Real-World Data on the Incidence of Macrovascular Complications in Japanese Patients with Type 2 Diabetes: The Sitagliptin Registration Type 2 Diabetes-Juntendo Collaborating Project.

INTRODUCTION: Type 2 diabetes is associated with vascular complications that deteriorate the quality of life and decrease the life expectancy of individuals. We previously reported the efficacy of sitagliptin for glucose control in patients with type 2 diabetes in the Sitagliptin Registration Type 2 Diabetes-Juntendo Collaborating Project (SPIRITS-J). Through the results of the SPIRITS-J study, we expected that optimal comprehensive management of type 2 diabetes according to current clinical practice guidelines in addition to achieving individualized glycemic goals would reduce macrovascular complications and all-cause mortality in Japan. The aim of this study was to evaluate this hypothesis. METHODS: We investigated the clinical outcomes prospectively in the extended SPIRITS-J study and compared these to previous Japanese cohort studies in the era before widespread use of guidelines. The primary clinical outcome was a composite of myocardial infarction (MI), stroke, and all-cause mortality. RESULTS: Mean duration of follow-up was 3.5 ± 1.3 years. The crude incidence of the primary outcome per 1000 person-years was 13.9 (non-fatal MI 1.44, non-fatal stroke 4.22, all-cause mortality 8.79 per 1000 person-years, respectively). It is noteworthy that the incidence of MI in the SPIRITS-J study was very much lower than that in a previous Japanese cohort study. In multivariate analysis, both the history of coronary artery disease and low-density lipoprotein cholesterol (LDL-C) were independently associated with incidence of primary clinical outcome. CONCLUSION: The extended SPIRITS-J study demonstrated that optimal comprehensive management in patients with type 2 diabetes according to the recent practice guidelines has succeeded in preventing macrovascular complications in Japan. This study suggests that more intensive LDL-C-lowering therapy is important for further prevention of macrovascular complications even in Japanese patients with type 2 diabetes (UMIN 000004121).

Significance of Serum p53 Antibody as a Tumor Marker in Colorectal Cancer.

OBJECTIVE: We examined serum anti-p53 antibodies (S-p53Ab) in colorectal cancer. Specifically, we retrospectively investigated the use of S-p53Ab as a prognostic marker after surgery for colorectal cancer. MATERIALS AND METHODS: The levels of S-p53Ab, carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9) were measured in 160 colorectal cancer patients who underwent surgical treatment. The rate of postoperative change (RPC) in the S-p53Ab titer was calculated as [subsequent antibody titer-lowest titer]/lowest titer. RESULTS: A relationship between recurrence and RPC in the S-p53Ab titer was not observed in patients who tested negative for S-p53Ab preoperatively. In addition, no patients, who tested negative for S-p53Ab preoperatively, tested positive for S-p53Ab at the follow-up after surgery. Of the patients who tested positive for S-p53Ab preoperatively, those recurrences had a significantly higher RPC compared with those who did not (p < 0.001). CONCLUSIONS: Although S-p53Ab is not a significant tumor marker in patients who test negative preoperatively, increases in the S-p53Ab titer should be continuously monitored and measured in patients who are positive for this antibody preoperatively, regardless of whether they later test negative.

A Simple Algorithm for Predicting Bacteremia Using Food Consumption and Shaking Chills: A Prospective Observational Study.

