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Medial displacement calcaneal osteotomy (MDCO) is the standard procedure for flatfoot. We investigated the effect of MDCO on the foot using a finite element analysis. Foot models were created from computed tomography data of 8 patients with flat feet. MDCO was performed on each model with bone translation distance of 4, 8, and 12 mm. The morphological changes, plantar pressures, and stress percentage on the talocrural and subtalar joints were evaluated before and after surgery. Morphological evaluation showed improvement in the medial longitudinal arch. The stress percentage of plantar pressure in the medial area decreased, and the stress percentage of plantar pressure in the mid- and lateral forefoot area increased. At the talocrural joint, the medial and middle stress percentage increased, while the lateral and posterior stress percentage decreased. In the subtalar joint, the stress percentage in the middle subtalar joint increased and that in the posterior subtalar joint decreased. Within the posterior subtalar joint, the anterior and medial stress percentage increased, while the posterior and lateral stress percentage decreased. Preoperative simulation using the finite element analysis may be useful in understanding postoperative morphological changes and loading conditions to perform patient-specific surgery. [ABSTRACT FROM AUTHOR]

The detection of spontaneous magnetic signals can be used for the non-invasive electrophysiological evaluation of induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs). We report that deep learning with a dataset that combines magnetic signals estimated using numerical simulation and actual noise data is effective in the detection of weak biomagnetic signals. To verify the feasibility of this method, we measured artificially generated magnetic signals that mimic cellular magnetic fields using a superconducting quantum interference device and attempted peak detection using a long short-term memory network. We correctly detected 80.0% of the peaks and the method achieved superior detection performance compared with conventional methods. Next, we attempted peak detection for magnetic signals measured from mouse iPS-CMs. The number of detected peaks was consistent with the spontaneous beats counted using microscopic observation and the average peak waveform achieved good similarity with the prediction. We also observed the synchronization of peak positions between simultaneously measured field potentials and magnetic signals. Furthermore, the magnetic measurements of cell samples treated with isoproterenol showed potential for the detection of chronotropic effects. These results suggest that the proposed method is effective and has potential application in the safety assessment of regenerative medicine and drug screening. [ABSTRACT FROM AUTHOR]

Rationale: The central cholinergic system is a major therapeutic target for restoring cognitive functions. Although manipulation of cholinergic signaling is known to alter working memory (WM), the underlying mechanism remains unclear. It is widely accepted that WM consists of multiple functional modules, one storing short-term memory and the other manipulating and utilizing it. A recently developed visual search task and a relevant model can be used to assess multiple components of WM during administration of acetylcholine receptor (AChR)–related substances. Objectives: The effects of systemic administration of AChR-related agents on WM and eye movements were examined during the oculomotor foraging task. Methods: Three monkeys performing the task received an intramuscular injection of saline or the following AChR-related agents: nicotine (24 or 56 μg/kg), mecamylamine (nicotinic AChR antagonist, 1.0 mg/kg), oxotremorine (muscarinic AChR agonist, 3.0 µg/kg), and scopolamine (muscarinic AChR antagonist, 20 μg/kg). The task was to find a target among 15 identical objects by making eye movements within 6 s. The data were analyzed according to the foraging model that incorporated three parameters. Results: Nicotine and mecamylamine significantly increased the utility but not the capacity of short-term memory, while muscarinic AChR-related agents did not alter any WM parameters. Further regression analyses with a mixed-effect model showed that the beneficial effect of nicotine on memory utility remained after considering eye movement variability, but the beneficial effect of mecamylamine disappeared. Conclusions: Nicotine improves visual search, mainly by increasing the utility of short-term memory, with minimal changes in oculomotor parameters. [ABSTRACT FROM AUTHOR]

Mitochondrial disorders are a group of clinically and genetically heterogeneous multisystem disorders and peripheral neuropathy is frequently described in the context of mutations in mitochondrial-related nuclear genes. This study aimed to identify the causative mutations in mitochondrial-related nuclear genes in suspected hereditary peripheral neuropathy patients. We enrolled a large Japanese cohort of clinically suspected hereditary peripheral neuropathy patients who were mutation negative in the prescreening of the known Charcot–Marie–Tooth disease-causing genes. We performed whole-exome sequencing on 247 patients with autosomal recessive or sporadic inheritance for further analysis of 167 mitochondrial-related nuclear genes. We detected novel bi-allelic likely pathogenic/pathogenic variants in four patients, from four mitochondrial-related nuclear genes: pyruvate dehydrogenase beta-polypeptide (PDHB), mitochondrial poly(A) polymerase (MTPAP), hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, beta subunit (HADHB), and succinate-CoA ligase ADP-forming beta subunit (SUCLA2). All these patients showed sensory and motor axonal polyneuropathy, combined with central nervous system or multisystem involvements. The pathological analysis of skeletal muscles revealed mild neurogenic changes without significant mitochondrial abnormalities. Targeted screening of mitochondria-related nuclear genes should be considered for patients with complex hereditary axonal polyneuropathy, accompanied by central nervous system dysfunctions, or with unexplainable multisystem disorders. [ABSTRACT FROM AUTHOR]

Backgound: Cold snare polypectomy (CSP) can minimize the risk of adverse events and has become a standard treatment for small colorectal polyps. CSP might also be suitable for small superficial non-ampullary duodenal epithelial tumors (SNADETs). This study aimed to evaluate the safety of CSP for SNADETs. Methods: The major indication criteria were as follows: (1) endoscopically diagnosed SNADET, (2) ≤ 10 mm, and (3) a single primary lesion. CSP was performed using an electrosurgical snare without electrocautery. Follow-up endoscopy and scar biopsy were performed 3 months after CSP. The primary endpoint was the delayed adverse events rate. Results: In total, 21 patients were enrolled. Two and 19 lesions were located in the duodenal bulb and 2nd portion, respectively; the median lesion size was 8 mm. CSP was attempted for all lesions; three lesions could not be resected without electrocautery and were removed by conventional endoscopic mucosal resection (EMR). The rate of spurting bleeding after CSP was 0%. The median procedure time was 12 min, the median resected specimen size was 12 mm, and the rate of en bloc resection was 81% (17/21). No adverse events were observed intraoperatively, with no delayed adverse events after CSP. Histopathology revealed 15 adenomas, 4 cancers (intramucosal), and 2 non-neoplastic lesions. The horizontal margins were negative/positive/undetermined in 9, 1, and 11 cases, respectively. All vertical margins were negative. Only one recurrence was detected by follow-up endoscopy 3 months after CSP. Conclusions: CSP can be performed safely for small SNADETs. Clinical trial registration: This trial was registered with the University Hospital Medical Information Network Clinical Trials Registry (http://www.umin.ac.jp/ctr/index.htm), and the registration number is UMIN000019157. [ABSTRACT FROM AUTHOR]

Movements synchronized with external rhythms are ubiquitous in our daily lives. Despite the involvement of the cerebellum, the underlying mechanism remains unclear. In monkeys performing synchronized saccades to periodically alternating visual stimuli, we found that neuronal activity in the cerebellar dentate nucleus correlated with the timing of the next saccade and the current temporal error. One-third of the neurons were active regardless of saccade direction and showed greater activity for synchronized than for reactive saccades. During the transition from reactive to predictive saccades in each trial, the activity of these neurons coincided with target onset, representing an internal model of rhythmic structure rather than a specific motor command. The behavioural changes induced by electrical stimulation were explained by activating different groups of neurons at various strengths, suggesting that the lateral cerebellum contains multiple functional modules for the acquisition of internal rhythms, predictive motor control, and error detection during synchronized movements. It remains unclear how the brain represents information regarding synchronized movements. Here, the authors investigated the response properties of cerebellar cells in macaques performing a synchronized saccade task and found three groups of cerebellar neurons with distinct peri-saccade response profiles. [ABSTRACT FROM AUTHOR]

