Inadequate care and excessive overprotection during childhood are associated with the presence of diabetes mellitus in adulthood in a general Japanese population: a cross-sectional analysis from the Hisayama Study.

OBJECTIVE: To investigate associations between parenting styles during childhood and diabetes in adulthood in a Japanese community. METHODS: In 2011, 710 community-dwelling Japanese residents aged ≥ 40 years were assessed for the presence of diabetes and for their perceptions of the parenting style of their parents, as measured using the "care" and "overprotection" scales of the Parental Bonding Instrument. Care and overprotection scores for each parent were dichotomized by age-specific median values. Diabetes mellitus was defined as a fasting plasma glucose level of ≥ 7.0 mmol/L, a 2-h post-loaded glucose level of ≥ 11.1 mmol/L, HbA1c ≥ 6.5%, and/or the current use of insulin or oral glucose-lowering agents. The odds ratios (ORs) for prevalent diabetes were calculated using a logistic regression model. RESULTS: The prevalence of diabetes was 14.9%. Subjects with a high paternal overprotection score had a significantly greater likelihood of prevalent diabetes than those with a low paternal overprotection score after adjusting for confounders (OR 1.71, 95% confidence interval [CI] 1.06-2.77), while there was no significant association between paternal care and diabetes. Additionally, the multivariable-adjusted ORs for the presence of diabetes were significantly higher in subjects with a low maternal care score (OR 1.61, 95%CI 1.00-2.60) or in subjects with a high maternal overprotection score (OR 1.73, 95%CI 1.08-2.80). Moreover, the subjects with a low care score and high overprotection score for both their father and mother had a significantly higher multivariable-adjusted OR of diabetes than those with a high care score and low overprotection score for both parents (OR 2,12, 95%CI 1.14-3.95). CONCLUSIONS: This study suggests that inadequate care and excessive overprotection during childhood may contribute to the development of diabetes in adulthood.

Association of white matter lesions and brain atrophy with the development of dementia in a community: the Hisayama Study.

AIM: To investigate the association of white matter lesions volume (WMLV) levels with dementia risk and the association between dementia risk and the combined measures of WMLV and either total brain atrophy or dementia-related gray matter atrophy in a general older population. METHODS: One thousand one hundred fifty-eight Japanese dementia-free community-residents aged ≥65 years who underwent brain magnetic resonance imaging were followed for 5.0 years. WMLV were segmented using the Lesion Segmentation Toolbox. Total brain volume (TBV) and regional gray matter volume were estimated by voxel-based morphometry. The WMLV-to-intracranial brain volume ratio (WMLV/ICV) was calculated, and its association with dementia risk was estimated using Cox proportional hazard models. Total brain atrophy, defined as the TBV-to-ICV ratio (TBV/ICV), and dementia-related regional brain atrophy defined based on our previous report were calculated. The association between dementia risk and the combined measures of WMLV/ICV and either total brain atrophy or the number of atrophied regions was also tested. RESULTS: During the follow-up, 113 participants developed dementia. The risks of dementia increased significantly with higher WMLV/ICV levels. In addition, dementia risk increased additively both in participants with higher WMLV/ICV levels and lower TBV/ICV levels and in those with higher WMLV/ICV levels and a higher number of dementia-related brain regional atrophy. CONCLUSION: The risk of dementia increased significantly with higher WMLV/ICV levels. An additive increment in dementia risk was observed with higher WMLV/ICV levels and lower TBV/ICV levels or a higher number of dementia-related brain regional atrophy, suggesting the importance of prevention or control of cardiovascular risk factors.

Higher-resolution quantification of white matter hypointensities by large-scale transfer learning from 2D images on the JPSC-AD cohort.

