Colloid Carcinoma Arising in an Intestinal-Type Intraductal Papillary Mucinous Neoplasm with High-Grade Dysplasia Appearing as Signet-Ring Cells of the Pancreas by Serial Pancreatic Juice Aspiration Cytology: A Case Report.

We report a case of colloid carcinoma (CC) arising from an intestinal-type intraductal papillary mucinous neoplasm with high-grade dysplasia (IPMNHGD) of the pancreas, diagnosed with serial pancreatic juice aspiration cytological examination (SPACE). A rapidly growing intraductal papillary mucinous neoplasm (IPMN) in a 71-year-old Japanese man accelerated his hospitalization in our institute. Clinically, a large, ruptured pancreatic cyst was suspected. Cytologically, several mucin-positive signet-ring cells were scattered in the inflammatory, necrotic, or mucinous background. Signet-ring cells in cell block specimens were immunoreactive for MUC2, MUC5AC, maspin, S100P, and claudin-18. The final cytologic diagnosis was CC arising in an intestinal-type IPMNHGD with intraperitoneal penetration. The patient died two months after an explorative laparotomy. The cytologic diagnosis was achieved through SPACE, and the presence of signet-ring cells was characteristic. Anti-claudin-18.2-specific monoclonal antibody therapy will likely be used to treat patients with IPMNHGD in the future. This case highlights the diagnostic utility of SPACE, with particular emphasis on the characteristic presence of signet-ring cells. Furthermore, it anticipates the potential use of anti-claudin-18.2- specific monoclonal antibody therapy in the management of IPMNHGD patients.

Neuromedin U-deficient rats do not lose body weight or food intake.

Studies in genetically modified mice establish that essential roles of endogenous neuromedin U (NMU) are anorexigenic function and metabolic regulation, indicating that NMU is expected to be a potential target for anti-obesity agents. However, in central administration experiments in rats, inconsistent results have been obtained, and the essential role of NMU energy metabolism in rats remain unclear. This study aims to elucidate the role of endogenous NMU in rats. We generated NMU knockout (KO) rats that unexpectedly showed no difference in body weight, adiposity, circulating metabolic markers, body temperature, locomotor activity, and food consumption in both normal and high fat chow feeding. Furthermore, unlike reported in mice, expressions of Nmu and NMU receptor type 2 (Nmur2) mRNA were hardly detectable in the rat hypothalamic nuclei regulating feeding and energy metabolism, including the arcuate nucleus and paraventricular nucleus, while Nmu was expressed in pars tuberalis and Nmur2 was expressed in the ependymal cell layer of the third ventricle. These results indicate that the species-specific expression pattern of Nmu and Nmur2 may allow NMU to have distinct functions across species, and that endogenous NMU does not function as an anorexigenic hormone in rats.

Azathioprine-induced severe myelosuppression accompanied by massive hair loss and painful oral ulcer in an autoimmune hepatitis patient with NUDT15 minor variant: A case report.

This report highlights azathioprine-induced severe myelosuppression in the patient with NUDT15 minor variant. This case report is particularly instructive because several typical symptoms are the clues to this critical adverse drug reaction.

Surgical outcomes of totally extraperitoneal repair for inguinal hernia: A retrospective multicenter propensity score-matched study.

BACKGROUND: Laparoscopic surgical approaches, including total extraperitoneal repair (TEP), have been widely accepted for inguinal hernia repair in Japan. However, there are limited data regarding recurrence after TEP in Japan, given the limited versatility of this procedure. This study retrospectively evaluated the rates of hernia recurrence after TEP and open mesh repair at multiple Japanese centers. METHODS: This retrospective study evaluated 1917 patients who underwent inguinal hernia repair at 32 institutions in the Oita prefecture between January 2014 and December 2015. Eligible patients were grouped according to whether they underwent TEP (1011 patients) or open mesh repair (636 patients). Propensity score matching was performed 1:1 (total: 1076 patients, 538 patients from each group). The outcomes of interest were recurrence, morbidity, and postoperative recovery. RESULTS: The TEP and open mesh repair groups had similar baseline characteristics. After propensity score matching, there was no significant difference between the two groups in terms of recurrence rate (TEP: 0.5% vs open mesh repair: 1.0%, P = .375). However, the TEP group had significantly longer operating times (median: 70.2 min vs 65.0 min, P < .001), significantly less blood loss (0-5.1 mL vs 0-20.4 mL, P < .001), and significantly shorter postoperative hospital stays (median: 5.0 days vs 6.4 days, P < .001). The overall incidences of morbidity were 6.2% in the TEP group and 7.2% in the open mesh repair group (P = .535). CONCLUSION: This multicenter retrospective study with propensity score matching revealed that the recurrence rates were similarly low for TEP and open mesh repair of inguinal hernia. Thus, a well-trained surgical team could use TEP as a standard procedure.