BACKGROUND: Predicting the presence of true bacteremia based on clinical examination is unreliable. OBJECTIVE: We aimed to construct a simple algorithm for predicting true bacteremia by using food consumption and shaking chills. DESIGN: A prospective multicenter observational study. SETTING: Three hospital centers in a large Japanese city. PARTICIPANTS: In total, 1,943 hospitalized patients aged 14 to 96 years who underwent blood culture acquisitions between April 2013 and August 2014 were enrolled. Patients with anorexia-inducing conditions were excluded. INTERVENTIONS: We assessed the patients' oral food intake based on the meal immediately prior to the blood culture with definition as "normal food consumption" when >80% of a meal was consumed and "poor food consumption" when <80% was consumed. We also concurrently evaluated for a history of shaking chills. MEASUREMENTS: We calculated the statistical characteristics of food consumption and shaking chills for the presence of true bacteremia, and subsequently built the algorithm by using recursive partitioning analysis. RESULTS: Among 1,943 patients, 223 cases were true bacteremia. Among patients with normal food consumption, without shaking chills, the incidence of true bacteremia was 2.4% (13/552). Among patients with poor food consumption and shaking chills, the incidence of true bacteremia was 47.7% (51/107). The presence of poor food consumption had a sensitivity of 93.7% (95% confidence interval [CI], 89.4%-97.9%) for true bacteremia, and the absence of poor food consumption (ie, normal food consumption) had a negative likelihood ratio (LR) of 0.18 (95% CI, 0.17-0.19) for excluding true bacteremia, respectively. Conversely, the presence of the shaking chills had a specificity of 95.1% (95% CI, 90.7%-99.4%) and a positive LR of 4.78 (95% CI, 4.56-5.00) for true bacteremia. CONCLUSION: A 2-item screening checklist for food consumption and shaking chills had excellent statistical properties as a brief screening instrument for predicting true bacteremia.

Relationship between alcohol metabolism and chemotherapy-induced emetic events in breast cancer patients.

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) can negatively affect quality of life and treatment compliance in breast cancer patients. Habitual alcohol consumption reportedly shows an inverse correlation with CINV, though the underlying mechanism is unknown. Acetaldehyde dehydrogenase 2 (ALDH2), one of the two ALDH isozymes, is reportedly the major factor among several genetic polymorphisms possibly affecting alcohol metabolism. More than 40% of Japanese have ALDH2 mutations, while almost all Westerners have the wild type. We hypothesized that ALDH2 polymorphism status might relate to the metabolism of emetic chemotherapeutic drugs. Relationships among habitual alcohol consumption, ALDH2 polymorphisms, and CINV in Japanese breast cancer patients given adjuvant chemotherapy containing high-emetic drugs were, thus, investigated. METHODS: We enrolled 81 women, between 20 and 55 years of age, who had been diagnosed with primary breast cancer and received (neo-) adjuvant chemotherapy at our institution. ALDH2 genotypes were analyzed employing the smart amplification process in peripheral blood samples. RESULTS: The wild type (ALDH2*1/*1), heterozygote (ALDH2*1/*2), and mutant homozygote (ALDH2*2/*2) genotypes were found in 53, 44, and 3% of patients, respectively. Complete response, i.e., no vomiting without rescue anti-emetics, was more frequent in patients who habitually consumed alcohol than in those who did not (p = 0.036). This trend remained only in ALDH2 heterozygotes when patients were categorized according to ALDH2 genotype. Logistic regression analysis revealed alcohol intake to be an independent predictive factor for complete response (p = 0.013). CONCLUSIONS: Our results revealed habitual alcohol intake to be related to a lower CINV incidence. The impact of alcohol intake on CINV in patients with ALDH2 polymorphisms merits further investigation.

Predictive factors for mortality in elderly Japanese patients with severe microscopic polyangiitis: A retrospective single-center study.

PURPOSE: To determine mortality and its predictive factors in elderly Japanese patients with severe microscopic polyangiitis (MPA). METHOD: This retrospective single-center study determined the mortality of 52 patients with MPA who were admitted to our geriatric medical center from 2002 to 2014. The variables at baseline, including patient demographics, clinical characteristics, and treatment, were analyzed for their association with mortality. RESULT: Mean age at onset of MPA was 73.2 years, and the one-year survival rate was 65.9%. Relapse was observed in 32.7%. Among variables at diagnosis, age, cardiomyopathy, central nervous system (CNS) involvement, alveolar hemorrhage, disease severity, the 1996 Five-Factor Score (FFS), and the 2009 FFS were associated with mortality in univariate analysis. Cardiomyopathy, CNS involvement, age >65 years, disease severity, Birmingham Vasculitis Activity Score, the 1996 FFS, and the 2009 FFS were associated with relapse-free survival in univariate analysis. CONCLUSION: We investigated mortality and relapse-free survival and their predictive factors in elderly Japanese patients with severe MPA. Age, disease severity, the 1996 FFS, and the 2009 FFS at diagnosis were prognostic factors for both mortality and relapse-free survival.

Activated Caspase 3 Expression in Remnant Disease After Neoadjuvant Chemotherapy May Predict Outcomes of Breast Cancer Patients.

