Observational Studies on the Association Between Post-diagnostic Metformin Use and Survival in Ovarian Cancer: A Systematic Review and Meta-Analysis

Objectives: To summarize and quantify the relationship between post-diagnostic metformin use and ovarian cancer (OC) survival.Methods: We systematically conducted an updated meta-analysis based on observational studies published up to December 31, 2018, identified from PubMed and Web of Science. Two team members independently extracted data and assessed the quality of each study. Summary Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using a random-effects model.Results: Five cohort studies including 3,582 OC patients were included. All studies were graded as low risk of bias according to the Newcastle-Ottawa quality assessment scale. Post-diagnostic metformin use was associated with improved overall survival (summarized HR = 0.42, 95% CI = 0.31–0.56; I2 = 0%, P = 0.842) and progression-free survival (summarized HR = 0.69, 95% CI = 0.45–1.07; I2 = 61.9%, P = 0.049) of OC patients. For OC patients with diabetes, post-diagnostic metformin use was associated with improved overall survival (summarized HR = 0.51, 95% CI = 0.28–0.95; I2 = 47.6%, P = 0.149) and progression-free survival (summarized HR = 0.38, 95% CI = 0.27–0.55; I2 = 0%, P = 0.594). No significant publication bias was detected in these analyses.Conclusions: Post-diagnostic metformin use is consistently associated with better survival of OC patients regardless of diabetes status. Studies with larger sample sizes and prospective designs are required to confirm these findings and obtain detailed information, including standardized references for comparison, intensity and dose of metformin use, and further adjustment for potential confounders

CCR6+ MCAM+ Th17 Cell Numbers Increase in Patients with Psoriasis and Correlate with Disease Severity

Psoriasis is a chronic immune-mediated disease in which the interleukin (IL)-23/IL-17 axis plays a key role in the inflammatory cascade. We recently reported that co-expression of CCR6 and melanoma cell adhesion molecule (MCAM) in effector memory CD4 T cells (TEM) of peripheral blood might be a useful marker for T helper (Th) 17 cells. In this study, we monitored changes in TEM expressing CCR6 and MCAM using the Psoriasis Area and Severity Index (PASI) score during anti-tumor necrosis factor (TNF) therapy. We also studied CCR6+ MCAM+ Th17 cells histologically in skin biopsy samples from psoriasis patients. In psoriasis patients treated with anti-TNF therapy, the PASI score and the percentage of CCR6+ MCAM+ TEM cells in the blood changed almost in parallel. In immunohistochemical analyses, the proportions of IL-17+ T cells and MCAM+ T cells in the lesional skin of severely psoriatic patients were significantly higher than in mildly psoriatic patients (P<0.05), and the number of IL17+ T cells correlated with the PASI score (r=0.400, P<0.05). Taken together, these results indicate that CCR6+ MCAM+ Th17 cells in peripheral blood and lesional skin might play an important role in the pathology of psoriasis

Involvement of Adrenomedullin Expression in Tumor Cells and Stroma in the Development of Diabetes in Pancreatic Cancer Patients

Some studies have reported that adrenomedullin （AM） is involved in diabetes mellitus （DM） associated with pancreatic cancer. Therefore, in this study we investigated the relationship between diabetes and AM expression in patients with pancreatic cancer. We examined 48 biopsies and 26 surgical resections from 74 patients with histologically diagnosed pancreatic cancer. Patients were classified into either DM or non-DM groups. The immunohistochemical expression of AM and various clinicopathological factors were compared between the two groups. Among the biopsy cases, 21 were classified as DM and 27 as non-DM. AM expression in pancreatic cancer cells was significantly lower in the DM group （p＝0.03）. No significant differences were noted in age, body mass index, tumor diameter or location, serum CA19-9, amylase, or C-reactive protein levels, pancreatic ductal dilatation, portal vein invasion, clinical stage, or histological differentiation between the DM and non-DM groups. The proportion of men was significantly lower in the DM group （p＝0.04）, as was the frequency of liver metastasis at diagnosis （p＝0.03）. Among the resection cases, 13 were classified as DM and 13 as non-DM. There were no significant differences in AM expression in pancreatic cancer cells between the two groups. However, marked AM expression was observed in the inflammatory cells and fibroblasts of the tumor stroma in all cases. In addition, the inflammatory response in the tumor stroma tended to be stronger in the DM group. Although the present study failed to find a positive correlation between diabetes and AM expression in pancreatic cancer cells, the results indicate that AM expression in stromal cells may be more closely related to the development of DM in pancreatic cancer patients