Estrogen-related receptor (ERR), a member of the nuclear receptor superfamily, consists of three subtypes (α, β, γ) and has strong homology with estrogen receptor. No endogenous ligands have been identified for ERRs, but they play key roles in metabolic, hormonal, and developmental processes as transcription factors without ligand binding. Although subnuclear dynamics are essential for nuclear events including nuclear receptor-mediated transcriptional regulation, the dynamics of ERRs are poorly understood. Here, we report that ERRs show subcellular kinetic changes in response to diethylstilbestrol (DES), a synthetic estrogen that represses the transactivity of all three ERR subtypes, using live-cell imaging with fluorescent protein labeling. Upon DES treatment, all ERR subtypes formed discrete clusters in the nucleus, with ERRγ also displaying nuclear export. Fluorescence recovery after photobleaching analyses revealed significant reductions in the intranuclear mobility of DES-bound ERRα and ERRβ, and a slight reduction in the intranuclear mobility of DES-bound ERRγ. After DES treatment, colocalization of all ERR subtypes with scaffold attachment factor B1 (SAFB1), a nuclear matrix-associated protein, was observed in dot-like subnuclear clusters, suggesting interactions of the ERRs with the nuclear matrix. Consistently, co-immunoprecipitation analyses confirmed enhanced interactions between ERRs and SAFB1 in the presence of DES. SAFB1 was clarified to repress the transactivity of all ERR subtypes through the ERR-response element. These results demonstrate ligand-dependent cluster formation of ERRs in the nucleus that is closely associated with SAFB1-mediated transrepression. Taken together, the present findings provide a new understanding of the pathophysiology regulated by ERR/SAFB1 signaling pathways and their subcellular dynamics. [ABSTRACT FROM AUTHOR]

Purpose: The current study aimed to determine the efficacy of trifluridine/tipiracil for elderly patients with advanced colorectal cancer. Methods: This single-arm, open-label, multicenter, phase II study included elderly patients aged 65 years or more who had fluoropyrimidine-refractory advanced colorectal cancer and received trifluridine/tipiracil (70 mg/m2, days 1–5 and 8–12, every 4 weeks). The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS), overall response rate (ORR), toxicities, association between efficacy and geriatric assessment scores, and association between toxicity and plasma drug concentrations. Results: A total of 30 patients with a mean age of 73 years were enrolled. Median PFS was 2.3 months (95% confidence interval, 1.9–4.3 months), while median OS was 5.7 months (95% confidence interval, 3.7–8.9 months). Patients had an ORR of 0%, with 57% having stable disease. Grade 4 neutropenia was observed in 13% of the patients. Patients with a higher G8 score (15 or more) showed longer PFS than those with a lower G8 score (median 4.6 vs. 2.0 months; p = 0.047). Moreover, patients with grade 3 or 4 neutropenia showed higher maximum trifluridine concentrations than those with grade 1 or 2 neutropenia (mean 2945 vs. 2107 ng/mL; p = 0.036). Discussion: The current phase II trial demonstrated that trifluridine/tipiracil was an effective and well-tolerated option for elderly patients with advanced colorectal cancer. Moreover, geriatric assessment tools and/or plasma drug concentration monitoring might be helpful in predicting the efficacy and toxicities in elderly patients receiving this drug. Trial registration number: UMIN000017589, 15/May/2015 (The University Hospital Medical Information Network) [ABSTRACT FROM AUTHOR]

Background: Sigmoid volvulus is a common condition in elderly patients with elongated colons. Although endoscopic de-torsion is effective as the primary treatment of sigmoid volvulus, elective surgery is recommended because of the high risk of recurrence and high mortality rate. Aim: The aim of this study was to determine the risk factors for the recurrence of sigmoid volvulus. Methods: Clinical records of patients treated at Shimane Prefectural Central Hospital were reviewed retrospectively. Among 41 sigmoid volvulus patients who were successfully treated by endoscopic de-torsion and followed up, 30 were observed over 1 year. Among the 30 patients, eight (26.7%) did not experience recurrence, while 22 (73.3%) did. Initial computed tomography (CT) findings indicating the sigmoid colon extending to the diaphragm or ventral to the liver were defined as "extension findings." Extension findings and sigmoid diameter were evaluated in relation to sigmoid volvulus recurrence. Results: Extension findings were significantly more frequent in the recurrent group (77.3%) than in the nonrecurrent group (25.0%) (P = 0.009). Distended sigmoid colon diameter was significantly larger in the recurrent group (11.7 ± 3.8 cm) than in the nonrecurrent group (7.1 ± 1.1 cm) (P = 0.044). Receiver operating characteristic curve analysis demonstrated that the performance threshold was greater than 8.9 cm. Kaplan–Meier analysis showed the significantly high sigmoid volvulus recurrence rate in the patients with extension findings and a distended sigmoid colon greater than 8.9 cm. Conclusions: CT findings of a long and distended sigmoid colon in initial sigmoid volvulus are risk factors for the recurrence of sigmoid volvulus. [ABSTRACT FROM AUTHOR]

Organic light-emitting diodes (OLEDs) are a promising light-source technology for future generations of display1,2. Despite great progress3–12, it is still challenging to produce blue OLEDs with sufficient colour purity, lifetime and efficiency for applications. Here, we report pure-blue (Commission Internationale de l' Eclairage (CIE) coordinates of 0.13, 0.16) OLEDs with high efficiency (external quantum efficiency of 32 per cent at 1,000 cd m−2), narrow emission (full-width at half-maximum of 19 nm) and good stability (95% of the initial luminacnce (LT95) of 18 hours at an initial luminance of 1,000 cd m−2). The design is based on a two-unit stacked tandem hyperfluorescence OLED with improved singlet-excited-state energy transfer from a sky-blue assistant dopant exhibiting thermally activated delayed fluorescence (TADF) called hetero-donor-type TADF(HDT-1) to a pure-blue emitter. With stricter control of device fabrication and procedures it is expected that device lifetimes will further improve to rival commercial fluorescent blue OLEDs. Pure-blue organic LEDs with narrow emission and improved stability show promise for display applications. [ABSTRACT FROM AUTHOR]

Aromatic organic deep-blue emitters that exhibit thermally activated delayed fluorescence (TADF) can harvest all excitons in electrically generated singlets and triplets as light emission. However, blue TADF emitters generally have long exciton lifetimes, leading to severe efficiency decrease, i.e., rolloff, at high current density and luminance by exciton annihilations in organic light-emitting diodes (OLEDs). Here, we report a deep-blue TADF emitter employing simple molecular design, in which an activation energy as well as spin–orbit coupling between excited states with different spin multiplicities, were simultaneously controlled. An extremely fast exciton lifetime of 750 ns was realized in a donor–acceptor-type molecular structure without heavy metal elements. An OLED utilizing this TADF emitter displayed deep-blue electroluminescence (EL) with CIE chromaticity coordinates of (0.14, 0.18) and a high maximum EL quantum efficiency of 20.7%. Further, the high maximum efficiency were retained to be 20.2% and 17.4% even at high luminance. Deep-blue emitting organic materials with low exciton lifetime are required to realize efficient organic light-emitting diodes (OLEDs) at high brightness. Here, the authors report deep-blue OLEDs featuring thermally activated delayed fluorescence molecules with subnano-second exciton lifetime. [ABSTRACT FROM AUTHOR]

Purpose: The aim of the present study was to evaluate the incidence and explore the risk factors of febrile neutropenia (FN) in patients with esophageal cancer receiving neoadjuvant docetaxel, cisplatin, and 5-fluorouracil (DCF) chemotherapy in real-world settings.Methods: We retrospectively reviewed clinical data of 128 consecutive patients with esophageal cancer. Specifically, these patients underwent neoadjuvant DCF chemotherapy with prophylactic antibiotic administration at our institution between July 2009 and January 2015. Two FN-related endpoints were set as follows: definite FN (dFN) defined as grade 4 neutropenia at the onset of fever and clinically suspected FN (csFN), which included both patients with dFN and patients without grade 4 neutropenia but with deteriorating grade 3 neutropenia at the onset of fever who were clinically diagnosed with FN for which they underwent treatment. The risk factors for dFN and csFN were evaluated based on patients' characteristics.Results: A total of 72 (56.3%) patients developed grade 3 or grade 4 neutropenia and 26 (20.3%) developed csFN including 14 (10.9%) with dFN. Multivariate analysis revealed that older age (OR 3.57, CI 1.27-10.1, P = 0.016) and living alone (OR 5.17, 95% CI 1.26-21.3, P = 0.023) were statistically significant risk factors for csFN development. As to dFN, no statistically significant risk factors were identified.Conclusions: Older age and living alone are significant risk factors for developing FN, and thus, particularly for patients with risk factors for FN, G-CSF should be considered instead of prophylactic antibiotics with careful observation. [ABSTRACT FROM AUTHOR]

