Mari Kogo

Concordant DNA Methylation in Synchronous Colorectal Carcinomas

Epigenetic changes have been proposed as mediators of the field defect in colorectal carcinogenesis, which has implications for risk assessment and cancer prevention. As a test of this hypothesis, we evaluated the methylation status of eight genes (MINT1, 2, 31, MLH1, p16, p14, MGMT, and ESR1), as well as BRAF and KRAS mutations, in 57 multiple colorectal neoplasias (M-CRN) and compared these to 69 solitary colorectal cancers (S-CRC). There were no significant differences in methylation between M-CRNs and S-CRCs except for p14 and MGMT that was significantly higher in M-CRNs than S-CRCs (16.1% versus 9.3%; 26.5% versus 17.3%, respectively; P < 0.05). We found significant (P < 0.05) correlations for MINT1 (r = 0.8), p16 (r = 0.8), MLH1 (r = 0.9), and MGMT (r = 0.6) methylation between tumors pairs of the same site (proximal/proximal and distal/distal). KRAS showed no concordance in mutations. BRAF mutation showed concordance in proximal site pairs but was discordant in different site pairs. Histologically, eight of 10 paired cancers with similar locations were concordant for a cribriform glandular configuration. We conclude that synchronous colorectal tumors of the same site are highly concordant for methylation of multiple genes, BRAF mutations, and a cribriform glandular configuration, all consistent with a patient-specific predisposition to particular subtypes of colorectal cancers. Screening for and secondary prevention of colon cancer should take this fact into account.

Distinct molecular features of different macroscopic subtypes of colorectal neoplasms.

BACKGROUND Colorectal adenoma develops into cancer with the accumulation of genetic and epigenetic changes. We studied the underlying molecular and clinicopathological features to better understand the heterogeneity of colorectal neoplasms (CRNs). METHODS We evaluated both genetic (mutations of KRAS, BRAF, TP53, and PIK3CA, and microsatellite instability [MSI]) and epigenetic (methylation status of nine genes or sequences, including the CpG island methylator phenotype [CIMP] markers) alterations in 158 CRNs including 56 polypoid neoplasms (PNs), 25 granular type laterally spreading tumors (LST-Gs), 48 non-granular type LSTs (LST-NGs), 19 depressed neoplasms (DNs) and 10 small flat-elevated neoplasms (S-FNs) on the basis of macroscopic appearance. RESULTS S-FNs showed few molecular changes except SFRP1 methylation. Significant differences in the frequency of KRAS mutations were observed among subtypes (68% for LST-Gs, 36% for PNs, 16% for DNs and 6% for LST-NGs) (P<0.001). By contrast, the frequency of TP53 mutation was higher in DNs than PNs or LST-Gs (32% vs. 5% or 0%, respectively) (P<0.007). We also observed significant differences in the frequency of CIMP between LST-Gs and LST-NGs or PNs (32% vs. 6% or 5%, respectively) (P<0.005). Moreover, the methylation level of LINE-1 was significantly lower in DNs or LST-Gs than in PNs (58.3% or 60.5% vs. 63.2%, P<0.05). PIK3CA mutations were detected only in LSTs. Finally, multivariate analyses showed that macroscopic morphologies were significantly associated with an increased risk of molecular changes (PN or LST-G for KRAS mutation, odds ratio [OR] 9.11; LST-NG or DN for TP53 mutation, OR 5.30; LST-G for PIK3CA mutation, OR 26.53; LST-G or DN for LINE-1 hypomethylation, OR 3.41). CONCLUSION We demonstrated that CRNs could be classified into five macroscopic subtypes according to clinicopathological and molecular differences, suggesting that different mechanisms are involved in the pathogenesis of colorectal tumorigenesis.

Efficacy and safety of prednisolone in patients with autoimmune hepatitis.

