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Although rectal neuroendocrine tumor (NET-G1) have potential metastatic capability, even among small tumors, no predictive biomarker for invasion and metastasis has been reported. We analyzed microRNA (miRNA) expression profiles in rectal NET-G1 tissues with and without lymphovascular invasion (LVI). Moreover, we then investigated their target genes to clarify the mechanism of invasion/metastasis in NET-G1.miRNA array analysis was performed using seven rectal NET-G1 tissues with LVI and seven without LVI. miRNA expression was confirmed by quantitative real-time PCR. A NET cell line H727 was transfected with miRNA mimic or target gene small interfering RNA, and migration and invasion assays were performed.The expression levels of miR-144-3p and miR-451a were significantly higher in NET-G1 with LVI versus without LVI, as determined by miRNA array analysis and RT-qPCR. A significant correlation was observed between miR-144-3p and miR-451a expression levels, strongly suggesting miR144/451 cluster overexpression in NET-G1 with LVI. Bioinformatic analysis of target genes revealed that miR-144-3p and miR-451a directly interact with PTEN and p19 mRNA, respectively. Immunohistochemistry revealed significantly lower expression of PTEN and p19 in NET-G1 tissues with LVI than in those without LVI. The miR-144-3p and miR-451a mimic significantly increased cell migration/invasion capability, respectively. Knockdown of PTEN and p19 induced significant augmentation of cell invasion and migration capability, respectively.Our data suggest that overexpression of miR-144/miR-451 cluster promotes LVI via repression of PTEN and p19 in rectal NET-G1 cells. miR-144/451 cluster may be a novel biomarker for predicting invasion/metastasis in rectal NET-G1.

General rules for treatment of early carcinoma have been determined in cooperation by clinicians, pathologists, and radiologists belonging to the Japan Esophageal Society (JES) [1], the Japanese Research Society for Gastric Cancer (JRSGC) [2], and the Japanese Society for Cancer of the Colon and Rectum (JSCCR) [3, 4], with repeated revision from the 1960s to the 1990s in Japan. One of the purposes of this chapter is to introduce the latest information on them.

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

AIM To clarify the diagnostic performance of endocytoscopy for differentiation between neoplastic and non-neoplastic colorectal diminutive polyps. METHODS Patients who underwent endocytoscopy between October and December 2016 at Sano Hospital were prospectively recruited. When diminutive polyps (≤ 5 mm) were detected, the lesions were evaluated by endocytoscopy after being stained with 0.05% crystal violet and 1% methylene blue. The diminutive polyps were classified into five categories (EC 1a, 1b, 2, 3a, and 3b). Endoscopists were asked to take a biopsy from any lesion diagnosed as EC1b (indicator of hyperplastic polyp) or EC2 (indicator of adenoma). We have assessed the diagnostic performance of endocytoscopy for EC2 and EC1b lesions by comparison with the histopathology of the biopsy specimen. RESULTS A total of 39 patients with 63 diminutive polyps were analyzed. All polyps were evaluated by endocytoscopy. The mean polyp size was 3.3 ± 0.9 mm. Among the 63 diminutive polyps, 60 were flat and 3 were pedunculated. The mean time required for EC observation, including the time for staining with crystal violet and methylene blue, was 3.0 ± 1.9 min. Histopathologic evaluation showed that 13 polyps were hyperplastic and 50 were adenomas. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of EC2 for adenoma compared with EC1b for hyperplastic polyp were 98.0%, 92.3%, 96.8%, 98.0% and 92.3%, respectively. There were only two cases of disagreement between the endoscopic diagnosis made by endocytoscopy and the corresponding histopathological diagnosis. CONCLUSION Endocytoscopy showed a high diagnostic performance for differentiating between neoplastic and non-neoplastic colorectal diminutive polyps, and therefore has the potential to be used for “real-time histopathology”.

Background and aim Magnifying chromoendoscopy has been one of the most reliable diagnostic methods for distinguishing neoplastic from non-neoplastic lesions. The aim of this prospective study was to clarify the clinical usefulness of magnifying chromoendoscopy for colorectal polyps initially diagnosed with low confidence (LC) by magnifying narrow-band imaging (NBI). Methods Consecutive adult patients who underwent total colonoscopic examination with magnifying NBI between July and December 2016 at Sano Hospital were prospectively recruited. Endoscopists were asked to carry out additional magnifying chromoendoscopy for cases that had been initially diagnosed as Japan NBI Expert Team (JNET) Type 1 or 2A with LC by magnifying NBI. We investigated the diagnostic performance of magnifying NBI for polyps diagnosed as JNET Type 1 or 2A with LC (first phase) and that of subsequent magnifying chromoendoscopy (second phase) in differentiating neoplasia from non-neoplasia. Results In 50 patients, we analyzed 53 polyps classified as JNET Type 1 or 2A with LC prediction. Accuracy and negative predictive value of magnifying NBI (first phase) were 58.5% (95% CI, 44.1-71.9%) and 66.0% (95% CI, 36.6-77.9%), and those of magnifying chromoendoscopy (second phase) were 66.0% (95% CI, 51.7-78.5%) and 61.1% (95% CI, 43.5-76.9%), respectively. Conclusion Regardless of the findings of additional chromoendoscopy, all polyps should be resected and submitted for histopathological examination when the confidence level in differentiating adenomatous from hyperplastic polyps by magnifying NBI is low.

Background and aim Although sessile serrated adenoma/polyps (SSA/Ps) are considered to be premalignant lesions and rapidly progress to carcinomas after they develop cytological dysplasia (CD), a treatment strategy for SSA/Ps in Asian countries is still being debated and has not yet been established. The present study aimed to propose a treatment strategy for SSA/Ps. Methods Histopathological data of patients, who underwent colonoscopy at our center between January 2011 and December 2016, were reviewed. Data of patients with ≥ 1 SSA/P were retrieved, and clinicopathological characteristics were retrospectively analyzed. Results A total of 281 patients with 326 SSA/Ps, including 258 patients who had 300 SSA/Ps without CD (SSA/Ps-CD[-]) and 23 patients who had 26 SSA/Ps with CD (SSA/Ps-CD[+]), were evaluated in this study. Although SSA/Ps-CD(+) were often found in older female patients and in the proximal colon, there were no significant differences between SSA/Ps-CD(-) and SSA/Ps-CD(+). Endoscopic morphological findings, such as large or small nodules on the surface and partial protrusion of the lesions, were significantly more common in SSA/Ps-CD(+) than in SSA/Ps-CD(-). Although the diagnostic ability of nodule/protrusion in lesions to predict CD within SSA/Ps was very high with an accuracy of 93.9% and a negative predictive value of 95.4%, sensitivity was low at 46.2%. SSA/Ps-CD(+) were significantly larger than SSA/Ps-CD(-), and the rate of CD within SSA/Ps significantly increased with lesion size (≤ 5 mm, 0%; 6-9 mm, 6.0%; ≥ 10 mm, 13.6%). Conclusion The study proposes removing all SSA/Ps ≥ 6 mm in order to remove high-risk SSA/Ps-CD(+), with high sensitivity.

