. Discussion In the presence of a mobile cecum, the clinical findings of acute appendicitis may be atypical owing to the abnormal position of the appendix. In such cases, there is the possibility of a missed diagnosis. In our case, a CT examination that was performed in view of the clinical diagnosis of mild peritonitis aided in establishing the diagnosis of acute appendicitis and a mobile cecum. Conclusion Anatomical variations of the cecum and the appendix may result in atypical presentation of acute appendicitis. A high index of suspicion, and a CT examination may be helpful in establishing the diagnosis in such cases.

Introduction: Inflammatory fibroid polyps (IFPs) are rare, benign lesions of the gastrointestinal tract. Their occurrence in the colon is rare. They are often surgically resected for various reasons. Case presentation: A 60-year-old woman presented to our institution. She had a history of gynecologic surgery for cervical cancer at 37 years of age. Colonoscopy was performed by a local doctor and a type I tumor on Bauhin’s valve was suspected. Colonoscopy performed by us revealed a pedunculated polypoid tumor with a 20-mm head that was found to have a long stalk in the cecum. It was inferred that the stalk was entering and exiting through the valve since submucosal bleeding was observed. Polypectomy was performed. The histopathological diagnosis was IFP. Colonoscopy performed after 6 months showed no polyp recurrence. Discussion: According to previous reports, the treatment of colonic IFP was surgical in 58% of cases and endoscopic resection was performed in only 23% of cases. The decision to perform surgery was based on various factors, such as polyp size and position, difficulty in diagnosis by biopsy, and patient symptoms. In the present case, we could successfully perform polypectomy before the appearance of symptoms. Endoscopic resection seems to be an appropriate treatment approach due to the benign nature of IFP. The etiology of IFP remains unknown. Conclusion: The decision to perform surgery or endoscopic resection should be done on a case-by-case basis, but we think that a favorable increase in the number of endoscopic resections will occur in the future.

Familial adenomatous polyposis (FAP) of the colon is characterized by multiple polyps in the intestine and extra-colonic manifestations. Most FAP cases are caused by a germline mutation in the tumor-suppressor gene APC, but some cases of adenomatous polyposis result from germline mutations in MUTYH, POLD1 or POLE. Although sequence analysis of APC by the Sanger method is routinely performed for genetic testing, there remain cases whose mutations are not detected by the analysis. Next-generation sequencing has enabled us to analyze the comprehensive human genome, improving the chance of identifying disease causative variants. In this study, we conducted whole-genome sequencing of a sporadic FAP patient in which we did not find any pathogenic APC mutations by the conventional Sanger sequencing. Whole-genome sequencing and subsequent deep sequencing identified a mosaic mutation of c.3175G>T, p.E1059X in ~12% of his peripheral leukocytes. Additional deep sequencing of his buccal mucosa, hair follicles, non-cancerous mucosa of the stomach and colon disclosed that these tissues harbored the APC mutation at different frequencies. Our data implied that genetic analysis by next-generation sequencing is an effective strategy to identify genetic mosaicism in hereditary diseases.

The authors have developed the laser backlight for displays that uses laser diodes (LDs) for the red light sources. While laser beams are favorable because of their high color purity, they develop extremely disadvantageous thermal characteristics. Therefore, thermal management is a critical issue for LDs used as display light sources. As for the backlight used on a large screen flat panel display in particular, where light sources with high heat flux are laid out in a dispersed fashion, the cooling performance of the light sources directly influences the product performance and quality. The authors used a CFD simulation to review a cooling system optimum for the laser backlight.

The color gamut is one of the critical parameters that dictate the image quality of displays. The liquid crystal displays using white color light-emitting diodes (LEDs) as the backlight, though having been widely employed recently, are not very satisfactory in terms of their color gamut because of the broad spectrum inherent to white LEDs. This prompted the authors to develop improved liquid crystal displays using an edge-lit wide color gamut backlight that used red laser diodes and cyan LEDs. Generating laser beams with high color purity, the laser diodes are light sources with a significant effect on expanding the color gamut. However, laser diodes, red ones in particular, have unfavorable thermal characteristics. To cope with this shortcoming, the authors clearly defined the restrictive criteria for laying out two kinds of light source on the edge-lit backlight and made a prototype 55-type laser backlight for performance evaluation.

