Chihaya Koriyama

Isolated annular dilation does not usually cause important functional mitral regurgitation: comparison between patients with lone atrial fibrillation and those with idiopathic or ischemic cardiomyopathy.

OBJECTIVES We sought to test whether isolated mitral annular (MA) dilation can cause important functional mitral regurgitation (MR). BACKGROUND Mitral annular dilation has been considered a primary cause of functional MR. Patients with functional MR, however, usually have both MA dilation and left ventricular (LV) dilation and dysfunction. Lone atrial fibrillation (AF) can potentially cause isolated MA dilation, offering a unique opportunity to relate MA dilation to leaflet function. METHODS Mid-systolic MA area, MR fraction, LV volumes and papillary muscle (PM) leaflet tethering length were compared by echocardiography among 18 control subjects, 25 patients with lone AF and 24 patients with idiopathic or ischemic cardiomyopathy (ICM). RESULTS Patients with lone AF had a normal LV size and function but MA dilation (isolated MA dialtion) significant and comparable to that of patients with ICM (MA AREA: 8.0 +/- 1.2 vs. 11.6 +/- 2.3 vs. 12.5 +/- 2.9 cm(2) [control vs. lone AF vs. ICM]; p < 0.001 for both lone AF and ICM). However, patients with lone AF had only modest MR, compared with that of patients with ICM (MR fraction: -3 +/- 8% vs. 3 +/- 9% vs. 36 +/- 25%; p < 0.001 for patients with ICM). Multivariate analysis identified PM tethering length, not MA dilation, as an independent primary contributor to MR. CONCLUSIONS Isolated annular dilation does not usually cause moderate or severe MR. Important functional MR also depends on LV dilation and dysfunction, leading to an altered force balance on the leaflets, which impairs coaptation.

Mechanism of Persistent Ischemic Mitral Regurgitation After Annuloplasty Importance of Augmented Posterior Mitral Leaflet Tethering

Background—We hypothesized that surgical annuloplasty for ischemic mitral regurgitation (MR) that displaces the posterior annulus anteriorly can potentially augment posterior leaflet (PML) tethering, leading to persistent MR. Relationships between leaflet configurations and persistent ischemic MR after the annuloplasty were investigated. Methods and Results—In 31 patients with surgical annuloplasty for ischemic MR and 20 controls, posterior and apical displacement of the leaflet coaptation, the anterior leaflet (AML) and PML tethering angles relative to the line connecting annuli, coaptation length (CL), and the MR grade were quantified before and early after surgery in echocardiographic left ventricular long-axis views. Six of the 31 patients showed persistent MR despite annuloplasty. Compared with patients without persistent MR, those with MR showed no improvement in the left ventricular ejection fraction and systolic volume, similar reduction in the annular area, significant increase in posterior displacement of the coaptation (P<0.01), no improvement in AML tethering, greater worsening in PML tethering (P<0.01), and no increase in the CL. All tethering variables were significantly correlated with both preoperative and postoperative MR in univariate analysis, and reduced CL was the primary independent determinant of both preoperative and postoperative MR. Although increased AML tethering was the primary determinant of the preoperative CL (r2=0.46, P<0.0001), increased PML tethering was the primary determinant afterward (r2=0.60, P<0.0001). Conclusion—Although tethering of both leaflets is the major determinant of ischemic MR before surgical annuloplasty, both leaflets tethering but with predominant and augmented PML tethering is related to persistent ischemic MR after the annnuloplasty.

Improved survival of gastric cancer with tumour Epstein–Barr virus positivity: an international pooled analysis