Regarding viral infection of intestinal mucosa, there have been only a few studies on limited diseases, targeting a few herpes family viruses. In this study, we analyzed 12 kinds of DNA viruses including 8 species of herpes family viruses in the gastrointestinal mucosa of patients with hematologic malignancies, inflammatory bowel diseases, collagen diseases, or other miscellaneous forms of gastroenteritis using the multiplex virus PCR assay, which we recently developed. The virus PCR assay yielded positive results in 63 of 102 patients; Epstein-Barr virus (EBV) was the most frequently detected, followed by cytomegalovirus (CMV), human herpes virus 6 (HHV-6), HHV-7, parvovirus B19, and herpes simplex virus type 1. The frequencies of viral detection in the 4 diseases were similar involving these 6 viruses. Regarding CMV colitis, the multiplex virus PCR assay was superior to the immunohistopathologic method in detecting CMV. All viruses were more efficiently detected in the mucosa than in the blood in individual patients. These results suggest that CMV, EBV, and HHV-6 were commonly detected in the gastrointestinal mucosa of patients with these 4 diseases, and our multiplex virus PCR assay was useful for the early diagnosis of gastrointestinal virus infection, especially CMV colitis.

Background/Aims: Sessile serrated adenomas/polyps (SSA/Ps) are a putative precursor lesion of colon cancer. Although the relevance of DNA hypermethylation in the SSA/P-cancer sequence is well documented, the role of DNA hypomethylation is unknown. We investigated the biological relevance of DNA hypomethylation in the SSA/P-cancer sequence by using 3-dimensional organoids of SSA/P. Methods: We first analyzed hypomethylated genes using datasets from our previous DNA methylation array analysis on 7 SSA/P and 2 cancer in SSA/P specimens. Expression levels of hypomethylated genes in SSA/P specimens were determined by RT-PCR and immunohistochemistry. We established 3-dimensional SSA/P organoids and performed knockdown experiments using a lentiviral shRNA vector. DNA hypomethylation at CpG sites of the gene was quantitated by MassARRAY analysis. Results: The mean number of hypomethylated genes in SSA/P and cancer in SSA/P was 41.6 ± 27.5 and 214 ± 19.8, respectively, showing a stepwise increment in hypomethylation during the SSA/P-cancer sequence. S100P, S100α2, PKP3, and MUC2 were most commonly hypomethylated in SSA/P specimens. The mRNA and protein expression levels of S100P, S100α2, and MUC2 were significantly elevated in SSA/P compared with normal colon tissues, as revealed by RT-PCR and immunohistochemistry, respectively. Among these, mRNA and protein levels were highest for S100P. Knockdown of the S100P gene using a lentiviral shRNA vector in 3-dimensional SSA/P organoids inhibited cell growth by >50% (p < 0.01). The mean diameter of SSA/P organoids with S100P gene knockdown was significantly smaller compared with control organoids. MassARRAY analysis of DNA hypomethylation in the S100P gene revealed significant hypomethylation at specific CpG sites in intron 1, exon 1, and the 5′-flanking promoter region. Conclusion: These results suggest that DNA hypomethylation, including S100P hypomethylation, is supposedly associated with the SSA/P-cancer sequence. S100P overexpression via DNA hypomethylation plays an important role in promoting cell growth in the SSA/P-cancer sequence.

The patient was a 67-year-old woman with type 2 diabetes and non-alcoholic steatohepatitis (NASH). The administration of the sodium-glucose cotransporter 2 (SGLT2) inhibitor, ipragliflozin improved her liver dysfunction clinically and histologically. The serum alanine aminotransferase (ALT) and ferritin levels decreased to normal limits after treatment for four months. Type IV collagen and hyaluronic acid, both of which were serum fibrotic markers, decreased after treatment. Ultrasonography and computed tomography showed a decrease in the fat deposits in her liver. Her liver sample showed marked improvement, especially in steatosis, inflammation, and ballooning. The SGLT2 inhibitor ipragliflozin may be useful as a specific therapeutic drug for NASH.

In this study, we generated transgenic (Tg) mice, which overexpressed transforming growth factor (TGF)-β stimulated clone-22 (TSC-22), and investigate the functional role of TSC-22 on their development and pathogenesis. We obtained 13 Tg-founders (two mice from C57BL6/J and 11 mice from BDF1). Three of 13 Tg-founders were sterile, and the remaining Tg-founders also could generate only a limited number of the F1 generation. We obtained 32 Tg-F1 mice. Most of the Tg-mice showed marked obesity. Histopathological examination could be performed on 31 Tg-mice; seventeen mice died by some disease in their entire life and 14 mice were killed for examination. Most of the Tg-mice examined showed splenic abnormality, in which marked increase of the megakaryocytes, unclearness of the margin of the red pulp and the white pulp, and the enlargement of the white pulp was observed. B cell lymphoma was developed in 10 (71%) of 14 disease-died F1 mice. These results indicate that constitutive over-expression of TSC-22 might disturb the normal embryogenesis and the normal lipid metabolism, and induce the oncogenic differentiation of hematopoietic cells.

In this study, we examined usefulness of α−AMY activity value in saliva as a non−invasive stress marker in the enduring exercise. In experiment 1, nine high school students participated in the measurement of the day−to−day variation and diurnal variation of saliva α−AMY activity value at rest. In experiment 2, seven adult male athletes participated in the measurement of α−AMY activity value in saliva during gradually increased or decreased exercise test. In Experiment 3, two adult males of identical twins and fraternal twins who specialize in long−distance run, we verified the constitutional impact on α−AMY activity value change in saliva during gradually increased or decreased exercise test. Summaries of knowledge obtained from these experiments are as follows. 1．A day change of α−AMY activity value in saliva at rest showed transition reflecting circadian rhythm. 2．Diurnal change for four days of α−AMY activity value in saliva at rest didn’t show significant change. 3．A strongly positive correlation was observed between α−AMY activity value in saliva and heart rate in endurance exercise. 4．The α−AMY activity value in saliva during endurance exercise changed reflecting the exercise intensity, but large individual differences were also observed. 5．From the ups and downs of α−AMY activity value in saliva of identical twins during endurance exercise, constitutional influence was little suggested. From the above results, α−AMY activity value in saliva was suggested to be useful as a non−invasive stress marker in enduring exercise. However, the change is observed to correspond to individual differences, and personal factors such as physical condition and characteristics of the subject seem to be related to, which will be the future work to verify.

