Updated evidence of the effectiveness and safety of transanal drainage tube for the prevention of anastomotic leakage after rectal low anterior resection: a systematic review and meta-analysis.

BACKGROUNDS: Anastomotic leakage (AL) represents a major complication after rectal low anterior resection (LAR). Transanal drainage tube (TDT) placement offers a potential strategy for AL prevention; however, its efficacy and safety remain contentious. METHODS: A systematic review and meta-analysis were used to evaluate the influence of TDT subsequent to LAR as part of the revision of the surgical site infection prevention guidelines of the Japanese Society of Surgical Infectious Diseases (PROSPERO registration; CRD42023476655). We searched each database, and included randomized controlled trials (RCTs) and observational studies (OBSs) comparing TDT and non-TDT outcomes. The main outcome was AL. Data were independently extracted by three authors and random-effects models were implemented. RESULTS: A total of three RCTs and 18 OBSs were included. RCTs reported no significant difference in AL rate between the TDT and non-TDT groups [relative risk (RR): 0.69, 95% confidence interval (CI) 0.42-1.15]. OBSs reported that TDT reduced AL risk [odds ratio (OR): 0.45, 95% CI 0.31-0.64]. In the subgroup excluding diverting stoma (DS), TDT significantly lowered the AL rate in RCTs (RR: 0.57, 95% CI 0.33-0.99) and OBSs (OR: 0.41, 95% CI 0.27-0.62). Reoperation rates were significantly lower in the TDT without DS groups in both RCTs (RR: 0.26, 95% CI 0.07-0.94) and OBSs (OR: 0.40, 95% CI 0.24-0.66). TDT groups exhibited a higher anastomotic bleeding rate only in RCTs (RR: 4.28, 95% CI 2.14-8.54), while shorter hospital stays were observed in RCTs [standard mean difference (SMD): -0.44, 95% CI -0.65 to -0.23] and OBSs (SMD: -0.54, 95% CI -0.97 to -0.11) compared with the non-TDT group. CONCLUSIONS: A universal TDT placement cannot be recommended for all rectal LAR patients. Some patients may benefit from TDT, such as patients without DS creation. Further investigation is necessary to identify the specific beneficiaries.

Prediction of pouchitis after ileal pouch-anal anastomosis in patients with ulcerative colitis using artificial intelligence and deep learning.

BACKGROUND: Pouchitis is one of the major postoperative complications of ulcerative colitis (UC), and it is still difficult to predict the development of pouchitis after ileal pouch-anal anastomosis (IPAA) in UC patients. In this study, we examined whether a deep learning (DL) model could predict the development of pouchitis. METHODS: UC patients who underwent two-stage restorative proctocolectomy with IPAA at Keio University Hospital were included in this retrospective analysis. The modified pouchitis disease activity index (mPDAI) was evaluated by the clinical and endoscopic findings. Pouchitis was defined as an mPDAI ≥ 5.860; endoscopic pouch images before ileostomy closure were collected. A convolutional neural network was used as the DL model, and the prediction rates of pouchitis after ileostomy closure were evaluated by fivefold cross-validation. RESULTS: A total of 43 patients were included (24 males and 19 females, mean age 39.2 ± 13.2 years). Pouchitis occurred in 14 (33%) patients after ileostomy closure. In less than half of the patients, mPDAI scores matched before and after ileostomy closure. Most of patients whose mPDAI scores did not match before and after ileostomy closure had worse mPDAI scores after than before. The prediction rate of pouchitis calculated by the area under the curve using the DL model was 84%. Conversely, the prediction rate of pouchitis using mPDAI before ileostomy closure was 62%. CONCLUSION: The prediction rate of pouchitis using the DL model was more than 20% higher than that using mPDAI, suggesting the utility of the DL model as a prediction model for the development of pouchitis. It could also be used to determine early interventions for pouchitis.

A proposal for uniformity in classification of lymph node stations in esophageal cancer.