BACKGROUND: A number of studies have indicated that patients obtaining a pathological complete response (pCR) from neoadjuvant chemotherapy (NAC) have a good prognosis; however, prognostic factors for non-pCR patients are not yet well-established. By examining remnant cancer in non-pCR patients, the expression of cleaved Caspase 3 (Casp3), an activated apoptotic marker, was immunohistochemically investigated to determine whether this protein has the potential to serve as a novel marker for predicting patient outcomes. METHODS: We investigated 218 patients with invasive breast cancer who received NAC and underwent surgery during the 2006 through 2008 period at our institution. Following surgery, standard adjuvant endocrine therapy was administered if a tumor was hormone receptor-positive. Casp3 was evaluated in remnant cancer based on the number of positive cells in five high-power fields. RESULTS: pCR was obtained in 49 patients, and 50 of the 169 non-pCR patients developed recurrences during the median 82-month observation period. We found large tumor size, lymph node involvement, lymph vessel invasion, estrogen receptor-negative, progesterone receptor-negative, high Ki67 and high Casp3 expression to be factors related to tumor recurrence. A logistic regression model revealed that lymph node involvement, as well as high Ki67 and Casp3, to be factors independently predicting recurrence, while lymph vessel invasion and high Ki67 expression were found to be related to breast cancer mortality. CONCLUSIONS: Patients with remnant cancer showing high Casp3 expression had poor outcomes. Our results showed that Casp3 is a potential prognostic marker for non-pCR patients.

Menstrual cycle could affect Ki67 expression in estrogen receptor-positive breast cancer patients.

BACKGROUND: Ki67 is a potent prognostic marker for determining systemic treatment of patients with hormone receptor-positive breast cancer. However, evaluation of Ki67 expression can be difficult, due mostly to its heterogeneity. The Ki67 expression level, which indicates that a cell is undergoing division (cell cycle), rises when proliferation activity increases. Thus, Ki67 expression might be affected by hormonal stimuli. We hypothesised that Ki67 expression level might change during the menstrual cycle. We examined pairs of biopsy and surgical specimens from individual patients to evaluate this hypothesis. METHODS: First, the effects of estradiol on Ki67 expression in breast cancer cell lines were examined employing immunocytochemistry and Western blotting. Next, differences in Ki67 expression between biopsy and surgical specimens from 131 patients with estrogen receptor-positive tumours were retrospectively examined. RESULTS: In vitro experiments showed Ki67 expression in estrogen receptor-positive cancer cells to be dependent on estradiol stimulation. Ki67 expression was higher in biopsy samples collected in the luteal phase than in those from other phases. When biopsy and surgical samples were obtained at different times during the menstrual cycle in the same individual, there were differences in Ki67 expression between these samples. Those collected in the luteal phase showed higher Ki67 expression than samples obtained during other phases (p<0.01). CONCLUSIONS: Ki67 expression varied in the same patients according to menstrual cycle phase. Our results suggest that Ki67 expression in estrogen receptor-positive breast cancer should be carefully assessed bearing in mind the patient's menstrual cycle, since the interpretation of expression could affect treatment decisions.

Circulating TNF receptors 1 and 2 are associated with the severity of renal interstitial fibrosis in IgA nephropathy.

The current study aimed to examine whether the levels of TNF receptors 1 and 2 (TNFR1 and TNFR2) in serum and urine were associated with other markers of kidney injury and renal histological findings, including TNFR expression, in IgA nephropathy (IgAN). The levels of the parameters of interest were measured by immunoassay in 106 biopsy-proven IgAN patients using samples obtained immediately before renal biopsy and in 34 healthy subjects. Renal histological findings were evaluated using immunohistochemistry. The levels of serum TNFRs were higher in IgAN patients than in healthy subjects. The levels of both TNFRs in serum or urine were strongly correlated with each other (r > 0.9). Serum TNFR levels were positively correlated with the urinary protein to creatinine ratio (UPCR) and four markers of tubular damage of interest (N-acetyl-ß-D-glucosaminidase [NAG], ß2 microglobulin [ß2m], liver-type fatty acid-binding protein [L-FABP], and kidney injury molecule-1 [KIM-1]) and negatively correlated with estimated glomerular filtration rate (eGFR). Patients in the highest tertile of serum TNFR levels showed more severe renal interstitial fibrosis than did those in the lowest or second tertiles. The tubulointerstitial TNFR2-, but not TNFR1-, positive area was significantly correlated with the serum levels of TNFRs and eGFR. Stepwise multiple regression analysis revealed that elevated serum TNFR1 or TNFR2 levels were a significant determinant of renal interstitial fibrosis after adjusting for eGFR, UPCR, and other markers of tubular damage. In conclusion, elevated serum TNFR levels were significantly associated with the severity of renal interstitial fibrosis in IgAN patients. However, the source of TNFRs in serum and urine remains unclear.