Although sessile serrated adenoma/polyps (SSA/Ps) are considered to be premalignant lesions and rapidly progress to carcinomas after they develop cytological dysplasia (CD), a treatment strategy for SSA/Ps in Asian countries is still being debated and has not yet been established. The present study aimed to propose a treatment strategy for SSA/Ps.Histopathological data of patients, who underwent colonoscopy at our center between January 2011 and December 2016, were reviewed. Data of patients with ≥ 1 SSA/P were retrieved, and clinicopathological characteristics were retrospectively analyzed.A total of 281 patients with 326 SSA/Ps, including 258 patients who had 300 SSA/Ps without CD (SSA/Ps-CD[-]) and 23 patients who had 26 SSA/Ps with CD (SSA/Ps-CD[+]), were evaluated in this study. Although SSA/Ps-CD(+) were often found in older female patients and in the proximal colon, there were no significant differences between SSA/Ps-CD(-) and SSA/Ps-CD(+). Endoscopic morphological findings, such as large or small nodules on the surface and partial protrusion of the lesions, were significantly more common in SSA/Ps-CD(+) than in SSA/Ps-CD(-). Although the diagnostic ability of nodule/protrusion in lesions to predict CD within SSA/Ps was very high with an accuracy of 93.9% and a negative predictive value of 95.4%, sensitivity was low at 46.2%. SSA/Ps-CD(+) were significantly larger than SSA/Ps-CD(-), and the rate of CD within SSA/Ps significantly increased with lesion size (≤ 5 mm, 0%; 6-9 mm, 6.0%; ≥ 10 mm, 13.6%).The study proposes removing all SSA/Ps ≥ 6 mm in order to remove high-risk SSA/Ps-CD(+), with high sensitivity.

Colorectal cancer is a major cause of death in Japan, where it accounts for the largest number of deaths from malignant neoplasms in women and the third largest number in men. Many new treatment methods have been developed over the last few decades. The Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2010 for the treatment of colorectal cancer (JSCCR Guidelines 2010) have been prepared to show standard treatment strategies for colorectal cancer, to eliminate disparities among institutions in terms of treatment, to eliminate unnecessary treatment and insufficient treatment, and to deepen mutual understanding between health-care professionals and patients by making these Guidelines available to the general public. These Guidelines have been prepared by consensuses reached by the JSCCR Guideline Committee, based on a careful review of the evidence retrieved by literature searches and in view of the medical health insurance system and actual clinical practice settings in Japan. Therefore, these Guidelines can be used as a tool for treating colorectal cancer in actual clinical practice settings. More specifically, they can be used as a guide to obtaining informed consent from patients and choosing the method of treatment for each patient. As a result of the discussions held by the Guideline Committee, controversial issues were selected as Clinical Questions, and recommendations were made. Each recommendation is accompanied by a classification of the evidence and a classification of recommendation categories based on the consensus reached by the Guideline Committee members. Here we present the English version of the JSCCR Guidelines 2010.

A Satoyama landscape is an important reservoir of biodiversity; however, in post-industrial era traditional Satoyama management became economically unfeasible. To maintain Satoyama, labor-saving management styles have begun to be implemented. In contrast to the traditional styles based on labor-intensive practices such as rotational tree clear-cutting, the labor-saving styles consist mainly in tree thinning and ground vegetation cutting within a small spatial range. The consequences of this new approach are unclear, and our study aimed at filling this gap in our knowledge by analyzing the effects of small scale management on ground beetle community in suburban Satoyama (Kashiwa city, central Japan). We applied labor-saving management at limited spatial range, and sampled and analyzed ground beetles both before and after management. Cluster analysis revealed three groups of beetle assemblages, corresponding to three habitats: forest, bamboo stand and grassland. Comparison of wing traits showed that, before management, brachypterous beetles dominated forest plots and macropterous beetles were more prominent in the grassland plot, while in the bamboo stand both types of wing morphology were evenly represented. This trend can be linked to habitat structural stability driven by vegetation regeneration cycles which reflect dominant plant longevity. After management, macroptery increased in all three habitats. Probably, habitat disturbance created by vegetation management gave advantage to macropterous beetles over brachypterous beetles. These results suggest that wing type can be linked to vegetation structural stability. In some species, decline in abundance was accompanied with decline in body size. Our study shows that small scale Satoyama management can have pronounced effects on beetle assemblages.

Background: Sessile serrated adenomas/polyps (SSA/Ps) are a putative precursor of colon cancer with microsatellite instability (MSI). However, the developmental mechanism of SSA/P remains unknown. We performed genetic analysis and genome-wide DNA methylation analysis in aberrant crypt foci (ACF), SSA/P, and cancer in SSA/P specimens to show a close association between ACF and the SSA/P-cancer sequence. We also evaluated the prevalence and number of ACF in SSA/P patients. Methods: ACF in the right-side colon were observed in 36 patients with SSA/Ps alone, 2 with cancers in SSA/P, and 20 normal subjects and biopsied under magnifying endoscopy. B-RAF mutation and MSI were analysed by PCR–restriction fragment length polymorphism (RFLP) and PCR–SSCP, respectively, in 15 ACF, 20 SSA/P, and 2 cancer specimens. DNA methylation array analysis of seven ACF, seven SSA/P, and two cancer in SSA/P specimens was performed using the microarray-based integrated analysis of methylation by isochizomers (MIAMI) method. Results: B-RAF mutations were frequently detected in ACF, SSA/P, and cancer in SSA/P tissues. The number of methylated genes increased significantly in the order of ACF

Background: Interleukin-22 (IL-22) has been recently highlighted owing to its biological significance in the modulation of tissue responses during inflammation. However, the role of IL-22 in carcinogenesis has remained unclear. Here, we investigated the pathophysiological significance of IL-22 expression in gastric cancer tissues and examined the mechanism by which IL-22 promotes gastric cancer cell invasion. Methods: Human gastric cancer specimens were analysed by immunohistochemistry for expression of IL-22 and IL-22 receptor 1 (IL-22R1). The effects of IL-22-induced STAT3 and ERK signalling on invasive ability of gastric cancer cells were examined using a small-interfering RNA system and specific inhibitors. AGS cells were co-cultured with cancer-associated fibroblasts (CAFs) from human gastric cancer tissues and assessed by invasion assay. Results: Interleukin-22 and its receptor were expressed in α-smooth muscle actin-positive stromal cells and tumour cells at the invasive front of gastric cancer tissues, respectively. The expression of IL-22 and IL-22R1 was significantly related to lymphatic invasion. Interleukin-22 treatment promoted the invasive ability of gastric cancer cells through STAT3 and ERK activation. The invasive ability of gastric cancer cells was significantly enhanced by co-culture with IL-22-expressing CAFs. Conclusions: Interleukin-22 produced by CAFs promotes gastric cancer cell invasion via STAT3 and ERK signalling.

