Akira Tari

Long-term clinical outcome of gastric MALT lymphoma after eradication of Helicobacter pylori: a multicentre cohort follow-up study of 420 patients in Japan

Objective A multicentre cohort follow-up study of a large number of patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma was conducted to elucidate the long-term outcome of the disease after Helicobacter pylori eradication. Methods 420 patients with gastric low-grade MALT lymphoma who had undergone successful H pylori eradication and been followed up for at least 3 years were registered from 21 participating institutes. Responders to treatment were defined as patients whose post-treatment biopsies showed complete histological response (ChR) or probable minimal residual disease (pMRD). Treatment failure was defined as the status of progressive disease or lymphoma relapse after ChR/pMRD. Results 323 patients (77%) responded to H pylori eradication. A logistic regression analysis showed that absence of H pylori, submucosal invasion determined by endoscopic ultrasonography and t(11;18)/API2-MALT1 were independent predictors of resistance to H pylori eradication. During the follow-up periods ranging from 3.0 to 14.6 years (mean 6.5 years, median 6.04 years), the disease relapsed in 10 of 323 responders (3.1%) while progressive disease was found in 27 of 97 non-responders (27%). Thus, 37 of 420 patients (8.8%) were regarded as treatment failures. Of these 37 patients, transformation into diffuse large B cell lymphoma occurred in nine patients. Among the non-responders and relapsed patients, 17 patients were subjected to a ‘watch and wait’ strategy while 90 patients underwent second-line treatments including radiotherapy (n=49), chemotherapy (n=26), surgical resection (n=6), chemoradiotherapy (n=5), antibiotic treatment (n=2), rituximab monotherapy (n=1) or endoscopic resection (n=1). Probabilities of freedom from treatment failure, overall survival and event-free survival after 10 years were 90%, 95% and 86%, respectively. Cox multivariate analysis revealed endoscopic non-superficial type to be an independent prognostic factor for adverse freedom from treatment failure, overall survival and event-free survival. Conclusions The excellent long-term outcome of gastric MALT lymphoma after H pylori eradication was confirmed by this large-scale follow-up study.

Primary gastrointestinal follicular lymphoma involving the duodenal second portion is a distinct entity: A multicenter, retrospective analysis in Japan

We conducted a multicenter, retrospective study to determine the anatomical distribution and prognostic factors of gastrointestinal (GI) follicular lymphoma (FL). This study included 125 patients with stage I and II1 GI–FL. Of the 125 patients, the small intestine was examined in 70 patients, with double‐balloon endoscopy and/or capsule endoscopy. The most frequently involved GI–FL site was the duodenal second portion (DSP) (81%), followed by the jejunum (40%); 85% of patients with involvement of the DSP also had jejunal or ileal lesions. The absence of abdominal symptoms and macroscopic appearance of multiple nodules were significantly present in the DSP‐positive group. During a median follow up of 40 months, six patients showed disease progression. Patients with involvement of the DSP had better progression‐free survival (PFS) than those without such involvement (P = 0.001). A multivariate analysis revealed that male sex, the presence of abdominal symptoms, and negative involvement of the DSP were independently associated with poor PFS. In conclusion, most patients with GI–FL have duodenal lesions associated with multiple jejunal or ileal lesions. Gastrointestinal follicular lymphomas involving the DSP might be a distinct entity showing a favorable clinical course. (Cancer Sci 2011; 102: 1532–1536)

Duodenal and nodal follicular lymphomas are distinct: the former lacks activation-induced cytidine deaminase and follicular dendritic cells despite ongoing somatic hypermutations