White matter lesions (WML) commonly occur in older brains and are quantifiable on MRI, often used as a biomarker in Aging research. Although algorithms are regularly proposed that identify these lesions from T2-fluid-attenuated inversion recovery (FLAIR) sequences, none so far can estimate lesions directly from T1-weighted images with acceptable accuracy. Since 3D T1 is a polyvalent and higher-resolution sequence, it could be beneficial to obtain the distribution of WML directly from it. However a serious difficulty, both for algorithms and human, can be found in the ambiguities of brain signal intensity in T1 images. This manuscript shows that a cross-domain ConvNet (Convolutional Neural Network) approach can help solve this problem. Still, this is non-trivial, as it would appear to require a large and varied dataset (for robustness) labelled at the same high resolution (for spatial accuracy). Instead, our model was taught from two-dimensional FLAIR images with a loss function designed to handle the super-resolution need. And crucially, we leveraged a very large training set for this task, the recently assembled, multi-sites Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD) cohort. We describe the two-step procedure that we followed to handle such a large number of imperfectly labeled samples. A large-scale accuracy evaluation conducted against FreeSurfer 7, and a further visual expert rating revealed that WML segmentation from our ConvNet was consistently better. Finally, we made a directly usable software program based on that trained ConvNet model, available at https://github.com/bthyreau/deep-T1-WMH.

Multiple-region grey matter atrophy as a predictor for the development of dementia in a community: the Hisayama Study.

OBJECTIVE: To assess the association of regional grey matter atrophy with dementia risk in a general older Japanese population. METHODS: We followed 1158 dementia-free Japanese residents aged ≥65 years for 5.0 years. Regional grey matter volume (GMV) at baseline was estimated by applying voxel-based morphometry methods. The GMV-to-total brain volume ratio (GMV/TBV) was calculated, and its association with dementia risk was estimated using Cox proportional hazard models. We assessed whether the predictive ability of a model based on known dementia risk factors could be improved by adding the total number of regions with grey matter atrophy among dementia-related brain regions, where the cut-off value for grey matter atrophy in each region was determined by receiver operating characteristic curves. RESULTS: During the follow-up, 113 participants developed all-cause dementia, including 83 with Alzheimer's disease (AD). Lower GMV/TBV of the medial temporal lobe, insula, hippocampus and amygdala were significantly/marginally associated with higher risk of all-cause dementia and AD (all p for trend ≤0.08). The risks of all-cause dementia and AD increased significantly with increasing total number of brain regions exhibiting grey matter atrophy (both p for trend <0.01). Adding the total number of regions with grey matter atrophy into a model consisting of known risk factors significantly improved the predictive ability for AD (Harrell's c-statistics: 0.765-0.802; p=0.02). CONCLUSIONS: Our findings suggest that the total number of regions with grey matter atrophy among the medial temporal lobe, insula, hippocampus and amygdala is a significant predictor for developing dementia, especially AD, in the general older population.

Association of Albuminuria With White Matter Hyperintensities Volume on Brain Magnetic Resonance Imaging in Elderly Japanese　- The Hisayama Study.

BACKGROUND: Both chronic kidney disease and brain white matter hyperintensities (WMH) are known to be risk factors of dementia and mortality.Methods and Results:In 2012, 1,214 community-dwelling Japanese subjects aged ≥65 years underwent brain magnetic resonance imaging (MRI) scans and a comprehensive health examination. This study investigated associations of the urinary albumin : creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) with the WMH volume to intracranial volume (WMHV : ICV) ratio, and the association of the combination of UACR and the WMHV : ICV ratio with cognitive decline and mortality risk. The geometric mean of the WMHV : ICV ratio was 0.223% in the entire study population, and increased significantly with higher UACR levels after adjusting for potential confounding factors (0.213% for normoalbuminuria, 0.248% for microalbuminuria, and 0.332% for macroalbuminuria; Ptrend=0.01). In contrast, there was no clear association between eGFR and the WMHV : ICV ratio. Compared with subjects with normoalbuminuria and a smaller WMHV : ICV ratio (<0.257% [median]), subjects with albuminuria and a larger WMHV : ICV ratio (≥0.257%) had higher probabilities of cognitive decline at baseline and all-cause death during the follow-up. CONCLUSIONS: This study suggests that subjects with albuminuria have a greater risk of WMH enlargement and that the combination of albuminuria and WMH enlargement increases the risk of cognitive decline and all-cause mortality in an elderly Japanese population.

