Clinicopathological features and phenotypic classification of de novo-type colorectal carcinomas differ from those of colorectal carcinomas derived from flat adenomas.

Since adenoma components disappear with tumor progression, it is not known whether colorectal carcinomas (CRCs) are derived from an adenoma-carcinoma sequence or are de novo. We compared 38 cases of ≤10-mm flat CRCs without an adenoma component (de novo type) with 39 cases of ≤10-mm flat CRCs with an adenoma component (carcinoma in adenoma (CIA) type). Compared to the CIA type, the de novo-type CRCs were more frequently located in the proximal colon; more frequently invaded submucosa, and more frequently had venous permeation. Regarding the phenotypic classification based on the immunohistochemical expressions of CD10, MUC2 and MUC5AC, the incidence of unclassified type (CD10-, MUC2- and MUC5AC-) was significantly more frequent in the de novo (32%) than CIA (5%) type. In one de novo-type case, mismatch repair (MMR) protein loss was judged, because MLH1 and PMS2 protein expressions were immunohistochemically negative. BRAF mutation (V600E) was seen in one de novo-type case and two CIA-type cases, but none of these cases had MMR protein loss. In conclusion, small-intestinal type (CD10+ and MUC5AC-) is the most common in flat CRC and unclassified type is mainly characteristic of de novo type. In this study, small flat CRCs with BRAF mutation do not have MMR protein loss.

Gastric neuroendocrine tumor with hypergastrinemia following type B chronic atrophic gastritis: a case report.

A man in his 60s was referred to our institution for the evaluation of a gastric neuroendocrine tumor (G-NET) located in the fornix and that measured 13mm in size. Blood test results revealed hypergastrinemia (up to 3376pg/ml). Additional tests, including esophagogastroduodenoscopy, computed tomography, and intragastric pH monitoring, indicated that hypergastrinemia was not associated with type A autoimmune gastritis or gastrinoma. The patient was positive for the immunoglobulin G antibody against Helicobacter pylori, suggesting type B chronic atrophic gastritis as the cause for the condition. This report describes a rare case of G-NET with hypergastrinemia following type B chronic atrophic gastritis. Evaluation of similar cases is necessary to determine if H. pylori-associated chronic atrophic gastritis is frequently associated with G-NET.

Prognostic value of chromosomal translocations in small-bowel diffuse large B-cell lymphoma.

AIMS: The objective of this study was to investigate the incidence and clinical significance of lymphoma-associated chromosomal translocations, particularly those involving the immunoglobulin heavy chain gene (IGH) locus, in patients with small-bowel diffuse large B-cell lymphoma (DLBCL). METHODS AND RESULTS: Translocations involving IGH, bcl-6, MYC and bcl-2 were investigated with interphase fluorescence in-situ hybridization on paraffin-embedded tissues in 35 patients with primary small-bowel DLBCL, and the overall survival (OS) and progression-free survival (PFS) rates were evaluated with the Kaplan-Meier method. Translocations involving IGH, bcl-6, MYC and bcl-2 were detected in 23 (70%), 12 (36%), eight (24%) and six (18%) of 33 cases, respectively. The patients with IGH translocations showed less frequent relapse or progression of lymphoma (17%) than those without (60%, P = 0.034). Univariate analyses demonstrated that young age, a low international prognostic index, translocations involving IGH, extra copies of MALT1/bcl-2 and bcl-6 immunoexpression were significantly associated with better OS and PFS. Cox multivariate analysis revealed translocations involving IGH to constitute an independent prognostic factor for better PFS, but not better OS. CONCLUSIONS: Translocations involving IGH are frequent in cases of small-bowel DLBCL. These translocations may be predictive of a favourable clinical course.

Efficacy and safety analysis of chemotherapy for advanced colitis-associated colorectal cancer in Japan.

