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The study aimed to evaluate the impact of sarcopenia on short- and long-term outcomes for laparoscopic colorectal cancer surgery.Study participants were 209 patients who underwent laparoscopic surgery for any stage of colorectal cancer between 2016 and 2017. Skeletal muscle indices were calculated with preoperative computed tomography. Patients were divided into sarcopenic and non-sarcopenic groups based on index cut-off values and variables were compared.The prevalence of sarcopenia was 41.1%. Sarcopenic patients experienced shorter operative times and a lower incidence of surgical site infections; however, the incidence of severe postoperative complications and readmission were increased for this group. Although the 3-year disease-free survival rate was not statistically different between groups, sarcopenic patients had a significantly worse 3-year overall survival rate compared with than the non-sarcopenic group.Sarcopenia has both favorable and unfavorable effects on patients who underwent laparoscopic colorectal cancer surgery.

Complex interactions among endogenous and exogenous factors influence the incidence of colorectal cancer (CRC). Germline mutations in mismatch repair (MMR) genes causing Lynch syndrome (LS) are major endogenous factors. The exogenous factor, alcohol consumption, is potentially associated with CRC incidence among patients with LS. However, insufficient data are available to determine whether alcohol consumption influences the time of the first onset of CRC associated with sex, MMR gene mutations, and anatomical tumor site.Among 316 patients with LS identified in a Japanese LS cohort, we included 288 with data on age, sex, proband status, alcohol status, smoking status, tumor location, and MMR gene mutations. Multivariable analysis assessed the association of alcohol consumption with earlier onset of the first CRC.Ever drinkers were associated with higher risk of the first onset of CRC than never drinkers (HR 1.54, 95%CI 1.14-2.07, P = 0.004). The association of the first onset of CRC with alcohol consumption was stronger in men, carriers of pathogenic MLH1 and MSH2 mutations (vs those with pathogenic MSH6, PMS2 and EPCAM mutations), and tumors in the proximal colon cancer (vs distal colon and rectal cancer).Alcohol consumption was associated with earlier onset of the first CRC in Japanese LS cohort. The association was stronger in men, carriers of pathogenic MLH1 and MSH2 mutations, and tumors located in the proximal colon. Our findings illuminate the mechanism of LS-associated carcinogenesis and serve as a recommendation for discontinuing or ceasing alcohol consumption.

Background: Stoma-related obstruction (SRO) is defined as small bowel obstruction occurring around the limbs of diverting ileostomy (DI). This study was aimed to investigate the incidence, risk factors, and management of SRO after laparoscopic colorectal surgery with DI creation. Methods: This study included 155 patients who underwent laparoscopic colorectal surgery with DI creation for rectal cancer (n = 138), ulcerative colitis (UC) (n = 14), and familial adenomatous polyposis (FAP) (n = 3) between 2011 and 2019. Univariate and multivariate analyses were performed to identify the risk factors of SRO. Results: The incidence of SRO was 7.7% (n = 12), and it was significantly lower (P

There is a paucity of evidence pertaining to long-term survival outcomes of laparoscopic versus open surgery for locally advanced rectal cancer.This study aimed to evaluate the long-term survival outcomes of laparoscopic surgery for locally advanced rectal cancer and to investigate the recurrence pattern.This was a prospective analysis of a registered cohort.This study was conducted at 69 institutions across Japan.A total of 1500 patients with clinical stage II-III rectal cancer located below the peritoneal reflection between January 2010 and December 2011 were included. After propensity score matching, all eligible patients, including the matched patients registered in 2014, were prospectively followed up.Five-year relapse-free survival was the primary outcome.The median follow-up period was 5.6 years. Among the 964 matched patients, the 5-year relapse-free survival was 65.1% in the open group versus 63.5% in the laparoscopic group (HR 1.04; p = 0.71). Distant recurrences at rare sites, which were more frequently observed in the laparoscopic group, were significantly less salvaged (adjusted OR 0.74; p = 0.045). Postrecurrence 5-year overall survival was significantly better for patients who underwent salvage surgery than for those who did not; 55.3% vs 29.5% for patients with initial local recurrence ( p = 0.03) and 64.4% vs 30.7% for patients with distant recurrence alone ( p0.001).Potential heterogeneity and influence of unknown confounding.Five-year follow-up data demonstrated that laparoscopic surgery for locally advanced rectal cancer was safely performed in terms of long-term prognosis. In addition, salvage surgery for recurrent lesions was associated with prolonged postrecurrence survival, both in patients with local and distant recurrence. However, recurrence at rare sites may require further investigation. See Video Abstract at http://links.lww.com/DCR/B793 .ANTECEDENTES:Existe una escasez de pruebas relacionadas con los resultados de supervivencia a largo plazo de la cirugía laparoscópica versus abierta para el cáncer de recto localmente avanzado.OBJETIVO:Este estudio tuvo como objetivo evaluar los resultados de supervivencia a largo plazo de la cirugía laparoscópica para el cáncer de recto localmente avanzado e investigar el patrón de recurrencia.DISEÑO:Fue un análisis prospectivo de una cohorte registrada.ENTORNO CLÍNICO:El estudio se llevó a cabo en 69 instituciones en todo Japón.PACIENTES:Se incluyó un total de 1500 pacientes con cáncer de recto en estadio clínico II-III ubicados por debajo de la reflección peritoneal, entre enero del 2010 y diciembre del 2011. Después del pareamiento por puntaje de propensión, se realizó un seguimiento prospectivo de todos los pacientes elegibles, incluidos los pacientes emparejados registrados en 2014.PRINCIPALES MEDIDAS DE VALORACIÓN:La supervivencia sin recaídas a cinco años fue el resultado primario.RESULTADOS:El período de seguimiento medio fue de 5,6 años. Entre los 964 pacientes emparejados, la supervivencia libre de recaída a 5 años fue del 65,1% en el grupo abierto frente al 63,5% en el grupo laparoscópico (cociente de riesgo 1,04; p = 0,71). Las recurrencias a distancia en sitios raros, que se observaron con mayor frecuencia en el grupo laparoscópico, tuvieron menor sobrevida (razón de posibilidades ajustada 0,74; p = 0,045). La supervivencia general a los 5 años después de la recidiva fue significativamente menor en los pacientes sometidos a una cirugía de rescate; 55,3% frente al 29,5% para los pacientes con recidiva local inicial ( p = 0,03) y 64,4% frente al 30,7% para los pacientes con recidiva a distancia sola ( p0,001).LIMITACIONES:Potencial heterogeneidad e influencia de factores de confusión desconocidos.CONCLUSIONES:El seguimiento a cinco años demostró que la cirugía laparoscópica para el cáncer de recto localmente avanzado es segura en términos de pronóstico a largo plazo. Además, la cirugía de rescate de las lesiones recurrentes se asoció con una mayor supervivencia posrecurrencia, tanto en pacientes con recurrencia local como a distancia. Sin embargo, la recurrencia en sitios raros puede requerir una mayor investigación. Consulte Video Resumen en http://links.lww.com/DCR/B793 . (Traducción- Dr. Ingrid Melo ).

