Toll-like receptor 2 -196 to 174del polymorphism influences the susceptibility of Japanese people to gastric cancer

Toll like receptors (TLR) play important roles in the signaling of many pathogen-related molecules and endogenous proteins associated with immune activation. The –196 to –174del polymorphism affects the TLR2 gene and alters its promoter activity. We investigated the influence of the TLR2 –196 to –174del polymorphism on the occurrence of non-cardiac gastric cancer (NCGC) in a Japanese population. The study was carried out with 289 patients with NCGC, 309 non-cancer patients with abdominal discomfort and 146 healthy controls. The –196 to –174del TLR2 polymorphism was investigated using the allele-specific polymerase chain reaction method in all of the subjects. The –196 to –174del/del genotype of TLR2 showed a significantly higher frequency in NCGC patients than in healthy controls (adjusted odds ratio [OR] = 6.06; 95% confidence interval [CI] = 1.86–19.72). Similarly, the frequency of the –196 to –174del/del genotype was significantly higher among NCGC patients than in non-cancer patients (adjusted OR = 2.02; 95% CI = 1.22–3.34). The same genotype was associated with an increased risk of both intestinal (OR = 2.00, 95% CI = 1.12–3.60) and diffuse-type (OR = 2.05; 95% CI = 1.11–3.79) histopathology. There were no significant associations between TLR2 genotypes and tumor stage and anatomical location. Our data suggest that the –196 to –174del/del genotype of TLR2 may increase the risk of gastric cancer in the Japanese population. ( Cancer Sci 2007; 98: 1790–1794)     

Geriatric nutritional risk index as an easy-to-use assessment tool for nutritional status in hepatocellular carcinoma treated with atezolizumab plus bevacizumab

Aim

The present study focused on Geriatric Nutritional Risk Index (GNRI), which is based on bodyweight and serum albumin, and known as an easy-to-use nutritional assessment tool in clinical settings, to elucidate the prognostic predictive ability of GNRI in patients treated with atezolizumab plus bevacizumab (Atez/Bev) for hepatocellular carcinoma (HCC).

Methods

A total of 525 HCC patients treated with Atez/Bev, based on their classification of unsuitable status for curative treatments and/or transarterial catheter chemoembolization, were enrolled (Child–Pugh A:B:C = 484:40:1, Barcelona Clinic Liver Cancer stage 0:A:B:C:D = 7:25:192:283:18). Prognosis was evaluated retrospectively using GNRI.

Results

Atez/Bev was used in 338 of the present cohort as first-line systemic chemotherapy (64.4%). Median progression-free survival based on GNRI indicating normal, mild decline, moderate decline, and severe decline was 8.3, 6.7, 5.3, and 2.4 months, respectively, whereas median overall survival was 21.4, 17.0, 11.5. and 7.3 months, respectively (both p < 0.001). The concordance index (c-index) values of GNRI for predicting prognosis (progression-free survival/overall survival) were superior to those of Child–Pugh class and albumin-bilirubin grade (0.574/0.632 vs. 0.527/0.570 vs. 0.565/0.629). As a subanalysis, muscle volume loss was observed in 37.5% of 256 patients with computed tomography data available. Along with GNRI decline, frequency of muscle volume loss became progressively larger (normal vs. mild vs. moderate vs. severe = 17.6% vs. 29.2% vs. 41.2% vs. 57.9%, p < 0.001), and a GNRI value of 97.8 was predictive of its occurrence (AUC 0.715, 95% CI 0.649–0.781; specificity/sensitivity = 0.644/0.688).

Conclusion

These findings indicate that GNRI is an effective nutritional prognostic tool for predicting prognosis and muscle volume loss complication in HCC patients treated with Atez/Bev.     

Remission induction therapy containing rituximab markedly improved the outcome of untreated mature B cell lymphoma

Many controlled clinical trials have proven that rituximab improves the clinical outcome of patients with mature B cell lymphoma. This study was conducted to assess the contribution of rituximab in the actual clinical practice. Patients with newly diagnosed mature B cell lymphoma treated at 20 National Hospital Organization hospitals from January 2000 to December 2004 were consecutively registered. Rituximab was approved in September 2002 for indolent B cell lymphoma and in September 2003 for aggressive B cell lymphoma in Japan. The patients were divided into two groups depending on whether they received induction therapy containing rituximab. The endpoint was to evaluate the rituximab benefit based on 2-year progression-free survival (PFS) and 2-year overall survival (OS). A total 1126 patients received chemotherapies. Of these, 762 were diagnosed as diffuse large B cell lymphoma (DLBCL) and 215 as follicular lymphoma (FL). PFS and OS were markedly improved in the rituximab group compared with the non-rituximab group in patients with DLBCL (both P < 0.001) and in patients with FL (P < 0.001 and P = 0.003 respectively). Rituximab, when used for remission induction therapy, significantly improved the clinical outcome of the mature B cell lymphoma patient in actual clinical practice.     