Chemotherapy for advanced colitis-associated colorectal cancer (CAC) has been insufficiently evaluated. The goal of this study was to clarify the efficacy and safety of chemotherapy for CAC in Japan. CAC patients who were treated with chemotherapy between 2005 and 2015 were retrospectively examined. Twenty-nine patients (median age, 48 years; 23 men) were assessed. Eighteen patients had ulcerative colitis, and 11 had Crohn's disease. Three ulcerative colitis and four Crohn's disease patients were in the active disease phase. Primary tumors were located in the rectum/anus (n=16), the left colon (n=9), or the right colon (n=4). Palliative or adjuvant chemotherapy was performed in 13 and 16 patients, respectively. First-line palliative chemotherapy regimens were as follows: fluorouracil, leucovorin, and oxaliplatin (FOLFOX; n=6), FOLFOX+bevacizumab (n=3), and others (n=4). Adjuvant chemotherapy regimens were S-1 (n=7), oxaliplatin-based (n=4) and others (n=5). In palliative chemotherapy, the objective response rate was 15%, and the median progression-free survival and overall survival were 182 and 315 days, respectively. In adjuvant chemotherapy, the 5-year relapse-free survival rate was 78%. Grade 3/4 adverse events (AEs) were observed in 16 patients (55%). Active and remission inflammatory bowel disease patients suffered grade 3/4 nonhematological AEs at an incidence of 71 and 23%, respectively (P<0.01). Dose reduction was required in 11 patients (38%), eight of whom required it for hematological AEs. Adjuvant chemotherapy for CAC exhibited sufficient efficacy, whereas modest efficacy was shown for palliative chemotherapy for CAC. AEs, particularly nonhematological AEs, were closely associated with disease activity of colitis.

Differentiation of early gastric cancer with ulceration and resectable advanced gastric cancer using multiphasic dynamic multidetector CT.

OBJECTIVES: Early gastric cancer with ulceration (EGC-U) mimics advanced gastric cancer (AGC), as EGC-Us and ACGs often have similar endoscopic appearance to ulceration. The purpose of this retrospective study was to determine whether multiphasic dynamic multidetector CT (MDCT) can help differentiate EGC-Us from AGCs. METHODS: Patients with EGC-Us with ulcer stages Ul-III or IV and AGCs with tumour stages T2 to T4a were enrolled. MDCT images were obtained 40 s (arterial phase), 70 s (portal phase) and 240 s (delayed phase) after injection of non-ionic contrast material. Two readers independently measured the attenuation values of the lesions by placing regions of interest. We compared the EGC-Us and AGCs using the mean attenuation values in each phase and peak enhancement phase. We analysed the diagnostic performance of CT for differentiating EGC-Us from AGCs. RESULTS: Forty cases (16 EGC-Us and 24 AGCs) were analysed. The mean attenuation values of the EGC-Us were significantly lower than those of the AGCs in both the arterial and portal phases (all p < 0.0001 for each reader). The peak enhancement was significantly different between the EGC-Us and AGCs for both readers (Reader 1, p = 0.0131; Reader 2, p = 0.0006). CONCLUSION: Multiphasic dynamic contrast-enhanced MDCT can help differentiate EGC-Us from AGCs. KEY POINTS: • Early gastric cancer with ulceration and advanced gastric cancer have similar endoscopic appearances. • EGC-U shows significantly lower attenuation values in both arterial and portal phases. • Multiphasic dynamic contrast-enhanced MDCT differentiates EGC-U from AGC.

Endoscopic Submucosal Dissection is Feasible for Very Elderly Patients with Early Gastric Cancer : Comparison of Short-Term and Long-Term Outcomes in Very Elderly and Non-Elderly Patients.

Background/Aims: Endoscopic submucosal dissection (ESD) has become a standard procedure for the resection of early gastric cancer (EGC). However, the feasibility of ESD for very elderly patients, aged ≥ 80 years, has not been determined. Methodology: The study population included 67 non-elderly (NE) patients aged ≤ 65 years (80 lesions) and 22 very elderly (VE) patients ≥ 80 years (26 lesions) with EGC who underwent ESD and met the criteria for absolute or expanded indications. Eighteen patients (18 lesions) who underwent ESD but did not meet the criteria for absolute and expanded indications were defined as the outside the indications (OI) group. Results: En bloc and complete resection rates were excellent in both the VE and NE groups, without differing significantly. Although the rates of ischemic heart disease and antithrombotic agent use were higher in the VE than in the NE group, procedure-related complication rates did not differ significantly. Of the seven very elderly patients in the OI group, two underwent additional gastrectomy, and the other five were followed-up without surgery. No patient in any group experienced local recurrence, metastasis or disease-specific death. Conclusions: Short- and long-term outcomes of ESD for VE patients with EGC were favorable and did not differ significantly from outcomes in NE patients. ESD may therefore be a good therapeutic option for both VE and NE patients with EGC.