It is very important to continue the muscle training for the crippled due to spastic cerebral palsy. By this research, we gave the experiment of isokinetic training by CYBEX770 on both of knee joints, both of hip joints and muscle training by free weight on the crippled due to spastic cerebral palsy on a daily life basis for one and a half years within detraining period. As a result, unexpectedly in training period, in detraining period, there were significant differences regarding some more items in muscle strength of the knee joints than in muscle strength of the hip joints. There is not a decline in effect of detraining but rather effectiveness and it is confirmed that the detraining had an influence more on muscle strength of the hip joints than on muscle strength of the knee joints which are slightly symptomatic part of the crippled test subject due to spastic cerebral palsy. It is necessary to be inspected about the influence of the detraining period.

In spite of the evidence that the malignant transformation of gastric hyperplastic polyps (HPs) is a rare event, it must always be taken into account during diagnosis. The aim of the current study was to clarify the mechanism of the malignant transformation of gastric hyperplasia polyps, with focus on phenotypic expression, cell proliferation and p53 overexpression. Immunohistochemistry for mucin phenotypic markers, including MUC1, MUC2, MUC5AC, MUC6, tight junction factors (claudin-3, -4 and -18), an intestinal phenotypic marker [caudal type homeobox 2 (Cdx2)], Ki-67 proliferative index and p53 overexpression, was performed on archival specimens of gastric polyps excised from six patients. Histologically, the intermingled components of several lesions were present in these polyps. Furthermore, the cancer components were predominantly differentiated adenocarcinoma. Immunohistochemically, all hyperplastic components expressed MUC5AC, but did not exhibit positivity for MUC2. Additionally, the majority of hyperplastic components were immunonegative for claudin-3, while claudin-3 positivity was observed in the majority of areas of dysplasia and carcinoma. Expression of claudin-4 was also observed in the majority of cases and claudin-18 was preserved in the hyperplastic, dysplastic and adenocarcinomatous lesions of all cases. Nuclear accumulation of Cdx2 was detected in almost all the samples with dysplasia and carcinoma, while nuclear p53 was detected in 24-80% of the dysplastic areas and >85% of the cancer components. The Ki-67 labeling index appeared to correlate with neoplastic progression. The observations provided evidence that the mechanism underlying malignant transformation of gastric HPs may occur by multistep carcinogenesis, such as the hyperplasia-adenoma (dysplasia)-adenocarcinoma sequence, and these neoplastic cells may acquire various phenotypes during this process.

The aim of this study was to investigate the expression pattern of manganese superoxide dismutase (MnSOD) in relation to inflammatory factors in ulcerative colitis (UC) and characterize this enzyme as a newly identified biomarker potentially linked to disease pathogenesis of UC. MnSOD expression was analyzed immunohistochemically in 48 formalin-fixed and paraffin-embedded specimens from patients with UC who had undergone endoscopical biopsy. MnSOD expression was observed in vascular endothelium, macrophages, and polymorphonuclear leukocytes within lamina propria of inflamed mucosa. The patients who did not express MnSOD tended to have stabilization of symptoms, but accompanied with status of inflammation. The MnSOD expression pattern was strongly correlated with disease type. MnSOD was expressed in polymorphonuclear leukocytes of all disease types, but cases of chronically counting and exacerbation type had particularly high frequency of immunopositive cells. MnSOD expression in macrophages was frequently observed in cases of symptom remaining type. The cases with MnSOD expression in the vascular endothelium showed a tendency to express in relapse-remission and exacerbation of symptoms. Immunohistochemical evaluation for MnSOD expression may be useful for predicting disease severity and activity in patients with UC.

Objective: Colorectal cancer patients bearing wild-type KRAS benefit from anti-epidermal growth factor receptor (EGFR) antibody treatment. Since clinical studies showed the efficacy of anti-EGFR antibody treatment for metastatic colorectal cancer (mCRC), we analyzed KRAS mutations in mCRC to gain insight into the association between these mutations and clinicopathological characteristics. Methods:KRAS mutations were analyzed in 109 tissue samples of mCRC using amplification refractory mutation system-Scorpion (ARMS/S) assay (68 samples) and direct sequencing (41 samples). Results: In the ARMS/S assay, 36.5 and 7.4% of mCRCs harbored mutations at codons 12 and 13, respectively. In direct sequencing, corresponding values were 24.4 and 19.5%. Overall, 37.6% (codon 12/13, 25.7/11.9%) of mCRCs harbored KRAS mutations. No significant differences were found between KRAS mutations and clinicopathological variables. Among mCRC patients KRAS mutations at codon 13 was significantly higher in female than male patients (p = 0.035). Conclusion: The incidence of KRAS mutations in mCRC was similar to that of non-mCRC as previously reported. KRAS codon 13 mutations might be associated with younger female patients with mCRC, but further investigation is necessary to clarify the association between this type of mutation and metastatic potential in female CRC patients.

We previously reported a relationship between depth of submucosal invasion of early colorectal carcinomas and desmoplastic reaction (DR). However, poor inter-observer agreement on the histopathological diagnosis of DR in biopsy specimens with hematoxylin and eosin (H&E) staining has been the major critique of this tool. In this study, reproducibility of the histopathological diagnosis of DR was evaluated. Furthermore, we investigated the possible improvement of the reproducibility after education about histological characteristics and tried to identify histological characteristics that are most important in the recognition of DR. A total of 34 H&E stained slides were included in this study and analyzed by three pathologists. Slides were reviewed before and after education about histological characteristics of DR. Kappa statistics were used to compare the inter-observer variability. We investigated the relationship between DR and histopathological factor. The inter-observer agreement during the first session varied between 0.30 and 0.63, which improved during the second session toward an agreement between 0.58 and 0.71. Myofibroblast proliferation associated with cancer invasion was found to be the most useful in the diagnosis of DR. In conclusion, the correct detection of myofibroblasts may facilitate the standardization of diagnosis of DR.

