Terasu Honma

Nuclear translocation of beta-catenin in colorectal cancer

Post-translational stabilization of beta-catenin through mutation of the adenomatous polyposis coli (APC) gene has been proposed as an early step in colorectal carcinogenesis. Beta-catenin may translocate from the cytoplasm to the nucleus, where it might serve as a transcriptional factor to stimulate tumour formation. We investigated intracellular localization of beta-catenin in sporadic colorectal adenomas and cancers as well as familial adenomatous polyposis (FAP). Nuclear over-expression of beta-catenin was observed in 35% (7/20) of intramucosal cancers and 42% (23/55) of invasive cancers but was not seen in any adenomas from sporadic or FAP cases. Cytoplasmic beta-catenin in adenomas was significantly higher than that of normal mucosa in both sporadic and FAP cases. The cytoplasmic intensity index of cancers was significantly higher than that of sporadic adenomas, but the index was not correlated with nuclear expression in cancers. These findings suggest that nuclear translocation of beta-catenin is involved in development of intramucosal cancer rather than adenoma, independent of APC mutations. Cytoplasmic accumulation of beta-catenin may occur in adenomas, but it remains to be determined whether this is a cause or a consequence of colorectal cancer.

Adsorptive granulocyte and monocyte apheresis for refractory Crohn's disease : an open multicenter prospective study

BackgroundActive Crohn’s disease (CD) is often associated with elevated levels of platelets, granulocytes, and monocytes that are activated and resistant to apoptosis. The level of neutrophils in the intestinal mucosa has been quantitatively related to the severity of intestinal inflammation in CD. We postulated that patients with CD that is refractory to conventional medications might respond to a reduction of granulocytes and monocytes by adsorptive apheresis.MethodsTwenty-one patients with a CD activity index (CDAI) of 200–399 and unresponsive to standard medication, which included nutritional intervention, received granulocyte and monocyte adsorptive apheresis (GCAP) as an adjunct to their ongoing medication. GCAP was performed with an Adacolumn, which adsorbs granulocytes, monocytes, and a small fraction of lymphocytes (FcγR and complement receptor-bearing leucocytes). Patients received one GCAP session/week for 5 consecutive weeks. CDAI, International Organization for the Study of Inflammatory Bowel Disease (IOIBD), and IBD questionnaire (IBDQ) scores were evaluated.ResultsDuring the initial conventional/nutritional therapy, no significant improvement was seen in any patient. However, at week 7 of GCAP therapy, significant improvements in CDAI, IOIBD, and IBDQ scores were observed. The CDAI, IOIBD, and IBDQ scores before GCAP were 275.6 ± 54.2, 3.4 ± 1.4, and 152 ± 22, respectively. The corresponding values after GCAP were 214.8 ± 89.2 (P = 0.0005), 2.54 ± 1.5 (P = 0.0224), and 165 ± 29 (P = 0.0327), respectively.ConclusionsGCAP could be effective for inducing remission and improving quality of life in patients with active CD that is refractory to conventional therapy.

Effect of K-ras mutation on morphogenesis of colorectal adenomas and early cancers: Relationship to distribution of proliferating cells☆

The authors evaluated the association of the K-ras mutation with the distribution of proliferating cells and the macroscopic appearance of colorectal tumors. A total of 122 colorectal adenomas and 96 early cancers were classified macroscopically as follows: (1) polypoid, exceeding 3 mm in height; (2) flat or hemispherically elevated 3 mm or less; and (3) depressed. The intramucosal areas of these tumors were examined by Ki-67 immunostaining and nested polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to detect proliferating cells and the K-ras codon 12 mutation. The distribution pattern of the Ki-67-positive cells was of two types: diffuse (D), being positive throughout the crypts, and superficial (S), being positive mainly in the superficial areas of the crypts. The K-ras mutation and the D type distribution of the Ki-67-positive cells were significantly less common (P < .005) in the nonpolypoid, depressed, or elevated tumors versus the polypoid tumors. The incidence of the K-ras mutation was significantly (P < .0001) associated with the D type distribution. The K-ras mutation may involve a disorder of cell proliferation that leads to the polypoid growth of colorectal tumors.