Background/aim The impact of diverting ileostomy on the feasibility of adjuvant chemotherapy (ACT) remains unclear. We retrospectively investigated the tolerability and adverse events of ACT for rectal cancer in patients with diverting ileostomy. Patients and methods Thirty-three patients who received ACT after curative resection with ileostomy construction for rectal cancer were analyzed. We assessed completion rate, the mean relative dose intensities, and the factors affecting the tolerability of ACT. Results The completion rate of each chemotherapy regimen was 10 out of 16 patients in oral uracil-tegafur plus leucovorin (UFT/LV), 1 out of 3 patients in oral capecitabine (Capecitabine) and 2 out of 14 patients in capecitabine plus oxaliplatin (CAPOX). The mean relative dose intensities were 77% in UFT/LV, 48% in Capecitabine, and 57% of capecitabine and 42% of oxaliplatin in CAPOX. In multivariate analysis, laparoscopic surgery (Odds ratio=11.6, p=0.021) and receiving preoperative chemoradiotherapy (Odds ratio=32.4, p=0.021) were associated with treatment completion. Conclusion Completion rate of ACT in patients with diverting ileostomy was lower than that of colorectal cancer patients in the previous studies. UFT/LV may be a more tolerable regimen than Capecitabine or CAPOX in colorectal cancer patients with diverting ileostomy.

IntroductionSurgical site infection (SSI) is one of the most common complications after gastrointestinal surgery, with a reported incidence of approximately 10%–25%, which is higher than the rates after other types of surgery. Intraoperative wound irrigation (IOWI) is a simple intervention for SSI prevention, and recent studies have reported that IOWI with aqueous povidone–iodine (PVP-I) is significantly more effective at reducing the incidence of SSI than saline. However, the evidence level of previous trials evaluating the efficacy of aqueous PVP-I solution for preventing SSI has been low.Methods and analysesWe propose a single-institute, prospective, randomised, blinded-endpoint trial to assess the superiority of IOWI with aqueous 10% PVP-I solution compared with normal saline for reducing SSI in clean-contaminated wounds after elective gastrointestinal surgery. In the study group, IOWI with 40 mL of aqueous 10% PVP-I solution is performed for 1 min before skin suture, and in the control group, IOWI with 100 mL of saline is performed for 1 min before skin suture. We hypothesise that IOWI with aqueous 10% PVP-I solution will achieve a 50% reduction in the incidence of SSIs. The target number of cases is set at 950. The primary outcome is the incidence of incisional SSI up to postoperative day 30 and will be analysed in the modified intention-to-treat set.Ethics and disseminationThis trial was designed and is being conducted by Saitama Medical Center, Jichi Medical University, with approval from the Bioethics Committee for Clinical Research, Saitama Medical Center, Jichi Medical University. Participant recruitment began in June 2019. The final results will be reported in international peer-reviewed journals immediately after trial completion.Trial registration numberUMIN000036889.

Idiopathic mesenteric phlebosclerosis is a rare entity characterized by chronic intestinal ischemia due to calcification and obstruction of the mesenteric veins. Here, we report a patient with idiopathic mesenteric phlebosclerosis treated with laparoscopic subtotal colectomy after evaluation by imaging studies. The patient was a 68-year-old Japanese woman with recurrent abdominal pain who had taken a Chinese herbal medicine for more than 20 years. Abdominal CT showed wall thickening of the right colon with calcification of branches of the superior mesenteric vein. Colonoscopy showed cyanotic mucosa from the cecum to the sigmoid colon. The affected area seen on colonoscopy extended to the distal colon. Despite discontinuation of the herbal medicine, her symptoms did not improve. Laparoscopic subtotal colectomy was performed. This report highlights the importance of appropriately evaluating the extent of the affected preoperatively area based on findings from colonoscopy, CT, and contrast enema.

Intraductal papillary mucinous neoplasm (IPMN) has been associated with a high incidence of extrapancreatic malignancies (EPMs). However, it is controversial whether IPMN is prognostic for EPM. We aimed to help clarify the issue studying this association in patients with histologically proven IPMN. We reviewed 51 surgically resected IPMNs in Saitama Medical Center, Jichi Medical University between January 1991 and June 2012. Mean follow-up was 63.7±47.8 months. The observed EPM incidence was compared with the expected incidence of cancer in Japan. Of the 51 IPMNs, 14 were malignant and the rest benign. Seventeen EPMs developed in 15 patients (29.4%), nine of which occurred prior to IPMN diagnosis. For all IPMNs, the standardized incidence ratio (SIR) was significantly increased for the six types of reported EPMs (SIR=2.18, CI=1.31-3.42, P=0.004). Benign IPMNs showed no association with EPMs (SIR=0.92, CI=0.43-1,76, P=0.87). In contrast, malignant IPMNs showed a higher association (SIR=3.83, CI=1.87-7.03, P=0.0009). However, the association was mostly due to the prior EPMs, as removal of metachronous EPMs had no significant effect (SIR=3.63, CI=1.59-7.17, P=0.005). Thus, only malignant IPMNs drive the significant association with prior EPMs, showing a near 4-fold increased incidence compared to the general Japanese population. Histological characterization of IPMNs may offer clinical value for EPM patient management. We hypothesize that these observations may be explained if some patients with EPMs present a higher risk to develop IPMNs (and vice versa), possibly resulting from an uncharacterized multiple cancer predisposition condition.