A retrospective cohort study involving 29 Japanese patients with autoimmune hepatitis (AIH) was performed to clarify factors that predict the efficacy of prednisolone and the occurrence of various serious adverse effects. Independent predictors were identified by logistic analysis and with use of the Cox proportional hazard model. Responses to prednisolone were noted in 28 patients, who were classified into the complete remission group (52%) or the relapse group (48%). Multivariate analysis identified alanine aminotransferase, alkaline phosphatase, and immoglobulin G levels as independent predictors of relapse. The adverse effects most frequently observed were diabetes mellitus (37.9%), psychiatric/ neurologic symptoms (34.5%), and circulatory symptoms (34.5%). Predictive factors included lactate dehydrogenase, albumin, and fasting blood glucose levels for diabetes mellitus, alkaline phosphatase and C-reactive protein for psychiatric/neurologic symptoms, and autoimmune hepatitis score and lactate dehydrogenase for circulatory symptoms. Selection of an optimal treatment method for individual patients may be possible after the risks of relapse and adverse effects have been estimated.

Prognostic Index for Survival in Patients After Treatment for Primary Hepatocellular Carcinoma

We retrospectively evaluated clinical factors affecting long-term survival after treatment for hepatocellular carcinoma (HCC) to predict the reliability of the prognosis of patients with HCC. We analyzed 157 patients who received treatment for HCC. The prognostic index (PI) was evaluated using the Cox regression model. The overall cumulative survival rates were 79.7% at 1 year, 51.1% at 3 years, and 24.9% at 5 years. The PI was calculated by the following formula, consisting of five factors: PI=0.637×number of tumor lesions+0.103×tumor diameter+1.003×ascites+0.915×portal vein tumor thrombosis – 0.006×cholinesterase+2.0. It was found that liver function and progression of the tumor are the most important factors for prognosis after treatment for HCC. The PI, based on five factors, will in future be an appropriate index to predict the prognosis of patients with HCC.

Clinical predictive factors for preterm birth in women with threatened preterm labour or preterm premature ruptured membranes

Background: Independent predictive factors of preterm delivery were evaluated using clinical data at hospitalisation by multivariate analysis.

Factors involved in resistance to early treatment of acute cholangitis patients.

BACKGROUND/AIMS Severity-based treatment is not homogenously effective for acute cholangitis patients and some are resistant to early treatment. We performed a retrospective cohort study involving acute cholangitis patients and analyzed factors strongly associated with resistance to early treatment. METHODOLOGY The subjects were 94 patients admitted to the Department of Gastroenterology, Showa University Hospital and diagnosed with acute cholangitis. The endpoint was set as the presence or absence of resistance to early treatment. Background and blood test results of the patients immediately after admission were surveyed and significant factors independently contributing to resistance to early treatment were extracted from the surveyed factors employing a logistic regression model. RESULTS The mean age of the patients was 73.2 ± 11.6 years and 58 were male (61.7%). Jaundice, fever and abdominal pain were observed in 46 (48.9%), 66 (70.2%) and 85 patients (90.4%), respectively. Twenty-eight patients (29.8%) were resistant to early treatment. On multivariate analysis, 3 factors (fever, serum amylase level and systolic blood pressure (below 100 mm Hg)) were extracted as significant factors independently contributing to resistance to early treatment (p<0.05). CONCLUSIONS If such resistance can be predicted before treatment, appropriate treatment may be selected to shorten the persistence of symptoms, improving the patients QOL.

Introducing novel learning methods to a pharmacy school in Japan: A preliminary analysis

Problem-based learning (PBL) and small group discussions (SGD) have gained the attention of many Japanese pharmacy schools as a new education tool. However, the effectiveness of these methods may be influenced by students’ attitudes and culture. This paper describes how a School of Pharmacy in Japan has been piloting PBL and tutorial SGD sessions and reports results of a preliminary analysis of their efficacy as educational tools. The results showed that PBL and tutorial SGD could be valuable educational tools for Japanese pharmacy schools. Further research is suggested in order to confirm these results.