Gastric carcinoid tumors without autoimmune gastritis in Japan: A relationship with Helicobacter pylori infection

In Japan, most cases of gastric carcinoid tumor (GCT) are unassociated with either autoimmune gastritis (AIG) showing type-A chronic atrophic gastritis (CAG-A) or Zollinger-Ellison syndrome (ZES). However, the pathogenesis of this tumor remains unknown. Recent studies have determined that Helicobacter pylori infection induces gastric carcinoid in Mongolian gerbils and that H. pylori lipopolysaccharide exerts a mitogenic effect on ECL cells. We examined five patients with histologically diagnosed GCT, 40 patients with H. pylori-positive gastric ulcer (Hp+GU), 24 patients with H. pylori-positive duodenal ulcer (Hp+DU), and 12 patients with AIG showing CAG-A topographically. We compared the prevalence of H. pylori infection, and the levels of gastrin and pepsinogen (PG) in the serum of patients with GCT with those of patients with Hp+GU, or Hp+DU, and AIG. We also investigated the histological characteristics of the tumor and the gastric corpus mucosa in the GCT patients. The levels of serum gastrin and PG I and II were measured using an RIA kit. In all five (100%) patients with GCT, H. pylori infection was present, without any evidence of AIG or ZES. The serum levels of gastrin in the GCT patients were higher than those in either Hp+GU or Hp+DU patients and lower than those in the AIG patients. In contrast, serum PG I levels and the PG I/II ratio were lower in the GCT group than in the Hp+GU or Hp+DU groups. Histologically, all GCTs were ECL cell tumors and peritumoral corporal mucosal atrophy was observed in four of the five patients with GCT. In conclusions, H. pylori infection and hypergastrinemia were found in the patients with GCT without AIG. This finding suggests that H. pylori infection may induce corporal mucosal atrophy and hypergastrinemia that can produce a GCT with time.

Size-dependent expression of cyclooxygenase-2 in sporadic colorectal adenomas relative to adenomas in patients with familial adenomatous polyposis.

Several studies have indicated that administration of non‐steroidal anti‐inflammatory drugs (NSAID) to patients with familial adenomatous polyposis (FAP) results in a regression of colorectal adenomas through inhibition of cyclooxygenase‐2 (COX‐2). It is thought that sporadic colorectal adenomas might also be useful targets for the chemoprevention of colorectal cancer, but a marked effect of NSAID on the regression of sporadic adenomas has not been observed. We investigated the immunohistochemical expression of COX‐2 in sporadic tubular adenomas (n = 100) from 63 patients and in tubular adenomas (n = 121) from 12 patients with FAP, in order to determine if chemoprevention might be more successful in sporadic adenomas once they have reached a certain size. COX‐2 scores were significantly lower (P < 0.0001) in small (< 5 mm in diameter) adenomas than in large (≥ 5 mm) adenomas. This was observed in both sporadic cases and in cases involving patients with FAP. With regard to small (< 5 mm) adenomas, significantly higher (P = 0.02) COX‐2 scores were obtained in adenomas resulting from FAP than sporadic adenomas. The variation in COX‐2 expression observed among sporadic adenomas of different sizes should be taken into account when making decisions regarding attempts at chemoprevention using NSAID. Sporadic adenomas 5 mm or larger with upregulated COX‐2 expression are potentially useful targets for the antiproliferative effects of NSAID.

Bidirectional gastric differentiation in cellular mucin phenotype (foveolar and pyloric) in serrated adenoma and hyperplastic polyp of the colorectum

This study examined whether gastric pyloric gland‐type mucin is expressed in serrated adenoma (SA) and in hyperplastic polyp (HP) of the colorectum, and whether cellular position‐based gastric differentiation is observed in these lesions as previously hypothesized. Immunostaining was performed for MUC6 and α‐linked GlcNAc residue (pyloric gland‐type mucin markers), human gastric mucin (HGM; foveolar‐type mucin marker) and Ki‐67 (proliferating cell marker) for 31 SA, 22 HP, 21 traditional tubular adenoma (TA) and 20 hyperplastic nodule (HN). MUC6 showed varying expression in SA, 22/31 (71.0%); HP, 15/22 (68.2%); TA, 2/21 (9.5%); and HN, 0/20 (0%) with significantly higher frequencies in SA and HP compared to those in TA and HN. The α‐linked GlcNAc residue was found only in SA (3/31, 9.7%) and in HP (2/22, 9.1%). In SA and HP, HGM was typically expressed in the entire crypt length, but some reduction in expression was shown in the basal crypt portion below the proliferative zone. MUC6 and α‐linked GlcNAc residues were expressed in the basal crypt portion below or below and including proliferative zone. These data demonstrate that SA and HP show bidirectional gastric (foveolar and pyloric gland) differentiation with respect to mucin cellular phenotype and the potential for cellular position‐based differentiation, which mimics the gastric antral mucosa.