Patients with submucosal invasive colorectal cancer (SM-CRC) treated with endoscopic resection who are at low risk of lymph node metastasis and local recurrence may be followed up with observation alone, while additional surgery is recommended for those with high risk features. However, the long-term outcomes that these strategies offer are still unclear. The objective of our study was to retrospectively evaluate the long-term outcomes of patients with SM-CRC managed with endoscopic resection.We retrospectively analyzed all patients with SM-CRC treated by endoscopic resection at six institutions between 2000 and 2007. SM-CRCs with (i) negative vertical margin, (ii) well or moderately differentiated adenocarcinoma, (iii) absence of lymphovascular invasion, and (iv) invasion depth1000 µm were classified as low risk. Patients with SM-CRCs without these characteristics were classified as high risk. Outcomes were assessed by 5-year recurrence-free survival (RFS) and recurrence rate.During the study period, 428 patients with SM-CRC (low risk, 126; high risk, 302) who underwent endoscopic resection as their first treatment were enrolled (median follow-up 61 months). Among the 120 patients with low risk features treated by endoscopic resection alone, the 5-year RFS and recurrence rates were 98 % and 0.8 %, respectively. Of the 302 patients with high risk features, 196 underwent additional surgery and 106 were managed with endoscopic resection alone. For those who underwent additional surgery, the 5-year RFS and recurrence rates were 97 % and 3.6 %, respectively. Among the 106 patients managed with endoscopic resection alone, RFS and recurrence rates were 89 % (P0.05 vs. low risk patients treated by endoscopic resection alone) and 6.6 % (P0.05), respectively.Endoscopic resection alone is adequate for the management of patients with SM-CRC and low risk features. However, in those patients with SM-CRC and high risk features, surgery should be considered in addition to endoscopic resection.

The aim of our study was to evaluate the diagnosis of desmoplastic reaction (DR) by immunostaining for α-smooth muscle actin (αSMA) and desmin, for predicting the depth of submucosal invasion in biopsy specimens of early colorectal carcinomas (CRCs). Thirty-eight cases of non-pedunculated early CRCs were included in this study. Positive for DR was defined as αSMA-positive and desmin-negative stroma in the CRC. The depth of submucosal invasion was measured in endoscopically or surgically resected specimens and the lesions were subsequently divided into two groups: Group A (carcinoma in situ/intramucosal carcinoma and submucosal invasive carcinoma with a depth

The use of antibodies against epidermal growth factor receptor( EGFR) in conjunction with conventionalchemotherapy for metastatic colorectal cancer (CRC) in patients with KRAS wild-type tumors has beenproven to be efficacious. Recently, KRAS testing prior to anti-EGFR therapy has become mandatory formetastatic CRC patients. Although newly developed pyrosequencing is expected to be one of the highthroughput procedures detecting such mutations, the accuracy of the procedure has not been well evaluated.In the present study, we aimed to validate the accuracy, especially the potential for a false-negative result,in detecting KRAS mutations by pyrosequencing using cultured tumor cells. DNA extracted from culturedìNOZî gallbladder cancer cells( known to contain KRAS mutation G12V) at concentrations of 1%, 5%, 10%, and 25%, as well as 2 DNA samples extracted from a resected CRC specimen( known to contain anotherKRAS mutation, G12C) at concentrations of 5% and 25%, were prepared. We analyzed KRAS mutationalstatus and nonexistent and/or nonfunctional mutations of these 6 samples using pyrosequencing. TheKRAS mutation detection rates in the 4 NOZ samples( 1%, 5%, 10%, and 25%) were 0.37%, 2.79%, 5.28%,and 13.85%, respectively. Some artifacts of KRAS mutations unlikely to be present were detected in 1%samples of NOZ at a rate similar to that of the G12V mutation( G12C, 0.29%;G13C, 0.42%). Although theKRAS mutation G12C was detected at rates of 1.26% and 6.49% in samples with 5% and 25% DNA extractedfrom resected CRC specimen, respectively, no other type of KRAS mutation was detected in suchsamples. Pyrosequencing could not detect KRAS mutations correctly in the sample containing 1% DNA.This might cause false negatives. A sample mutated DNA concentration of at least 5% was necessary forprecise analyses by this procedure.

Objective:Oral lichen planus( OLP) is a chronic inflammatory oral mucosal disease of unknown etiology.Due to similar histological features of OLP with other oral diseases. IgG4-related disease has been identified,but whether or not there are organ-specific characteristics related to the etiologic factors is still unknown.In the present study, we investigated the significance of IgG4-positive plasma cells as a marker for OLP.Methods:Biopsy specimens from 63 patients with white papules, erythema and erosive mucosa in theoral cavity were obtained. The lesions were evaluated for inflammatory cell spreading pattern classified ashorizontal superficial type and/or expanding type(s), for lymphoid-plasma cell markers (CD3, CD20,CD79a), Immunoglobulin G( IgG, IgG4) immunoreactivity, and for monoclonality.Results:In the horizontal superficial type with only CD3-positive lymphocytic inflammatory cells wererestricted to the epithelial layer of connective tissue without presence of IgG4-positive plasma cells. Lesionswere further demonstrated to contain CD3-, CD20- and CD79a-positive lympho-plasma cells with focal cytoplasmicIgG4 expression. However, in IgG4-rich cases, there were no monoclonality. The inflammatorycell spreading pattern differed significantly between the horizontal superficial type with only CD3-positivelymphoid cells and expanding types, and was significantly associated with IgG4-positive plasma cells.Conclusions:Detection of IgG4-positive plasma cells and inflammatory cell spreading pattern may beuseful for differential diagnosis and selection of treatable cases in OLP.

Little is known about the long-term outcomes of patients with submucosal invasive colorectal cancer who undergo endoscopic or surgical resection. We performed a retrospective analysis of long-term outcomes of patients treated for submucosal colon and rectal cancer.We collected data on 549 patients with submucosal colon cancer and 209 patients with submucosal rectal cancer who underwent endoscopic or surgical resection at 6 institutions over a median follow-up period of 60.5 months. Patients were classified into one of 3 groups: low-risk patients undergoing only endoscopic resection (group A), high-risk patients undergoing only endoscopic resection (group B), and high-risk patients undergoing surgical resection that included lymph node dissection (group C). We assessed recurrence rates, 5-year disease-free survival, and 5-year overall survival. Cox regression analysis was used to compare recurrences.The rates of recurrence, disease-free survival, and overall survival in group A for submucosal colon and rectal cancer were 0% versus 6.3% (P.05), 96% versus 90%, and 96% versus 89%, respectively. For group B, these values were 1.4% versus 16.2% (P.01), 96% versus 77% (P.01), and 98% versus 96%, respectively; local recurrence was observed in 5 patients (one with submucosal colon cancer and 4 with submucosal rectal cancer). Tumor location was the only factor that contributed significantly to disease recurrence and death (hazard ratio, 6.73; P = .045). For group C, these values were 1.9% versus 4.5%, 97% versus 95%, and 99% versus 97%, respectively.The risk for local recurrence was significantly higher in high-risk patients with submucosal rectal cancer than in patients with submucosal colon cancer when treated with only endoscopic resection. The addition of surgery is therefore recommended for patients with submucosal rectal cancer with pathologic features indicating a high risk of tumor progression; University Hospital Medical Network Clinical Trials Registry, Number: UMIN 000008635.