Moving objects are often occluded behind larger, stationary objects, but we can easily predict when and where they reappear. Here, we show that the prediction of object reappearance is subject to adaptive learning. When monkeys generated predictive saccades to the location of target reappearance, systematic changes in the location or timing of target reappearance independently altered the endpoint or latency of the saccades. Furthermore, spatial adaptation of predictive saccades did not alter visually triggered reactive saccades, whereas adaptation of reactive saccades altered the metrics of predictive saccades. Our results suggest that the extrapolation of motion trajectory may be subject to spatial and temporal recalibration mechanisms located upstream from the site of reactive saccade adaptation. Repetitive exposure of visual error for saccades induces qualitatively different adaptation, which might be attributable to different regions in the cerebellum that regulate learning of trajectory prediction and saccades. [ABSTRACT FROM AUTHOR]

α-Synuclein (αSyn), the major constituent of Lewy bodies and Lewy neurites, is generally expressed in presynapses and is involved in synaptic function. However, we previously demonstrated that some neurons, including those in the olfactory bulb, show high αSyn expression levels in the cell body under normal conditions. αSyn is also known to be important for adult neurogenesis. Thus, in present study, we examined the role of αSyn in juxtaglomerular neurons (JGNs) with high αSyn expression in the mouse olfactory bulb. Most αSyn-enriched JGNs expressed sex-determining region Y-box 2 (Sox2), which functions to maintain neural immature identity. Interestingly, in αSyn homozygous (-/-) knockout (KO) mice, Sox2-positive JGNs were significantly increased compared with heterozygous (+/-) KO mice. Following global brain ischemia using wild-type mice, there was also a significant decrease in Sox2-positive JGNs, and in the co-expression ratio of Sox2 in αSyn-enriched JGNs. By contrast, the co-expression ratio of neuronal nuclei (NeuN, mature neuronal marker) was significantly increased in αSyn-enriched JGNs. However, this ischemia-induced decrease of Sox2-positive JGNs was not observed in αSyn homozygous KO mice. Overall, these data suggest that αSyn functions to promote the maturation of immature JGNs in the mouse olfactory bulb. [ABSTRACT FROM AUTHOR]

Background: In elderly patients with superficial esophageal squamous cell carcinoma (ESCC), the optimal treatment strategy after non-curative endoscopic submucosal dissection (ESD) remains unclear. We aimed to evaluate the validity of additional treatments after non-curative ESD and post-ESD survival predictors in elderly patients with ESCC.Methods: Elderly patients (age > 75 years) treated with ESD for ESCC between January 2010 and July 2014 at six tertiary referral hospitals in Japan were retrospectively investigated and stratified according to lymph node metastasis risk, based on histological findings (high-risk factors: positive lymphovascular invasion, submucosal invasion, and positive/indeterminate vertical margin) and post-ESD treatment strategy: group A (287 patients; low risk), group B (41 patients; high risk, without additional treatment), and group C (32 patients; high risk, with additional treatment). We evaluated 3- and 5-year overall survival and disease-specific survival, and prognostic factors for post-ESD survival.Results: At a median follow-up of 38, 40, and 49 months, respectively, there was 1 esophageal cancer-related death in group A, 1 in group B, and none in group C, whereas 22, 9, and 3 patients in groups A, B, and C died of other diseases. The groups differed significantly in overall survival (92.4%; 87.6%; 93.4%, p = 0.022), although not in disease-specific survival (99.4%; 96.3%; 100%, p = 0.217). On multivariate analysis, Charlson Comorbidity Index (CCI) ≥ 2 was the only independent risk factor for post-ESD death (hazard ratio 7.92; 95% confidence interval 3.42-18.3; p < 0.001).Conclusions: A follow-up strategy without additional treatment after ESD for ESCC may be acceptable in high-risk elderly patients, especially for CCI ≥ 2. [ABSTRACT FROM AUTHOR]

Background: Endoscopic submucosal dissection (ESD) is the standard treatment for superficial esophageal cancer (SEC); however, it is sometimes technically difficult. Our aim was to identify the predictors of technical difficulty during ESD for SEC.Methods: We reviewed the records of patients who underwent ESD for superficial esophageal squamous cell carcinomas at a tertiary cancer center between April 2008 and March 2016. Patients undergoing ESD after esophagectomy or for residual/recurrent lesions were excluded. Preoperative factors such as tumor subsite, localization, preoperative size, macroscopic type, endoscopic depth of invasion, and treatment for synchronous multiple SECs or previous history of radiation therapy were analyzed. Logistic regression analysis was performed to identify the predictors of technical difficulty, defined as (1) long procedure time (≥ 120 min), (2) adverse events (perforation, pneumomediastinum), or (3) incomplete resection (piecemeal resection, positive or indeterminate vertical margin).Results: A total of 679 lesions in 511 patients were analyzed. Difficultly was experienced in 60 cases. The procedure time was > 120 min in 43 (6.3%) patients, adverse events occurred in 16 (2.8%), and incomplete resection occurred in 17 (2.5%). Multivariate logistic regression revealed that tumors in the left esophageal wall (OR 2.15; 95% CI 1.17-3.91; p = 0.014) and those encompassing ≥ 1/2 its circumference (OR 5.06; 95% CI 2.40-11.34; p < 0.001) were independently associated with difficulty.Conclusions: Tumors in the left esophageal wall and tumors measuring > 1/2 of the esophageal circumference are predictors of difficult esophageal ESD. These results may contribute to better patient selection according to each endoscopist's skill. [ABSTRACT FROM AUTHOR]

Background: Among all types of gastric cancer (GC), signet-ring cell carcinoma (sig-GC) accounts for 4–17% of cases. The prognosis of early sig-GC is relatively good, with the 5-year survival rate at 99.7%. However, the correlation between histological features and lymph node metastasis (LNM) among pT1a (M) sig-GC remains unclear. Sig-GC often exhibits a double-layer structure (DLS) in the intramucosal layer, demonstrating functional differentiation into the normal gastric gland. Assumedly, the loss of the differentiation makes the DLS deranged, accounting for the occurrence of submucosal invasion and LNM. This study aimed to assess the proportion of DLS, to elucidate the correlation between histological features (including DLS) and LNM status, and to determine the LNM-negative condition in pT1a (M) sig-GC. Methods: We reviewed the pathological data of 310 patients with 310 intramucosal sig-GCs who received gastrectomy with lymph node dissection. Immunohistochemistry was performed on all specimens to evaluate the presence of DLS. Furthermore, we review the clinicopathological features, including tumor size, lymphovascular invasion (LVI), ulceration (UL), and DLS results, and then statistically analyze the correlation between these features and LNM status. Results: Overall, 129 pT1a (M) sig-GCs (42%) were DLS present. The univariate analysis revealed that "Tumor size > 20 mm", "UL present", and "DLS absent" were significant risk factors of LNM. The multivariate logistic regression analysis revealed only "DLS absent" as statistically significant. Conclusions: "DLS absent" is a risk factor of LNM detected by the multivariate analysis. In pT1a (M), LVI absent, UL absent, tumor size > 20 mm, sig-GC, no LNM occurred in "DLS present" cases. [ABSTRACT FROM AUTHOR]

Background: Endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) in the remnant stomach is a minimally invasive treatment. Few studies compared the technical difficulty of ESD involving the suture line and anastomosis, and information on long-term outcomes is insufficient. This study aimed to elucidate the short- and long-term outcomes of ESD for EGC in the remnant stomach.Methods: We investigated patients who underwent ESD for EGC in the remnant stomach between September 2002 and March 2016. Clinicopathological data were retrieved to assess en bloc resection rates, complications, and long-term outcomes including overall survival and cause-specific survival.Results: A total of 136 consecutive patients with 165 lesions resected by 157 ESD procedures were retrospectively evaluated. The en bloc resection rate was 95.5%. Complications included 16 intraoperative perforations (10.2%), 2 delayed perforations (1.3%), and 15 delayed bleeding (9.6%), which were successfully treated with endoscopy. The en bloc resection rate was significantly higher in the suture line group (100%) and the non-anastomosis or suture line group (98.8%) than in the anastomosis group (82.9%). However, the intraoperative perforation rate was significantly higher in the anastomosis group (31.4%) than in other groups. The 5-year overall and cause-specific survival rates were 88.4% and 97.6%, respectively, during a median follow-up period of 50.7 months (interquartile range 30.8-91.3).Conclusions: The long-term outcomes of ESD for EGC in the remnant stomach were favorable. However, ESD involving the anastomosis was a technically demanding procedure due to the low en bloc resection rate and high perforation rate. [ABSTRACT FROM AUTHOR]