Although most follicular lymphomas are believed to be of nodal origin, they sometimes originate from the duodenum. We have reported that the latter differ from nodal follicular lymphomas in having lower clinical stages and uniformly low histological grades, along with variable region of immunoglobulin heavy chain gene (VH) usage that is more similar to mucosa-associated lymphoid tissue (MALT) lymphomas. Little is known, however, about whether they possess other characteristics of nodal follicular lymphomas, particularly ongoing mutations with follicular dendritic cells. We examined 17 cases for which PCR identified the monoclonal bands of the immunoglobulin gene. The duodenal cases showed ongoing mutations, but they lacked activation-induced cytidine deaminase (AID) expression, a statistically significant difference from the nodal cases (P<0.001), and their follicular dendritic cell networks were disrupted. Moreover, not only were VH deviations observed but also they used very restricted VH genes. Although the mechanisms of ongoing mutation without AID and follicular dendritic cell were not clarified, restricted VH usage strongly suggested that antigen stimulation was involved, and that was similar to MALT lymphomas. In conclusion, duodenal follicular lymphomas were shown to be unique, in that they had ongoing hypermutations such as nodal cases, but the mechanisms involved in the hypermutation were quite different; furthermore, restricted VH usage suggested a strong similarity to the antigen-dependent origin of MALT lymphomas.

Rebamipide, an Antiulcer Drug, Prevents DSS-Induced Colitis Formation in Rats

This study was conducted to investigate the efficacy of rebamipide against experimental colitis induced by dextran sulfate sodium (DSS) in a rat model of inflammatory bowel disease. Experimental colitis was induced in male Wistar rats by oral administration of 3% DSS solution for one week. The rats were provided with standard diet containing 0.105% rebamipide (160 mg/kg/day) for 1 week. In rats treated with rebamipide, clinical (body weight loss, bloody diarrhea, reduced physical activity, severe anemia, shortened colonic length, and perianal injury) and histopathological (pathological lesion score) findings of DSS colitis were significantly less than in rats with DSS colitis not treated with rebamipide. Rebamipide thus inhibited the induction of colitis. Rebamipide significantly reduced concentrations of both interleukin-1α and GRO/CINC-1 (IL-8-like substance) and cell infiltrates in colonic wall, in parallel with decreased activity of myeloperoxidase. It also reduced expression of IL-1 mRNA but did not influence expression of GRO/CINC-1 mRNA. The attenuation of colonic indices of colitis by rebamipide in this rat model suggests that this drug might have beneficial effects in the treatment of human ulcerative colitis. These effects of rebamipide are attributable to its inhibition of inflammatory cytokine-mediated granulocyte (neutrophil) infiltration into the colon.

Gastric Acid Secretion, Serum Pepsinogen I, and Serum Gastrin in Japanese with Gastric Hyperplastic Polyps or Polypoid-Type Early Gastric Carcinoma

We determined the maximum secretion of gastric acid and the fasting serum levels of pepsinogen I and gastrin in Japanese patients with gastric hyperplastic polyps or polypoid-type early gastric carcinoma, comparing those findings with observations in control subjects. Both the maximum acid secretion and fasting levels of serum pepsinogen I were significantly lower in the patients with gastric hyperplastic polyps or polypoid-type early gastric carcinoma than in the controls. Fasting serum gastrin levels were significantly higher in the patients with gastric hyperplastic polyps than in the other two groups of subjects. These data demonstrated that the combination of hypochlorhydria, a low level of pepsinogen I, and hypergastrinemia (type-A gastritis) was common in the patients with gastric hyperplastic polyps, whereas hypochlorhydria and a low pepsinogen I without hypergastrinemia (type-B gastritis) were common in those with polypoid-type early gastric carcinoma.

Duodenal follicular lymphoma lacks AID but expresses BACH2 and has memory B-cell characteristics