A cross-sectional study on metabolic similarities and differences between inpatients with schizophrenia and those with mood disorders.

BACKGROUND: One of the main causes of death in psychiatric patients is cardiovascular diseases which are closely related with lifestyle-related diseases. Psychiatric disorders include schizophrenia and mood disorders, whose symptoms and treatment medicines are different, suggesting that they might have different metabolic disorders. Thus, we studied the differences of lifestyle-related diseases between schizophrenia and mood disorders in Japan. METHODS: This cross-sectional study was performed from 2015 to 2017. Study participants were 189 Japanese hospitalized patients (144 schizophrenia group, 45 mood disorders group) in the department of psychiatry at Kohnodai hospital. We examined physical disorders, metabolic status of glucose and lipid, estimated glomerular filtration rate (eGFR) and brain magnetic resonance imaging. We compared these data between schizophrenia and mood disorders groups using analysis of covariance or logistic regression analysis. In comparisons between inpatients with schizophrenia or mood disorders group and the standard, we quoted 'The National Health and Nutrition Survey in Japan 2015' by Ministry of Health, Labor and Welfare as the standard. RESULTS: eGFR and prevalence of smoking were significantly lower in patients with mood disorder group than those with schizophrenia group by adjustment for age. In comparisons between patients with schizophrenia group or mood disorders group and each standard, the ratio of silent brain infarction (SBI) and cerebral infarction were significantly high in both groups. Schizophrenia group showed significantly higher prevalence of diabetes, low high-density lipoprotein (HDL) cholesterolemia, metabolic syndrome and smoking than the standard. Mood disorders group had significantly high prevalence of low HDL-cholesterolemia compared with the standard. Fasting blood glucose and HbA1c were significantly higher in schizophrenia group and female mood disorders group than the standard. Female mood disorders group had significantly decreased eGFR with increased ratio of eGFR < 60 ml/min than the standard. CONCLUSIONS: Participants of both groups had increased ratio of SBI and cerebral infarction, accompanied with glucose and lipid disorders. Compared with schizophrenia group, mood disorders group showed significantly low eGFR and prevalence of smoking.

Fucosyltransferase 8 plays a crucial role in the invasion and metastasis of pancreatic ductal adenocarcinoma.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer. It is an aggressive malignancy associated with poor prognosis because of recurrence, metastasis, and treatment resistance. Aberrant glycosylation of cancer cells triggers their migration and invasion and is considered one of the most important prognostic cancer biomarkers. The current study aimed to identify glycan alterations and their relationship with the malignant potential of PDAC. METHODS: Using a lectin microarray, we evaluated glycan expression in 62 PDAC samples. Expression of fucosyltransferase 8 (FUT8), the only enzyme catalyzing core fucosylation, was investigated by immunohistochemistry. The role of FUT8 in PDAC invasion and metastasis was confirmed using an in vitro assay and a xenograft peritoneal metastasis mouse model. RESULTS: The microarray data demonstrated that core fucose-binding lectins were significantly higher in carcinoma than in normal pancreatic duct tissues. Similarly, FUT8 protein expression was significantly higher in carcinoma than in normal pancreatic duct tissues. High FUT8 protein expression was significantly associated with lymph-node metastases and relapse-free survival. FUT8 knockdown significantly reduced the invasion in PDAC cell lines and impaired peritoneal metastasis in the xenograft model. CONCLUSIONS: The findings of this study provide evidence that FUT8 plays a pivotal role in PDAC invasion and metastasis and might be a therapeutic target for this disease.