Background and aim: Patients with stage T3 or T4 rectal cancer are candidates for neoadjuvant chemoradiation therapy. The aim of this study is to clarify the usefulness of circumferential tumor extent determined by computed tomography (CT) colonography in differentiating T3 or T4 from T1 or T2 rectal cancer. Methods: Seventy consecutive rectal cancer patients who underwent curative-intent surgery were enrolled in this study. All patients underwent colonoscopy and CT colonography on the same day. The circumferential tumor extent was estimated in 10% increments. The pathological T stage was used as the reference. Results: The median circumferential tumor extent evaluated by colonoscopy for T1 (n = 6), T2 (n = 21), and T3/T4 (n = 43) were 10%, 30%, and 80%, respectively (T1/T2 vs. T3/T4, p

Endocrine cell carcinoma, according to the Japanese classification criteria for colorectal cancer, corresponds to neuroendocrine carcinoma (NEC) and mixed adenoneuroendocrine carcinoma (MANEC), as defined in the 2010 World Health Organization (WHO) classification. We retrospectively reviewed the clinical features of patients with these tumors diagnosed and treated at our institution. The clinicopathological features of endocrine cell carcinomas of the colon and rectum diagnosed by neuroendocrine markers from January 2000 to December 2012 were retrospectively evaluated in 12 patients. Surgical specimens were obtained from eight of the 12 patients. MANEC was diagnosed in six patients and NEC in one. One tumor was unclassifiable. The tumors were not resected in four patients, and all died within 3 months. Of the eight patients who underwent resection, four received an R0 resection, two of whom underwent adjuvant chemotherapy and survived more than 5 years. One patient who underwent an R2 resection and continuous chemotherapy survived for 53 months. One patient with NEC underwent surgery and radiotherapy, and died 17 months later. Most endocrine cell carcinomas of the colon and rectum reviewed were MANECs. Though their prognosis was generally poor, chemotherapy may be effective in some patients.

We hypothesized that a reduction in the size of the lymph nodes after neoadjuvant therapy for locally advanced rectal carcinoma would be associated with decreased lymph node metastases and/or a better prognosis. Between March 2006 and April 2012, 71 patients with primary rectal cancer received neoadjuvant chemoradiation therapy (CRT). For all lymph nodes 5 mm or larger in size, the major and minor axes were measured on CT scan images, and the product was calculated. The lymph node size was determined before and after CRT. The patients were divided into three groups based on the lymph node size before and after treatment. Group A exhibited a reduction in size of 60 % or more, Group B a reduction of less than 60 % and Group C had no lymph node enlargement before treatment. The incidence of lymph node metastases on pathological examination was 15 % in Group A and 50 % in Group B (p = 0.006). The five-year disease-free survival in Group A was 84 % compared with 78 % in Group B (log rank p = 0.34). The five-year overall survival in Group A was 92 % compared with 74 % in Group B (log rank p = 0.088). A reduction in the size of enlarged lymph nodes after neoadjuvant therapy may be a useful prognostic factor for recurrence and survival.

The purpose of this study was to evaluate the clinical features, pathology, and etiology of adenocarcinoma in patients with anal fistulae. We identified seven patients diagnosed with adenocarcinoma associated with anal fistulae from a retrospective chart review. Five patients were diagnosed with primary adenocarcinoma associated with anal fistulae. Two patients were diagnosed with secondary adenocarcinoma associated with anal fistulae originating from rectal cancer on the proximal side. The primary adenocarcinomas included cancers arising from long-standing anal fistulae fulfilling established diagnostic criteria in two patients, and cancer arising from short-duration anal fistulae in three patients. Excision of the fistula was performed based on the initial diagnosis of the anal fistula for all five patients. Increased suspicion of cancer was due to the existence of gelatinous material in the anal fistula in three patients and induration in the resected specimens in two patients. The etiologies of the secondary adenocarcinomas associated with anal fistulae included implantation in the anal fistula from rectal cancer and fistula formation originating due to the progression of rectal cancer. Anal fistulae are commonly seen in the coloproctology clinic, but special attention to similar conditions associated with malignant disease is needed.

In vitro assessment of chemosensitivity are important for experiments evaluating cancer therapies. The Scepter 2.0 cell counter, an automated handheld device based on the Coulter principle of impedance-based particle detection, enables the accurate discrimination of cell populations according to cell size and volume. In this study, the effects of SN-38, the active metabolite of irinotecan, on the colon cancer cell lines HCT116 and HT29 were evaluated using this device. The cell count data obtained with the Scepter counter were compared with those obtained with the (3)H-thymidine uptake assay, which has been used to measure cell proliferation in many previous studies. In addition, we examined whether the changes in the size distributions of these cells reflected alterations in the frequency of cell cycle arrest and/or apoptosis induced by SN-38 treatment. In our experiments using the Scepter 2.0 cell counter, the cell counts were demonstrated to be accurate and reproducible measure and alterations of cell diameter reflected G2/M cell cycle arrest and apoptosis. Our data show that easy-to-use cell counting tools can be utilized to evaluate the cell-killing effects of novel treatments on cancer cells in vitro.

Regorafenib has shown survival benefits in metastatic colorectal cancer patients who were exacerbated after all standard therapies. Some patients, however, exhibit severe adverse events (AEs) resulting in treatment discontinuation. Therefore, the selection of patients likely to benefit from regorafenib is crucial. Twenty patients were treated with regorafenib for metastatic colorectal cancer; 122 plasma samples were taken from 16 of these patients for monitoring of circulating tumor DNA (ctDNA) in the blood. The treatment response, AEs, overall survival (OS), progression-free survival (PFS) and tumor morphologic changes on CT images were evaluated. KRAS mutant ctDNA was determined using digital PCR. Median PFS and OS were 2.5 and 5.9 months, respectively. Treatment was discontinued because of disease progression (PD) in 10 patients, and AEs in another 10 patients. AEs included hyperbilirubinemia, severe fatigue and skin rash. Hyperbilirubinemia was seen in two patients with multiple bilateral liver metastases, and severe fatigue in another 2 patients with poor performance status (PS). These severe AEs resulted in treatment discontinuation. Ten patients had a median PFS of 2.1 months with AE related discontinuation; PD occurred at 3.5 months (p=0.00334). Four patients exhibited a morphologic response, achieving better PFS times of 3.5, 5.3, 5.6 and 14.2 months. Emergence of the KRAS mutation in ctDNA was observed during anti-EGFR antibody treatment in 3 patients among 11 with KRAS wild-type tumors; it was detectable in the blood prior to radiographic detection of PD. Moreover, the KRAS mutation declined in two patients during regorafenib monotherapy. These patients were re-challenged with anti-EGFR antibody. Patients with extensive multiple liver metastases or poor PS are unlikely to benefit from regorafenib. Patients with a morphologic response will probably benefit from regorafenib with adequate management of other AEs. KRAS monitoring in ctDNA could be useful regarding treatment response and in determining treatment strategy.