[Comorbid Meckel's diverticulum and omphalomesenteric cyst evaluated by small bowel series under double-balloon enteroscopy: a case report].

A 59-year-old man was referred to our hospital for examination of intermittent abdominal pain. Computed tomography scan showed a cystic lesion adjoining the ileum, and small bowel series demonstrated a small bowel diverticulum. Double-balloon enteroscopy (DBE) revealed a diverticulum in the ileum and a soft and smooth elevated lesion with a small hole at the base of the diverticulum. Small bowel series under DBE demonstrated that the cystic lesion communicated with the diverticulum through the small hole. The diagnosis was Meckel's diverticulum and an omphalomesenteric cyst. This is the first reported case of a Meckel's diverticulum and omphalomesenteric cyst communicating through a small hole without a fibrous ligament. In addition, precise evaluation was possible by small bowel series and DBE.

Loss of heterozygosity of PTEN (encoding phosphate and tensin homolog) associated with elevated HER2 expression is an adverse prognostic indicator in gastric cancer.

OBJECTIVE: PTEN (the encoding phosphate and tensin homolog) is a well-known cancer suppressor gene and its mutation and loss of heterozygosity (LOH) occurs in various types of carcinomas. This study aimed to examine the association between LOH of PTEN and prognosis in HER2-expressing and nonexpressing gastric cancer patients. METHODS: Fresh-frozen tumor samples of 221 gastric cancer patients with a primary diagnosis of gastric carcinoma were examined for LOH of PTEN. The results were compared with pathological parameters and the HER2 status. To elucidate the role of LOH of PTEN, the activation of the PI3K/AKT pathway was examined immunohistochemically using a phosphorylation-specific antibody. RESULTS: LOH of PTEN was observed in 20% of the patients (39 of 195 cases). LOH of PTEN was associated with vascular involvement (25 of 39 cases; p = 0.0083), equivocal to positive staining for HER2 (p = 0.0080), and phospho-Akt expression (p = 0.0067). Patients with HER2-expressing gastric cancer with LOH of PTEN had a significantly worse prognosis (p = 0.0050). CONCLUSIONS: Although HER2 expression itself was not a prognostic factor, the combination of HER2 expression and LOH of PTEN exacerbates the malignant potential of gastric cancer through its proliferative function.

Risk of cancer in the rectal remnant after ileorectal anastomosis in patients with familial adenomatous polyposis: single center experience.

BACKGROUND AND AIM: We aimed to evaluate the long-term risk of cancer in the rectal remnant in patients with familial adenomatous polyposis after ileorectal anastomosis. METHODS: Cumulative incidence and clinicopathological characteristics of cancer in the rectal remnant were retrospectively investigated in 27 patients with familial adenomatous polyposis who had undergone ileorectal anastomosis. RESULTS: During the follow-up period ranging from 3.0 to 35.0 years (median, 21.1 years), cancer in the rectal remnant developed in 10 patients. Cumulative risk of cancer in the rectal remnant 30 years after surgery was 57%. Five patients had metastases and three patients died of cancer in the rectal remnant after proctectomy. There was a trend towards a higher incidence of cancer in the rectal remnant in patients with small-intestinal adenoma and congenital hypertrophy of the retinal pigment epithelium. Multivariate analysis revealed that the ocular lesion was an independent risk factor associated with cancer in the rectal remnant. CONCLUSION: Subtotal colectomy with ileorectal anastomosis does not seem to be an appropriate prophylactic surgery in patients with familial adenomatous polyposis.

Tumor deposit is a poor prognostic indicator for patients who have stage II and III colorectal cancer with fewer than 4 lymph node metastases but not for those with 4 or more.