α-Synuclein, the major component of Lewy bodies (LBs) and Lewy neurites (LNs), is expressed in presynapses under physiologically normal conditions and is involved in synaptic function. Abnormal intracellular aggregates of misfolded α-synuclein such as LBs and LNs are pathological hallmarks of synucleinopathies, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). According to previous studies using pathological models overexpressing α-synuclein, high expression of this protein in neurons is a critical risk factor for neurodegeneration. Therefore, it is important to know the endogenous expression levels of α-synuclein in each neuronal cell type. We previously reported differential expression profiles of α-synuclein in vitro and in vivo. In the wild-type mouse brain, particularly in vulnerable regions affected during the progression of idiopathic PD, α-synuclein is highly expressed in neuronal cell bodies of some early PD-affected regions, such as the olfactory bulb, the dorsal motor nucleus of the vagus, and the substantia nigra pars compacta. Synaptic expression of α-synuclein is mostly accompanied by expression of vesicular glutamate transporter-1, an excitatory synapse marker protein. In contrast, α-synuclein expression in inhibitory synapses differs among brain regions. Recently accumulated evidence indicates the close relationship between differential expression profiles of α-synuclein and selective vulnerability of certain neuronal populations. Further studies on the regulation of α-synuclein expression will help to understand the mechanism of LB pathology and provide an innovative therapeutic strategy to prevent PD and DLB onset. [ABSTRACT FROM AUTHOR]

Background: The aim was to investigate the relationships between total sunitinib plasma concentrations (sunitinib plus its active metabolite; N-desethyl sunitinib) and clinical outcomes in Japanese patients with metastatic renal cell carcinoma (mRCC).Methods: Twenty patients with mRCC were enrolled following treatment with sunitinib. To assess safety, the total sunitinib concentration range up to discontinuation of treatment and dosage reduction associated with adverse events within 6 weeks from initiating administration were analyzed. The longest administered sunitinib dosage was defined as the maintenance dose, and the relationship between total sunitinib concentration at the maintenance dosage and sunitinib efficacy was investigated.Results: Total sunitinib concentration was significantly higher in patients who discontinued treatment or had dosage reduction due to adverse events within 6 weeks after initiation of sunitinib than in patients who continued treatment with the initial dosage. The time to treatment failure, progression-free survival, and overall survival were better in patients with total sunitinib concentrations < 50 ng/mL than in those with concentrations ≥ 50 ng/mL.Conclusions: The present study demonstrated that the effective range of total sunitinib concentration in Japanese patients with mRCC was lower than 50-100 ng/mL which was previously reported. These results indicate that therapeutic drug monitoring could maintain the therapeutic effect of sunitinib while minimizing adverse events by personalizing sunitinib dosages for Japanese patients with mRCC. [ABSTRACT FROM AUTHOR]

Background: A novel method for the prevention of bleeding after gastric endoscopic submucosal dissection (ESD) is necessary, as the numbers of patients taking antithrombotic agents have increased. This study aimed to assess the efficacy and safety of the covering method using polyglycolic acid (PGA) sheets and fibrin glue for ESD-induced ulcer in preventing post-ESD bleeding in patients under continued antithrombotic agents.Methods: One hundred five consecutive gastric tumors among 84 patients who were treated by ESD under continued antithrombotic agents between April 2014 and September 2015 were enrolled in this study. The patients were classified into two groups, the covering group (52 lesions among 38 patients; those with ESD in whom PGA sheets and fibrin glue were used as the covering method) and the control group (53 lesions among 46 patients; ESD only), and their post-ESD bleeding rates were compared.Results: No significant differences were seen in the number and type of antithrombotic agents, lesion location, median procedure time, and median resected specimen size between the groups. ESD was completed in all cases, with no cases of uncontrollable bleeding during the procedure. Post-ESD bleeding occurred in 5.8% (3/52) and 20.8% (11/53) in the covering and control groups, respectively. The post-ESD bleeding rate significantly differed between the groups (P = 0.04; odds ratio, 0.23; 95% confidential interval, 0.06-0.89). No adverse events were associated with the use of PGA sheets and fibrin glue.Conclusions: The covering method using PGA sheets and fibrin glue has the potential to reduce post-ESD bleeding in patients receiving continued antithrombotic agents. [ABSTRACT FROM AUTHOR]

Background: Stenosis is a troublesome complication after wide endoscopic submucosal dissection (ESD). As steroids are known to prevent post-ESD esophageal stenosis, this study aimed to clarify the gastric effects.Methods: This was a retrospective single-institution study. Between September 2002 and June 2015, 132 patients with a post-ESD mucosal defect exceeding three-fourths of the circumference were identified. Among them, 107 patients who did not undergo additional surgery for non-curative resection were reviewed. Steroid treatment (local injection and/or systemic) for stenosis prevention was administered to 28 patients within 10 days after ESD (steroid group). The incidence of stenosis and course of therapeutic endoscopic balloon dilation (EBD) were analyzed between the steroid and non-steroid group.Results: Stenosis occurred in 31% (33/107) of patients. Full circumferential defect and defect extending to the pyloric ring were significantly related with stenosis. The proportion of patients with a full circumferential defect was relatively higher in the steroid group (14%) compared to the non-steroid group (5%) (p = 0.111). There was no significant relationship between the incidence of stenosis and the use of steroids (steroid group 39%, non-steroid group 28%, p = 0.260). However, the interval from ESD to stenosis was significantly delayed among steroid-treated patients with a near-circumferential to three-fourth mucosal defect (p = 0.001) and among patients with ESD in the lower stomach (p = 0.002). The number of therapeutic EBDs and treatment duration did not differ significantly between the groups. Steroid treatment did not increase the incidence of ESD- and EBD-related complications.Conclusion: Despite the retardation of the occurrence of stenosis in some subgroups, early steroid treatment did not a show a significant effect on stenosis prevention after wide gastric ESD. Further evaluation is needed to determine the dose and timing of steroid treatment for stenosis after wide gastric ESD. [ABSTRACT FROM AUTHOR]

Background: The standard treatment for clinical submucosal invasive (cT1b) early gastric cancer is gastrectomy. However, Japanese gastric cancer treatment guidelines list endoscopic submucosal dissection (ESD) as an option for treating limited early gastric cancer cases. ESD can be curative depending on the pathological characteristics of resected specimens. Thus, we aimed to clarify the benefits and disadvantages of preceding ESD for early gastric cancer. Methods: We retrospectively analyzed patients who underwent ESD or curative gastrectomy for cT1b gastric cancer with differentiated adenocarcinoma 30 mm or less in diameter. Patients who underwent ESD irrespective of undergoing gastrectomy were assigned to the ESD group ( n = 107), and those who underwent gastrectomy without undergoing ESD were assigned to the non-ESD group ( n = 181). Clinicopathological characteristics were assessed, and the short-term and long-term outcomes of patients were compared. Results: The criteria for curative resection were satisfied by 83 patients (28.8%), and preceding ESD did not affect the surgical outcomes of gastrectomy. Two patients (1.9%) who underwent ESD had an unscheduled total gastrectomy. The en bloc and complete resection rates of ESD were 99.0% and 84.1% respectively. Nine patients (8.4%) experienced intraprocedure perforation and postprocedure bleeding caused by ESD. Overall survival (hazard ratio 1.38; P = 0.302) and cause-specific survival (hazard ratio 0.96; P = 0.944) were comparable between groups. Conclusions: The stomach was preserved in 28.8% of patients, and preceding ESD did not show obvious disadvantages. Therefore, diagnostic ESD should be considered as an initial treatment for limited cT1b gastric cancer cases. [ABSTRACT FROM AUTHOR]

Background: Although endoscopic submucosal dissection (ESD) represents a significant progress in therapeutic endoscopy, little is known about how trainees attain its technical proficiency. The aims of this study were to evaluate the learning curve and clinical outcomes of gastric ESD performed by trainee endoscopists.Methods: Between April 2009 and March 2014, 334 gastric ESD procedures were performed by seven trainees (42-50 consecutive cases per trainee). The learning curve for gastric ESD was evaluated using the cumulative sum (CUSUM) method. Long-term outcomes were also analyzed.Results: The calculated CUSUM learning curve comprised three phases: Phase I (the initial 15 cases), Phase II (the middle 15 cases), and Phase III (the final 20 cases). The resection speed was 5.7 ± 3.2 min/cm2 in Phase I, 4.7 ± 2.7 min/cm2 in Phase II, and 4.3 ± 2.2 min/cm2 in Phase III. The resection speed was significantly faster in Phase II than in Phase I (p = 0.019). The rate of self-completion reached more than 95% in Phases II and III. The overall complete resection rate was 95%, showing no significant differences between the three phases. Local recurrence was diagnosed in none of the patients during a median follow-up of 38 months.Conclusions: For the trainees, 30 cases were required to attain a higher technical level of competence in gastric ESD. After the learning curve phase, trainee operators could be expected to complete the procedure successfully with favorable long-term outcomes. [ABSTRACT FROM AUTHOR]