Although epithelial-mesenchymal transition (EMT) has been implicated as the pivotal event in metastasis, there is insufficient evidence related to EMT in clinical settings. Intratumor heterogeneity may lead to underestimation of gene expression representing EMT. In the present study, we investigated the expression of EMT-associated genes and microRNAs in primary colorectal cancer while considering intratumor heterogeneity. One-hundred and thirty-three multiple spatially separated samples were obtained from 8 patients with metastatic colorectal cancers and 8 with non-metastatic colorectal cancers, from the tumor center (TC), invasive front (IF) and metastasis. Differences in gene and microRNA expression were investigated by microarray and quantitative reverse-transcription PCR. Gene expression microarray analysis detected 7920 sites showing differing levels of gene expression among the TC, IF and metastasis. Expression of the EMT-associated gene zinc-finger E-box-binding homeobox 1 (ZEB1) significantly increased in the IF (p

Intestinal strangulation caused by a mucocele of the appendix is extremely rare and difficult to diagnose. It is not usually suspected pre-operatively. This report presents a case of intestinal strangulation due to a mucous containing cystic lesion that was wrapped around the base of a loop of the small bowel. An 89-year-old female was transferred after an acute onset of abdominal pain. A physical examination revealed severe tenderness with guarding in the right upper quadrant. CT of the abdomen showed a loop of dilated small bowel with edema on the right side of the abdominal cavity suggesting a closed loop obstruction. In addition, a low-density thin-walled mass measuring 5 cm in diameter was also seen in the pelvis. Intestinal strangulation was suspected and emergency laparotomy was thus performed. A loop of terminal ileum 25 cm in length was strangulated by a dilated appendix, and ileocecal resection was performed. The resected appendix measured 9 × 3 cm in size and contained mucus. A histopathological examination showed a mucous containing cystic appendix without mucin-producing, neoplastic epithelial cells. A mucocele of the appendix can present in various ways and it is important to recognize this entity at the time of surgery.

This study was designed to confirm the safety of not removing small adenoma in patients who undergo colorectal cancer surgery. Patients who underwent surveillance colonoscopy after surgery were enrolled. The study was approved by our institutional review board. Colonoscopy was performed with magnification chromocolonoscopy. Benign adenomas of 6 mm or less in size, diagnosed based on both nonmagnified and magnified observation, were left unresected with a maximum of three polyps per patient. The sites of the polyps were marked by tattooing. Interval colonoscopy was performed predominantly yearly or biennially. Increase in size by 2 mm or larger was defined as significant. In follow-up, polyps were removed if they grew larger than 6 mm, were suspicious for high-grade dysplasia, or the patients requested to have polyps removal. Five hundred polyps in 284 patients met the above criteria and were not resected, and 412 polyps were followed by repeat colonoscopy. The mean observation period was 3.6 ± 2.2 years and the mean number of repeat colonoscopy was 3.6 ± 1.6. At the final colonoscopy, 71 percent of 412 polyps showed no change in size, 15 percent increased, 3 percent decreased, and 11 percent could not be identified. Eighty-eight polyps were resected endoscopically, and histology showed neither cancer nor adenomas with high-grade dysplasia. Two hundred fifty-five polyps detected in the same patient cohort during index/repeat colonoscopy were removed, including four adenomas with high-grade dysplasia and two T1 cancers. Leaving small polyps is safe even in patients who have undergone colorectal cancer surgery, provided that careful observation is guaranteed.

An accurate assessment of the depth of tumor invasion in patients with colon cancer is an important part of the preoperative evaluation. Whether computed tomographic colonography (CTC) or optical colonoscopy (OC) is better to accurately determine tumor location and invasion depth has not been definitively determined. The aim of this study was to determine the diagnostic accuracy of tumor localization and tumor invasion depth of colon cancer by preoperative OC alone or combined with CTC.Study participants include 143 patients who underwent both preoperative CTC using automated COThe accuracy of tumor localization was significantly better with CTC than with OC (OC, 90%; CTC, 98%; P 0.05). No tumor in the descending colon was localized accurately via OC alone. The accuracy of tumor invasion depth was better with CTC plus OC than with OC alone (OC, 55%; CTC, 73%; P 0.05).OC combined with CTC provides a more accurate preoperative determination of tumor localization and invasion depth than OC alone.

Distant metastasis is a significant prognostic factor of colon carcinoma. Adjuvant chemotherapy has been shown to decrease its recurrence. However, there are no definitive methods for the diagnosis of hepatic recurrence after potentially curative surgery. The aim of this study was to evaluate the accuracy of mRNA expression profiling using samples obtained from primary tumors to predict hepatic recurrence.Patients with stage III colorectal carcinoma without any recurrence for at least 5 years (group A: n = 9) and patients with stage IV carcinoma with hepatic metastasis (group B: n = 10) were included in this study. Tissue samples were collected from the primary tumor and adjacent normal colonic mucosa at the time of surgery in each patient. Total RNA was extracted and the mRNA expression profile was examined using a cDNA macroarray.A hierarchical clustering analysis revealed a dendrogram in which the patients were divided into two clusters. One cluster consisted of seven patients in group A and two in group B. The other consisted of two patients in group A and eight in group B. Therefore, the positive and negative predictive value of hierarchical clustering analysis for hepatic metastasis was 80.0% and 78.8%, respectively. Fifteen genes were revealed to be upregulated and 12 were downregulated in group B. The upregulated genes included CCNA2, TP53, and MDM2, while the downregulated genes included CDH1, GADD45A, and BCL2L2.mRNA expression profiling by a cDNA array analysis of specimens obtained from primary tumors was found to be useful for distinguishing patients with and without hepatic metastasis. This method is expected to contribute to the identification of patients at high risk for hepatic recurrence, while also helping in the administration of intensive adjuvant chemotherapy for such high risk patients.