Treatment of T-Cell lymphoma

T-cell lymphoma composes 25% of lymphoid malignancies in Japan. Peripheral T-cell lymphoma (PTCL) unspecified and adult T-cell leukemia/lymphoma (ATLL) are major subtypes of T-cell lymphoma. The Japan Clinical Oncology Group (JCOG) has conducted 7 clinical trials for aggressive non-Hodgkin's lymphoma (NHL) including T-cell lymphoma. JCOG trials revealed that patients with ATLL had an extremely poor prognosis as compared with other peripheral T-cell lymphomas. A second generation combination chemotherapy including pentostatin (JCOG9109) could not improve the prognosis of patients with aggressive ATLL with the median survival time (MST) of 7.4 months. Subsequently, JCOG developed a new alternating multi-agent chemotherapy including MCNU and carboplatin with prophyractic use of G-CSF, resulting 35% of CR rate and 31% of 2-year OS. Considering the poor prognosis of aggressive ATLL patients, allogeneic stem cell transplantation seems to be another promising approach for a cure of the disease. New active agents such as chimeric monoclonal anti-CCR antibody are under developing for PTCL and ATLL.     

Assessment of ablative margin after radiofrequency ablation for hepatocellular carcinoma; comparison between magnetic resonance imaging with ferucarbotran and enhanced CT with iodized oil deposition

Background and purpose

Our aim was to investigate whether magnetic resonance imaging (MRI) with ferucarbotran administered prior to radiofrequency ablation could accurately assess ablative margin when compared with enhanced computed tomography (CT) with iodized oil marking.

Materials and methods

We enrolled 27 patients with 32 hepatocellular carcinomas in which iodized oil deposits were visible throughout the nodule after transcatheter arterial chemoembolization. For these nodules, radiofrequency ablation was performed after ferucarbotran administration. We then performed T2-weighted MRI after 1 week and enhanced CT after 1 month. T2-weighted MRI demonstrated the ablative margin as a low-intensity rim. We classified the margin into three grades; margin (+): high-intensity area with a continuous low-intensity rim; margin zero: high-intensity area with a discontinuous low-intensity rim; and margin (−): high-intensity area extending beyond the low-intensity rim.

Results

In 28 (86%) of 32 nodules, there was agreement between MRI and CT. The overall agreement between for the two modalities in the assessment of ablative margin was good (κ = 0.759, 95% confidence interval: 0.480–1.000, p < 0.001). In four nodules, ablative margins on MRI were underestimated by one grade compared with CT.

Conclusion

MRI using ferucarbotran is less invasive and allows earlier assessment than CT. The MRI technique performed similarly to enhanced CT with iodized oil marking in evaluating the ablative margin after radiofrequency ablation.     

A possible relationship of natural killer T cells with humoral immune response to 23-valent pneumococcal polysaccharide vaccine in clinical settings

Pneumococcal polysaccharide vaccine (PPV), a type-2 thymus-independent antigen, induces the activation of B cells by directly triggering their antigen receptors. Although this type of antigen generally does not undergo class switching from IgM to IgG, PPV has been known to induce IgG2 in vaccinated subjects, which suggests the possible involvement of certain innate immune lymphocytes supporting the activation of B cells and their class switching. In the present study, we addressed the possibility that natural killer (NK) T cells are involved in Ab production caused by PPV. We measured serum levels of IgG against pneumococcal capsular polysaccharides and the numbers of CD4(+), CD8(+) and CD4(-)CD8(-) double negative (DN) invariant NKT (iNKT) cells and CD3(+)CD56(+) NKT cells in the peripheral blood before and after PPV injection. IgG was increased after PPV injection, peaking at 4 weeks after injection in serotypes 6B, 19F and 23F and at 3 months in serotype 14. Low responders, whose serum concentrations of IgG peaked at less than double their original levels, constituted 16%, 13%, 13% and 16% of vaccinated subjects with regard to serotypes 6B, 14, 19F and 23F, respectively. A significant positive correlation was detected between an increase in DN iNKT cells and the elevation of anti-serotype 14 IgG; in serotype 19F, DN iNKT cells were more markedly increased in responders than in low responders. These results suggest that DN iNKT cells may be involved in IgG production caused by vaccination against pneumococcal capsular polysaccharides.     