Making a clinicopathological diagnosis of dysplasia is crucial. We herein assess the significance of the DNA methyltransferase 3b (DNMT3b) expression as a diagnostic marker of ulcerative colitis (UC)-associated neoplasia. Thirty-one patients with long-standing and extensive UC were included in this study. The expression of DNMT3b in non-neoplastic rectal epithelium (non-dysplasia in 31 patients) and colorectal neoplasia (dysplasia in 43 patients and invasive cancer in 34 patients) was determined using immunohistochemistry. The presence of immunoreactive DNMT3b was assessed in the areas with the highest density of cells with positively staining nuclei. DNMT3b was expressed as the percentage of positive cells relative to the total number of cells counted under high power magnification. The DNMT3b expression in neoplastic rectal epithelium (0.76, range 0.59–0.84) was increased compared to that observed in non-neoplastic epithelium (0.32, range 0.18–0.67, P

The 6th Diagnostic Pathology Summer Fest, held in Tokyo on August 25-26, 2012, opened its gates for everyone in the medical profession. Basic pathology training can contribute to the improvement of algorithms for diagnosis and treatment. The 6th Summer Fest with the theme ‘Pathology and Clinical Treatment of Gastrointestinal Diseases' was held at the Ito International Research Center, The University of Tokyo. On August 25, ‘Treatment of Early Gastrointestinal Cancer and New Guidelines' was discussed in the first session, followed by ‘Biopsy Diagnosis of Digestive Tract: Key Points of Pathological Diagnosis for Inflammation and Their Clinical Significance' in the second session. On August 26, cases were discussed in the third session, and issues on pathological diagnosis and classification of neuroendorcrine tumor in the fourth session. The summaries of speeches and discussions are introduced along with the statements of each speaker. This meeting was not a formal evidence-based consensus conference, and 20 experts gave talks on their areas of specialty. Discussion was focused on how the management strategy should be standardized on the algorithm of patient care.

Colorectal cancer is a frequently occurring cancer whose incidence has shown a marked increase in recent years. Additionally, an increase in right side colon in elderly patients has been identified. Therefore, a clinicopathological study was conducted in 49 patients with unresectable advanced colorectal carcinomas to elucidate the association of clinicopathological characteristics and K-ras mutation. Of the 49 patients included in this study, 24 were aged

A hyperplastic polyp (HP) >10 mm is described as a large hyperplastic polyp (LHP). Previous studies have considered LHP and sessile serrated adenoma/polyp (SSA/P) as synonymous. Although HP and SSA/P have previously been morphologically distinguished, differences between LHP and SSA/P have not yet been reported. The present study aimed to define the differences between SSA/P and non-SSA/P in LHP using immunohistochemistry for Ki67. Colorectal serrated lesions (>10 mm) that were completely resected by endoscope and derived from 11 institutions in Japan [Dokkyo Medical University School of Medicine (Mibu), Takahiro Fujii Clinic (Tokyo), Sano Hospital (Kobe), Oda GI Clinic, Hattori GI Endoscopy and Oncology Clinic (Kumamoto), Ohta Clinic (Nagoya), Hiroshima University (Hiroshima), Iwate Medical University (Morioka), Juntendo and Kyorin Universities (Tokyo) as well as Toyama University (Toyama)] affiliated with the Japanese Society for Cancer of the Colon and Rectum (JSCCR) between January 2003 and December 2010 were selected. The histological criteria of the Japanese Society for Cancer of the Colon and Rectum (JSCCR, project meeting; editor-in chief, Takashi Yao) were used to distinguish SSA/P and non-SSA/P from LHP. Non-SSA/P comprises both incomplete SSA/P and HP. A total of 154 samples diagnosed as SSA/P or non-SSA/P from 148 patients were used. This study comprised 107 SSA/P and 47 non-SSA/P cases, whereby lesions were located on the right side of the colon (73.2 and 26.8%, respectively). Ki67-positivity in SSA/Ps was significantly higher compared to non-SSA/Ps. A greater number of SSA/Ps in LHP were located on the right side of the colon compared to the left side. SSA/Ps occurring on the right side of the colon may be precursor lesions of colorectal carcinoma in serrated neoplasia pathways. In conclusion, LHPs and SSA/Ps limited to the right side of the colon are suggested to be clinically treated as the same type of lesions.

The aim of this study was to evaluate the significance of an endoscopic atrophic border and irregular arrangement of collecting venules (IRAC) in the diagnosis of Helicobacter pylori (H. pylori)-induced gastritis. Upper gastrointestinal tract endoscopy was performed on 723 patients, who were screened them for H. pylori infection. Any patients who had undergone H. pylori eradication therapy were excluded from the study. The endoscopic atrophic border and IRAC in each patient were assessed. The H. pylori status was determined in the patients by combination of a serological test and/or histopathological examination. The H. pylori infection rates were 95.4% (455/477) in the group with an endoscopic atrophic border and 22.3% (55/246) in the group without an endoscopic atrophic border. In the diagnostic validity check, presence of an endoscopic atrophic border had a sensitivity of 89.2% and a specificity of 89.7%. Furthermore, the H. pylori infection rates were 95.5% (506/530) in the IRAC group and 2.1% (4/193) in the regular arrangement of collecting venules (RAC) group. In the diagnostic validity check, IRAC had a sensitivity of 99.2% and a specificity of 88.7%. In conclusion, the presence of an endoscopic atrophic border and IRAC are highly indicative of an H. pylori-infected gastric mucosa.