Aim The aim of this study was to elucidate risk factors for the development of colorectal neoplasia in the young population. In particular, we focused on the family history of gastric cancer. Method Young Japanese subjects aged 30–49 years old who underwent colonoscopy for the first time from August 2007 to August 2008 were included in this study. A total of 300 unselected consecutive patients (mean age 40.5 years) were eligible for analysis, and family history of colorectal cancer and gastric cancer, sex, age, body mass index, positivity of faecal occult blood test and the presence of symptoms were evaluated. Risk factors for developing colorectal adenoma and/or carcinoma were assessed. Results Colorectal neoplasias were detected in 83 (27.7%) cases. Two were found to have invasive carcinoma. Univariate and multivariate analyses revealed that family history of gastric cancer (OR 2.09, 95% CI 1.12–3.92, P = 0.02) was an independent risk factor for the development of colorectal neoplasia, as well as male sex (OR 1.89, 95% CI 1.10–3.27, P = 0.02), older age (OR 2.05, 95% CI 1.18–3.55, P = 0.01) and positive faecal occult blood test (OR 1.99, 95% CI 1.14–3.48, P = 0.02). Conclusion In the young population under 50 years of age, a family history of gastric cancer is an independent risk factor for the development of colorectal neoplasia.

Background and aim The risk of developing colorectal cancer is higher in patients with ulcerative colitis (UC) than in the general population. Guidelines recommend surveillance colonoscopy (SCS) to reduce mortality; however, few studies have assessed physicians’ adherence to guidelines. This study was aimed to clarify the current status of SCS and adherence to guidelines through the characteristics of cancer/dysplasia surveillance for UC patients in Japan. Methods A questionnaire was mailed to 541 physicians who attended meetings on inflammatory bowel disease. Results The respondents encountered a median of 100 UC cases. Thirty percent of the respondents had never managed a UC patient with cancer. Fifty-one percent of the respondents had never diagnosed colorectal cancer with UC. Forty-seven percent of the respondents considered total colitis and left-sided colitis as indications for SCS, and 38% performed SCS regardless of the disease extent. Sixty-three percent of the respondents started SCS at 7–10 years after UC onset, whereas 20% started SCS at 3 years or less. Fifty-two percent of the respondents obtained targeted biopsies only, and chromoendoscopy was employed by 49% of the respondents as a special technique for surveillance. The median number of biopsies at SCS was 5 per patient; it was 3 among patients performed by physicians who obtained targeted biopsies only and 7 among those performed by physicians who obtained step biopsies and targeted biopsies (p < 0.0001). Conclusion A considerable proportion of the respondents did not follow the guidelines when selecting patients for surveillance and performing SCS. This article is protected by copyright. All rights reserved.

Most pancreatic cancer patients are diagnosed at the advanced stages, and no therapy is superior to gemcitabine alone. To confirm the feasibility and efficacy of a novel clinical intervention using tumor vessel-specific anti-angiogenic peptide vaccination, we conducted a clinical phase I/II trial using HLA-A*2402/A*0201-restricted vascular endothelial growth factor receptor type 1 (VEGFR1)-derived peptide vaccination in combination with gemcitabine for advanced pancreatic cancer (http://www.clinical-trials.gov; NCT00683358 and NCT00683085). Four of the enrolled patients (n = 2 for HLA-A*2402 and n = 2 for HLA-A*0201 protocol, respectively), defined as having progressive disease according to the Response Evaluation Criteria in Solid Tumors version 1.0 (RECIST v.1.0), failed to respond to the therapy. Another two patients enrolled in HLA-A*2402 protocol dropped out of the study due to rapid disease progression. Grade 2-3 hematologic toxicities were observed in all cases, but the treatment was well tolerated with minimal systemic adverse events. One case in HLA-A*2402 protocol and another case in HLA-A*0201 protocol suffered complicated gastrointestinal (GI) bleeding during vaccination. The causal relationship between GI bleeding and VEGFR1-peptide vaccination is unclear according to the pathologic examination. These studies terminated prematurely because of the advanced stage of the disease in the enrolled patients on entry to the study. Despite GI bleeding, peptide vaccination provides a feasible treatment option for many advanced pancreatic cancer patients.