Background: Little is known about the specific risks of metastasis in esophageal adenocarcinoma in relation to invasion depth or other pathologic factors.Methods: We conducted a multicenter retrospective study in 13 high-volume centers in Japan from January 2000 to October 2014 to elucidate the risk of metastasis of esophageal adenocarcinoma. A total of 458 patients (217 surgically resected and 241 endoscopically resected) with esophageal adenocarcinoma or esophagogastric adenocarcinoma involving the esophagus were included. Metastasis was considered positive if there was histologically confirmed metastasis in the surgical specimen or clinically confirmed metastasis during follow-up. Metastasis was considered negative if no metastasis was identified in resected specimens and during follow-up in patients treated surgically or no metastasis during follow-up for >5 years in patients treated by endoscopic resection.Results: Metastasis was identified in 72 patients. Multivariate analysis confirmed lymphovascular involvement [odds ratio (OR) 6.20; 95 % confidence interval (CI) 3.12-12.32; p < 0.001], a poorly differentiated component (OR 3.69; 95 % CI 1.92-7.10; p < 0.001), and lesion size >30 mm (OR 3.12; 95 % CI 1.63-5.97; p = 0.001) as independent risk factors for metastasis. No metastasis was detected in patients with mucosal cancer without lymphovascular involvement and a poorly differentiated component (0/186 lesions) or in patients with cancer invading the submucosa (1-500 µm) without lymphovascular involvement, a poorly differentiated component, and ≤30 mm (0/32 lesions).Conclusions: Mucosal and submucosal cancers (1-500 µm invasion) without risk factors have a low incidence of metastasis and may thus be good candidates for endoscopic resection. [ABSTRACT FROM AUTHOR]

Background: The long-term outcomes after non-curative gastric endoscopic submucosal dissection (ESD) are still unknown. We aimed to clarify the pathological risk factors for lymph node metastasis (LNM) of early gastric cancer (EGC) and the long-term outcomes among patients who were judged to have had non-curative ESD.Methods: From September 2002 to December 2012, 506 patients who were judged to have had non-curative gastric ESD were enrolled and classified into two groups: (1) those who subsequently underwent additional surgical resection (surgical group, n = 323) and (2) those followed up without additional surgical resection (nonsurgical group, n = 183). We analyzed pathological risk factors for LNM of EGC in the surgical group. Additionally, we compared long-term outcomes in the two groups.Results: LNM was found pathologically in 9.3 % of the surgical group (30/323) at the additional surgical resection after non-curative ESD. In the multivariate logistic regression analysis, lymphovascular invasion (LVI) was an independent risk factor for LNM in the surgical group (odds ratio 8.57, 95 % confidence interval 2.76-38.14, P < 0.0001). The 5-year cause-specific survival rate was similar in the surgical and nonsurgical groups (98.7 and 96.5 %, respectively; log-rank test, P = 0.07). In contrast, the 5-year cause-specific survival rate of patients with LVI in the surgical group was better than that in the nonsurgical group (98.2 and 79.1 %, respectively; log-rank test, P < 0.0001).Conclusions: A detailed assessment of LVI is essential to the pathological evaluation of endoscopically resected specimens. An additional surgical resection should be strongly recommended for patients with LVI. [ABSTRACT FROM AUTHOR]

Background: The management of antithrombotic therapy in the patients undergoing gastric endoscopic submucosal dissection (ESD) is of concern. This study aimed to assess delayed bleeding rate after gastric ESD in the patients receiving antithrombotic therapy.Methods: This study was a retrospective observational study held in a single institute. The patients undergoing gastric ESD from January 2009 to October 2014 were reviewed. Delayed bleeding rate in the patients receiving antithrombotic therapy was compared with that in matched controls. We also compared delayed bleeding rate in the patients continuing antithrombotic therapy with that in the patients with heparin bridging or cessation of antithrombotic therapy. Among 2388 lesions resected by gastric ESD, 367 lesions were resected in the patients with antithrombotic therapy, and 722 lesions were selected as controls. The lesions in the patients receiving antithrombotic therapy were divided into three subgroups: 54 lesions without preoperative cessation (continuation group), 37 lesions with heparin bridging (heparin group), and 276 lesions with cessation of antithrombotic therapy (cessation group).Results: The incidence of delayed bleeding was significantly higher in the patients receiving antithrombotic therapy (9.5 % [35/367] vs. 4.2 % [30/722]; p < 0.01). Delayed bleeding rate in continuation group, heparin group, and cessation group was 9.2 % (5/54), 10.8 % (4/37), and 9.4 % (26/276), respectively, and no significant difference was observed. Thrombosis occurred only in cessation group (1.6 %).Conclusions: Delayed bleeding rate associated with gastric ESD is significantly higher in the patients receiving antithrombotic therapy. No significant difference in delayed bleeding rate was observed among patients with and without cessation of antithrombotic therapy. To prevent thrombosis, gastric ESD without cessation may be feasible. [ABSTRACT FROM AUTHOR]

Background: Although a high incidence of bacteremia after esophageal endoscopic procedures has been reported, the incidence of bacteremia associated with esophageal endoscopic submucosal dissection (ESD) remains unknown. Therefore, we investigated the incidence of bacteremia associated with esophageal ESD.Methods: From April 2013 to March 2014, patients who underwent esophageal ESD were enrolled prospectively. Two sets of blood cultures were collected from patients at the following time points: (1) immediately after ESD; (2) the next morning; and (3) when fever ≥38 °C was present after ESD.Results: A total of 424 blood culture sets were collected from 101 patients. Six patients had positive blood cultures immediately after ESD (4 %, 7/202 sets). Another patient had a positive blood culture the next morning (0.5 %, 1/202 sets). Ten patients (10 %) developed a post-ESD fever ≥38 °C, and blood cultures from these patients were all negative (0/20 sets). The seven patients with positive blood cultures had no post-ESD fever or infectious symptoms. Growth of Bacteroides thetaiotaomicron was only observed in one patient (1 %) with positive blood cultures immediately after ESD, and this patient was diagnosed with transient bacteremia. The other six patients were considered to have contaminants in their blood cultures. Thus, the incidence of bacteremia after esophageal ESD was 1 % [95 % confidence interval (CI) 0-5 %]. No patient had infectious symptoms, and none required antibiotics after ESD.Conclusions: The incidence of bacteremia after esophageal ESD was low and post-ESD fever was not associated with bacteremia. We conclude that use of routine prophylactic antibiotics to patients undergoing esophageal ESD is unnecessary.Clinical Trial Registry Number: UMIN000012908. [ABSTRACT FROM AUTHOR]

Background: Endoscopic resection has been used to treat small rectal neuroendocrine tumors (NETs). However, the indication for additional surgery after endoscopic resection is unclear. The aim of this study was to identify risk factors for rectal NET metastasis and to determine the indication for additional surgery.Methods: Fifty-five patients with a total of 57 rectal NETs, treated between October 2003 and January 2013, were retrospectively divided into metastatic (11 lesions) and non-metastatic (46 lesions) groups. Tumor size, central depression, invasion depth, lymphatic and venous permeation, mitotic activity, nuclear abnormality, Ki-67 labeling index, and World Health Organization grading classification (G1 or G2) were compared between the groups. Patients underwent endoscopic submucosal resection with a ligation device, transanal full-thickness surgical resection, or radical surgery.Results: By univariate analysis, the odds ratios (OR) for a Ki-67 labeling index >3.0 %, positive lymphatic or venous permeation, World Health Organization grading classification G2, tumor size >10 mm, submucosal invasion >4000 μm, and central depression were 120 (P < 0.001), 67.6 (P < 0.001), 58.7 (P < 0.001), 9.8 (P = 0.0037), 6.8 (P = 0.012), and 5.7 (P = 0.018), respectively. Multivariate logistic regression analyses showed that vascular permeation (OR 111; P = 0.006) and a Ki-67 labeling index >3.0 % (OR 88; P = 0.012) were independent risk factors for metastasis.Conclusions: The Ki-67 labeling index and lymphatic/venous permeation were reliable predictors of rectal NET metastases. [ABSTRACT FROM AUTHOR]