BACKGROUND: Extranodal tumor deposits are involved in TNM classification. However, it is uncertain whether a tumor deposit is a regular lymph node metastasis, and its prognostic significance in patients with stage II or III colorectal cancer remains to be established. OBJECTIVE: This study aimed to determine the prognostic significance of tumor deposits for stage II and III colorectal cancer. DESIGN: This study is a retrospective review of clinicopathological data. SETTING: This study was conducted at a tertiary care hospital/referral center in Japan. PATIENTS: We reviewed the clinical course of 171 stage II and 173 stage III consecutive patients between January 1999 and December 2006. MAIN OUTCOME MEASURES: We examined the clinicopathological features of colorectal cancers with tumor deposits and calculated overall survival and recurrence-free survival of the patients according to the status of tumor deposits. The primary outcome was the impact of tumor deposits on patient survival. RESULTS: Thirty-five (10.2%) patients with colorectal cancers had tumor deposits in the pericolic and/or mesocolic region. Survival rates among the patients with tumor deposits were significantly lower than those without (5-year overall survival: 58.4% vs 81.0%, p < 0.0001; 5-year recurrence-free survival: 47.1% vs 73.4%, p < 0.0001). Tumor deposit was an independent prognostic factor for patients with colorectal cancer in multivariate analysis (overall survival: HR, 2.30; 95% CI, 1.26-4.04; p = 0.04; recurrence-free survival: HR, 2.42; 95% CI, 1.04-4.90; p = 0.04). Tumor deposit was an independent prognostic factor in N0 and N1 colorectal cancer, whereas N2 cancer had poor survival outcome regardless of tumor deposit. LIMITATIONS: Our study was a single-institution retrospective study, and the numbers of patients were relatively small to draw firm conclusions. CONCLUSION: Tumor deposit may be an independent adverse prognostic factor for stage II and III N1 colorectal cancer.

Induced nitric oxide synthetase and peroxiredoxin expression in intramucosal poorly differentiated gastric cancer of young patients.

To investigate the relationship between oxidative stress and gastric carcinogenesis of poorly differentiated adenocarcinoma in young patients, we analyzed the surgically resected specimens of 22 young patients (21-30 years) and 29 older patients (41-72 years) with intramucosal gastric cancer of the poorly differentiated type. We used immunohistochemical staining to evaluate the expression of 8-hydroxydeoxyguanosine (8OHdG), induced nitric oxide synthetase (iNOS), and antioxidant enzymes (thioredoxin [TRX] and peroxiredoxin [PRDX1, 2 and 3]). We assessed these proteins in the cancer, noncancerous gastric foveolar epithelium and noncancerous mucosal neck. In both the young and older patient groups, the 8OHdG and TRX expressions were gradually increased in cancer cells compared with the noncancerous foveolar epithelial cells and the noncancerous mucosal neck cells (P < 0.001). Although the iNOS and PRDXs expressions were increased in the noncancerous mucosal neck cells compared with the noncancerous foveolar epithelial cells, regardless of age (P < 0.001), the iNOS and PRDX2 expression in the cancer cells were significantly reduced in the young patients compared with the older patients (P < 0.001, P < 0.05). In conclusion, the reduced expression of iNOS or PRDX2 may play an important role in the carcinogenesis of gastric cancer associated with Helicobacter pylori-induced chronic active gastritis in young patients.

Endoscopic Resection is Infeasible for Early Gastric Cancers with Undifferentiated Components.

BACKGROUND/AIMS: Aim of this study is to find subgroup of early gastric cancer with lymph node metastasis for which successive further surgical operation is needed after endoscopic resection. METHODOLOGY: A total of 559 lesions of early gastric cancer, which had undergone curative gastrectomy, were enrolled in this study. We retrospectively investigated 10 clinicopathological factors predictive of lymph node metastasis by univariate and multivariate analysis. We showed the frequency of lymph node metastasis of subgroups in combination of independent factors selected by multivariate analysis. RESULTS: Lymph node metastases were detected in 57 lesions (10.2%). Univariate analysis revealed that lesion size > 30 mm, undifferentiated components, sm massive invasion, lymphatic invasion and venous invasion were factors significantly correlated with lymph node metastasis. By multivariate analysis, risk factors for lymph node metastasis were lesion size > 30 mm, undifferentiated components, sm massive invasion, and lymphatic invasion, with odds ratios of 2.17, 2.30, 5.88 and 8.24, respectively. In lesions with undifferentiated components, LNM were found in all subgroups. CONCLUSIONS: When we treat early gastric cancers contained undifferentiated components, even if they are predominantly differentiated-type intramucosal lesions, an additional surgical procedure should be considered or careful follow-up is required.