Purpose: Somatic B-RAF gene mutation has been identified in many malignancies and detected at a high frequency in cutaneous malignant melanoma. However, the significance of the B-RAF mutation (B-RAFmt) in terms of its prognostic and predictive capabilities for treatment response or disease outcome is not known. We hypothesized that circulating serum B-RAFmt (B-RAFsmt) at V600E, detected in serum, predicts response in melanoma patients receiving concurrent biochemotherapy. Experimental Design: A real-time clamp quantitative reverse transcription-PCR assay was designed to assess B-RAFsmt by peptide nucleic acid clamping and a locked nucleic acid hybrid probe. Normal (n = 18) and American Joint Committee on Cancer stage I to IV melanoma patients (n = 103) were evaluated. These included stage IV patients (n = 48) with blood drawn before and after biochemotherapy. Patients were classified as biochemotherapy responders or nonresponders. Responders (n = 24) had a complete or partial response following biochemotherapy; nonresponders (n = 24) developed progressive disease. Results: Of the 103 melanoma patients, 38 (37%) had B-RAFsmt DNA, of which 11 of 34 (32%) were stage I or II, and 27 of 69 (39%) were stage III or IV. Of the 48 biochemotherapy patients, 10 of 24 (42%) patients were positive for the B-RAFsmt in the respective responder and nonresponder groups before treatment. After biochemotherapy, B-RAFsmt was detected in only 1 of 10 patients (10%) in the responder group and 7 of 10 patients (70%) in the nonresponder group. B-RAFsmt is associated with significantly worse (P = 0.039) overall survival in patients receiving biochemotherapy. Conclusion: These studies show the presence and utility of circulating B-RAFsmt DNA in melanoma patients.

APAF-1 gene, located at chromosome locus 12q23, is a key factor in the mitochondrial apoptotic pathway downstream of p53, and is a potential tumor suppressor gene. We hypothesized that APAF-1 gene dysfunction due to allelic imbalance (AI) contributes to the development and progression of colorectal carcinoma (CRC). AI at APAF-1 locus and microsatellite instability (MIN) in CRCs and adenomas were assessed by multiple microsatellite markers. The frequency of AI significantly increased with tumor progression; 0 of 33 (0%) adenomas, 14 of 49 (29%) primary CRCs, and 18 of 34 (53%) liver metastases had AI. A total of 12 metastases were matched with corresponding primary CRCs; in 11 of 12 (92%) pairs, the metastasis had same AI status as the corresponding primary tumor. APAF-1 mRNA transcription level was significantly decreased with AI in liver metastases (P=0.009). Promoter hypermethylation was found in three of 35 (9%) primary CRCs and one of 15 (7%) liver metastases by methylation-specific PCR but was not correlated with AI. MIN was observed in 11 of 49 (23%) primary CRCs and was a favorable prognostic factor. Our results suggest that APAF-1 gene haploinsufficiency caused by AI increases with tumor progression, and relates to hepatic metastasis.

Restorative proctocolectomy and ileal pouch-anal anastomosis (IPAA) have been the surgical treatments of choice for ulcerative colitis (UC). However, the IPAA is sometimes complicated with pouchitis. Furthermore, the cumulative risk and risk factors for developing pouchitis in patients with UC undergoing IPAA have not been reported in any Asian population. The aim of our study is to clarify the cumulative risk and risk factors for developing pouchitis in Japanese patients with UC undergoing IPAA.Fifty-eight patients with UC undergoing IPAA were retrospectively evaluated for the presence of pouchitis, gender, age of onset, history of smoking, presence of extraintestinal manifestations (EIMs) and type of operation. The diagnosis of pouchitis was based on the pouchitis disease activity index. The cumulative risk and risk factors for developing pouchitis were assessed.The cumulative risks for developing pouchitis at 1 and 5 years were 9.0% and 14.4%, respectively. The estimated risks of pouchitis at 5 years was 48.1% in patients with EIMs and 4.6% in those without. Both univariate and multivariate analyses revealed that the presence of EIMs is a significant risk factor (hazard ratio 16.85, 95% confidence interval 3.12-91.00; P=0.001).The presence of EIMs is a significant risk factor for the development of pouchitis in Japanese patients with UC undergoing IPAA.