Background & Aims: Methylation of the h MLH 1 promoter region is frequently observed in microsatellite instability (MSI)-positive sporadic colorectal carcinomas. We studied h MLH 1 promoter methylation in peripheral blood lymphocytes of 87 index patients representing 29 cases of hereditary nonpolyposis colorectal cancers (HNPCCs), 28 cases of atypical HNPCCs, and 30 sporadic cases of the development of early-onset colorectal carcinomas or multiple primary cancers. Methods Methylation of the h MLH 1 promoter region was analyzed by Na-bisulfite polymerase chain reaction/single-strand conformation polymorphism analysis or methylation-specific polymerase chain reaction. MSI, allelic status of the h MLH 1 locus, and loss of hMLH1 protein expression were examined in cases for which tumor tissues were available. Results Extensive methylation of the h MLH 1 promoter was detected in peripheral blood lymphocytes of 4 of 30 patients with sporadic early-onset colon cancer, among whom multiple primary cancers (1 colon and 1 endometrial cancer) developed in 2 cases. This methylation was not detected in analyses of HNPCC or atypical HNPCC groups or healthy control subjects. MSI was positive, and extensive methylation was detected in both cancers (colon and endometrial cancer) and normal tissues (colon, gastric mucosa, endometrium, and bone marrow) in all of the examined cases (3 of 3). Analysis of a polymorphic site in the h MLH 1 promoter in 2 informative cases showed that methylation was hemiallelic. In 1 case, the unmethylated allele was lost in the colon cancer but not in the metachronous endometrial cancer. Conclusions Constitutive, hemiallelic methylation of the h MLH 1 promoter region was shown to be associated with carcinogenesis in sporadic, early-onset MSI-positive colon cancers.

Purpose. The correlation between age and the outcome following an operation for colorectal cancer (CRC) has not yet been determined. We studied the appropriate operation for elderly CRC patients based upon the assessment of preoperative risk factors. Methods. Seventy patients with Dukes' stages B or C CRC (more than 80 years old: aged group) and 66 stage-matched patients (50–69 years old: control group) were studied. The preoperative condition, the grade of surgical intervention, the perioperative activities of daily life (ADL), and the survival rate were compared between the two groups. Results. The preoperative conditions were significantly worse and the frequencies of patients with a deterioration in ADL during the perioperative period were significantly higher in the aged group. In the aged group, the peripheral lymphocyte count was significantly lower in patients with major postoperative complications, and the 1.0% forced expiratory volume (FEV1.0%) was significantly lower in patients with a deterioration in ADL. The low grade of surgical intervention tended to be related to a poor prognosis in rectal cancer of the aged group. Conclusion. The indications for operation in elderly CRC patients should be determined based upon an appropriate assessment of preoperative conditions, such as the lymphocyte count and FEV1.0%.

PURPOSE: In case-control studies, it was reported that microsatellite instability might be helpful in predicting the development of metachronous multiple colorectal cancers. The purpose of this cohort-like study was to determine whether microsatellite instability is a novel independent marker in predicting metachronous colorectal carcinomas after colorectal cancer surgery. METHODS: Three hundred twenty-eight colorectal carcinoma patients were surveyed by periodic colonoscopy for at least three years after surgery. Among these, DNA from paraffin-embedded sections was available for 272 cases. DNA of these cases was studied for six microsatellite markers (five dinucleotide repeats, one mononucleotide repeat). Microsatellite instability phenotype was defined as alterations in one or more loci. RESULTS: Median follow-up period was 74 months, and the median number of colonoscopies was 4.6. The percentage of microsatellite instability-positive cases was 26.4 percent (72/272). Seventeen metachronous colorectal carcinomas were detected during the follow-up period. Incidences of metachronous colorectal carcinomas in microsatellite instability-positive and microsatellite instability-negative cases were 15.3 and 3 percent, respectively (P < 0.001). The cumulative five-year incidence of metachronous colorectal carcinomas was significantly higher in microsatellite instability-positive cases than in microsatellite instability-negative cases (12.5 vs. 2.5 percent, P < 0.0001). Logistic regression analysis of the relationship between incidence of metachronous colorectal carcinomas and possible risk factors (namely, coexistence of adenoma at the time of surgery, family history of colorectal carcinoma , history of extracolonic malignancy, and microsatellite instability status) showed that microsatellite instability and coexistence of adenoma were significant independent risk factors for the occurrence of metachronous colorectal carcinomas, with values of P = 0.001 and 0.02, respectively. CONCLUSION: These data indicate that microsatellite instability can be regarded as a novel independent and important marker for predicting the development of metachronous colorectal carcinoma after surgery.

Background Methylation of the MLH1 promoter region has been suggested to be a major mechanism of gene inactivation in sporadic microsatellite instability-positive (MSI-H) colorectal cancers (CRCs). Recently, single-nucleotide polymorphism (SNP) in the MLH1 promoter region (MLH1-93G/A; rs1800734) has been proposed to be associated with MLH1 promoter methylation, loss of MLH1 protein expression and MSI-H tumors. We examined the association of MLH1-93G/A and six other SNPs surrounding MLH1-93G/A with the methylation status in 210 consecutive sporadic CRCs in Japanese patients. Methods Methylation of the MLH1 promoter region was evaluated by Na-bisulfite polymerase chain reaction (PCR)/single-strand conformation polymorphism (SSCP) analysis. The genotype frequencies of SNPs located in the 54-kb region surrounding the MLH1-93G/A SNP were examined by SSCP analysis. Results Methylation of the MLH1 promoter region was observed in 28.6% (60/210) of sporadic CRCs. The proportions of MLH1-93G/A genotypes A/A, A/G and G/G were 26% (n = 54), 51% (n = 108) and 23% (n = 48), respectively, and they were significantly associated with the methylation status (p = 0.01). There were no significant associations between genotype frequency of the six other SNPs and methylation status. The A-allele of MLH1-93G/A was more common in cases with methylation than the G-allele (p = 0.0094), especially in females (p = 0.0067). In logistic regression, the A/A genotype of the MLH1-93G/A SNP was shown to be the most significant risk factor for methylation of the MLH1 promoter region (odds ratio 2.82, p = 0.003). Furthermore, a haplotype of the A-allele of rs2276807 located -47 kb upstream from the MLH1-93G/A SNP and the A-allele of MLH1-93G/A SNP was significantly associated with MLH1 promoter methylation. Conclusions These results indicate that individuals, and particularly females, carrying the A-allele at the MLH1-93G/A SNP, especially in association with the A-allele of rs2276807, may harbor an increased risk of methylation of the MLH1 promoter region.