Background and objective About 9% of gastric carcinomas have Epstein–Barr virus (EBV) in the tumour cells, but it is unclear whether viral presence influences clinical progression. We therefore examined a large multicentre case series for the association of tumour EBV status with survival after gastric cancer diagnosis, accounting for surgical stage and other prognostic factors. Methods We combined individual-level data on 4599 gastric cancer patients diagnosed between 1976 and 2010 from 13 studies in Asia (n=8), Europe (n=3), and Latin America (n=2). EBV positivity of tumours was assessed by in situ hybridisation. Mortality HRs for EBV positivity were estimated by Cox regression models stratified by study, adjusted for distributions of sex (71% male), age (mean 58 years), stage (52% tumour-node-metastasis stages III or IV), tumour histology (49% poorly differentiated, 57% Lauren intestinal-type), anatomic subsite (70% non-cardia) and year of diagnosis. Variations by study and continent were assessed using study-specific HRs for EBV positivity. Results During median 3.0 years follow-up, 49% of patients died. Stage was strongly predictive of mortality, with unadjusted HRs (vs stage I) of 3.1 for stage II, 8.1 for stage III and 13.2 for stage IV. Tumour EBV positivity was 8.2% overall and inversely associated with stage (adjusted OR: 0.79 per unit change). Adjusted for stage and other confounders, EBV positivity was associated with lower mortality (HR, 0.72; 95% CI 0.61 to 0.86), with low heterogeneity among the study populations (p=0.2). The association did not significantly vary across patient or tumour characteristics. There was no significant variation among the three continent-specific HRs (p=0.4). Conclusions Our findings suggest that tumour EBV positivity is an additional prognostic indicator in gastric cancer. Further studies are warranted to identify the mechanisms underlying this protective association.

Epstein-Barr virus associated gastric carcinoma: Epidemiological and clinicopathological features

In this paper, the roles of Epstein‐Barr virus (EBV) in gastric carcinogenesis are discussed, reviewing mainly epidemiological and clinicopathological studies. About 10% of gastric carcinomas harbor clonal EBV. LMP1, an important EBV oncoprotein, is only rarely expressed in EBV‐associated gastric carcinoma (EBV‐GC) while EBV‐encoded small RNA is expressed in almost every EBV‐GC cell, suggesting its importance for developing and maintaining this carcinoma. In addition, the hypermethylation‐driven suppressor gene downregulation, frequently observed in EBV‐GC, appears to give a selective advantage for carcinoma cells. EBV reactivation is suspected to precede EBV‐GC development since antibodies against EBV‐related antigens, including EBV capsid antigen (VCA), are elevated in prediagnostic sera. Interestingly, the average anti‐VCA immunoglobulin G antibody titer in EBV‐GC patients was significantly higher among men than among women, whereas EBV‐negative GC cases did not show such a sex difference. A higher frequency of human leucocyte antigen‐DR11 in EBV‐GCs suggests that major histocompatibility complex‐restricted EBV nuclear antigen 1 epitope recognition may enhance EBV reactivation. EBV infection of gastric cells by lymphocytes with reactivated EBV is suspected to be the first step of EBV‐GC development. Male predominance of EBV‐GC suggests the involvement of lifestyles and occupational factors common among men. The predominance of EBV with XhoI+ and BamHI type i polymorphisms in EBV‐GC in Latin America suggests a possibility of some EBV oncogene expressions being affected by EBV polymorphism. The lack of such predominance in Asian countries, however, indicates an interaction between EBV polymorphism and the host response. In conclusion, further studies are necessary to examine the interaction between EBV infection, its polymorphisms, environmental factors, and genetic backgrounds. (Cancer Sci 2008; 99: 195 –201)

Wnt‐5a signaling is correlated with infiltrative activity in human glioma by inducing cellular migration and MMP‐2

Wnts are secreted ligands that consist of 19 members in humans, regulate cell proliferation, differentiation, motility and fate in many stages including the embryonic stage and tumorigenesis. Wnts bind to cell surface receptors named Frizzleds and LRPs, and transduce their signals through β‐catenin‐dependent and ‐independent intracellular pathways. Gliomas are one of the most common intracranial tumors. Gliomas exhibit a progression associated with widespread infiltration into surrounding neuronal tissues. However, the molecular mechanisms that stimulate the invasion of glioma cells are not fully understood. We established two cell lines from human glioma cases and analyzed the expression of all Wnt and Frizzled members in these cell lines and other well‐known glioma cell lines by real‐time PCR study. The mRNA of Wnt‐5a and ‐7b and Frizzled‐2, ‐6 and ‐7 were overexpressed in glioma cells. The elevation of Wnt‐5a expression was most remarkable. Although Wnt‐5a is reported to have oncogenic and antioncogenic activity in several cancers, the role of Wnt‐5a signaling in human glioma cells remains unclear. Immunohistochemical study also revealed high expression of Wnt‐5a in 26 (79%) of 33 human glioma cases. The positivity of Wnt‐5a expression was correlated with the clinical grade. Knockdown of Wnt‐5a expression suppressed migration, invasion and expression of matrix metalloproteinase‐2 of glioma cells. Reciprocally, treatment with purified Wnt‐5a ligand resulted in stimulation of cell migration and invasion. MMP‐2 inhibitor suppressed the Wnt‐5a‐dependent invasion of U251 cells. These results suggested that Wnt‐5a is not only a prognostic factor but also a therapeutic target molecule in gliomas for preventing tumor cell infiltration. (Cancer Sci 2011; 102: 540–548)