横浜市民病院で治療した潰瘍性大腸炎680例中7例(1.0%)が死亡した.内訳は男性5例,女性2例,平均年齢は44.7歳,全例手術例で,死因は悪性疾患3例,手術後の合併症4例であった.悪性疾患は大腸癌2例,carcinoidl例であり,surveillanceを受けていない例で,平均26.7カ月で再発死亡した.重症例の死亡は4例で,死因はMOFであった.重症の手術死亡率(9.8%,4/41)はそれ以外の手術死亡率(0%,0/190)と比較して有意に高く,重症死亡例の総steroid投与量はそれ以外の195例の投与量と有意差はなかったが,手術前1カ月の投与量は有意に高かった.死亡例を減少させるには大腸癌を早期に発見するsurveillanceと重症例に対してsteroidを長期間大量に使用しないことが重要である.

The status of genetic alterations in ulcerative colitis (UC)-associated neoplasia (UCAN) was investigated focusing on microsatellite instability (MSI) which is seen in a certain fraction of colorectal carcinomas, and adenomatous polyposis coli (APC) gene and K-ras gene, in which mutations occur in the early stage of sporadic colorectal tumorigenesis. Thirty-one UCAN from 15 UC patients who had undergone colorectal resection at our institution were investigated. There were 8 lesions of invasive carcinoma, 15 high-grade dysplasia (HGD) and 8 low-grade dysplasia (LGD). DNA was extracted from each neoplastic lesion and corresponding non-neoplastic tissue by a microdissection method. MSI status at 9 microsatellite loci, loss of heterozygosity (LOH) at the APC locus, and K-ras codon 12 point mutation were examined. As for MSI, 4/31 (13%) UCAN (carcinoma: 1/8 (13%), HGD: 2/15 (13%), LGD: 1/8 (13%)) were MSI-high (3 or more unstable loci) and 12/31 (39%) UCAN (carcinoma: 3/8 (38%), HGD: 6/15 (40%), LGD: 3/8 (38%)) were MSI-low (1 or 2 unstable loci). LOH at the APC locus was not found in 9 UCAN from 6 informative (heterozygous) cases. The K-ras mutation rate of UCAN was 3/31 (9.7%) (carcinoma: 2/8 (25%), HGD: 1/15 (7%) and LGD: 0/8). MSI is relatively common in UCAN and is present at the early stage of tumorigenesis of UCAN, while the involvement of genetic alterations of the APC gene and K-ras gene is small. MSI may be one of the mechanisms of the increased neoplastic risk in UC, and UCAN may develop through a different carcinogenic pathway from sporadic carcinomas.

We report two cases affected by neoplasia after colectomy with ileo-rectal anastomosis (IRA) with a positive family history of colon cancer. Case 1, a 41-year-old ulcerative colitis (UC) patient, underwent IRA in 1977. In 1986, biopsies showed high-grade dysplasia. She underwent resection of the rectal stump in 1986. Submucosal invasive carcinoma was found in the surgical specimen. The immunohistological study demonstrated p53 protein overexpression in the neoplastic lesion. Her family history fulfilled the Amsterdam criteria of hereditary non-polyposis colorectal cancer (HNPCC). Case 2, a 47-year-old UC patient, underwent ascending colostomy in 1975 and the following year IRA. Endoscopic mucosal resection (EMR) for a sessile adenoma was performed in 1995 and subsequently polypectomy was performed for the residual tumor. Recurrent adenoma and dysplasia in another area were detected. The immunohistological study demonstrated p53 protein overexpression only in dysplasia. Renal cancer in the right kidney was detected. Resection of the rectal stump with ileal pouch-anal anastomosis (IAA), loop ileostomy and right nephrectomy were performed in 1998. Her mother and her mother's sister had been diagnosed with colon cancer. Only in the dysplastic lesion did we detect microsatellite instability at D5S644. Both cases with neoplasia had two relatives with colorectal carcinoma. In 33 cases with UC who had been followed up, 30 cases (96.8%) without neoplasia had no family history of colorectal carcinoma. These findings suggest that UC patients with a family history of colon cancer should be put under close surveillance. It should also be emphasized that IAA is the procedure of choice for UC patients with this particular condition.