Potent application of topoisomerase I inhibitor plus PARP inhibitor has been suggested to be an effective strategy for cancer therapy. Reportedly, mismatch repair (MMR)–deficient colon cancer cells are sensitive to topoisomerase I inhibitor, presumably due to microsatellite instability (MSI) of the MRE11 locus. We examined the synergy of SN-38, an active metabolite of irinotecan, in combination with the PARP inhibitor olaparib in colon cancer cells showing different MMR status, such as MSI or microsatellite stable (MSS) phenotype. Treatment with SN-38 and olaparib in combination almost halved the IC50 of SN-38 for a broad spectrum of colon cancer cells independent of the MMR status. Furthermore, olaparib potentiated S-phase–specific double-strand DNA breaks (DSB) induced by SN-38, which is followed by Rad51 recruitment. siRNA-mediated knockdown of Rad51, but not Mre11 or Rad50, increased the sensitivity to olaparib and/or SN-38 treatment in colon cancer cells. In vivo study using mouse xenograft demonstrated that olaparib was effective to potentiate the antitumor effect of irinotecan. In conclusion, olaparib shows a synergistic effect in colon cancer cells in combination with SN-38 or irinotecan, potentiated by the Rad51-mediated HR pathway, irrespective of the Mre11-mediated failure of the MRN complex. These results may contribute to future clinical trials using PARP inhibitor plus topoisomerase I inhibitor in combination. Furthermore, the synergistic effect comprising topoisomerase I-mediated DNA breakage–reunion reaction, PARP and Rad51-mediated HR pathway suggests the triple synthetic lethal pathways contribute to this event and are applicable as a potential target for future chemotherapy. Mol Cancer Ther; 13(5); 1170–80. ©2014 AACR.

The purpose of this study was to compare the degree of colorectal distention between manual insufflation using room air and automatic insufflation using carbon dioxide for computed tomography colonography performed as a preoperative examination for patients with colon cancer. Participants comprised 200 patients who underwent computed tomography colonography immediately after colonoscopy from October 2011–2012. The first 100 patients were examined using manual insufflation, and the remaining 100 patients were examined using automated insufflation. Two radiologists independently assessed colorectal distention using a 4-point scale in six segments: cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum. Mean scores of the two radiologists were used to analyze whether any differences existed between techniques in terms of the degree of distention per segment. Mean distention values for the colonic lumen were better using the automated technique than with the manual technique in both positions (p

We report the first case of sigmoid volvulus after laparoscopic surgery for sigmoid colon cancer. The patient is a 75-year-old man who presented with the sudden onset of severe abdominal pain. He had undergone laparoscopic sigmoidectomy for cancer 2 years before presentation. CT scan showed a distended sigmoid colon with a mesenteric twist, or "whirl sign." Colonoscopy showed a mucosal spiral and luminal stenosis with dilated sigmoid colon distally and ischemic mucosa. The diagnosis of ischemic colonic necrosis due to sigmoid volvulus was established. Resection of the necrotic sigmoid colon was performed and a descending colon stoma was created. A long remnant sigmoid colon and chronic constipation may contribute to the development of sigmoid volvulus after laparoscopic sigmoidectomy. Prompt diagnosis is essential for adequate treatment, and colonoscopy aids in the diagnosis of ischemic changes in patients without definitive findings of a gangrenous colon.

Lynch syndrome, also referred to as hereditary nonpolyposis colorectal cancer, is the most common form of hereditary colorectal cancer, and is associated with a high incidence of multiple primary neoplasms in various organs. A 79-year-old woman (patient 1) diagnosed with ascending colon cancer had a history of previous carcinomas of the uterus, stomach, uroepithelial tract, and colon. One year later, she developed a brain tumor (glioblastoma). A 54-year-old female (patient 2) was diagnosed with endometrial cancer and sigmoid colon cancer. Both patients underwent genetic evaluations independently. No mutations were found in an exon-by-exon analysis of genomic DNA by polymerase chain reaction (PCR) and reverse transcription (RT)-PCR. However, multiplex ligation-dependent probe amplification (MLPA) identified genomic duplication spanning from exon 7 to exon 14 of the MSH2 gene in both patients. Due to the presence of this characteristic gene duplication, their pedigrees were investigated further, and these showed that they are paternal half-sisters, consistent with paternal inheritance. Large genomic duplication from intron 6 through intron 14 in MSH2 is a very rare cause of Lynch syndrome and is difficult to identify with conventional methods. MLPA may be an alternative approach for detecting large-scale genomic rearrangements.

K-ras mutation is the most common oncogenic alteration in various human cancers including colorectal carcinomas. Point mutations have the potential to activate the K-ras gene if they occur in the critical coding sequences. Almost all of these mutations have been localized in codons 12, 13 and 61. We report a case of colon cancer presenting point mutations at both codons 12 and 22 of the K-ras gene. PCR-SSCP and subsequent sequencing revealed that GGT (glycine, wild-type) to AGT (serine) substitution at codon 12 and CAG (glutamine, wild-type) to CGG (arginine) substitution at codon 22 occurred in the same allele.

Lynch syndrome is caused by germline mutations of the DNA mismatch repair genes. Missense mutations are often difficult to evaluate as pathogenic. Previously, we reported a missense mutation in exon 12 at codon 600 of the MSH2 gene, causing a substitution of GTT (Val) for GCT (Ala) in a 35-year-old-man with rectal cancer, while the pathogenicity of this mutation is still unclear. In this report, we confirm the same mutation in his 66-year-old mother who had cecal cancer. PCR/direct sequencing analysis of peripheral blood lymphocytes revealed the same missense mutation in exon 12 at codon 600 of the MSH2 gene. The wave height of the capillary sequencer from the wild-type allele was decreased in tumor tissue, indicating loss of heterozygosity in the wild-type allele. Analysis of the tumor showed microsatellite instability high and loss of MSH2 protein expression. This sequence variant has not been reported in another family. This mutation is considered to play a significant and causative role in Lynch syndrome.