[Inverted Variant of Urothelial Carcinoma of the Urinary Bladder : A Case Report].

A 69-year-old male complained of gross hematuria. Cystoscopy revealed a papillary pedunculated tumor. The tumor was approximately 4 cm in length, and mimicked an inverted papilloma with a small stalk and smooth surface, located on the bladder trigone. Transurethral resection of the bladder tumor was performed, and the tumor was resected en bloc. Histopathological examination revealed thick and irregular epithelial cords. Immunohistochemically, Ki-67 labeling index was 5%, p40 and CK7 were positive, and CK20 was negative. Then, this tumor was diagnosed as inverted variant of urothelial carcinoma. Even when gross appearance is compatible with inverted papilloma, pathological and immunohistochemical examinations are essential for accurate diagnosis of inverted bladder tumor. No recurrence was observed by cystoscopy 13 months after the resection.

[A Case of Primary Small Cell Carcinoma in the Breast with Neoadjuvant Chemotherapy That Were Difficult to Select Chemotherapy].

Primary small cell carcinoma in the breast is a rare and aggressive tumor, and a standard treatment strategy has not been established. Herein, we report a 35-year-old woman with primary small cell carcinoma in the breast. She had an 8 cm diameter tumor in the right breast. She was diagnosed with small cell carcinoma(cT3N1M0, cStage ⅢA)in the right breast, and neoadjuvant chemotherapy was planned. She received a combination chemotherapy of cisplatin(CDDP)and etoposide(VP- 16)based on the regimen for pulmonary small cell carcinoma; however, the disease showed progression. Therefore, 5-FU plus epirubicin plus cyclophosphamide(FEC)and weekly paclitaxel(PTX)chemotherapy based on a regimen for breast cancer were administered, and the tumor was partially reduced in size. Modified radical mastectomy followed by radiotherapy and hormonal therapy was performed. Ten months after the surgery, multiple liver and bone metastases occurred, and the patient died the following month. Further studies in other such patients are needed.

A phase II trial of capecitabine plus cisplatin (XP) for patients with advanced gastric cancer with early relapse after S-1 adjuvant therapy: XParTS-I trial.

BACKGROUNDS: In Japan, standard regimens for advanced gastric cancer (AGC) include S-1 chemotherapy. The standard treatment for early relapse after adjuvant chemotherapy with fluoropyrimidine alone is platinum-based chemotherapy, while the standard treatment for early relapse after adjuvant chemotherapy with fluoropyrimidine plus platinum is second-line chemotherapy. To evaluate the efficacy and safety of capecitabine plus cisplatin (XP) treatment for AGC patients who relapse within 6 months after S-1-based therapy, we conducted a multicenter phase II trial (NCT01412294). METHODS: HER2-negative gastric cancer patients treated with adjuvant chemotherapy including S-1 for more than 12 weeks and relapsed within 6 months were treated with capecitabine 1000 mg/m2 bid for 14 days plus cisplatin 80 mg/m2 on day 1 of a 3-week cycle. The primary endpoint was PFS; secondary endpoints were OS, time to treatment failure, overall response rate (ORR) and safety. RESULTS: Forty patients (median age 64) were enrolled; of those, 37 (92.5%) received adjuvant S-1 monotherapy. Median PFS was 4.4 months (95% CI 3.6-5.1), which was longer than the 2-month protocol-specified threshold (p < 0.001). Median OS was 13.7 months (95% CI 9.0-17.7) and ORR was 8/30 (26.7%) (95% CI 14.2-44.4). Most common grade ≥ 3 adverse events were neutropenia (23%), anemia (18%), elevated serum creatinine (18%), fatigue (13%), diarrhea (7.5%), and anorexia (7.5%). CONCLUSIONS: XP was safe and effective in patients with early relapse after S-1 adjuvant chemotherapy for curatively resected gastric cancers. XP may be a good option for the treatment of patients after early failure after adjuvant S-1. TRIAL REGISTRATION: NCT01412294.

Coexistence of gastrointestinal stromal tumor and leiomyosarcoma of the stomach presenting as a collision tumor: A case report and review of literature.