Objective: To completely and safely remove a large colorectal lesion in a single fragment, we have developed an endoscopic electrosurgical knife( B-Knife) for a more effective bipolar cutting adevelopedannd coagulation system.The aim of this study was to evaluate the effectiveness and safety of the B-Knife in patients with large colorectal tumors.Methods:Endoscopic submucosal dissection (ESD) using the B-Knife was performed initially in 3 patients with large colorectal tumors in a pilot study. Subsequently, we examined the clinical outcomes of ESDusing the B-Knife in 25 patients with colorectal tumors.Results:During initial clinical use of the B-Knife, en bloc resection was achieved in all 3 cases, and themean operating time was 43 minutes. All margins of resected material were histologically free of neoplasia.There were no cases of delayed bleeding or perforation. In a series of 25 ESD cases, which consisted of 8adenomas, 15 intramucosal carcinomas, one slightly submucosal invasive carcinoma, and one massive submucosalinvasive carcinoma, the en bloc resection rate was 84% . The mean operation time was 91.6 minutes and the mean size of resected specimens was 36.4 mm (range:19-80 mm). Perforations occurred in one( 4%) case, but delayed bleeding did not occur in any of the cases. Additional surgery was required for2 cases( 8%).Conclusions:ESD using the B-Knife is reliable and safe for the complete resection of select large flat lesions in the colorectum.

We previously reported that detection of desmoplastic reaction (DR) in pretreatment biopsy specimens was useful for predicting the depth of submucosal invasion (SM depth) in nonpedunculated early colorectal cancers (ECRCs) in a retrospective study. Here, we performed a prospective multicenter study for verification of our previous findings. Subjects were diagnosed with ECRC by endoscopy, and with adenocarcinoma from the biopsy specimens. Eleven institutions affiliated with the Japanese Society for Cancer of the Colon and Rectum participated in this collaborative study. A total of 112 patients with ECRC were enrolled. For nonpedunculated ECRCs, presence of DR was significantly correlated with SM depth. The sensitivity and specificity of detection of DR for prediction of pSM2 (tumor invasion ≥1000 µm) in nonpedunculated ECRCs were 68.6% and 92.0%, respectively. Evaluation of DR in pretreatment biopsy specimens may be useful for the clinicopathological diagnosis of colorectal carcinoma with massive invasion into the submucosal layer.

It is important to improve the efficacy of surveillance in UC patients with neoplasia.In the present study, we assessed the cut-off value of expression of DNMT-1 and DNMT-3b expression in the non-neoplastic rectal epithelium of patients with long-standing and extensive UC. Sixty patients with long-standing and extensive UC participated in this study( 30 with colorectal neoplasia and 30 without). Immunohistochemical analysis was performed to determine the expression of DNMT-1 and 3b in non-neoplasticrectal epithelium of UC patients without neoplasia, and in non-neoplastic rectal epithelium of UC patients with neoplasia. The level of immunoreactive DNMT-1 and DNMT-3b expression was determined as the percentage of positive cells relative to the total number of cells counted under high power magnification.DNMT-1 and 3b expression in non-neoplastic rectal epithelium of UC patients with neoplasia (0.57, range0.53-0.63)(0.32, range 0.18-0.67) was higher than in the non-neoplastic epithelium of UC patients without neoplasia (0.41, range 0.25-0.54, P=.001)(0.0, range 0.0-0.13, P

Background and Aim: For large colorectal tumors, the en bloc resection rate achieved by endoscopic mucosal resection (EMR) is insufficient, and this leads to a high rate of local recurrence. As endoscopic submucosal dissection (ESD) has been reported to achieve a higher rate of en bloc resection and a lower rate of local recurrence in the short-term, it is expected to overcome the limitations of EMR. We conducted a matched case-control study between ESD and EMR to clarify the effectiveness of ESD for colorectal tumors. Methods: Between April 2005 and February 2009, a total of 28 colorectal tumors in 28 patients were resected by ESD and were followed up by colonoscopy at least once. As a control group, 56 EMR cases from our prospectively completed database were matched. En bloc resection, complication and recurrence rates were compared between the two groups. Results: The mean sizes of the lesions were 27.1 mm in the ESD group and 25.0 mm in the EMR group. The en bloc resection rate was significantly higher in the ESD group (92.9% vs 37.5% with ESD vs EMR), and the rate of perforation was also significantly higher (10.7% vs 0%). All cases of perforation were managed conservatively. No recur- rence was observed in the ESD group, whereas local recurrences were detected in 12 EMR cases (21.4%). Eleven of the 12 recurrences (91.7%) were managed endoscopically, and one required surgical resection. Conclusions: Endoscopic submucosal dissection is a promising technique for the treat- ment of colorectal tumors, giving an excellent outcome in comparison with EMR.

Colorectal cancer is a major cause of death in Japan, where it accounts for the largest number of deaths from malignant neoplasms in women and the third largest number in men. Many new treatment methods have been developed over the last few decades. The Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2010 for the treatment of colorectal cancer (JSCCR Guidelines 2010) have been prepared to show standard treatment strategies for colorectal cancer, to eliminate disparities among institutions in terms of treatment, to eliminate unnecessary treatment and insufficient treatment, and to deepen mutual understanding between health-care professionals and patients by making these Guidelines available to the general public. These Guidelines have been prepared by consensuses reached by the JSCCR Guideline Committee, based on a careful review of the evidence retrieved by literature searches and in view of the medical health insurance system and actual clinical practice settings in Japan. Therefore, these Guidelines can be used as a tool for treating colorectal cancer in actual clinical practice settings. More specifically, they can be used as a guide to obtaining informed consent from patients and choosing the method of treatment for each patient. As a result of the discussions held by the Guideline Committee, controversial issues were selected as Clinical Questions, and recommendations were made. Each recommendation is accompanied by a classification of the evidence and a classification of recommendation categories based on the consensus reached by the Guideline Committee members. Here we present the English version of the JSCCR Guidelines 2010.

Background and Aims: The regenerating gene (REG)Iα has been identified by microarray analysis as a gene that is distinctly overexpressed in ulcerative colitis (UC), and its protein product is suggested to play a pivotal role in the development of UC-associated carcinoma. In the present study, we investigated the significance of REG Iα expression as a diagnostic marker of UC-associated neoplasia. Methods: Tissue samples were obtained from colectomy specimens from 31 patients with long-standing UC (mean disease duration 17.2 years, range 5–29). The lesions were evaluated according to the International Classification for Dysplasia in Inflammatory Bowel Diseases, and the sections were examined using immunohistochemistry for REG Iα and p53. Results: In the ‘regenerating atypia’ group, REG Iα immunoreactivity was restricted to the lower third of the UC mucosa (grade 1). Lesions classified as ‘indefinite for dysplasia’ also showed predominantly basal-type staining for REG Iα. However, in ‘low-grade dysplasia’ and ‘high-grade dysplasia’ lesions, the localization of REG Iα immunoreactivity expanded to the middle (grade 2) and upper (grade 3) third of the UC mucosa, respectively. The REG Iα immunostaining pattern differed significantly (p < 0.0001) between non-neoplastic and neoplastic lesions, and was significantly (p < 0.0001) associated with p53 overexpression. Conclusions: Immunohistochemical analysis of REG Iα expression is useful for differential diagnosis of non-neoplastic and neoplastic lesions in UC tissues.