The current paradigm concerning the mechanism of peritoneal dissemination of gastric cancer is that it occurs through an invasive process in which cancer cells directly penetrate the gastric wall and exfoliate into the peritoneal cavity. However, some experimental studies suggest the lymphatic route as an alternative. We present five early gastric cancer cases, which support this alternative pathway of peritoneal dissemination without direct invasion in the serosa. We investigated all patients with early gastric cancer who underwent curative gastrectomy between September 2002 and February 2015 at the Shizuoka Cancer Center, Japan. We examined them by intraoperative peritoneal lavage cytology and frozen section diagnosis of peritoneal nodules during laparotomy. Peritoneal dissemination was defined as peritoneal metastasis by positive cytology or histological diagnosis. Among 1509 early gastric cancers, five cases (0.3 %, 95 % CI 0.1-0.8 %) presented peritoneal dissemination detected by lavage cytology and frozen section diagnosis of peritoneal nodules. Histological examination revealed that the primary tumors invaded the submucosal layer using the lymphatic route, through which they metastasized to regional lymph nodes. Our data indicate that gastric cancer may give rise to peritoneal dissemination even at an early stage, probably through the lymphatic route without direct invasion into the serosa. [ABSTRACT FROM AUTHOR]

Background: Providing appropriate tension to the lesion and securing a stable view of the submucosal layer is important for accomplishing successful endoscopic submucosal dissection (ESD) in gastric cancer. Dental floss clip traction (DFC), a new traction method, is proposed to reduce the difficulty of ESD. The objective of this pilot study was to investigate the efficacy of DFC for gastric ESD.Methods: From August to November 2014, a total of 95 patients with 104 gastric epithelial neoplasms underwent DFC-ESD (DFC group). Historical controls treated by conventional ESD (control group) were individually matched to cases at a 1:1 ratio by lesion location, ulcer findings, resected specimen size, and the proficiency of the operator (trainee/expert). The outcomes of the procedure in the two groups were then compared.Results: The mean ± SD procedure time was 43 ± 24 min in the DFC group and 52 ± 30 min in the control group (P < 0.01). Fewer lesions in the DFC group needed >80 min compared with the control group (3-vs-16 cases, P = 0.01). There were no significant differences in adverse events between the groups. Perforation and delayed bleeding occurred in one and four lesions, respectively, in the DFC group, and three and nine in the control group. En bloc resection was achieved in all cases. No significant differences were found regarding curability of ESD between the groups.Conclusions: DFC effectively reduced ESD procedure time without increasing adverse events. DFC is helpful for rapid, safe ESD. [ABSTRACT FROM AUTHOR]

The serotonin 2C receptor (5-HTR) is a G-protein-coupled receptor implicated in emotion, feeding, reward, and cognition. 5-HTRs are pharmacological targets for mental disorders and metabolic and reward system abnormalities, as alterations in 5-HTR expression, RNA editing, and SNPs are involved in these disturbances. To date, 5-HTR activity has mainly been measured by quantifying inositol phosphate production and intracellular Ca release, but these assays are not suitable for in vivo analysis. Here, we developed a 5-HTR-Tango assay system, a novel analysis tool of 5-HTR activity based on the G-protein-coupled receptor (GPCR)-arrestin interaction. With desensitization of activated 5-HTR by arrestin, this system converts the 5-HTR-arrestin interaction into EGFP reporter gene signal via the LexA transcriptional activation system. For validation of our system, we measured activity of two 5-HTR RNA-editing isoforms (INI and VGV) in HEK293 cells transfected with EGFP reporter gene. The INI isoform displayed both higher basal- and 5-HT-stimulated activities than the VGV isoform. Moreover, an inhibitory effect of 5-HTR antagonist SB242084 was also detected by 5-HT2R-Tango system. This novel tool is useful for in vitro high-throughput targeted 5-HTR drug screening and can be applied to future in vivo brain function studies associated with 5-HTRs in transgenic animal models. [ABSTRACT FROM AUTHOR]

Acute graft-versus-host-disease (aGVHD) is a rare complication in the setting of pancreas-kidney transplantation (PKT). We herein describe the case of a 37-year-old male with severe type 1 diabetes with chronic renal failure who received simultaneous PKT from a female donor. Diarrhea developed on postoperative day (POD) 10. Subsequently, fever and liver dysfunction occurred on POD 32. Skin rashes appeared with pain and itching on his trunk and extremities on POD 40. As pancytopenia occurred on POD 63, bone marrow biopsies demonstrated profound hypoplastic marrow. On POD 69, we eventually made a definitive diagnosis of aGVHD because skin biopsies revealed the XX chromosome signal in a fluorescence in situ hybridization analysis. Thereafter, 100 mg of prednisolone was administered for 5 days. Although every symptom was temporarily improved, on POD 156, the patient expired from the septic pneumonia without any effects of antibiotics. Clinician should be aware that PKT has the potential to induce aGVHD. [ABSTRACT FROM AUTHOR]

Background: Gastric stenosis is a major problem after endoscopic submucosal dissection (ESD) for large early gastric cancer, but little is known about the incidence of adverse events associated with endoscopic dilation (ED) for stenosis caused by gastric ESD. The aims of this study were to determine the incidence and risk of bleeding and perforation associated with ED for gastric stenosis after ESD.Methods: This was a single-center, retrospective cohort study conducted at a specialized center for treating cancer. A total of 342 procedures of wire-guided balloon ED were performed for stenosis after gastric ESD in 64 patients. The incidence of adverse events and related clinical characteristics was analyzed.Results: The incidence of bleeding was 3.1% (2/64) per patient and 0.6% (2/342) per procedure. One bleeding case with incomplete cessation of antithrombotics before ED required blood transfusion. The incidence of perforation was 7.8% (5/64) per patient and 1.5% (5/342) per procedure. All perforations occurred in the lower part of the stomach. Two of the five perforation cases were inappropriate for nonoperative therapy, and thus, emergency surgery was performed. Among the other three perforation cases, one case required surgery for refractory stenosis and ED was continued in one case after nonoperative therapy.Conclusions: The incidence of bleeding caused by ED for gastric stenosis after ESD was small. Although not significant, ED in the lower stomach presents a substantial risk of perforation. [ABSTRACT FROM AUTHOR]

Background: Endoscopic dilation (ED) is used for the treatment of benign strictures caused by reflux esophagitis or anastomotic stenosis after esophagectomy. Esophageal stenosis is a major complication after endoscopic submucosal dissection (ESD) of large superficial esophageal cancer, but little is known regarding the incidence of complications of ED for stenosis caused by esophageal ESD.Methods: This was a retrospective study conducted at a single institution. From September 2002 to December 2012, a total of 1,337 ED procedures were performed for stenosis after esophageal ESD in 121 patients. The incidence of complications of ED and related clinical characteristics were analyzed.Results: The incidence of bleeding was 0.8 % (1/121) per patient and 0.07 % (1/1,337) per procedure. The incidence of perforation was 4.1 % (5/121) per patient and 0.37 % (5/1,337) per procedure. Perforation occurred at a median of third time of ED procedures (range 2-9 procedures) and at a median of 18 days (range 8-29 days) after ESD. There were no significant characteristics correlated to perforation, such as location, circumferential extent, or diameter of mucosal defect after ESD. The total number of ED procedures was significantly larger among perforation cases (37, range 6-57) compared with those without perforation (7, range 1-70) (p = 0.01), and the treatment duration tended to be longer (190 vs. 69 days, respectively).Conclusions: The incidence of bleeding caused by ED for esophageal stenosis after ESD was very low. Relevant risk of perforation should be considered for patients requiring multiple ED procedures. [ABSTRACT FROM AUTHOR]