Collision tumor of the stomach is rare. We report a rare case of a gastric collision tumor consisting of gastrointestinal stromal tumors (GISTs) and leiomyosarcoma (LMS). Computed tomography scan revealed a 15 cm sized mass in the posterior wall of the body of the stomach. Gross examination of the wedge resection specimen showed the tumor located in the muscularis propria with extramural protrusion into the peritoneal cavity and the gastric cavity with geographic necrosis, hemorrhage, and mucosal ulceration. Histologically, the majority of the tumor consisted of the GIST component and the minor area in the submucosal region consisted of the LMS component. The tumor showed an abrupt transition between GIST and LMS by histologically and immunohistochemically, suggesting a collision tumor. Furthermore, the GIST components exhibited a c-kit exon 11 mutation. On the other hand, LMS component exhibited neither c-kit nor platelet-derived growth factor receptor-alpha (PDGFRA) mutation. Here we describe a case of the collision tumor consisting of GIST and LMS and its literature review.

Short-term outcomes of laparoscopic surgery in octogenarians with colorectal cancer: a single-institution analysis.

PURPOSE: The number of elderly patients with colorectal cancer (CRC) treated with surgery has gradually increased. The aim of this study was to evaluate the short-term outcomes in patients ≥80 years of age who underwent laparoscopic or open surgery for CRC using a propensity score-matched analysis to make uniform the patient background characteristics affecting the postoperative morbidity and mortality. METHODS: We compared the short-term outcomes of open vs. laparoscopic surgery in patients with CRC ≥80 years of age between 2010 and 2015. Fifty-two patients undergoing laparoscopic colectomy for CRC were matched to 52 patients undergoing open colectomy with respect to gender, age, body mass index, performance status, prognostic nutritional index, Charlson Comorbidity Index score, tumor-node-metastasis stage, and tumor location. The operative time, blood loss, length of hospital stay, and postoperative complications were investigated. RESULTS: Blood loss was less during laparoscopic surgery than during open surgery (40 vs. 140 ml, p < 0.001). In the laparoscopic surgery group, the hospital stay was shorter (11 vs. 14 days, p < 0.001) and the morbidity rate lower (21.2 vs. 40.4%) than in the open surgery group. The mortality for both groups was similar (0 vs. 1.9% for laparoscopic surgery vs. open surgery). CONCLUSION: Laparoscopic surgery in octogenarians with CRC is a safe, low-invasive alternative to open surgery with less blood loss and a shorter hospital stay.

Effect of early oral feeding on length of hospital stay following gastrectomy for gastric cancer: a Japanese multicenter, randomized controlled trial.

PURPOSE: This multicenter, randomized controlled study evaluates the safety of early oral feeding following gastrectomy, and its effect on the length of postoperative hospital stay. METHODS: The subjects of this study were patients who underwent distal gastrectomy (DG) or total gastrectomy (TG) for gastric cancer between January 2014 and December 2015. Patients were randomly assigned to the early oral feeding group (intervention group) or the conventional postoperative management group (control group) for each procedure. We evaluated the length of postoperative hospital stay and the incidence of postoperative complications in each group. RESULTS: No significant differences in length of postoperative stay were found between the intervention and control groups of the patients who underwent DG. The incidence of postoperative complications was significantly greater in the DG intervention group. In contrast, the length of postoperative stay was significantly shorter in the TG intervention group, although the TG group did not attain the established target sample size. CONCLUSION: Early oral feeding did not shorten the postoperative hospital stay after DG. The higher incidence of postoperative complications precluded the unselected adoption of early oral feeding for DG patients. Further confirmative studies are required to definitively establish the potential benefits of early oral feeding for TG patients.

Invasive micropapillary carcinoma component is an independent prognosticator of poorer survival in Stage III colorectal cancer patients.