Crohn病腸手術156例中3例 (1.9%) においては術後早期に再発, 遺残病変がないにもかかわらず, 吻合部を中心に縫合不全による瘻孔を繰り返した. 症例は男性2例, 女性1例, Crohn病の平均発症年齢19歳で, 術後に瘻孔を平均4.7回 (4, 5, 5回) 合併し, それぞれ3回の再手術を要したが, 1例は治癒し, 1例は未治癒, 1例は死亡した.3例とも術前の経過, 全身状態, 検査結果に特記すべきことはなく, 腸の創傷治癒機転の障害が認められた. このような例はまれではあるが, 原因はCrohn病そのものにあるのか, 他に原因があるか不明である. この原因が解明されれば, 手術はより安全になると期待される.

There is an increased risk of developing colorectal neoplasia in ulcerative colitis (UC) and surveillance colonoscopy is recommended for early detection. We investigated the precise features of UC retrospectively to identify a subgroup with longstanding extensive UC at increased risk of neoplasia. From 1985 to August 1997, we experienced eight UC patients with colorectal cancer and eight with definite dysplasia. All 16 had extensive disease of seven years or more in duration. During the same period, 61 of 334 UC patients without colorectal neoplasia were available for detailed study, allowing evaluation of non-surgical patients with extensive colitis of seven years or more in duration. Basic clinical factors including family history of cancer, expressions of disease activity and durations of pharmacotherapy were investigated. Univariate analysis revealed four significant factors: intractability (P=0.001), periods of inflammation persisting for 3 months or more (P

Background: The management of patients with multiple colorectal adenomas, 10-100 in number, is often troublesome clinically. To establish the reasonable management of such cases, genetic backgrounds should be made clear. Methods: For a total of 19 adenomas and four carcinomas from four patients with multiple colorectal adenomas, we analyzed genetic instability at four selected microsatellite loci and screened exon 1-4 of the APC gene with special reference to macroscopic configurations of adenomas and carcinomas. Results: RER-positive phenotypes were detected in none of 13 protruded type adenomas, two (33%) out of six superficial elevated type adenomas and two (50%) out of four carcinomas. We detected no mutation of exon 1-4 of the APC gene in any sample. In patients with multiple colorectral adenomas, the proportion of superficial elevated type adenomas exhibiting genetic instability was significantly higher than that of protruded type adenomas. Conclusions: The results suggested that RER-positive phenotype was an early event in tumorigenesis through superficial elevated type adenomas.

The major operative indication for ulcerative colitis is intractability. Although steroid side effects appear to be closely associated with surgical indications for intractable ulcerative colitis, this relationship has yet to be analyzed in detail. To elucidate this relationship, we investigated 39 surgical patients with intractable ulcerative colitis, as defined by the Research Committee for Intractable Diseases of the Ministry of Health and welfare of Japan, and 66 conservatively treated patients with ulcerative colitis, of whom 6 had intractable disease. All patients with major steroid side effects and 17/24 (71%) patients with minor side effects underwent surgery. The median number of admissions was higher in patients with major side effects than in those with less severe or no side effects in the operative series, while this value was lower in the non-operative series than in the operative series. This tendency was similar for the total duration of hospitalization and the number of relapses. In the operative series, markedly higher steroid doses were administered to patients with side effects than to those without, and lower doses were given in the non-operative series. On multivariate regression analysis, the presence of steroid side effects, disease extent, and disease duration were significantly associated with surgery. Patients without side effects had a higher postoperative complication rate than those with minor side effects. We conclude that major side effects are a surgical indication for patients with intractable ulcerative colitis, and that even minor side effects should be taken as a surgical indication in view of the patient's quality of life.

PURPOSE: This study was undertaken to investigate factors that influenced differential diagnosis of dysplasia-associated lesion or mass and coincidental adenoma in patients with ulcerative colitis. METHODS: Among 346 patients with ulcerative colitis who underwent colonoscopy between 1979 and 1995, 27 patients had macroscopic neoplastic lesions and were divided into two groups: those with dysplasia-associated lesion or mass (16 patients) and those with adenoma (11 patients), each being categorized by the presence and absence of dysplasia in the flat mucosa adjacent to the elevated lesions, respectively. RESULTS: Thirteen of 27 patients had dysplasia-associated lesion or mass detected by colonoscopic biopsy; 10 of these patients underwent colectomy, and all had dysplasia-associated lesion or mass in the colectomy specimens. Two patients whose biopsy findings were adenoma had an unsuspected dysplasia-associated lesion or mass in the operative specimens. In the remaining 12 patients, the macroscopic lesions were excised during colonoscopy because of clinical and colonoscopic evidence of adenoma. One of them was proved to have dysplasia-associated lesion or mass, and the other 11 were confirmed as having adenoma in the polypectomy specimens. Patients with dysplasia-associated lesion or mass were significantly younger (P