Background: In cases of synchronous gastric cancers (SGC) that include one for surgical indication and another for endoscopic resection (ER) in two different regions of the stomach, patients can avoid total gastrectomy and undergo subtotal gastrectomy following successful pre-emptive ER. The aim of this study was to evaluate the feasibility and efficacy of pre-emptive endoscopic resection and surgery (PRES) with curative intent for such SGCs. Methods: Between September 2002 and December 2012, 34 patients with SGCs (72 lesions) underwent PRES. Our institutional principals of PRES ensure the following: (1) treatment with curative intent, (2) multiple lesions indicated for ER and surgery, (3) evasion of TG following successful pre-emptive ER, (4) exclusion of type 4 and large type 3 (>80 mm) tumors, and (5) nonemergent cases such as hemorrhage, perforation, and obstruction. Clinicopathological characteristics and technical data were evaluated for all patients, and long-term outcomes were analyzed in patients who obtained curative ER and underwent subtotal gastrectomy. Results: Curative ER was obtained in 31 patients (91.1 %), and subtotal gastrectomy was performed a median of 44 days after ER. Final stages were as follows: stage I, 25 patients (80.6 %); stage II, four patients (12.9 %); stage III, one patient (3.2 %); and stage IV, one patient (3.2 %). The 5-year overall and cause-specific survival rates were 96.3 % (95 % confidence interval 89.4-100 %) and 100 %, respectively. Conclusions: PRES was feasible and effective as the first treatment of choice for multiple SGCs. PRES enables minimally invasive surgery with promising oncological outcomes. [ABSTRACT FROM AUTHOR]

We report here a case of esophageal perforation made by an endoscope while treating cicatrical stenosis that developed after wide circumferential dissection of superficial esophageal carcinoma. Perforation closure with a conventional endoclip was difficult as the perforation was large and the surrounding tissue was fragile as a result of steroids administration for stenosis prevention. To avoid surgical intervention, we employed the over-the-scope-clip system and successfully closed the perforation. The favorable outcome suggests the utility of the over-the-scope-clip system for closing perforations when conventional methods are ineffective. [ABSTRACT FROM AUTHOR]

Background: Adjuvant chemotherapy (AC) is recommended as a standard treatment after curative resection in patients with pancreatic adenocarcinoma (PA). Although patients who failed to complete AC had significantly worse survival compared with those who completed AC for cancers in various organs, the effects of complete AC on survival in patients with PA have not been investigated. The purpose of this study was to clarify the impact of complete AC on PA patient survival and to identify independent risk factors for incomplete AC. Methods: Medical records of 236 consecutive PA patients who planned to undergo surgical resection with curative intent between January 2000 and September 2012 at Kobe University Hospital were retrospectively reviewed. Of these, the complete AC ( n = 75) and the incomplete AC ( n = 30) groups due to adverse events were compared. Results: Patient survival was significantly better in the complete AC group than in the incomplete AC group (median survival time 48.9 vs. 17.9 months; 5-year survival rate 42.7 vs. 17.1 %; p < 0.0001). Preoperative white blood cell count and postoperative serum albumin level were identified as independent risk factors for incomplete AC. By receiver operating characteristic curve analysis, the cutoff value of postoperative serum albumin level was 3.1 mg/dL. Conclusions: PA patients who completed AC had significantly better survival than those who failed to complete AC. Postoperative serum albumin level is a marker for failure to complete AC. Further prospective studies are needed to determine whether perioperative nutritional intervention could increase AC completion rate and improve prognosis in PA patients. [ABSTRACT FROM AUTHOR]

Background: Widespread application of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) results in noncurative resection in some patients. The influence of preceding ESD on additional gastric resections has not been completely evaluated. Methods: Endoscopic, surgical, and pathological records of 255 patients who underwent additional gastrectomy after noncurative ESD at a single prefectural cancer center from September 2002 to December 2010 were reviewed. The estimated gastric resection based on endoscopic images before ESD was compared with the actual gastric resection performed after ESD. Results: Altered gastric resection was performed in 4 (1.6 %) of the 255 patients. In 3 patients, total gastrectomy was performed instead of distal gastrectomy; in 1 patient, distal gastrectomy was performed instead of pylorus-preserving gastrectomy because of an insufficient distance from the cardia or pylorus caused by contraction of the ESD scar. Standard gastrectomy including total or distal gastrectomy with D2 lymph node dissection was performed in 33 patients because of deep submucosal invasion with positive/indefinite vertical margins. The final pathology revealed pT2 or deeper in 10 patients. Conclusions: In conclusion, 98.4 % patients underwent the scheduled gastric resection before ESD, and the preceding gastric ESD had almost no influence on changing the gastric resection of the additional surgery. Although rare, the preceding ESD may necessitate alterations in gastric resection to widen the surgical area because of contraction of ESD scar for lesions near the cardia or pylorus. Mini abstract: A retrospective study of additional gastrectomy after noncurative ESD showed that the preceding ESD had almost no influence on changing the gastric resection of the additional surgery. [ABSTRACT FROM AUTHOR]

Background: Currently, granular-type laterally spreading tumors (LST-G) have been classified into uniform [LST-G (UNI)] and nodular mixed [LST-G (MIX)] subtypes. However, the progression pattern of each subtype has not been evaluated in detail. The present study was designed to assign adequate treatment strategies to each LST-G subtype, based on the progression pattern. Methods: This retrospective study included 457 consecutive patients with 482 LST-Gs that had been removed endoscopically or surgically in a tertiary cancer center between September 2002 and December 2011. We classified the tumors as LST-G (UNI) or LST-G (MIX) subtypes. We analyzed clinicopathological characteristics and submucosal invasion rates for both subtypes, and we determined the incidence of submucosal invasions associated with the largest nodules for each subtype. Results: We evaluated the histopathological data from 136 LST-G (UNI) and 316 LST-G (MIX) lesions with diameters of 10-19 mm (14 %), 20-29 mm (26 %), 30-39 mm (25 %), or >40 mm (35 %). Submucosal invasions were observed in 3 (1.8 %) LST-G (UNI) and 49 (15.5 %) LST-G (MIX) lesions. In LST-G (MIX) lesions, the submucosal invasion incidences (within a tumor-size category) were as follows: 5.8 % (10-19 mm), 11.1 % (20-29 mm), 14.7 % (30-39 mm), and 19.1 % (>40 mm), respectively. In LST-G (MIX) lesions that showed submucosal invasions, the invasive cancers were located under the largest nodule (69 %; 34/49), outside the largest nodule (25 %; 12/49), or in both sites (6 %; 3/49). Conclusions: Our results indicated that, for LST-G (UNI) lesions, piecemeal resections would be acceptable due to the low risk of submucosal invasion. For LST-G (MIX) lesions, particularly those with diameters ≥20 mm, en bloc removal in an endoscopic resection is preferable for sufficient histological evaluation. [ABSTRACT FROM AUTHOR]

We report two cases of early gastric cancer (EGC) with spreading to heterotopic gastric glands (HGG). The first case was a submucosal-tumor-like EGC and proximal gastrectomy was performed. The second case was a slightly elevated EGC and endoscopic submucosal dissection was performed. In both cases, pathological results showed adenocarcinoma spreading to the HGG in the submucosa. The depth of cancer was diagnosed as intramucosal carcinoma because cancer was limited to the epithelium of HGG without invasion to the submucosal stroma. There is no clear guideline concerning the management of early gastric cancers with spreading to heterotopic gastric glands. [ABSTRACT FROM AUTHOR]

Purpose: Carbon dioxide (CO) insufflation reduces abdominal pain and discomfort after endoscopic procedures; however, there is no previous study focusing the safety of CO insufflation for patients with obstructive ventilatory disturbance. Here, we investigated the safety of CO insufflation during colorectal endoscopic submucosal dissection (ESD) for patients with obstructive disturbance. Methods: Between January 2010 and January 2013, colorectal ESD was performed using CO insufflation for 385 consecutive patients. End-tidal CO (EtCO) and transcutaneous oxygen saturation (SpO) were consecutively measured from the time before insertion of the colonoscope to the end of ESD. Patients were monitored by two nurses during the procedure and controlled for clinical symptoms of hypercapnia such as apnea or a depressed level of consciousness. According to their respiratory function, patients were stratified into a normal group and an obstructive disturbance group. We retrospectively compared EtCO and SpO during the procedures and the incidence of symptoms related to CO retention between the two groups. Results: The obstructive disturbance group consisted of 77 patients. There were similar changes of EtCO in the obstructive disturbance group and normal group and no significant rise in EtCO The maximum EtCO level in any patient was <60 mmHg. In the obstructive disturbance group, there were no symptoms associated with CO retention. There were no significant differences in the median SpO between both groups and no prolonged drop of SpO. Conclusions: CO insufflation during colorectal ESD is safe for patients with obstructive ventilatory disturbance. [ABSTRACT FROM AUTHOR]