BACKGROUND: Invasive micropapillary carcinoma (IMPC) is an aggressive variant of adenocarcinoma found in several organs. Recent studies showed that IMPC in colorectal cancer leads to poorer prognosis than conventional colorectal cancer; however, the influence of IMPC on outcomes remains unclear. The present study aimed to identify the clinicopathological characteristics of colorectal cancers with IMPCs, and to evaluate the prognostic significance of IMPCs per se. METHODS: We retrospectively analyzed data from 837 patients with colorectal cancer who underwent surgical treatment. We compared the clinicopathological characteristics and survival outcomes of colorectal cancer patients with IMPCs to those without. RESULTS: Among 837 patients, 130 (16%) had an IMPC component, including 0 (0%) of 18, 9 (4.2%) of 215, 34 (13%) of 254, 59 (24%) of 249 and 28 (27%) of 101 patients with TNM Stages 0, I, II, III and IV, respectively. The 3-year disease-free survival (DFS) rates were significantly worse for Stage III patients with IMPC than for those without (55.3% vs. 78.7% respectively, P < 0.001), but not in patients with other stages. Multivariate analyses of patients with Stage III colorectal cancer found IMPC to be associated with significantly worse DFS (P = 0.026), as were high CEA levels, tumor budding and TNM staging. IMPC was only significantly associated with tumor invasion (P = 0.045) and venous invasion (P = 0.045) in Stage III tumors. CONCLUSIONS: Identifying IMPC components in Stage III colorectal cancer is crucial, as their presence is significantly associated with poorer survival.

[Abdominoperineal Resection for Anal Metastasis of Rectal Cancer].

Anal metastasis of colorectal cancer is rare, and no standardized effective therapeutic strategy exists. We report a case of abdominoperineal resection for anal metastasis of rectal cancer. A 65-year-old man underwent laparoscopic low anterior resection for rectal cancer in August 2013. Histopathological examination revealed a moderately differentiated adenocarcinoma( tub2, pSS, ly3, v2, pN1, H0, P0, M0, Stage III a, Cur A). In February 2015, he complained of anal discomfort, and tumor markers were elevated. Enhanced CT revealed a 15-mm high-density solid tumor in the anal canal. The results of needle biopsy indicated a moderately differentiated adenocarcinoma. This tumor was suspected to be metastasis from rectal cancer, and we performed abdominoperineal resection. Histopathological examination revealed a moderately differentiated adenocarcinoma, which was the same histological type as the primary rectal cancer and was covered with normal anal epithelium. Collectively, the findings indicated anal metastasis from rectal cancer. The patient is alive without recurrence for 18 months after resection. Anal metastasis should be considered as a differential diagnosis in patients with anal discomfort who have a history of colon/rectal cancer. Abdominoperineal resection may be an effective treatment modality for this condition.

[Pathological Complete Response to SOX plus Bevacizumab for Treating Stage IV Sigmoid Colon Cancer].

Advanced sigmoid colon cancer with stenosis was discovered in a man in his 50's who presented with constipation. A radiological examination revealed peritoneal dissemination. Transverse colostomy was scheduled for the treatment of bowel obstruction. Multiple disseminated nodules were confirmed, and adenocarcinoma was detected from a nodule in the omentum. Eight courses of SOX plus bevacizumab caused the primary tumor to shrink and disseminated nodules to become radiologically undetectable. The patient underwent sigmoid colectomy 8 weeks after the last bevacizumab administration, and no disseminated nodules were found during the procedure. Histological assessment revealed no evidence of cancer cells in the colon and lymph nodes, and the histological effect was judged as Grade 3.

Matched pair analysis to examine the effects of a planned preoperative exercise program in early gastric cancer patients with metabolic syndrome to reduce operative risk: the Adjuvant Exercise for General Elective Surgery (AEGES) study group.