Pharmacokinetic and toxicodynamic evaluation of 5-fluorouracil administration after major hepatectomy in a rat model.

BACKGROUND: Chemotherapy after hepatectomy for colorectal liver metastasis has not been established, due to the toxic side effects, which are likely related to impaired drug clearance during liver regeneration. We investigated the pharmacokinetic and toxicodynamic evaluation of 5-fluorouracil (5-FU) during liver regeneration after major hepatectomy in a rat model. METHODS: Thirty-six male Wistar rats were divided into control (C), control with chemotherapy (CC), hepatectomy (H), and hepatectomy with chemotherapy (HC) groups. The CC and HC groups were administered 5-FU for 4 days. Plasma 5-FU, liver weight, and liver dihydropyrimidine dehydrogenase (DPD) were measured. The ileal villous height was measured to determine adverse effects. RESULTS: The area under the curve and maximum plasma concentration of 5-FU increased by up to 51% and 32%, respectively, in the HC group compared to the CC group. The liver regeneration rate was significantly lower in the HC group than in the H group (67.3 ± 7.4 vs 33.0 ± 5.7%, p < 0.001). The HC group had a significantly lower liver DPD than the CC group (4.4 ± 1.1 mg vs 6.9 ± 1.1 mg, p < 0.01). The HC group had a significantly lower ileal villous height than the CC group (253 ± 40 µm vs. 318 ± 36 µm, p < 0.05). CONCLUSIONS: Reduction of the total liver DPD following major hepatectomy caused increased plasma 5-FU levels and 5-FU-associated toxicity.

Efficacy and safety of leuprorelin acetate for subjects with spinal and bulbar muscular atrophy: pooled analyses of two randomized-controlled trials.

BACKGROUND: Spinal and bulbar muscular atrophy (SBMA) is an adult-onset, hereditary neuromuscular disease characterized by muscle atrophy, weakness, contraction fasciculation, and bulbar involvement. Although the causative gene, androgen receptor, has been identified, the development of novel therapeutics for SBMA is incomplete. In this study, the efficacy and safety of leuprorelin acetate administration for patients with SBMA, using the pooled data of two randomized-controlled trials, was studied. METHODS: Two randomized double-blinded studies (JASMITT-06DB and JASMITT-11DB) were done as multicentric, investigator-initiated clinical trials in Japan. In both studies, eligible patients were randomly assigned 1:1 to receive leuprorelin acetate administration once per 12 weeks for 48 weeks. The primary endpoint was the longitudinal change of pharyngeal barium residues from the baseline data measured with videofluorographic swallowing analyses. The pooled analysis plan was decided upon after the 06B study was finished and before the 11DB study began. RESULTS: The primary endpoint difference between the leuprorelin group and the placebo group was pharyngeal barium residue after initial swallowing, - 4.12% (95% CI, - 8.40-0.15; p = 0.058). The primary endpoint of this study does not reach significant results, although inter-group differences of pharyngeal barium residues after the initial swallowing indicated that leuprorelin acetate may be effective at each assessment point in both study groups. CONCLUSIONS: The efficacy of leuprorelin acetate for patients with SBMA was statistically similar in two randomized-controlled trials, and suggested that leuprorelin acetate may be effective and safe. Further investigations are needed to clarify the promising efficacy of the drug.

[Automated Classification of Calcification and Stent on Computed Tomography Coronary Angiography Using Deep Learning].

In computed tomography coronary angiography (CTCA), calcification and stent make it difficult to evaluate intravascular lumen. This is a cause of low positive-predictive value of coronary stenosis. Therefore, it is expected to develop a computer-aided diagnosis (CAD) system that can automatically detect stenosis in coronary arteries. The purpose of this study is to automatically recognize calcifications or stents in coronary arteries and classify them from the normal coronary artery in CTCA. We used 4960 coronary-cross-sectional images, which consisted of 1113 images with calcification, 1353 images with a stent, and 2494 normal artery images. These images were automatically classified using the deep convolutional neural network (LeNet, AlexNet, and GoogLeNet). The classification accuracy of LeNet, AlexNet, and GoogLeNet were 58.4%, 75.9%, and 81.3%, respectively. The proposed method would be a fundamental technique of CAD in CTCA.