We have reported previously that duodenal follicular lymphoma (FL) is distinct from nodal FL and showed more resemblance to mucosa-associated lymphoid tissue lymphoma, and that FL frequently involved the duodenal second portion. In the present study, we examined duodenal FLs and gastric/colonic FLs to clarify the clinicopathological and immunological differences between the tumor types. We analyzed 8 samples of gastric FL, 17 of duodenal ones, and 5 of colonic/rectal ones, and characterized them by immunohistochemistry, immunogenotyping, and histology. Gastric and colonic FLs presented in submucosal to subserosal areas, whereas duodenal ones presented in the mucosal to submucosal layers. Immunohistochemical analysis revealed that duodenal FLs exhibited the following phenotypes: CD10 (+), B-cell lymphoma 2 (BCL-2) (+), BCL-6 (+), activation-induced cytidine deaminase (AID) (−), BACH2 (+), CD27 (+), MUM-1 (−), Blimp-1 (−), and loose CD21 network (duodenal pattern). Gastric/colonic FLs exhibited the following phenotypes: CD10 (+), BCL-2 (+), BCL-6 (+), AID (+), BACH2 (+), CD27 (−), MUM-1 (−), Blimp-1 (−), and a dense CD21 network (nodal pattern). Expression of AID and CD27 in lymphoma cells and the CD21 network pattern were considerably different between duodenal FLs and gastric/colonic ones. Moreover, in situ hybridization revealed that, in the duodenal FLs, BACH2 was expressed at the periphery of the tumor follicle and tumor villi. The number of immunoglobulin heavy-chain variable domains VH4 and VH5 were higher in duodenal follicular lymphomoas than in gastric FLs. The lymphoma cells of duodenal FLs are different from those of gastric/colonic FLs, and duodenal FL is distinct even within the gastrointestinal tract. Somatic hypermutation in immunoglobulin genes and CD27 expression are hallmarks of memory B cells. We suggest that duodenal FL cells are in the memory B-cell stage, and require BACH2 instead of AID for ongoing mutation.

Serum soluble interleukin‐2 receptor level and immunophenotype are prognostic factors for patients with diffuse large B‐cell lymphoma

Diffuse large B‐cell lymphoma is the most common form of non‐Hodgkin lymphoma. Although many studies have attempted to identify prognostic factors, most have focused on conventionally treated patients. The influence of anti‐CD20 antibody (rituximab) should be considered now. We evaluated the prognostic significance of serum soluble interleukin‐2 receptor levels and germinal center B‐cell‐like or non‐germinal center B‐cell like subgroups in 80 patients with diffuse large B‐cell lymphoma, who had been treated with rituximab. Serum soluble interleukin‐2 receptor levels ranged from 322 to 39900 U/mL (median 1365 U/mL). Sixteen (20%) were germinal center B‐cell‐like subgroups, and the remainder (80%) non‐germinal center B‐cell‐like. Survival analysis associated lower serum soluble interleukin‐2 receptor level and germinal center B‐cell‐like phenotype with better overall survival (P = 0.015), whereas multivariate analysis, including International Prognostic Index factors, revealed that only higher performance status score and higher serum lactate dehydrogenase levels significantly affected survival. However, serum soluble interleukin‐2 receptor levels were elevated in patients with higher International Prognostic Index scores as well as in the non‐germinal center B‐cell‐like subgroup. Serum soluble interleukin‐2 receptor levels, International Prognostic Index, and subphenotypes were strongly correlated with each other. Our study showed that soluble interleukin‐2 receptor is quite useful and may serve as a substitute for the International Prognostic Index, especially for patients undergoing treatment. Moreover, the differentiation between the germinal center B‐cell‐like and non‐germinal center B‐cell‐like phenotypes is also useful for predicting patients with diffuse large B‐cell lymphoma, even among those treated with rituximab. (Cancer Sci 2009; 100: 1255–1260)

Duodenal follicular lymphoma: comprehensive gene expression analysis with insights into pathogenesis.