Significance of Ki-67 Expression and Risk Category (St. Gallen 2007) in Elderly Breast Cancer Patients, with Emphasis on the Need for Postoperative Adjuvant Therapy

Breast cancer is increasing in the elderly. Although elderly breast cancer patients frequently receive less invasive therapy, its appropriateness is debatable. Ki-67 expression is a controversial prognostic factor and predictor of the efficacy of postoperative adjuvant therapy. This study investigated the value of the Ki-67 labeling index (LI) in elderly breast cancer patients, especially with respect to adjuvant therapy. This retrospective study investigated 82 primary breast cancer patients aged 70 years who underwent surgery between 1995 and 2005. Their clinicopathological findings were reviewed and their Ki-67 LIs were determined. The patients\u27 mean age was 78 years, the mean observation period was 53.8 months, and 60 patients (73.2%) underwent adjuvant therapy. The St. Gallen (2007) risk category and the Ki-67 LI (mean, 15.3%) were both significantly correlated with relapse and prognosis. In the 31 cases with a low Ki-67 LI (< 10%), 1 patient who underwent adjuvant treatment relapsed, but there were no deaths. Among the intermediate- and high-risk patients, Ki-67 was low in 15; 1 patient who underwent adjuvant treatment relapsed, but there were no deaths. For elderly breast cancer patients aged 70 years categorized low risk by St. Gallen (2007) or with a low Ki-67 LI, the risk of relapse and death appears to be low regardless of adjuvant therapy. Though further investigation is needed to determine a method of measuring the Ki-67 LI and determining a cut-off value, our findings suggest that the Ki-67 LI helps with the selection of adjuvant therapy in elderly patients

CpG Island Methylator Phenotype in Primary Gastric Carcinoma

Gastric cancers (GC) with methylation of multiple CpG islands have a CpG island methylator phenotype (CIMP) and they can have different biological features. The aim of this study was to investigate the DNA methylation status of GCs and its association with their clinicopathological features. We evaluated the methylation status of four genes (MINT1, MINT2, MINT25 and MINT31) in 105 primary GCs using bisulfite-pyrosequencing analysis. We classified tumors as CIMP-high (CIMP-H), CIMP-low (CIMP-L) or CIMP-negative (CIMP-N) based on the methylation of MINT1, MINT2, MINT25, and MINT31. Overall, the prevalence of CIMP-H, CIMP-L and CIMP-N was 22% (23/105), 52% (55/105) and 26% (27/105), respectively. We observed a significant difference in tumor stage (stages I-II vs. stages III-IV) between CIMP-H and CIMP-N tumors (P = 0.0435). No significant differences were observed in clinicopathological characteristics (gender, age, location and tumor differentiation) among the CIMP phenotypes. The prognoses of patients with a CIMP-H tumor is likely to be better than those with CIMP-L or CIMP-N tumors, but these differences are not statistically significant (P = 0.074 and P = 0.200). Our results suggest that CIMP may define a subgroup of GCs with distinct biological features

Mast Cell Infiltration is Associated with Myelofibrosis and Angiogenesis in Myelodysplastic Syndromes

Myelodysplastic syndromes are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by persistent peripheral cytopenia with morphological and functional abnormalities of hematopoietic cells. Mast cells infiltrate into or around tumor tissues and play a role in remodeling of the stromal microenvironment, contributing to tumor progression. Increased mast cell numbers are associated with fibrosis, angiogenesis and a poor prognosis in human carcinomas. The aim of this study was to determine whether mast cell infiltration contributes to myelofibrosis or angiogenesis in myelodysplastic syndromes. We evaluated the correlation between mast cell density and the extent of myelofibrosis and angiogenesis in myelodysplastic syndromes. Fifty bone marrow biopsies taken from patients with a diagnosis of myelodysplastic syndromes were examined. Grading of myelofibrosis was evaluated by silver impregnation staining. Mast cell density and microvessel density were evaluated by immunohistochemistry. Human mast cells have been divided into two phenotypes. We designated a tryptase-positive mast cell as MCT and a chymase-positive mast cell as MCTC. Microvessels were identified by CD34-positive endothelial cells. Microvessel density and the extent of myelofibrosis were significantly greater in patients with high MCT and MCTC density compared to those with low MC density. Based on this, we suggest that the presence of high mast cell numbers is associated with myelofibrosis and angiogenesis in myelodysplastic syndromes

Magnifying Colonoscopy Findings for Differential Diagnosis of Sessile Serrated Adenoma/Polyps and Hyperplastic Polyps