Between 1989 and 2009, 10 patients with small bowel adenocarcinoma were treated in our hospital. These tumors appeared in the jejunum in 6 patients and in the ileum in the remaining 4 patients. All patients had some symptoms. The median size of the tumors was 50mm(30-110mm). All tumors were advanced type 2 lesion with severe stricture. Histologically there were 8 well, 1 moderately and 1 poorly differentiated adenocarcinomas. There were 8 tumors invading the serosa and 2 tumors invaded other organs. Positive lymph nodes were identified in 6 cases. Liver metastasis and peritoneal dissemination were identified in 3 and 4 cases, respectively. Eight cases were diagnosed as small bowel adenocarcinoma preoperatively by double balloon endoscopy. The 4 patients with stage II tumor and 2 patients with stage III tumor underwent curative-intent surgery. The 4 patients with stage II tumor are all surviving without evidence of disease now.

Evaluation of pathologic predictors of metastases in T1 stage colorectal cancer may be difficult with hematoxylin and eosin (HE) staining alone. The aim of this study was to clarify the role of pathologic predictors by using immunohistochemical staining and Elastica van Gieson (EVG) staining. One hundred and twenty-four patients who underwent bowel resection for single T1 stage colorectal cancer from 1990 to 2004 in 1 institution were studied. D2-40, EVG staining, and CAM5.2 were used to detect lymphatic invasion, venous invasion, and tumor budding, respectively. These 3 factors were separately evaluated based on HE staining. Histology was reviewed by 1 pathologist. Lymph node metastases in the surgical specimen were the standard reference, and distant metastases were identified by periodic computed tomography for 2 years or more after surgery. A logistic regression model was applied to analyze risk factors for lymph node metastases and a Cox regression model for distant metastases. In predicting lymph node metastases, univariate analysis demonstrated significance for all predictors except venous invasion by HE staining. Multivariate analysis showed that venous invasion by EVG and tumor budding by HE showed significance as predictors. In predicting distant metastases, univariate analysis showed significance for lymphatic invasion shown by D2-40, tumor budding shown by CAM5.2 and HE, and lymph node metastases. Multivariate analysis showed only venous invasion by EVG stain as being significantly associated with distant metastases (P=0.001). In conclusion, venous invasion evaluated shown by EVG staining is a useful pathologic predictor for metastases in T1 stage colorectal cancer.

A 34-year-old woman was referred to our hospital with ileus. She had undergone surgical resection following chemotherapy for yolk sac tumor at the age of 12 years, and had received additional surgery and radiation therapy for a local recurrence at age 13. Following evaluation, a sigmoid colon tumor was detected and was surgically resected. Histology proved well differentiated adenocarcinoma with chronic irradiation colitis, suggesting that irradiation may have induced the colon cancer.

Colorectal carcinoma (CRC) remains the major cause of cancer death in humans. Although chromosomal structural anomaly is presumed to play an important role in the carcinogenesis of CRC, chromosomal copy number alterations (CNA) and loss of heterozygosity (LOH) have not yet been analyzed extensively at high resolution in CRC. Here we aim to identify recurrent CNA and LOH in human CRC with the use of single nucleotide polymorphism-typing microarrays, and to reveal their relevance to clinical outcome. Surgically resected CRC specimens and paired normal mucosa were obtained from a consecutive series of 94 patients with CRC, and both of them were subjected to genotyping with Affymetrix Mapping 50K arrays. CNA and LOH were inferred computationally on every single nucleotide polymorphism site by integrating the array data for paired specimens. Our large dataset reveals recurrent CNA in CRC at chromosomes 7, 8, 13, 18, and 20, and recurrent LOH at chromosomes 1p, 4q, 5q, 8p, 11q, 14q, 15q, 17p, 18, and 22. Frequent uniparental disomy was also identified in chromosomes 8p, 17p, and 18q. Very common CNA and LOH were present at narrow loci of

Based on colonoscopy findings, we made a preoperative diagnosis of primary mucinous cystadenocarcinoma of the appendix with features of a submucosal tumor (SMT) in the ascending colon. A 59-year-old woman who presented with right lower quadrant abdominal pain underwent colonoscopy, which revealed an SMT with three nodules covered with mucus in the ascending colon. Examination of colonoscopic biopsy specimens indicated “very” well-differentiated adenocarcinoma with mucus lakes. Abdominal computed tomography showed irregular wall thickness from the cecum to the ascending colon. The adjacent appendix had an enhanced wall and unclear border against the ascending colon. Thus, we performed right hemicolectomy, with good results. Histopathological examination revealed mucinous cystadenocarcinoma of the appendix, invading the ascending colon with fistula formation. Appendiceal tumors can manifest with a variety of colonoscopic features, and curative surgical resection should be attempted even if there is fistula formation.

Background: Tumor-infiltrating lymphocytes (TIL) are strictly divided into two categories: those lymphocytes in stroma and those in between cancer cells. However, there has been no fully adequate comparison of these two categories, especially analysis in relation to microsatellite instability (MSI). Methods: The materials were derived from patients with colorectal cancer who underwent surgery in Jichi Medical School and Omiya Medical Center. There were 19 hereditary non-polyposis colorectal cancer (HNPCC) patients who were compatible with Japanese criteria A and 106 patients with sporadic colorectal cancer (sCRC) in either Dukes B or C stage. As microsatellite markers, the global standard five markers were selected. Immunohistochemical analysis was performed using the anti-CD3, -CD4, -CD8 and -S-100 antibodies and the results were evaluated according to the degree of infiltration, which was classified into three grades. Results: As for stroma-infiltrating lymphocytes (SIL) in sCRCs, severe infiltration was observed in 20% of high microsatellite instability (MSI-H) patients and 12.8% of low microsatellite instability (MSI-L)/stable microsatellite (MSS) patients without a statistically significant difference. In contrast, severe infiltration of intra-tumor cell-infiltrating lymphocytes (ITCIL) was observed in 41.7% of MSI-H sCRC patients and 4.3% of MSI-UMSS patients. Thus, there was a close correlation between ITCIL severity and increased microsatellite instability (P< 0.001). In examination of ITCIL, patients with severe infiltration tended to show a better survival rate than those with moderate or mild infiltration. Conclusions: The present study suggests that different factors are involved in the infiltration of SIL and ITCIL. Although there were no statistically significant differences, the cumulative survival rates tended to be higher in severe ITCIL cases than in those with moderate and poor ITCIL (P< 0.09). We suggest that there might be a possibility of ITCIL having a role for a better prognosis after colorectal cancer surgery, which is closely related to MSI.