FDG PET/CT and diffusion-weighted imaging for breast cancer: prognostic value of maximum standardized uptake values and apparent diffusion coefficient values of the primary lesion

PurposeTo correlate both primary lesion 18F-fluorodeoxyglucose (FDG) maximum standardized uptake value (SUVmax) and diffusion-weighted imaging (DWI) apparent diffusion coefficient (ADC) with clinicopathological prognostic factors and compare the prognostic value of these indexes in breast cancer.MethodsThe study population consisted of 44 patients with 44 breast cancers visible on both preoperative FDG PET/CT and DWI images. The breast cancers included 9 ductal carcinoma in situ (DCIS) and 35 invasive ductal carcinomas (IDC). The relationships between both SUVmax and ADC and clinicopathological prognostic factors were evaluated by univariate and multivariate regression analysis and the degree of correlation was determined by Spearman’s rank test. The patients were divided into a better prognosis group (n = 24) and a worse prognosis group (n = 20) based upon invasiveness (DCIS or IDC) and upon their prognostic group (good, moderate or poor) determined from the modified Nottingham prognostic index. Their prognostic values were examined by receiver operating characteristic analysis.ResultsBoth SUVmax and ADC were significantly associated (p<0.05) with histological grade (independently), nodal status and vascular invasion. Significant associations were also noted between SUVmax and tumour size (independently), oestrogen receptor status and human epidermal growth factor receptor-2 status, and between ADC and invasiveness. SUVmax and ADC were negatively correlated (ρ=−0.486, p = 0.001) and positively and negatively associated with increasing of histological grade, respectively. The threshold values for predicting a worse prognosis were ≥4.2 for SUVmax (with a sensitivity, specificity and accuracy of 80%, 75% and 77%, respectively) and ≤0.98 for ADC (with a sensitivity, specificity and accuracy of 90%, 67% and 77%, respectively).ConclusionSUVmax and ADC correlated with several of pathological prognostic factors and both indexes may have the same potential for predicting the prognosis of breast cancer.

Determinants of Epstein-Barr virus-positive gastric cancer: an international pooled analysis

Background:Meta-analyses of the published literature indicate that about 9% of gastric cancers contain Epstein-Barr virus (EBV), with consistent and significant differences by sex and anatomic subsite. This study aimed to identify additional determinants of EBV positivity and their joint effects.Methods:From 15 international populations with consistent laboratory testing for EBV, we pooled individual-level data for 5081 gastric cancer cases including information on age, sex, subsite, histologic type, diagnostic stage, geographic region, and period of diagnosis. First, we combined population-specific EBV prevalence estimates using random effects meta-analysis. We then aggregated individual-level data to estimate odds ratios of EBV positivity in relation to all variables, accounting for within-population clustering.Results:In unadjusted analyses, EBV positivity was significantly higher in males, young subjects, non-antral subsites, diffuse-type histology, and in studies from the Americas. Multivariable analyses confirmed significant associations with histology and region. Sex interacted with age (P=0.003) and subsite (P=0.002) such that male predominance decreased with age for both subsites. The positivity of EBV was not significantly associated with either stage or time period.Conclusion:Aggregating individual-level data provides additional information over meta-analyses. Distinguishing histologic and geographic features as well as interactions among age, sex, and subsite further support classification of EBV-associated gastric cancer as a distinct aetiologic entity.