Deoxycoformycin-containing combination chemotherapy for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study (JCOG9109)

Aggressive adult T-cell leukemia-lymphoma (ATL) generally has a very poor prognosis. Deoxycoformycin (DCF, pentostatin), an inhibitor of adenosine deaminase, has shown promising therapeutic efficacy for ATL. To develop a new effective therapy against aggressive ATL, we carried out a multicenter phase II study of DCF-containing combination chemotherapy. Sixty-two previously untreated patients with ATL (34, 21, and 7 patients with diseases of the acute, lymphoma, and unfavorable chronic types, respectively) were enrolled, but 2 were ineligible because they were judged to be favorable chronic types. A regimen of 1 mg/m2 vincristine intravenously on days 1 and 8, 40 mg/m2 doxorubicin intravenously on day 1, 100 mg/m2 etoposide intravenously on days 1 through 3, 40 mg/m2 prednisolone orally on days 1 and 2, and 5 mg/m2 DCF intravenously on days 8, 15, and 22 was administered every 28 days for 10 cycles unless disease progression or toxic complications occurred. Fifty-two percent of 60 eligible patients responded (95% confidence interval [CI], 38%-65%), with 17 patients (28%) achieving a complete response (CR) (95% CI, 17%-41%) and 14 achieving a partial response. The CR rate was inferior to those of both the previous Japan Clinical Oncology Group (JCOG) study (JCOG8701, 43%), a 9-drug combination chemotherapy of the second generation, and the subsequent JCOG9303 study (35%), a granulocyte colony-stimulating factor-supported, dose-intensified, 9-drug regimen. The median survival time of the 60 eligible patients in JCOG9109 was 7.4 months, and the estimated 2-year survival rate was 15.5%; these results were identical with those of JCOG8701 but inferior to those of JCOG9303. Grade 4 neutropenia and infection of grade 3 or greater were frequent (67% and 22%, respectively), and treatment-related death was observed in 4 patients (7%), septicemia in 2, and cytomegalovirus pneumonia in 2. We conclude that DCF-containing combination chemotherapy is not a promising regimen against aggressive ATL.     

ORMDL3/GSDMB genotype as a risk factor for early-onset adult asthma is linked to total serum IgE levels but not to allergic sensitization

BackgroundAn orosomucoid-like 3 (ORMDL3)/gasdermin B (GSDMB) gene locus on chromosome 17q is consistently associated with childhood-onset asthma, which is highly atopic. As some evidence suggests the relationship between asthma and allergic sensitization reflects asthma patient susceptibility to augmented IgE responses driven by common environmental allergens rather than an increased asthma risk after allergen exposure, we aimed to determine any relationships between this locus region and childhood-onset adult asthma with regard to serum total IgE levels or allergic sensitization.MethodsWe conducted a case–control association study using three independent Japanese populations (3869 total adults) and analyzed the ORs for association of rs7216389, an expression quantitative trait locus for ORMDL3/GSDMB, with adult asthma according to onset age. Additionally, associations between the rs7216389 genotype and total serum IgE levels or allergic sensitization was examined.ResultsRs7216389 was associated with both childhood-onset adult asthma (OR for asthmatic patients afflicted at the age of 10 years or younger = 1.61, p = 0.00021) and asthmatic patients with higher levels of total serum IgE (OR for asthmatic patients with IgE ≥1000IU/mL = 1.55, p = 0.0033). In both healthy controls and in the combined healthy and asthmatic individuals, rs7216389 was correlated with increased total serum IgE levels (p < 0.0005), but not allergic sensitization (p > 0.1).ConclusionsORMDL3/GSDMB is an important susceptibility gene for childhood-onset adult asthma in Japanese populations and this association is linked to elevated total serum IgE levels but not to allergic sensitization.     

COMT gene val158met polymorphism in patients with dyspeptic symptoms

BACKGROUND/AIMS: The role of genetics in the susceptibility to functional dyspepsia (FD) is unclear. Catechol-O-methyltransferase (COMT) has been an important enzyme in brain gut axis and pain sensitivity. Polymorphism in codon 158 of the COMT gene influences its activity. This study aimed to clarify the association between COMT polymorphism and dyspepsia in a Japanese population. METHODOLOGY: 91 dyspeptics and 94 non-dyspeptic subjects enrolled in this study. Dyspeptic symptoms were divided into 9 categories. COMT gene val158met polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The frequency of Met carriers was lower in over all dyspeptics than healthy control but the difference was not significant (OR=0.79, 95%CI=0.44-1.41) However, when the interaction between age, gender, H. pylori infection status and the number of COMT 158Met alleles was assessed using ANOVA, a slight interaction with gender + age + COMT polymorphism was found in relation to overall dyspeptics (p=0.0476) No correlation was found between COMT polymorphism and any of 9 symptoms. CONCLUSIONS: The data suggest that the COMT genotype seems to influence the susceptibility of dyspepsia when it interacts with gender and age. The role of genetics in the development of dyspepsia needs to further evaluation.