Follicular lymphoma (FL) of the gastrointestinal tract, particularly duodenal follicular lymphoma (DFL), is a rare variant of FL with indolent clinical behavior, and this disease is included in the 2008 World Health Organization classification system. In contrast to nodal follicular lymphoma (NFL), DFL occurs most frequently in the second part of the duodenum, lacks follicular dendritic cell meshworks and has memory B‐cell characteristics. However, its molecular pathogenesis is still unclear. In the present study, we examined 10 DFL, 18 NFL and 10 gastric MALT lymphoma samples using gene expression analysis. Quantitative RT‐PCR experiments and immunohistochemical analysis for 72 formalin‐fixed, paraffin‐embedded tissues from an independent series, including 32 DFL, 19 gastric MALT lymphoma and 27 NFL samples, were performed for validation of microarray data. Gene expression profiles of the three lymphoma types were compared using 2918 differentially expressed genes (DEG) and results suggested that DFL shares characteristics of MALT lymphoma. Among these DEG, CCL20 and MAdCAM‐1 were upregulated in DFL and MALT but downregulated in NFL. In contrast, protocadherin gamma subfamily genes were upregulated in DFL and NFL. Quantitative RT‐PCR and immunohistochemical studies demonstrated concordant results. Double immunofluorescence studies revealed that CCL20 and CCR6 were co‐expressed in both DFL and MALT. We hypothesize that increased expression of CCL20 and MAdCAM‐1 and co‐expression of CCL20 and CCR6 may play an important role in tumorigenesis.

Clinical Features of Gastrointestinal Follicular Lymphoma: Comparison with Nodal Follicular Lymphoma and Gastrointestinal MALT Lymphoma

We retrospectively compared the clinicopathological features of primary intestinal follicular lymphomas (FL-GIs), nodal follicular lymphomas (FL-LNs) and gastrointestinal MALT lymphomas (MALT-GIs), and investigated the distribution and the endoscopic appearances of FL-GI to evaluate the effectiveness of treatment modality. The subjects were 28 FL-GI patients, 135 FL-LN patients and 70 MALT-GI patients. In FL-LNs the clinical stage III–IV was 83%, while in FL-GIs clinical stage I–II was 68%. In MALT-GIs clinical stage I–II was 87%. The overall survival was significantly better in MALT-GI patients than in FL-LN patients. All FL-GI patients were alive at the time of evaluation. Regarding the histological grade (WHO), grade 1 was 81% in FL-GI, whereas in FL-LN grade 2 was 28% and grade 3 was 11%. The Follicular Lymphoma International Prognostic Index was low in 61% of FL-GIs, while in FL-LNs it was equally distributed to low, intermediate and high, suggesting that the prognosis is better in FL-GIs than in FL-LNs. The clinicopathological studies revealed the FL-GI has intermediate characteristics between FL-LN and MALT-GI. We recommend a ‘watch-and-wait’ policy or chemotherapy with rituximab for the therapy of FL-GIs because the lesions are often located in broader areas from the lower duodenum to the small intestine.

β-Endorphinlike immunoreactivity and somatostatinlike immunoreactivity in normal gastric mucosa, muscle layer, and adenocarcinoma

beta-Endorphinlike immunoreactivity and somatostatinlike immunoreactivity were detected in the mucosa and muscle layer of normal gastric antrum and corpus and in moderately differentiated adenocarcinoma derived from the antral mucosa. The concentration of beta-endorphinlike immunoreactivity in the normal gastric tissues was 4-15 pmol/g wet wt tissue; this value varied from 9.64 to 241.39 pmol/g wet wt tissue (81.38 +/- 37.82 pmol/g wet wt tissue) in adenocarcinomas. The concentration of somatostatinlike immunoreactivity was 18-25 pmol/g wet wt tissue in normal gastric mucosa, whereas it was 1-2 pmol/g wet wt tissue in adenocarcinomas. Gel exclusion chromatography of beta-endorphinlike immunoreactivity revealed two peaks corresponding to beta-endorphin and beta-lipotropin. In normal mucosa and in the whole layer of antrum, the major peak was eluted near the position of beta-lipotropin, and the minor broad peak was eluted near the position of beta-endorphin. In contrast, in adenocarcinoma, beta-endorphinlike immunoreactivity was eluted broadly at the position of beta-endorphin and the other smaller peak was at the position of beta-lipotropin. Gel exculsion chromatography of somatostatinlike immunoreactivity also showed different patterns between antral mucosa and adenocarcinoma. This study revealed the presence of the opioid peptide, beta-endorphinlike immunoreactivity, not only in normal gastric tissue but also in adenocarcinomas with highly increased concentration and different elution patterns in combination with decreased concentration of somatostatinlike immunoreactivity.