The Association between Fever and Prognosis in Lung Cancer Patients with Bone Metastases Receiving Zoledronic Acid

Zoledronic acid is an established agent used in the management of metastatic bone disease. The administration of zoledronic acid improves overall survival (OS) of lung cancer patients with bone metastases receiving chemotherapy. However, it is currently unknown whether zoledronic acid-induced fever is associated with OS. The purpose of this study was to examine the association between zoledronic acid-induced fever and prognosis in lung cancer patients with bone metastases. We retrospectively analyzed 98 lung cancer patients with bone metastases who had received zoledronic acid. The end point outcome measure was OS. Multivariate analyses were used to estimate the hazard ratio (HR) for OS due to fever after adjusting for covariates. In multivariate analysis, white blood cell (WBC) count, lactate dehydrogenase (LDH) level, fever, chemotherapy, and hypercalcemia were independent prognostic factors, with HRs of 2.834 for WBC count (<10 × 103/μL vs. ≥10 × 103/μL, p < 0.001), 3.044 for LDH level (<250 vs. ≥250 IU/L, p < 0.001), 0.603 for fever (<37.0 vs. ≥37.0°C, p = 0.039), 0.481 for chemotherapy (chemotherapy not administered vs. administered, p = 0.006), and 2.453 for hypercalcemia (<11.0 vs. ≥11.0 mg/dL, p = 0.001). Zoledronic acid-induced fever was the most important prognostic factor in this cohort of lung cancer patients with bone metastases.

Molecular features of colorectal polyps presenting Kudo's type II mucosal crypt pattern: are they based on the same mechanism of tumorigenesis?

Background and study aims: The molecular features of serrated polyps (SPs) with hyperplastic crypt pattern, also called Kudo’s type II observed by chromoendoscopy, were evaluated. Methods: The clinicopathological and molecular features of 114 SPs with a hyperplastic pit pattern detected under chromoendoscopy (five dysplastic SPs, 63 sessile serrated adenoma/polyps (SSA/Ps), 36 microvesicular hyperplastic polyps (MVHPs), and 10 goblet cell-rich hyperplastic polyps (GCHPs)) were examined. The frequency of KRAS and BRAF mutations and CpG island methylator phenotype (CIMP) were investigated. Results: Dysplastic SPs and SSA/Ps were frequently located in the proximal colon compared to others (SSA/Ps vs. MVHPs or GCHPs, P < 0.0001). No significant difference was found in the frequency of BRAF mutation among SPs apart from GCHP (60 % for dysplastic SPs, 44 % for SSA/Ps, 47 % for MVHPs, and 0 % for GCHPs). The frequency of CIMP was higher in dysplastic SPs or SSA/Ps than in MVHPs or GCHPs (60 % for dysplastic SPs, 56 % for SSA/Ps, 32 % for MVHPs, and 10 % for GCHPs) (SSA/Ps vs. GCHP, P = 0.0068). When serrated neoplasias (SNs) and MVHPs were classified into proximal and distal lesions, the frequency of CIMP was significantly higher in the proximal compared to the distal SNs (64 % vs. 11 %, P = 0.0032). Finally, multivariate analysis showed that proximal location and BRAF mutation were significantly associated with an increased risk of CIMP. Conclusions: Distinct molecular features were observed between proximal and distal SPs with hyperplastic crypt pattern. Proximal MVHPs may develop more frequently through SSA/Ps to CIMP cancers than distal MVHPs.

Factors predicting the appearance of neutropenia in patients with advanced pancreatic cancer undergoing gemcitabine therapy.

BACKGROUND/AIM Factors predicting the appearance of neutropenia were evaluated in patients with advanced pancreatic cancer undergoing gemcitabine hydrochloride (GEM) therapy. METHODOLOGY The subjects were 92 patients who were diagnosed with unresectable advanced pancreatic cancer and underwent GEM therapy. Mono- and multivariate analyses were performed concerning each evaluated factor. The toxicity index (TI) was also prepared by combining the extracted predictive factors. RESULTS Severe neutropenia occurred in 26 patients (28.2%). As a result of multivariate analysis, the white blood cell count (WBC), CA19-9 and liver metastasis were extracted as factors independently and significantly contributing to the appearance of severe neutropenia (p<0.05). The TI was prepared by combining these 3 factors and their regression coefficients: TI = 4.777-0.605xWBC (x103/microL)-0.511xlog (CA19-9)-1.285xliver metastasis. CONCLUSIONS The WBC, CA19-9 and liver metastasis before treatment were shown to be related to the appearance of severe neutropenia after GEM therapy.