Predictive Factor of Local Recurrence after Balloon-Occluded TACE with Miriplatin (MPT) in Hepatocellular Carcinoma

Background Miriplatin (MPT) is a novel platinum complex used in TACE that shows promise for the treatment of hepatocellular carcinoma (HCC). However, rapid washout has been reported in some cases. Therefore, various methods of administration with MPT have been attempted to increase its therapeutic efficacy. One hopeful method is balloon-occluded TACE (B-TACE), but the therapeutic efficacy of B-TACE with MPT has not been evaluated. Aim To investigate the treatment outcomes and factors involved in local recurrence after B-TACE with MPT in HCC. Methods This study included 51 patients (55 nodules) with HCC lesions equal or less than 5 cm in diameter who underwent B-TACE with MPT between January 2012 and June 2013. Local recurrence after B-TACE with MPT and factors associated with local recurrence were evaluated. Results The overall local recurrence rate was 11.1% at 6 months and 26.2% at 12 months. The local recurrence rate did differ significantly depending on CT values immediately after B-TACE with MPT. Multivariate analysis also showed that the CT value after B-TACE with MPT was the only factor related to local recurrence after B-TACE. Conclusions B-TACE with MPT achieves relatively good local control of HCC. The plain CT value immediately after B-TACE with MPT is a predictive factor for local recurrence. In patients with unsatisfactory CT values, locoregional therapy or additional treatment is required.

Leukocytapheresis is effective in inducing but not in maintaining remission in ulcerative colitis.

Goals and Background: Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by dense infiltration of lymphocytes, plasma cells, neutrophils, and monocyte-macrophages into the colonic mucosa. Leukocytapheresis is a procedure for selectively removing white blood cells from withdrawn blood. It is used for the treatment of several autoimmune diseases. This study was performed to evaluate the effectiveness of leukocytapheresis for inducing and maintaining remission in corticosteroid-resistant UC, as compared with corticosteroid-responsive UC. Study: Forty-five patients with active UC who were treated with a dose of 1 mg/kg per day or more of prednisolone given systemically for at least 2 weeks were evaluated. Twenty patients (6 males, 14 females) in whom improvement was induced only by high doses of prednisolone were allocated as the corticosteroid-responsive group. The other 25 patients (11 males, 14 females) who did not respond to the above-mentioned dose of prednisolone therapy were allocated as the corticosteroid-resistant group and received leukocytapheresis therapy once a week for 5 weeks. Of patients who had a remission, the corticosteroid-responsive group continued to have the conventional therapy and the corticosteroid-resistant group were given leukocytapheresis once every 4 weeks for at least 2 years as maintenance therapy. Results: Remission was induced by 5 weeks of leukocytapheresis in 23 of the 25 (92%) patients with corticosteroid-resistant active UC. The number of days required to achieve remission of UC was fewer in patients who received leukocytapheresis than in those who did not. Follow-up study of the patients who had remission showed similar relapse rates at 2 years in the patients who received leukocytapheresis and those given high doses of prednisolone alone. Conclusions: Leukocytapheresis is an effective treatment of acute corticosteroid-resistant UC but does not prevent the recurrence of UC.

Comparison of cyclo-oxygenase 2 expression in colorectal serrated adenomas to expression in tubular adenomas and hyperplastic polyps

Background and aims: Serrated adenoma (SA) is a newly defined category of colorectal neoplasia that contains features of both adenoma and hyperplastic polyp, and has two patterns, hyperplastic and cerebriform patterns. Since cyclo-oxygenase 2 (COX-2) has been found upregulated in colorectal cancers and adenomas, we examined whether either the hyperplastic or cerebriform pattern of SA has the potential for tumor progression and should be a target for clinical treatment. Patients and methods: An immunohistochemical scoring system was used to compare COX-2 expression in colorectal SAs (n=79), tubular adenomas (n=66), and hyperplastic polyps (n=21). Results: COX-2 scores were significantly higher in SA of the cerebriform pattern (n=44) than in SA of the hyperplastic pattern (n=35). There was no difference in COX-2 scores between SA of the cerebriform pattern and tubular adenoma. In SA accompanied by hyperplastic polyp (n=26) the hyperplastic components expressed little COX-2, the same as traditional hyperplastic polyps. COX-2 expression in the SA component was similar to that in pure SA. Conclusion: SA of the cerebriform pattern should be treated similarly as traditional tubular adenomas. COX-2 induction may additionally be involved in progression from hyperplastic polyp to SA.

Interleukin 6-producing malignant mesothelioma

SummarySystemic amyloidosis of the amyloid A (AA) type, is occasionally associated with various neoplasms, but the cause is still unclear. We obtained interleukin 6 (IL-6)-producing cells designated YO from a primary culture of a malignant peritoneal mesothelioma of epithelial type obtained from a 62-year-old woman. Post mortem examination revealed that the patient had systemic amyloidosis of the AA type. The supernatant media of YO cells, as well as recombinant human IL-6, successfully induced nonneoplastic liver cells to produce serum AA (SAA). Our data suggest that IL-6 produced by the tumor cells may have played an important role in the paraneoplastic syndrome of AA amyloidosis in this patient.