Background: Recurrent glioblastoma after initial radiotherapy plus concomitant and adjuvant temozolomide is problematic. Here, patients with temozolomide-refractory high-grade gliomas were treated with bevacizumab (BV) and evaluated using apparent diffusion coefficient (ADC) for response. Methods: Nine post-temozolomide recurrent or progressive high-grade glioma patients (seven with glioblastoma and two with anaplastic astrocytoma) were treated with BV monotherapy. Average age was 57 years (range, 22-78), median Karnofsky Performance Scale (KPS) was 70 (30-80) and median BV line number was 2 (2-5). Two had additional stereotactic radiotherapy within 6 months prior to BV. Magnetic resonance (MR) imaging after BV therapy was performed within 2 weeks with calculation of mean ADC (mADC) values of enhancing tumor contours. Results: Post-BV treatment MR imaging showed decreased tumor volumes in eight of nine cases (88.9 %). Partial response was obtained in four cases (44.4 %), four cases had stable disease, and one had progressive disease. Of 15 evaluable enhancing lesions, 11 shrank and four did not. Pretreatment mADC values were above 1100 (10 mm/s) in all responding tumors, while all non-responding lesions scored below 1100 ( p = 0.001). mADC decreased after the first BV treatment in all lesions except one. KPS improved in four cases (44.4 %). Median progression-free survival and overall survival for those having all lesions with high mADC (>1100) were significantly longer than those with a low mADC (<1100) lesion ( p = 0.018 and 0.046, respectively). Conclusions: Bevacizumab monotherapy is effective in patients with temozolomide-refractory recurrent gliomas and tumor mean ADC value can be a useful marker for prediction of BV response and survival. [ABSTRACT FROM AUTHOR]

Background: The behavior of early gastric cancer (EGC) with mixed-type histology (differentiated and undifferentiated) is incompletely understood. This study aimed to clarify the clinicopathological features of EGC with mixed-type histology in relation to lymph node (LN) metastasis. Methods: Clinicopathological data from 410 patients who underwent surgical resection for intramucosal EGC were reviewed. Lesions were classified into four types according to the proportion of differentiated and undifferentiated components at histopathology: pure differentiated (PD) type, mixed predominantly differentiated (MD) type, mixed predominantly undifferentiated (MU) type, and pure undifferentiated (PU) type. We examined the clinicopathological differences between PD and MD, and between PU and MU, and the rate of LN metastasis according to tumor size and ulceration. Results: Moderately differentiated adenocarcinoma was the primary component in MD relative to PD (90.7 vs. 46.1 %). Signet ring cell carcinoma was the main component in PU relative to MU (81.5 vs. 33.3 %). LN metastasis was more common in MU than PU (19.0 vs. 6.0 %). For intramucosal tumors larger than 20 mm without lymphovascular invasion and without ulceration, the rate of LN metastasis was 0 % for MD and 24 % for MU. For intramucosal lesions less than 30 mm with ulceration but without lymphovascular invasion, the rate of LN metastasis was 0 % for MD and 20 % for MU. Conclusions: Histologically mixed-type EGC with a predominantly undifferentiated component should be managed as an undifferentiated-type tumor. Further investigation is required to determine whether mixed-type EGC with a predominantly differentiated component could be managed the same way as a differentiated-type EGC. [ABSTRACT FROM AUTHOR]

Background: A few studies have shown promising results with endoscopic submucosal dissection (ESD) for adenocarcinoma at the esophagogastric junction (EGJAC). However, curative criteria on the histology of EGJAC have not been developed, and long-term clinical results are lacking. The purpose of this study was to validate the application of the Japanese curative criteria to EGJAC after ESD. Methods: Between September 2002 and March 2009, 1,350 superficial gastric neoplasms in 1,181 patients were treated by ESD at a single tertiary cancer center. For this retrospective cohort study, 49 patients with 50 superficial EGJACs were extracted from our database. Complications, en bloc resection rate, curative resection rate, overall survival, and cause-specific survival were evaluated in all patients. For assessment of curability, curative criteria proposed by the Japanese Gastric Cancer Association for early gastric carcinoma after endoscopic resection were used. Results: Delayed bleeding and postoperative stenosis each occurred in three (6 %) patients but were managed endoscopically. No other major complications were observed related to ESD. The en bloc resection rate was 98 % (49/50), and the curative resection rate was 72 % (36/50). With a median follow-up period of 47 (range 22-97) months, the overall survival rates and cause-specific survival rates at 5 years were 86.2 % [95 % confidence interval (CI) 76-97] and 100 % (95 % CI 91-100), respectively. Conclusions: Endoscopic submucosal dissection with application of the Japanese curative criteria may be a feasible and effective treatment for curative intent in patients with superficial EGJAC. [ABSTRACT FROM AUTHOR]

Background: A preoperative histologic diagnosis of neoplasia is a requirement for endoscopic resection (ER). However, discrepancies may occur between histologic diagnoses based on biopsy specimens versus ER specimens. The aim of this study was to assess the rate of discrepancy between histologic diagnoses from biopsy specimens and ER specimens. Methods: A total of 1705 gastric lesions, from 1419 patients with a biopsy diagnosis of neoplasia, were treated by ER from September 2002 to December 2008. We compared the histologic diagnosis from the biopsy sample and the final diagnosis from the ER specimen to assess the discrepancy rate. Clinicopathological characteristics of the lesions that were related to the histologic discrepancies were also studied. Results: An ER diagnosis of gastric cancer was made in 49% (118/241) of lesions diagnosed as borderline lesions from biopsy specimens; this included adenomas and lesions difficult to diagnose as regenerative or neoplastic. The size, existence of a depressed area, and ulceration findings were significant factors observed in these lesions. An ER diagnosis of differentiated type cancer was obtained for 17% (12/63) of lesions diagnosed as undifferentiated type cancer from the biopsy specimens; for these lesions, the color and a mixed histology were significant factors related to the histologic discrepancies. Conclusion: A biopsy diagnosis of borderline lesions or undifferentiated type cancer is more likely to disagree with the diagnosis from ER specimens. Endoscopic characteristics should be considered together with the biopsy diagnosis to determine the treatment strategy for these lesions. [ABSTRACT FROM AUTHOR]

Here, we report four cases of duodenal gastrointestinal stromal tumors (GISTs). In three patients, endoscopic ultrasonography-guided fine-needle aspiration biopsy (EUS FNAB) was performed, and in one patient, the tumor tissue was sampled via forceps biopsy. In all the cases, GISTs could be diagnosed by histopathological examination of the biopsy samples. Ki-67 labeling indexes (Ki-67 LIs) of the 3 EUS FNAB samples were very low. It should be noted that a sufficient amount of tissue sample could not be obtained in one of these cases. In two patients who underwent laparotomy, the Ki-67 LIs of the biopsy samples corresponded with the Ki-67 LIs of the surgically resected samples and were also consistent with the tumor risk grade. In two patients who did not undergo laparotomy, the low Ki-67 LIs corresponded with a good clinical course. [ABSTRACT FROM AUTHOR]

The three-dimensional structure of crack tip dislocations in single crystal silicon was observed by combining high-voltage electron microscopy and tomography. It was revealed that dislocations cross-slipped proximal to the crack tip even in the initial stages of plastic deformation. The local stress intensity factor along the crack front was calculated by taking into account the experimentally determined dislocation character. Based on these observations and calculations, a model to account for the sequential multiplication of dislocation sources along the crack front is proposed. [ABSTRACT FROM AUTHOR]

Relaxin-3 (RLN3) is a neuropeptide belonging to the insulin-relaxin superfamily. RLN3-expressing neurons are predominantly located in the dorsal pons known as the nucleus incertus, and project their axons to the forebrain including the hypothalamus. RLN3 has been suggested to be involved in the stress response. In the present study, we investigated the hypothalamic action of RLN3 in the stress-response system by intracerebroventricular (icv) administration of RLN3. Compared with saline icv injection, 1 nmol icv RLN3 injection induced c-Fos expression in the paraventricular nucleus of the hypothalamus (PVN) at 1 h after administration. Some RLN3-induced c-Fos-positive cells in the PVN were also corticotropin-releasing factor (CRF)-expressing neurons. CRF and c-fos mRNA levels in the PVN were increased at 2 h after RLN3 administration. Plasma adrenocorticotropic hormone (ACTH) levels were also increased after RLN3 administration. These results suggest that RLN3 is able to stimulate the hypothalamopituitary CRF-ACTH system during the acute response. [ABSTRACT FROM AUTHOR]