An enema containing beclomethasone dipropionate (BDP), with a strong anti-inflammatory action and few systemic side effects, was prepared and a pharmaceutical study of this enema was performed regarding its clinical application for the treatment of ulcerative colitis patients.The enemas were prepared by adding BDP ethanol to an aqueous solution consisting of 1% methylcellose, and this was divided into 50 ml (containing 1 mg of BDP) doses in plastic syringes. The pH, osmolarity and specific gravity of these enemas were approximately 5, 100 mOsm/kg·H20 and 1.0, respectively. The mean residual concentration of BDP in these enemas (n=6), preserved in dark under refrigeration at 4°C, declined to 93.4% after one week and 85.6% after four weeks, when compared, to the concentration determined immediately after preparation. Although the residual concentration of BDP enemas, preserved in light at 40°C, declined to 93.9% after one week and remained almost constant thereafter, the crystallization of BDP was observed the first day after preparation. Furthermore, the stability of BDP in the enemas was reduced by adjusting the pH of the enemas to 3 and 7, but it was improved by adding methyl p-hydroxybenzoate to these solutions.These BDP enemas were administered to three patients with ulcerative colitis. An improvement was seen in all three subjects regarding both the clinical symptoms and blood data (values related to inflammatory: white blood cells and C-reactive protein). In addition, the disappearance of side effects was also confirmed after administration of BDP enemas to two of the subjects who had developed such side effects as moon face and edema with prednisolone enemas.Based on these results, BDP enemas were thus suggested to be effective for of ulcerative colitis.

BACKGROUND: Although the pathogenesis of Crohn's disease remains unclear, an elemental diet has been shown to be clinically effective. Glutamine is an energy source for many cell types including colonocytes. PURPOSE: This study was designed to assess the potential clinical effects on colitis of changing the dietary quantity of glutamine. METHODS: Colitis was induced by intrarectal administration of 30 mg of trinitrobenzenesulfonic acid with 50 percent ethanol vehicle in Sprague-Dawley rats. Rats were randomly allocated into three dietary groups: Group 1, a commercial elemental diet-based diet without glutamine; Group 2, a commercial elemental diet (glutamine: 12 percent of amino acid content); Group 3, elemental diet with 24 percent glutamine. Diets were started one week before colitis induction and continued until sacrifice. Rats were killed at one, three, and five weeks after colitis induction, and colons were excised. Damage evaluation was based on the percent-age of rats with ulcer, macroscopic damage score, average ulcer area, and microscopic damage score. RESULTS: Group 2 rats weighed more than Group 1 rats at three weeks because of their higher dietary intake. At one week after colitis induction, all groups had comparable damage. At three weeks, the macroscopic damage score was higher in Group 3 than in Groups 1 and 2. At five weeks, rats in Group 3 had significantly more severe damage than those in Groups 1 and 2 in terms of all four indexes. CONCLUSION: We conclude that excess glutamine has a deleterious effect on ulcers in trinitrobenzenesulfonic acid-induced colitis.

潰瘍性大腸炎に対する外科治療は大腸全摘,回腸人工肛門,結腸全摘,回腸直腸吻合,大腸全摘,回腸嚢肛門吻合術などが行われているが,最近は大腸全摘回腸嚢肛門吻合術が一般化し,数多く行われている.この術式も肛門管を温存する変法もあり,これらの利点,欠点について要約した.

This study was made to evaluate the significance of fecal occult blood test (RPHA method) in screening surgical patients for the presence of colorectal neoplasms. The subjects were inpatients scheduled for operation for extracolonic diseases. From January 1990 to December 1991, 817 patients were admitted to our department and 599 had extracolonic diseases. Of the 599 patients, 434 (72%) had preoperative immunological fecal occult blood test of RPHA method. Twenty-eight (6.5%) patients showed positive, and among them, three had colorectal cancer and two, colonic polyp. The incidence of 0.50% of colorectal cancer in 599 patients with extracolonic diseases is higher than that reported for colorectal cancer screening in general population. We conclude that as the risk of colorectal disease is considerably high among inpatients with other diseases, the fecal occult blood test screening should be performed routinely in these patients.