Epstein-Barr virus in gastric carcinoma is associated with location in the cardia and with a diffuse histology: A study in one area of Chile

Epstein‐Barr virus (EBV) has been associated with the most common form of stomach neoplasms, the gastric carcinoma (GC). The presence of EBV‐encoded small RNAtype‐1 (EBER‐1), a marker for EBV infection was analyzed by in situ hybridization (ISH) in 185 formalin‐fixed and paraffin‐embedded cases of GC from a high risk region. We found 31 (16.8%) EBV‐positive cases with no relationship to age. Although male predominance (19% in males and 12.5% in females) was observed, the gender difference did not achieve statistical significance. Odds ratio (OR) for cardia location was 5.4 (95% CI 1.7–17.3) when antrum was used as referent category and the effects of gender and age were taken into account. The proportion of EBV‐positive cases in diffuse histology was higher than intestinal type (OR = 4.8, 95% CI = 2.0–11.1). Our findings are contrary to a previously accepted hypothesis, that high‐risk countries for GC have low rates of EBV‐associated GC. In addition, our findings regarding location, histology and weak male predominance are different from what has been described in Asian and European countries, but similar to those described in Mexico and Mexican descendants living in the U.S. suggesting unique characteristics of EBV‐associated GC in Latin‐America.

Functional mitral stenosis after surgical annuloplasty for ischemic mitral regurgitation: Importance of subvalvular tethering in the mechanism and dynamic deterioration during exertion

OBJECTIVE Diastolic subvalvular mitral leaflet tethering by left ventricular remodeling that restricts leaflet opening in the presence of annular size reduction by surgery for ischemic mitral regurgitation potentially causes functional mitral stenosis in the absence of organic leaflet lesions. Exercise, known to worsen systolic tethering and ischemic mitral regurgitation, might also dynamically exacerbate such mitral stenosis by increasing tethering. This study evaluates the mechanism and response of such mitral stenosis to exercise. METHODS We measured the diastolic mitral valve area, annular area, and peak and mean transmitral pressure gradient by echocardiography in 20 healthy individuals and 31 patients who underwent surgical annuloplasty for ischemic mitral regurgitation. RESULTS Although the mitral valve area and annular area did not significantly differ in healthy individuals (4.7 +/- 0.6 cm(2) vs 5.2 +/- 0.6 cm(2), not significant), mitral valve area was significantly smaller than the annular area in patients after annuloplasty (1.6 +/- 0.2 cm(2) vs 3.3 +/- 0.5 cm(2), P < .01). The mitral valve area was less than 1.5 cm(2) only after the surgery (P < .01) and was significantly correlated with restricted leaflet opening (r(2) = 0.74, P < .001), left ventricular dilatation (r(2) = 0.17, P < .05), and New York Heart Association functional class (P < .05). Exercise stress echocardiography of 12 patients demonstrated dynamic worsening in functional mitral stenosis (mitral valve area: 2.0 +/- 0.5 cm(2) to 1.4 +/- 0.2 cm(2), P < .01; mean pressure gradient: 1.5 +/- 0.9 mm Hg to 6.0 +/- 2.2 mm Hg, P < .01). CONCLUSIONS Persistent subvalvular leaflet tethering in the presence of annular size reduction by surgery in ischemic mitral regurgitation frequently causes functional mitral stenosis at the leaflet tip level, which is related to heart failure symptoms and can be dynamic with significant exercise-induced worsening.

Clinical implication of HLA class I expression in breast cancer

BackgroundHuman leukocyte antigen (HLA)-class I molecules on tumor cells have been regarded as crucial sites where cytotoxic T lymphocytes (CTL) can recognize tumor-specific antigens and are strongly associated with anti-tumor activity. However, the clinical impact of HLA class I expression in breast cancer has not been clarified.MethodsA total of 212 breast cancer patients who received curative surgery from 1993 to 2003 were enrolled in the current study. HLA class I expression was examined immunohistochemically using an anti-HLA class I monoclonal antibody. The correlation between HLA class I positivity and clinical factors was analyzed.ResultsThe downregulation of HLA class I expression in breast cancer was observed in 69 patients (32.5%). HLA class I downregulation was significantly associated with nodal involvement (p < 0.05), TNM stage (p < 0.05), lymphatic invasion (p < 0.01), and venous invasion (p < 0.05). Patients with preserved HLA class I had significantly better disease-free interval (DFI) than those with loss of HLA class I (p < 0.05). However, in multivariable analysis, HLA class I was not selected as one of the independent prognostic factors of disease-free interval.ConclusionThe examination of HLA class I expression is useful for the prediction of tumor progression and recurrent risk of breast cancer via the antitumor immune system.