Efficacy and safety of sitagliptin in Japanese patients with type 2 diabetes.

BACKGROUND: The aim of this study was to investigate the clinical efficacy and safety of sitagliptin in Japanese patients with type 2 diabetes. METHODS: A total of 3,247 subjects treated with sitagliptin were retrospectively recruited. Glucose parameters were collected at baseline, and 1, 3 and 6 months after initiation of sitagliptin. In addition, we explored factors that can be used to predict sitagliptin-induced reduction in HbA1c using linear mixed effect model. Factors associated with hypoglycemic events were examined by logistic analyses. RESULTS: We analyzed the available data of 3,201 subjects (1,287 females). Treatment of sitagliptin significantly reduced HbA1c level from 7.44±1.20% at baseline to 6.73±0.99% at 6 months (P < 0.0001). Linear mixed effect model analyses demonstrated that reduction of HbA1c was associated with higher baseline HbA1c level, younger age, lower BMI and sitagliptin monotherapy. During this study, 82 cases of hypoglycemia were recorded. Logistic analyses indicated that hypoglycemic events were more frequent in female patients, and patients with low BMI, long history of type 2 diabetes, high HbA1c and on combination therapy experienced. Other adverse events were rare and mild. CONCLUSIONS: Sitagliptin is effective for diabetic management and generally well tolerated in Japanese patients with type 2 diabetes. This trial was registered with UMIN (no. 000004121).

The incidence of and risk factors for developing atypical femoral fractures in Japan.

The long-term treatment with anti-resorptive drugs for osteoporotic patients is suggested to be associated with an increase in atypical femoral fractures (AFFs). However, their incidence, patient characteristics, and risk factors have not been fully elucidated especially in Asian countries. This retrospective observational cohort study found fourteen AFFs in ten patients (four bilateral fractures) among 2,238 hip and femoral shaft fractures treated in our associated hospitals between 2005 and 2010; this incidence (0.63%) was similar to Caucasians. Of the ten patients with AFFs, nine (90%) and six (60%) were using bisphosphonates (BPs) and glucocorticoids (GCs), respectively, compared to 14.3 and 8.6% for patients with typical femoral fractures who were using these agents. As comorbid conditions, five patients had collagen disease (CD) and two had diabetes. A fracture location-, age- and gender-matched (1:3) case-control study revealed that administration of BPs, GCs, and suffering from collagen disease (CD) were significant risk factors for developing AFFs [odds ratios 36.0 (95% confidence intervals 3.8-342.2), 13.0 (2.3-74.1) and 9.0 (1.6-50.3), respectively]. Interestingly, all of the patients with atypical subtrochanteric femoral fractures, defined as those within 5 cm of the lesser trochanter, were taking GCs due to CD, and the age of these patients (average of 54.8 years) was significantly younger than those with atypical diaphyseal femoral fractures (average of 77.2 years, p < 0.05). In conclusion, the incidence of AFFs in the Japanese population was similar to that of Caucasians, and taking BPs and GCs and suffering from CD were risk factors for developing AFFs.

Serum levels of galactose-deficient immunoglobulin (Ig) A1 and related immune complex are associated with disease activity of IgA nephropathy.