The role of surveillance endoscopic followup in colectomized patients with long standing total colitis is controversial. Here, we aimed to clarify its usefulness for the early detection of dysplasia and cancer in this group of patients. Ninety-seven colectomised UC patients followedup by surveillance endoscopy were retrospectively investigated by reviewing the pathological reports. Patients had received either subtotal colectomy and ileo-rectal anastomosis (IRA) or total proctocolectomy and ileal anal anastomosis (IPAA). Definite dysplasia was diagnosed in 4 patients, who had received IRA; among them, 2 were carcinoma with submucosal invasion, and one was a high-grade dysplasia. Postoperative surveillance endoscopy is useful for the detection of early cancer in the remaining colonic mucosa of UC patients, and those receiving IRA, in which rectal mucosa is left intact, would be good candidates. However, its effectiveness for patients receiving IPAA, in which the rectal mucosa is resected, needs further investigation.

Regional chemotherapy through a catheter placed in the hepatic artery is routinely used for treatment of unresectable liver metastasis from colon carcinoma. With some frequency, anatomical variations of the hepatic artery, including compression of the celiac axis, are found, and must be recognized preoperatively for appropriate management and placement of the catheter. We report a case of a colon cancer patient with multiple liver metastases and compression of the celiac axis, who received decompression of the celiac axis and catheterization of the hepatic artery.

We report a case of small-bowel perforation due to metastatic carcinoma of the breast during chemotherapy. Partial resection of the small intestine and primary anastomosis were performed. Although the patient made a good recovery from panperitonitis, she died of the disease on the 55th postoperative day. Since perforation during chemotherapy results in an extremely poor prognosis, special caution during chemotherapy is needed for patients with possible gastrointestinal involvement with tumor.

Portal vein thrombosis is a rare and potentially lethal complication of laparoscopic colectomy. In this paper, we present a case of portal vein thrombosis and pulmonary artery thromboembolism on the 11(th) day after laparoscopic colectomy without an evident congenital thrombotic disorder. Laparoscopic surgeons and their patients should be aware of such events, because the patients are usually discharged before the symptoms begin.

Reported is a case of advanced accessory breast cancer to which weekly injection of paclitaxel plus weekly oral administration of cyclophosphamide proved very effective. The patient was a 49-year-old woman who noticed a tumor in the right axilla around October 2007 but then left it alone. In October 2008, the patient visited a nearby physician who made a diagnosis of locally advanced accessory breast cancer. Because the tumor enlarged despite endocrinotherapy, the patient was referred to our hospital in July 2009. CT scan showed a tumor with a size of infant's head, multiple lymph node metastases and metastases to the skin, liver and bones. Following weekly injection of paclitaxel plus weekly oral administration of cyclophosphamide for 4 months, the tumor in the right axilla and metastases to the lymph nodes, skin and liver disappeared. Adverse events were alopecia and grade 1 peripheral neuropathy. The treatment continues at present. Weekly injection of paclitaxel plus weekly oral administration of cyclophosphamide has few adverse reactions and can be performed at an outpatient clinic, suggesting that it is a useful treatment.

Background: Prostate cancer (PCa) detection using serum-based prostate specific antigen (PSA) is limited by frequent false-positive and -negative results. Genetic aberrations such as allelic imbalance (AI) and epigenetic changes such as promoter hypermethylation have been detected in circulating DNA of cancer patients. We hypothesized that circulating multimarker DNA assays detecting both genetic and epigenetic markers in serum would be useful in assessing PCa patients.Methods: We assayed blood from healthy male donors (n = 40) and 83 patients with American Joint Cancer Committee (AJCC) stage I–IV PCa. DNA was assayed for AI of 6 genome microsatellites. We assessed methylation of RASSF1, RARB2, and GSTP1 using a methylation-specific PCR assay and analyzed the sensitivity of each assay for the detection of genetic or epigenetic changes in circulating DNA. The relation between circulating tumor-related DNA detection and prognostic factors was investigated.Results: The proportion of patients demonstrating AI for ≥1 marker was 47% (38 of 81 patients). Methylation biomarkers were detected in 24 of 83 patients (28%). By combining 2 DNA assays, the number of PCa patients positive for ≥1 methylated or LOH marker increased (52 of 83; 63%). The combined assays detected PCa in 15 of 24 patients (63%) with normal PSA concentrations. The combination of the DNA assays detected the presence of PCa regardless of AJCC stage or PSA concentration. Combination of the DNA and PSA assays gave 89% sensitivity.Conclusions: This pilot study demonstrates that the combined circulating DNA multimarker assay identifies patients with PCa and may yield information independent of AJCC stage or PSA concentration.