Duodenal adenomatosis in Japanese patients with familial adenomatous polyposis.

Duodenal adenomatosis is the most frequent extracolonic manifestation of familial adenomatous polyposis (FAP), and duodenal cancer has been assumed to be the second most significant cause of death in patients with the disease. To stratify the risk of duodenal cancer, Spigelman's classification was proposed for the staging of duodenal adenomatosis. According to Western guidelines, patients with stage IV of the classification are candidates for prophylactic duodenectomy. Since our institutional experience disclosed only 2% of duodenal or ampullary cancers among 130 patients with FAP, and because most duodenal adenomatosis remains unchanged under endoscopic surveillance, it seems likely that aggressive endoscopic or surgical removal is unnecessary for most FAP patients with duodenal adenomatosis. In the present article, we demonstrate our data and present our strategy for duodenal adenomatosis of FAP.

[Pancreatic and gastric metastases occurring a decade after nephrectomy for renal cell carcinoma].

We report the case of a 64-year-old man who underwent resection on two occasions for recurrent renal cell carcinoma. He first underwent right nephrectomy for renal cell carcinoma, and 10 years later, he underwent pylorus-preserving pancreaticoduodenectomy for pancreatic metastasis. Microscopic extracapsular invasion without lymph node metastasis was observed at that time. Twelve years after the first surgery, he was diagnosed with stomach metastasis. Clinically, metastases to other organs was not observed, and endoscopic ultrasonography revealed no changes in the submucosal layer; endoscopic submucosal dissection was subsequently performed. Pathologically, the tumor was found to be localized in the mucosal layer. There has been no occurrence of metastases for 2 years and 6 months since the last surgery.

Hedgehog Gli3 activator signal augments tumorigenicity of colorectal cancer via upregulation of adherence-related genes.

Hedgehog signal is re-activated in several cancers. In this study, we examined the role of Gli3 on malignant phenotype of tumorigenicity for colorectal cancer and its relationship with p53, WNT and ERK/AKT signals. Gli3 expression was detected in HT29 and SW480 (p53-mutant) cells, but not in DLD-1 (p53-mutant) or HCT116 (p53-wild type) cells by reverse transcription-polymerase chain reaction and immunocytochemistry. Full-length Gli3 transfection increased anchor-independent growth for all cells regardless of p53 status, with upregulation of adhesion-related genes. Exogenous Sonic-Hedgehog increased activator-type of Gli3 and colony formation in Gli3-positive HT29 and SW480 cells. After implantation of Gli3-FL or mock-transfectant DLD-1 cells into SCID mice, tumor formation was highly observed in only Gli3-FL-transfectant group. In clinical specimens, Gli3 expression was detected in subsets of colorectal cancer and related with poorly-differentiated histological type, while Sonic-Hedgehog was present with high incidence. In conclusion, activator Gli3 signal augments tumorigenicity of colorectal cancer irrespective of p53 status.

Podoplanin is expressed at the invasive front of esophageal squamous cell carcinomas and is involved in collective cell invasion.

The expression of podoplanin is reportedly involved in collective cell invasion, which is independent from the epithelial-mesenchymal transition (EMT). We focused on the expression of podoplanin in esophageal squamous cell carcinomas (ESCC) and investigated the correlation of podoplanin and EMT-related markers, and evaluated its prognostic significance. Five ESCC cell lines were subjected to western blot analysis for podoplanin and EMT markers. The effects of podoplanin on EMT and carcinoma invasion were evaluated with wound healing assays, invasion assays and 3-D culture. Transfection of ectopic podoplanin into a podoplanin-negative ESCC cell line (TE-15) induced cell migration and invasive activity (P < 0.001 and P < 0.05, respectively) without downregulation of E-cadherin. In contrast, transfection of si-podoplanin RNA into a podoplanin-positive ESCC cell line (TE-13) reduced cell migration and invasive activity (P < 0.05). We reviewed 101 patients who had undergone esophagectomy for ESCC. Podoplanin expression was observed in 58 patients (57.4%), and positive expression was positively correlated with expression of E-cadherin (P < 0.01), deeper wall invasion (P < 0.01), venous invasion (P < 0.05) and poorer prognosis (P < 0.01). Multivariate Cox analysis revealed that expression of podoplanin was a significant and independent unfavorable predictor of survival (P < 0.05). These data suggest that podoplanin is significantly associated with and likely contributes to ESCC invasion in the absence of EMT.