BACKGROUND: The primary abnormal manifestation in immunoglobulin A nephropathy (IgAN) is recurring bouts of hematuria with or without proteinuria. Although immunohistochemical analysis of renal biopsy tissue remains the gold standard not only for diagnosis but also for evaluating the activity of IgAN, new sensitive and reasonably specific noninvasive tests are emerging to guide therapeutic strategy applicable to all stages of IgAN. The present study examined serum levels of galactose-deficient IgA1 (Gd-IgA1) and its immune complex (IgA/IgG-IC) as noninvasive markers for the disease activity. METHODS: We enrolled 50 IgAN patients (male 40 %, median age 37 years) showing complete or partial clinical remission after steroid pulse therapy with tonsillectomy (TSP) whose clinical data and serum could be followed up for 3-5 years. RESULTS: Cross-sectional analysis revealed that the degree of hematuria and proteinuria were significantly associated with levels of Gd-IgA1 and levels of IgA/IgG-IC. Longitudinal analysis further showed that from the group of 44 patients with heavy hematuria before TSP, 31 patients showed complete disappearance of hematuria (group A), but the remaining patients did not (group B). Although the levels of Gd-IgA1 and IgA/IgG-IC in the two groups before TSP were similar, percentage decrease of Gd-IgA1 and IgA/IgG-IC levels in group A was significantly higher than in group B. CONCLUSION: Disease activity of IgAN assessed by hematuria and proteinuria correlated with serum levels and changes of Gd-IgA1 and IgA/IgG-IC. These new noninvasive disease activity markers can be useful for future activity scoring system and guiding therapeutic approaches.

Relationship between 24-h Holter recordings and clinical outcomes in patients with permanent atrial fibrillation.

OBJECTIVES: This study aimed to test the hypothesis that the range of 24-h total heart beats (24 h-tHB) correlates with cardiac outcomes (cardiac death and incidence of hospitalization with heart failure) in patients with permanent atrial fibrillation (AF). METHODS AND RESULTS: We divided 252 consecutive outpatients with permanent AF into 4 groups according to their 24 h-tHB and examined clinical outcomes. Initial 24 h-tHB at enrollment was significantly associated with patient characteristics including age, sex, presence of structural heart diseases, and left ventricular ejection fraction (EF). The cumulative incidence of heart failure was high in the lowest 24 h-tHB group compared with other groups and significantly different from the highest one (23.9% vs. 7.2% at 5 years, p=0.0074). Multivariate analysis showed that 24 h-tHB<100,000 was associated with cardiac events [hazard ratio, 2.45; 95% confidence interval (CI), 1.09-5.49; p=0.03), along with structural heart disease (hazard ratio, 9.81; 95% CI, 3.34-28.83; p=0.0001) and EF (hazard ratio, 0.97; 95% CI, 0.94-0.99; p=0.002). CONCLUSIONS: Surprisingly, low but not high heart rate was significantly associated with higher incidence of heart failure in Japanese patients. This finding should be further evaluated in future prospective studies.

Clonality status of multifocal lung adenocarcinomas based on the mutation patterns of EGFR and K-ras.

PURPOSE: The purpose of this study is to clarify the clonality status of multifocal lung adenocarcinomas based on the mutation patterns of epidermal growth factor receptor (EGFR) and K-ras. METHODS: We analyzed 82 multifocal lung adenocarcinomas from 36 patients who underwent surgical resection. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissue and analyzed for EGFR and K-ras mutations. We determined the clonality status of multifocal lung adenocarcinomas based on the mutation patterns of EGFR and K-ras. The actuarial survival time was estimated and the prognostic factors were evaluated for 31 patients with synchronous multifocal lung adenocarcinomas. RESULTS: EGFR and K-ras mutations were detected in 36 (44%) and 19 (23%) of the 82 tumors, respectively. EGFR mutations had occurred randomly in 20 (91%) of the 22 patients with at least one EGFR mutated tumor. K-ras mutations had occurred randomly in 14 (93%) of the 15 patients with at least one K-ras mutated tumor. Combining the results for the EGFR and K-ras mutation patterns, the clonality status of multifocal lung adenocarcinomas could be determined in 30 (83%) of the 36 patients. No statistically significant difference in the actuarial survival of the patient subgroups stratified according to the clonality status, which was based on the presence of EGFR and K-ras mutations, was observed. CONCLUSIONS: Both EGFR and K-ras mutations frequently occur randomly in multifocal lung adenocarcinomas. Combined mutation pattern analyses of EGFR and K-ras may be useful for making decisions regarding treatment strategies for patients with multifocal lung adenocarcinomas.

Tonsillar TLR9 expression and efficacy of tonsillectomy with steroid pulse therapy in IgA nephropathy patients.