BACKGROUND: Because obesity is a risk factor during surgery, the effects of a preoperative exercise program to reduce the incidence of peri- and postoperative complications in patients with a high body mass index (>25 kg/m(2)) and metabolic syndrome were investigated. An assessment of the effects of prospectively planned preoperative exercise was performed in a prospective matching study comparing an exercise testing group and a usual preoperative preparation group who underwent gastrectomy for gastric cancer in Japan. METHODS: Stage I gastric cancer patients with metabolic syndrome diagnosed according to the criteria of the Japanese Ministry of Health, Labor, and Welfare underwent surgery after preoperative exercise. The control group was selected from a database using an individual matching approach for surgery, sex, weight, body mass index, volume of visceral fat, and institution. The primary end point was the frequency of postoperative complications such as cardiovascular events, pneumonia, and surgery-related abdominal complications. RESULTS: Data from a total of 72 patients (54 in the surgery-alone group, 18 in the preoperative exercise group) were analyzed. The median operative time and amount of bleeding were 208 min and 130 ml in the surgery-alone group and 248 min and 105 ml in the exercise group, respectively. Postoperative complications occurred in one case (5.5 %) in the exercise group and 22 (40.7 %) cases in the surgery-alone group. CONCLUSIONS: Preoperative exercise is safe, and its benefits in reducing postoperative complications are promising and therefore warrant further investigation.

Induction of a pathological complete response by four courses of neoadjuvant chemotherapy for gastric cancer: early results of the randomized phase II COMPASS trial.

BACKGROUND: The prognosis for stage 3 gastric cancer is not satisfactory, even with S-1 adjuvant chemotherapy. A randomized phase II trial was conducted to compare two and four courses of neoadjuvant S-1/cisplatin (SC) and paclitaxel/cisplatin (PC) using a two-by-two factorial design for locally advanced gastric cancer. The primary endpoint was overall survival. We clarified the impact of these regimens on the secondary endpoints, including the clinical and pathological responses, chemotherapy-related toxicities, and surgical results. METHODS: Patients received S-1 (80 mg/m(2) for 21 days with 1 week's rest)/cisplatin (60 mg/m(2) at day 8) or paclitaxel/cisplatin (80 and 25 mg/m(2), respectively, on days 1, 8, and 15 with 1 week's rest) as neoadjuvant chemotherapy. RESULTS: Eighty-three patients were assigned to arm A (two courses of SC, n = 21), arm B (four courses of SC, n = 20), arm C (two courses of PC, n = 21), and arm D (four courses of PC, n = 21). Pathological response rate was 43 % in arm A, 40 % in arm B, 29 % in arm C, and 38 % in arm D. Pathological complete response was only observed in arms B (10 %) and D (10 %). Most bone marrow toxicities, nausea, vomiting, alopecia, and fatigue were slightly higher but acceptable in arms B and D. Grade 3/4 surgical morbidities were not commonly observed in all four arms. CONCLUSIONS: Pathological complete response could be induced by four courses of neoadjuvant chemotherapy without a marked increase of toxicities, regardless of a SC or PC regimen.

Phase II study of docetaxel and S-1 (DS) as neoadjuvant chemotherapy for clinical stage III resectable gastric cancer.

BACKGROUND: We conducted a phase II trial to evaluate the efficacy and safety of preoperative chemotherapy with docetaxel (DTX) plus S-1 for resectable advanced gastric cancer. PATIENTS AND METHODS: A total of 47 patients from 14 centers were centrally registered. Patients received DTX (35 mg/m(2)) on days 1 and 15, and daily oral administration of S-1 (80 mg/m(2)/day) for days 1-14 every 4 weeks for two courses, followed by gastrectomy with D2 lymphadenectomy. The primary endpoint was pathological response rate (pRR). This study was registered in the UMIN clinical trial registry (UMIN000000875). RESULTS: The primary endpoint pRR was 47 % (90 % confidence interval (CI), 34-60 %; p < 0.0001). The response rate to preoperative chemotherapy using Response Evaluation Criteria in Solid Tumors (RECIST) was 34 %. Forty-six patients (98 %) underwent surgery, and curative resection was performed in 44 patients. Thirty-seven patients completed the protocol treatment. The most common toxicities of neoadjuvant chemotherapy were grade 3/4 neutropenia (42 %), febrile neutropenia (4 %), grade 2 anorexia (21 %), and fatigue (15 %). Treatment-related death and operative mortality was not observed in this study. CONCLUSIONS: The combination of docetaxel and S-1 was well tolerated. This is promising as a preoperative chemotherapy regimen for patients with potentially resectable advanced gastric cancer.