Activating mutations of BRAF have been frequently observed in microsatellite unstable (MSI+) colorectal carcinomas (CRCs), in which mutations of BRAF and KRAS are mutually exclusive. Previously, we reported that hypermethylation of hMLH1 might play an important role in the tumorigenesis of right-sided sporadic CRCs with MSI showing less frequency of KRAS/TP53 alteration. Therefore, we have assumed that BRAF mutations might be highly associated with hMLH1 methylation status rather than MSI status. In this study, mutations of BRAF and KRAS and their relationship with MSI and hMLH1 methylation status were examined in 140 resected specimens of CRC. The methylation status was classified into 3 types: full methylation (FM), partial methylation (PM) and nonmethylation (NM). Only FM closely linked to reduced expression of hMLH1 protein. BRAF mutations were found in 16 cases (11%), all leading to the production of BRAF(V599E). As for MSI status, BRAF mutations were found in 43% of MSI+ and 4% of MSI- cases (p < 0.0001). Among the MSI+ individuals, BRAF mutations were more frequent in cases with hMLH1 deficiency (58%) than those with hMSH2 deficiency (0%; p=0.02). Moreover, they were found in 69% of FM, 4% of PM and 4% of NM, revealing a striking difference between FM and the other 2 groups (FM vs. PM or NM; p < 0.0001). These findings suggest that BRAF activation may participate in the carcinogenesis of sporadic CRCs with hMLH1 hypermethylation in the proximal colon, independently of KRAS activation.

Methylation of the MLH1 promoter region has been suggested to be a principal mechanism of gene inactivation in sporadic microsatellite instability (MSI)–positive colorectal carcinoma. Recently, we have shown a novel methylation profile of the MLH1 promoter region (i.e., full, partial, and no methylation), among which full methylation was strongly associated with MSI. In this study, to confirm whether methylation requires the involvement of both alleles, we studied the MLH1 promoter region concerning the methylation profile and allelic loss. Furthermore, we studied correlations of methylation profiles with genetic alternations such as loss of heterozygosity (LOH) of the TP53 locus and KRAS mutation. Eighty-eight tumors were classified as full (n = 14), partial (n = 26), and no methylation (n = 48). Full methylation was observed in 78% (14/18) of high-frequency MSI, in which all CpG sites in the promoter region were methylated. Full methylation differed significantly from partial methylation regarding absence of TP53 LOH (0/12) and KRAS mutation (0/14). In cases with full methylation, we could show biallelic methylation by use of a single-base nucleotide polymorphism in the promoter. However, this did not accompany LOH of the MLH1 locus. In contrast, there were no significant differences in molecular features between partial and no methylation, except for low frequencies of LOH of the MLH1 locus (P = 0.02). In conclusion, biallelic extensive methylation of the MLH1 promoter region plays a significant role in gene inactivation and is independent of KRAS mutation and TP53 LOH. © 2002 Wiley-Liss, Inc.

Background & Aims: Methylation of the h MLH 1 promoter region has been suggested to cause microsatellite instability (MSI) in sporadic colorectal carcinoma (CRC). We studied the methylation profile in a wide region of the h MLH 1 promoter and compared with the hMLH1 protein expression and MSI status in 88 cases of sporadic CRC. Methods: Na-bisulfite treatment and polymerase chain reaction single-strand conformation polymorphism analysis was performed using 5 sets of polymerase chain reaction primers spanning the promoter region of the h MLH 1 to examine methylation status. Results were compared with immunostaining using anti-hMLH1 monoclonal antibody and MSI status of the tumor samples. Results: Methylation status was classified as full or partial methylation. Full methylation indicates the methylation of all CpG sites in the examined regions. Methylation of the h MLH 1 promoter was observed in 88.9% (16 of 18) of CRCs showing high frequency MSI (MSI-H), among which 89% (14 of 16) had full methylation with reduced hMLH1 protein expression. All cases showing full methylation were proximal colon tumors with MSI-H. In cases with partial methylation, only the upstream region of the h MLH 1 promoter was methylated. Partial methylation was also shown in 33.3% (6 of 18) of the normal mucosa of MSI-H cases. Frequencies of methylation were significantly correlated with female gender ( P = 0.0009) and aging ( P = 0.007). Conclusions: Full methylation of the h MLH 1 promoter region and subsequent gene inactivation may play a crucial role in the carcinogenesis of MSI-H CRCs in the proximal colon. Methylation upstream of the h MLH 1 promoter appears to be an early event in the carcinogenesis of MSI-H tumors. GASTROENTEROLOGY 2001;121:1300-1309

Although size criteria have been proposed to identify lymph node metastases in patients with rectal cancer, size may not be an accurate predictor. Specimens from consecutive rectal cancer patients who underwent curative-intent radical surgery were examined. The long and short axes of lymph nodes were measured on the glass slides using micrometer calipers. The pathologic diagnosis was used as the reference. The diagnostic accuracy of metastatic status according to lymph node size was evaluated. Overall, 1283 lymph nodes from 78 patients were reviewed. The metastatic rate correlates with the length of both the long and short axes. However, metastases were present even in 1-mm lymph nodes, and the metastatic rate exceeds 5 per cent in lymph nodes measuring 3 mm along both axes. Cutoff values of ≥4 mm and ≥3 mm for the long and short axes result in a sensitivity of 76 per cent and 79 per cent, and a specificity of 36 per cent and 33 per cent, respectively, for each axis. Size criteria alone do not accurately predict the N-stage of rectal cancer. Diminutive lymph nodes, which are not seen on imaging studies, can contain metastatic disease.

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