Human Nanog pseudogene8 promotes the proliferation of gastrointestinal cancer cells.

There is emerging evidence that human solid tumor cells originate from cancer stem cells (CSCs). In cancer cell lines, tumor-initiating CSCs are mainly found in the side population (SP) that has the capacity to extrude dyes such as Hoechst 33342. We found that Nanog is expressed specifically in SP cells of human gastrointestinal (GI) cancer cells. Nucleotide sequencing revealed that NanogP8 but not Nanog was expressed in GI cancer cells. Transfection of NanogP8 into GI cancer cell lines promoted cell proliferation, while its inhibition by anti-Nanog siRNA suppressed the proliferation. Immunohistochemical staining of primary GI cancer tissues revealed NanogP8 protein to be strongly expressed in 3 out of 60 cases. In these cases, NanogP8 was found especially in an infiltrative part of the tumor, in proliferating cells with Ki67 expression. These data suggest that NanogP8 is involved in GI cancer development in a fraction of patients, in whom it presumably acts by supporting CSC proliferation.

Long-term effect of Helicobacter pylori eradication on the development of metachronous gastric cancer after endoscopic resection of early gastric cancer.

BACKGROUND: A prospective, randomized trial proved that Helicobacter pylori eradication significantly reduces the incidence of metachronous gastric cancer during a 3-year follow-up. OBJECTIVE: To investigate the long-term effect of H pylori eradication on the incidence of metachronous gastric cancer after endoscopic resection of early gastric cancer. DESIGN: Retrospective, multicenter study. SETTING: Kyushu University Hospital and 6 other hospitals in Fukuoka Prefecture, Japan. PATIENTS AND INTERVENTIONS: Follow-up data for 268 H pylori-positive patients who had undergone endoscopic resection of early gastric cancer were retrospectively investigated. A total of 177 patients underwent successful H pylori eradication (eradicated group), whereas 91 had persistent H pylori infection (persistent group). MAIN OUTCOME MEASUREMENTS: The incidence of metachronous gastric cancer was compared in these 2 groups. RESULTS: When the follow-up period was censored at 5 years, the incidence rate in the eradicated group was lower than that observed in the persistent group (P = .007). During the overall follow-up period ranging from 1.1 to 11.1 years (median 3.0 years), metachronous gastric cancer developed in 13 patients (14.3%) in the persistent group and in 15 patients (8.5%) in the eradicated group (P = .262, log-rank test). Based on a multivariate logistic regression analysis, baseline severe mucosal atrophy and a follow-up of more than 5 years were found to be independent risk factors for the development of metachronous gastric cancer. LIMITATIONS: Retrospective study. CONCLUSIONS: H pylori eradication does not reduce the incidence of metachronous gastric cancer. H pylori eradication should be performed before the progression of gastric mucosal atrophy.

The risk of lymph node metastasis in mucosal gastric carcinoma: especially for a mixture of differentiated and undifferentiated adenocarcinoma.

BACKGROUND/AIMS: Endoscopic submucosal dissection (ESD) is gaining wider acceptance for the treatment of early gastric carcinoma (EGC) and its indication has been extended to mucosal gastric carcinoma with undifferentiated component in some institutes. Our aims were to confirm the frequency of lymph node metastasis in such cases and clarify the demarcation in indications for ESD. METHODOLOGY: We evaluated medical data of 287 patients with mucosal gastric carcinoma who underwent surgical resection between 1996 and 2008. The tumours were histologically classified into purely differentiated (PD), differentiated-predominant mixed (DPM), undifferentiated-predominant mixed (UPM) and purely undifferentiated (PU) types. RESULTS: Lymph node metastasis was identified in seven (2.4%) of the 287 patients and was detected more frequently in UPM (10%, two of 20) and PU (4%, four of 98), compared with PD (none of 148) (p=0.01 and 0.02, respectively). In mixed-type carcinoma, size was a significant risk factor for lymph node metastasis (p=0.04). CONCLUSIONS: It might be better to select gastrectomy rather than ESD for the treatment of mucosal gastric carcinoma with an undifferentiated component.