In the small intestine, stem cells are considered to exist at the bottom of the crypt. Actively proliferatingtransitional cells supplied from stem cells are differentiated into two directions upward and downward. Upwardcells are differentiated into absorbing epithelial cells, goblet cells, and endocrine cells, and downwardcells differentiated into Paneth cells. However there are some difficulties to identify the stem cells becauseof their unique characteristics. At first, stem cells occur as actual stem cells and potential stem cells, andsecond, there is diversity in stem cells. Therefore, molecules suitable for a marker of small intestinal stemcells are necessary to distinguish "true" stem cells from others. Energetically searched for in recent years,Musashi-1, type 1A bone morphogenetic protein receptor (BMPR-1A), phospho-phosphatase and tensinhomolog deleted on chromosome ten( phospho-PTEN), doublecortin and calmodulin kinase-like-1( DCAMKL1),ephrin receptors( Eph receptors), integrins, and leucine-rich repeat-containing G protein-coupled receptor5 (Lgr5) are proposed. Among them, Musashi-1 draws attention as one of a candidate marker forsmall intestinal stem cells. We here introduce our reviews about expression of Musashi-1 and Hes1 proteinsin the small intestine, and would like to overview the way to identify the small intestinal stem cells.

A rare case of hepatocellular carcinoma (HCC) in a 78-year-old woman with a 10-year history of autoimmune hepatitis (AIH) without liver cirrhosis and no history of alcohol abuse, drug injection, or blood transfusion is presented. At the time HCC was diagnosed, based on imaging studies showing a 5-cm-diameter S6 liver tumor, she had normal liver function, positive anti-nuclear antibodies, negative hepatitis B and C markers, and elevated alfa-fetoprotein (AFP; 169 ng/ml) and protein-induced by vitamin K absence or antagonist II (PIVKA-II; 721 mAU/ml) levels. Following subsegmental S6 resection, no evidence of fibrosis or cirrhosis was observed.

Objective: Mucinous cystic neoplasm (MCN) and intraductal papillary mucinous neoplasm of the branch duct type (IPMN-BD) differ in biological and clinical behaviors, but MCN is often misdiagnosed as IPMN-BD. The purpose of this study was to find useful markers for the differential diagnosis of MCN and IPMN-BD. Methods: Immunohistochemically, the expression of the 2 types of mucin (MUC) 1 (MUC1/DF3 and MUC1/CORE), MUC2, MUC5AC, MUC6, human gastric mucin (HGM), caudal-related homeobox transcription factor 2 (CDX2), CD10, cytokeratin (CK) 7, and CK20 was examined in 7 cases of MCN and 16 cases of IPMN-BD. Results: Expression frequencies in MCN and IPMN-BD were 100% versus 44% for MUC1/DF3, 86% versus 31% for MUC1/CORE, 57% versus 19% for MUC2, 86% versus 100% for MUC5AC, 57% versus 88% for MUC6, 86% versus 100% for HGM, 57% versus 0% for CDX2, 71% versus 0% for CD10, 100% versus 69% for CK7, and 86% versus 6% for CK20. Conclusions: Mucin 1/DF3, MUC1/CORE, CDX2, CD10, and CK20 were expressed significantly more frequently in MCN than in IPMN-BD. In particular, CD10 and CK20 showed marked differences in immunohistochemical sensitivity and specificity between MCN and IPMN-BD. It is therefore proposed that CD10 and CK20 may be used for the differential diagnosis of MCN and IPMN-BD.

The patients with long-standing ulcerative colitis( UC) have a high-risk of neoplastic lesions in the colonicmucosa. The UC-associated neoplastic lesion is difficult to detect by endoscopic examination or diagnosehistologically. In the present study, we aimed to clarify whether immunohistochemistry for p53 is useful todiscriminate the UC-associated neoplasia from inflammed regenerating epithelium. Tissue samples were obtainedfrom colorectomy specimens from 20 patients with long-standing UC (range 6-29 years). The surfaceof microstructure of the tissues was observed by stereomicroscopy, and the sections were examined usingimmunohistochemistry for p53. All of T2-4 carcinomas were detectable by endoscopic examination beforesurgery, whereas considerable number of dysplasias (52.5%), Tis carcinomas (33.3%), and T1 carcinomas(60.0%) were undetectable. Fifty-three of 67 UC-associated neoplastic lesions (79.1%) were of flat-typemacroscopically. The detection rate of flat-type neoplasias( 45.3%) was significantly lower than that of protrudingones (100%). The positivity of p53 overexpression was 0 % in UC-II, 52.5 % in UC-III, and 70.4 %in UC-IV, respectively. UC-II lesions had lower positivity of p53 overexpression than UC-III( P=0.027) or-IV lesions( P=0.003). Immunohistochemical analysis of p53 protein is useful to discriminate the UC-associatedneoplasia from inflammed regenerating epithelium.

The regenerating gene( Reg) Ia protein has a trophic effect on gastric epithelial cells, and its overexpressionis reported in gastrointestinal cancers. The salivary gland is a component of the digestive system, andtherefore, REG Ia protein may play some role in the pathophysiology of salivary gland tumors. In the presentstudy, we determined the immunohistochemical localization of REG Ia protein in salivary gland tumorsand moreover investigated its relationship to clinicopathological features. Twenty-eight patients with salivarygland tumor were enrolled. The specimens resected by surgery from those patients were examinedusing immunohistochemistry for REG Ia protein and Ki67. Five of the 16 pleomorphic adenomas (31.3%)were positive for REG Ia protein. Regarding salivary gland carcinomas, four of five mucoepidermoid carcinomas(80%), three of five adenoid cystic carcinomas (60%), one of two polymorphous low-grade adenocarcinomas(50%) were also positive for REG Ia protein. However, no relationships were found betweenREG Ia protein expression and clinicopathological features. Regarding the Ki67 expression, strong signalwas observed in the tumor cells of patients with salivary gland adenoma as well as carcinoma. REG Ia proteinis expressed not only in adenocarcinoma but also precancerous adenoma cells proliferating actively,suggesting that REG Ia protein may play a role at least in part in the development of salivary gland tumors.