Sessile serrated adenoma/polyps (SSA/Ps) are thought to be precursors of colorectal cancers. However, current endoscopic techniques for differentiating SSA/Ps from conventional hyperplastic polyps (HPs) have low diagnostic accuracy. The aim of the present study was to assess the ability of mucosal crypt patterns to distinguish SSA/Ps from HPs. We examined 140 lesions from 93 patients that had been diagnosed histologically as SSA/Ps or HPs at the Showa University Hospital between June 2010 and May 2012. Three experienced colonoscopists reviewed the endoscopic findings of magnifying colonoscopy. Type II open-shape (Type II-O) pit patterns and varicose microvascular vessels (VMVs) were identified according to previously proposed definitions. Although 140 lesions were initially identified for the study, 27 lesions were excluded from analysis because of insufficient endoscopic findings. Thus, endoscopic findings from a total of 113 lesions (68 SSA/Ps and 45 HPs) were evaluated. Of 113 serrated polyps, 51 lesions (44 SSA/Ps and 7 HPs; P<0.01) had Type II-O pit patterns. The inter- and intra-observer agreement for these patterns among three colonoscopists was κ=0.61 (range 0.57–0.65) and κ=0.68 (range 0.52–0.94), respectively. The positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity of Type II-O pit patterns for differentiating between SSA/P and HP were 86%, 61%, 65%, and 84%, respectively. In contrast, the PPV, NPV, sensitivity, and specificity of VMVs were 68%, 43%, 37%, and 73%, respectively. The results indicate that Type II-O mucosal crypt patterns may be useful for the differential diagnosis of SSAPs and HPs

Sustainability of a rice husk recycling scheme

Purpose To ensure the sustainability of rice husk recycling schemes, there are essential conditions that should be considered. In this study, a system in which a fertilizer was obtained after rice husk heat treatment, which also produces hot water as a heat recovery strategy, was considered, and its financial sustainability, based on different conditions in place, was then evaluated. Method Based on a previous study, three essential conditions that are necessary for the sustainability of the system were identified (i.e., free or low-cost rice husk collection and hauling, production of silica in the amorphous state, and complete recycling of rice husk ash). The necessity of these conditions was confirmed based on the sustainability of the financial balance of the system. Results A 24-h d-1 operated system is more profitable than one that is operated at 6-h d-1. The pelletizing process is costly; however, the fertilizer in the pellet form can be sold at a relatively higher price. The system was unsustainable when rice husk collection and hauling as well as ash disposal fees were charged. Conclusion Therefore, the cost of rice husk collection, hauling, and ash disposal as well as the amorphous state of the ash were confirmed as conditions that are necessary to ensure the sustainability of a rice husk recycling scheme

Clinicopathological Study of Intracholecystic Papillary-Tubular Neoplasms (ICPNs) of the Gallbladder

Intracholecystic papillary-tubular neoplasm (ICPN) has recently been proposed as a new disease concept in the classification of gallbladder tumors. ICPN is defined as a papillary or polypoid glandular neoplasm forming a localized, non-invasive mass (≥ 1cm) in the gallbladder. We analyzed the clinicopathological characteristics of ICPN. Resected gallbladder cancer specimens from 57 patients were classified as ICPN or non-ICPN and clinicopathological characteristics were compared. ICPN cell characteristics were also analyzed using immunostaining and genetic analysis. Twenty-three cases were classified as ICPN and 34 as non-ICPN. In the ICPN and non-ICPN groups, mean ages were 69 and 74 years, male:female ratios were 14:9 and 15:19, mean tumor diameters were 2.8 and 2.6cm, invasion depths were Tis+T1/T2+T3 in 14/9 cases and 13/21 cases, lymph node metastases were present in 6% and 43%, distant metastases in 0% and 6% and 3-year survival rates were 91% and 52%, respectively. Significant intergroup differences were seen in lymph node metastases and the 3-year survival rate. ICPN cell lineage was biliary-type in 13 cases, gastric-type in 8 and intestinal-type in 2. This proportion differs from that of pancreatic intraductal papillary mucinous neoplasm (IPMN), in which gastric- and intestinal-type are more common. KRAS gene mutations were only seen in 1 of 13 ICPN cases. ICPN is frequently seen in gallbladder cancer, showing similar pathology to pancreatic IPMN, which is considered to have a relatively good prognosis among pancreatic cancers. However, ICPN cell characteristics are not necessarily identical to those of pancreatic IPMN