Pancreas Atrophy and Islet Amyloid Deposition in Patients With Elderly-Onset Type 2 Diabetes.

Context: With prolonged life expectancy, we often encounter patients with elderly-onset type 2 diabetes mellitus (eT2DM). Although the clinical features of eT2DM are suggested to be different from those in patients with middle-age-onset type 2 diabetes mellitus (mT2DM), the islet pathologic features in eT2DM have not been addressed. Objective: We attempted to characterize the pancreatic pathology in eT2DM and sought its clinical implications. Materials and Methods: Pancreata from 13 young nondiabetic (age, 20 to 29 years), 27 patients with mT2DM (age, 45 to 87 years), 22 middle-age subjects without T2DM, 15 subjects with eT2DM (age, 85 to 100 years), and 30 elderly subjects without T2DM were investigated. Together with conventional microscopic observations, morphometric analysis on the islet, islet endocrine cells, and amyloid deposition was conducted on immunostained sections. Results: The estimated age of diabetes onset was 80.8 ± 1.4 years (mean ± standard error) in the eT2DM group and that of the mT2DM group was 48.3 ± 2.4 years. The pancreatic weight was nearly 50% less in the eT2DM group than in the other groups, showing duct obstruction with epithelial hyperplasia, marked acinar atrophy, fibrosis, and amyloid deposition in the islet. The islet mass was significantly reduced in the eT2DM group. The amyloid volume density correlated inversely with the ß-cell volume density but not with the body mass index in the eT2DM group. Laboratory data showed mild elevation of serum amylase in the eT2DM group, although clinical signs and symptoms of pancreatitis were not apparent. Conclusions: eT2DM is distinct from mT2DM and characterized by pancreas atrophy, ductal lesions, and amyloid deposition.

Laparoscopic treatment for inguinal hernia combined with cryptorchidism: Totally extraperitoneal repair with orchiectomy under the same operative view.

INTRODUCTION: Approximately 7% of child patients with inguinal hernias also present with cryptorchidism. On the other hand, combined adult cases are uncommon. Here we report two adult cases of inguinal hernia combined with intra-canalicular cryptorchidism who underwent totally extraperitoneal (TEP) repair with orchiectomy under the same operative view. PRESENTATION OF CASES: We treated two patients (49- and 38-year-old men) with right indirect inguinal hernias and cryptorchidism. Both patients underwent TEP repair with orchiectomy. In operative findings, an atrophic testis was drawn out with a hernia sac from the internal inguinal ring. After the testis was separated from the sac and cord structure was sheared, it was removed. The procedure did not require special techniques and devices. In both patients, the postoperative courses were satisfactory. DISCUSSION: To our knowledge, there has been only one such reported case till date which demonstrated the feasibility of TEP repair accompanied by orchiectomy. CONCLUSIONS: TEP repair with orchiectomy under the same operative view could be safely performed in adults with an inguinal hernia combined with extra-abdominal cryptorchidism. This procedure could be an option for the treatment of such adult patients.