Introduction Estrogen receptor (ER)-positive breast cancers are considered prognostically more favorable than ER-negative tumors, whereas human epidermal growth factor receptor (HER)2/neu-positive breast cancers are associated with worse prognosis. The objective of the present study was to determine whether ER-positive and ER-negative status relates to epigenetic changes in breast cancer-related genes. To evaluate epigenetic differences in tumor-related genes relating to ER and HER2/neu status of primary tumors, we examined the promoter methylation status of the promoter region CpG islands of eight major breast tumor-related genes (RASSF1A, CCND2, GSPT1, TWIST, APC, NES1, RARβ2, and CDH1). Methods Paired ER-positive (n = 65) and ER-negative (n = 65) primary breast tumors (n = 130) matched for prognostic factors were assessed. DNA was extracted from paraffin-embedded tumor tissue after microdissection, and methylation-specific PCR and capillary-array electrophoresis analysis were performed. Results In early stages of tumor progression (T1 and N0), RASSF1A and CCND2 were significantly (P < 0.05) more methylated in ER-positive than in ER-negative tumors. GSTP1 hypermethylation was more frequent in the lymph node metastasis positive group than in the negative group. Double negative (ER-negative, HER2/neu-negative) breast cancers had significantly lesser frequencies of RASSF1A, GSTP1, and APC methylation (P < 0.0001, P < 0.0001, and P = 0.0035, respectively). Both ER and HER2/neu status correlated independently with these epigenetic alterations. Conclusion We demonstrated significant differences in tumor-related gene methylation patterns relevant to ER and HER2/neu status of breast tumors. This may be of significance in the assessment of targeted therapy resistance related to ER and HER2/neu status in breast cancer patients.

Familial adenomatous polyposis (FAP) is a hereditary disease characterized by the development of multiple adenomatous polyps ranging from hundreds to thousands in the large intestine, and extra-colonic tumors. Patients are predisposed to colorectal cancer that accounts for ∼1% of newly diagnosed colorectal cancer cases. Most of FAP cases result from germline mutations in the tumor suppressor gene APC (adenomatous polyposis coli), but some cases are caused by germline mutations in MUTYH, POLD1, or POLE. The rate of mutation detection depends on the methods used for genetic testing and the genes analyzed in the patients. Although sequence analysis of APC by the Sanger method is routinely performed for genetic testing, there remain cases whose mutations are not detected by the analysis. Next-generation sequencing (NGS) has enabled us to analyze the comprehensive human genome, improving the chance of identifying disease causative variants. In this study, we conducted whole-genome sequencing of a sporadic adenomatous polyposis patient in which we did not find any pathogenic APC mutations by the conventional Sanger sequencing. As a result, whole-genome sequencing and subsequent amplicon-based targeted sequencing identified a mosaic mutation of c.3175G>T, p.E1059X in approximately 12% of his peripheral leucocytes. Additional deep sequencing of his buccal mucosa, hair follicles, non-cancerous mucosa of the stomach and colon disclosed that these tissues harbored the APC mutation at different frequencies. Our data suggest that genetic testing by NGS facilitates the identification of genetic mosaicism responsible for hereditary diseases. NGS will improve genetic diagnosis of hereditary diseases whose mutations have been overlooked by conventional direct sequencing. Citation Format: Kiyoshi Yamaguchi, Mitsuhiro Komura, Rui Yamaguchi, Seiya Imoto, Eigo Shimizu, Shinichi Kasuya, Tetsuo Shibuya, Seira Hatakeyama, Norihiko Takahashi, Tsuneo Ikenoue, Keisuke Hata, Giichiro Tsurita, Masaru Shinozaki, Yutaka Suzuki, Sumio Sugano, Satoru Miyano, Yoichi Furukawa. Next-generation sequencing as a potential tool in the diagnostics of APC mosaicism in FAP patient. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4921. doi:10.1158/1538-7445.AM2015-4921