BACKGROUND: Patients with IgA nephropathy (IgAN) often show aggravation of renal injury with macroscopic hematuria after mucosal infections, especially tonsillitis. We previously demonstrated the important role of mucosal Toll-like receptor 9 (TLR9) activation in the pathogenesis of murine IgAN. Moreover, a single nucleotide polymorphism (SNP) in TLR9 was significantly associated with pathological severity in human IgAN. In this study, we investigated correlations between tonsillar TLR9 messenger RNA expression, TLR9 SNP genotypes and clinical outcomes following tonsillectomy with steroid pulse therapy (SPT) in IgAN patients. METHODS: Tonsillar TLR9 expression was examined in IgAN (n = 49) and control (n = 15) patients who had undergone tonsillectomy. The correlations between tonsillar TLR9 expression level, TLR9 SNP genotypes and clinical outcomes after tonsillectomy with SPT were examined. RESULTS: High expression of tonsillar TLR9 was observed in ∼23% of IgAN patients. These patients showed stronger and earlier remission of hematuria and proteinuria than those with low TLR9 expression. Patients with the TT genotype of TLR9 SNP (rs352140) had more severe renal damage than those with other genotypes. Patients whose serum IgA level decreased more than average after tonsillectomy (large ΔIgA) showed higher cumulative remission rates of proteinuria than patients with a smaller decrease in these levels (small ΔIgA). CT/CC genotypes were more dominant and tonsillar TLR9 expressions significantly higher in large ΔIgA patients than in small ΔIgA patients. CONCLUSION: In IgAN patients, expression levels of tonsillar TLR9 and TLR9 SNP were well correlated with the efficacy of tonsillectomy with SPT.

Risk factors for morbidity after pulmonary resection for lung cancer in younger and elderly patients.

The aim of this study was to evaluate the perioperative morbidity, mortality, and risk factors for morbidity after lung cancer resection in younger and elderly patients. This study retrospectively reviewed 1073 patients with non-small cell lung cancers (NSCLC) who underwent pulmonary resection. The risk factors for morbidity were analyzed independently in groups of 664 younger (<70 years) patients and 409 elderly (≥ 70 years) patients. Co-morbidities, such as hypertension, ischemic heart disease, and renal insufficiency were more frequently observed in the elderly group in comparison to the younger group. However, there were no statistical differences in the rates of overall morbidity and 30-day mortality between the younger and elderly groups (36% vs. 42% and 0.3% vs. 0.5%, respectively). Multivariate analyses revealed the risk factors for morbidity to be % forced expiratory volume in 1 s (FEV(1)), the extent of pulmonary resection and tumor histology in the younger group, and smoking, hypertension, renal insufficiency and % diffusing capacity of the lung to carbon monoxide (DLCO) in the elderly group, respectively. In conclusion, the rate of morbidity and mortality in elderly patients were similar to those observed in younger patients. However, perioperative management should be cautiously performed while taking into account the risk factors for morbidity especially in elderly patients because they frequently have various co-morbidities.

Reliability study on the Japanese version of the Clinician's Interview-Based Impression of Change.

The Japanese version of the Clinician's Interview-Based Impression of Change (CIBIC-plus J) is a semistructured interview format including a 7-point Likert type scale for the Clinician's Global Impression of Change. It comprises subscales of DAD for ADL, Behave-AD for behavioral and psychiatric symptoms and MENFIS for cognitive and emotional impairment. DAD and Behave-AD are used for caregivers and MENFIS for both caregivers and patients. The objective of this study was to examine the interrater reliability of the CIBIC-plus J by the videotape method. Twenty videotaped patients including 13 real and 7 virtual patients were independently assessed by 11 raters. The kappa coefficient from the full set of data of 20 patients and 11 raters was 0.453, and from the limited data of 13 real patients, 0.383. By permitting one-point disagreements on the 7-point scale or by collapsing it into the 3-point scale (improved, no change, or worsened), kappa improved to 0.894 and 0.731, or 0.734 and 0.504, respectively. From these results, it was concluded that the reliability of a 7-point Clinician's Global Impression of Change was halfway, i.e., neither sufficient nor insufficient. However, if one-point disagreements or collapsing into 3-point scale are allowable, the CIBIC-plus J will be sufficiently reliable.