Efficacy and safety of leuprorelin in patients with spinal and bulbar muscular atrophy (JASMITT study): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Spinal and bulbar muscular atrophy is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor. At present there are no treatments for spinal and bulbar muscular atrophy, although leuprorelin suppressed the accumulation of pathogenic androgen receptors in a phase 2 trial. We aimed to assess the efficacy and safety of leuprorelin for spinal and bulbar muscular atrophy. METHODS: The Japan SBMA Interventional Trial for TAP-144-SR (JASMITT) was a 48-week, randomised, double-blind, placebo-controlled trial done at 14 hospitals between August, 2006, and March, 2008. Patients with spinal and bulbar muscular atrophy were randomly assigned (1:1) by minimisation to subcutaneous 11.25 mg leuprorelin or identical placebo every 12 weeks. Patients and investigators were masked to treatment allocation. The primary endpoint was pharyngeal barium residue, which indicates incomplete bolus clearance, measured at week 48 by videofluorography. All patients who were randomly assigned and who were assessed with videofluorography at least once were included in the analyses. This study is registered with the JMACCT clinical trials registry, number JMA-IIA00009, and the UMIN clinical trials registry, number UMIN000000465. FINDINGS: 204 patients were randomly assigned and 199 started treatment: 100 with leuprorelin and 99 with placebo. At week 48, the pharyngeal barium residue after initial swallowing had changed by -5.1% (SD 21.0) in the leuprorelin group and by 0.2% (18.2) in the placebo group (difference between groups -5.3%; 95% CI -10.8 to 0.3; p=0.063). The mean difference in pharyngeal barium residue after piecemeal deglutition at week 48 was -3.2% (-6.4 to 0.0; p=0.049), but there was no significant difference between the groups after covariate adjustment for the baseline data (-4.1 to 1.6; p=0.392). In a predefined subgroup analysis, leuprorelin treatment was associated with a greater reduction in barium residue after initial swallowing than was placebo in patients with a disease duration less than 10 years (difference between groups -9.8, -17.1 to -2.5; p=0.009). There were no significant differences in the number of drug-related adverse events between groups (57 of 100 in the leuprorelin group and 54 of 99 in the placebo group; p=0.727). INTERPRETATION: 48 weeks of treatment with leuprorelin did not show significant effects on swallowing function in patients with spinal and bulbar muscular atrophy, although it was well tolerated. Disease duration might influence the efficacy of leuprorelin and thus further clinical trials with sensitive outcome measures should be done in subpopulations of patients. FUNDING: Large Scale Clinical Trial Network Project, Japan and Takeda Pharmaceuticals.

Phase 2 trial of leuprorelin in patients with spinal and bulbar muscular atrophy.

OBJECTIVE: Spinal and bulbar muscular atrophy (SBMA) is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor (AR). Animal studies have shown that the pathogenesis of SBMA is dependent on serum testosterone level. This study is aimed at evaluating the efficacy and safety of androgen deprivation by leuprorelin acetate in patients with SBMA. METHODS: Fifty SBMA patients underwent subcutaneous injections of leuprorelin acetate or placebo in a randomized, placebo-controlled trial for 48 weeks, followed by an open-label trial for an additional 96 weeks, in which 19 patients of the leuprorelin group and 15 of the placebo group received leuprorelin acetate. The patients who did not participate in the open-label trial were also followed up for the 96-week period (UMIN000000474). RESULTS: Leuprorelin acetate significantly extended the duration of cricopharyngeal opening in videofluorography and decreased mutant AR accumulation in scrotal skin biopsy. The patients treated with leuprorelin acetate for 144 weeks exhibited significantly greater functional scores and better swallowing parameters than those who received placebo. Autopsy of one patient who received leuprorelin acetate for 118 weeks suggested that androgen deprivation inhibits the nuclear accumulation or stabilization, or both, of mutant AR in the motor neurons of the spinal cord and brainstem. INTERPRETATION: These observations suggest that administration of leuprorelin acetate suppresses the deterioration of neuromuscular impairment in SBMA by inhibiting the toxic accumulation of mutant AR. The results of this phase 2 trial support the start of large-scale clinical trials of androgen deprivation for SBMA.

Molecular genetics and biomarkers of polyglutamine diseases.

Polyglutamine diseases are hereditary neurodegenerative disorders caused by an abnormal expansion of a trinucleotide CAG repeat, which encodes a polyglutamine tract. To date, nine polyglutamine diseases are known: Huntington's disease (HD), spinal and bulbar muscular atrophy (SBMA), dentatorubral-pallidoluysian atrophy (DRPLA) and six forms of spinocerebellar ataxia (SCA). The diseases are inherited in an autosomal dominant fashion except for SBMA, which shows an X-linked pattern of inheritance. Although the causative gene varies with each disorder, polyglutamine diseases share salient genetic features as well as molecular pathogenesis. CAG repeat size correlates well with the age of onset in each disease, shows both somatic and germline instability, and has a strong tendency to further expand in successive generations. Aggregation of the mutant protein followed by the disruption of cellular functions, such as transcription and axonal transport, has been implicated in the etiology of neurodegeneration in polyglutamine diseases. Although animal studies have provided promising therapeutic strategies for polyglutamine diseases, it remains difficult to translate these disease-modifying therapies to the clinic. To optimize "proof of concept", the process for testing candidate therapies in humans, it is of importance to identify biomarkers which can be used as surrogate endpoints in clinical trials for polyglutamine diseases.