The 11th edition of the "Japanese Classification of Esophageal Cancer" by the Japan Esophageal Society (JES) and the 8th edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) "Cancer Staging Manual" are two separate classification systems both widely used for the clinical and pathological staging of esophageal cancer. Furthermore, the lymph node stations from these classification systems are combined for research purposes in the multinational TIGER study, which investigates the distribution pattern of lymph node metastases. The existing classification systems greatly differ with regard to number, location and anatomical boundaries of locoregional lymph node stations. The differences in these classifications cause significant heterogeneity in studies on lymph node metastases in esophageal cancer. This makes data interpretation difficult and comparison of studies challenging. In this article, we propose a match for these two commonly used classification systems and additionally for the TIGER study classification, in order to be able to compare results of studies and exchange knowledge and to make steps towards one global uniform classification system for all patients with esophageal cancer.

JSCO-ESMO-ASCO-JSMO-TOS: international expert consensus recommendations for tumour-agnostic treatments in patients with solid tumours with microsatellite instability or NTRK fusions.

A Japan Society of Clinical Oncology (JSCO)-hosted expert meeting was held in Japan on 27 October 2019, which comprised experts from the JSCO, the Japanese Society of Medical Oncology (JSMO), the European Society for Medical Oncology (ESMO), the American Society of Clinical Oncology (ASCO), and the Taiwan Oncology Society (TOS). The purpose of the meeting was to focus on what we have learnt from both microsatellite instability (MSI)/deficient mismatch repair (dMMR) biomarkers in predicting the efficacy of anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) immunotherapy, and the neurotrophic tyrosine receptor kinase (NTRK) gene fusions in predicting the efficacy of inhibitors of the tropomyosin receptor kinase (TRK) proteins across a range of solid tumour types. The recent regulatory approvals of the anti-PD-1 antibody pembrolizumab and the TRK inhibitors larotrectinib and entrectinib, based on specific tumour biomarkers rather than specific tumour type, have heralded a paradigm shift in cancer treatment approaches. The purpose of the meeting was to develop international expert consensus recommendations on the use of such tumour-agnostic treatments in patients with solid tumours. The aim was to generate a reference document for clinical practice, for pharmaceutical companies in the design of clinical trials, for ethics committees in the approval of clinical trial protocols and for regulatory authorities in relation to drug approvals, with a particular emphasis on diagnostic testing and patient selection.

Minimally invasive oesophagectomy with extended lymph node dissection and thoracic duct resection for early-stage oesophageal squamous cell carcinoma.

BACKGROUND: Oesophageal squamous cell carcinoma is an aggressive disease owing to early and widespread lymph node metastases. Multimodal therapy and radical surgery may improve prognosis. Few studies have investigated the efficacy of radical lymph node and thoracic duct resection. METHODS: Patients with oesophageal squamous cell carcinoma who underwent transthoracic minimally invasive oesophagectomy (TMIE) for cancer at Keio University Hospital between January 2004 and December 2016 were selected. Between 2004 and 2008, TMIE was performed in the lateral decubitus position without thoracic duct resection (standard TMIE). From 2009 onwards, TMIE with extended lymph node and thoracic duct resection was introduced (extended TMIE). Demographics, co-morbidity, number of retrieved lymph nodes, pathology, postoperative complications and recurrence-free survival (RFS) were compared between groups. RESULTS: Forty-four patients underwent standard TMIE and 191 extended TMIE. There were no significant differences in clinical and pathological tumour stage or postoperative complications. The extended-TMIE group had more lymph nodes removed at nodal stations 106recL and 112. Among patients with cT1 N0 disease, RFS was better in the extended-TMIE group (P < 0·001), whereas there was no difference in RFS between groups in patients with advanced disease. CONCLUSION: Extended TMIE including thoracic duct resection increased the number of lymph nodes retrieved and was associated with improved survival in patients with cT1 N0 oesophageal squamous cell carcinoma.

Diagnostic criteria and symptom grading for delayed gastric conduit emptying after esophagectomy for cancer: international expert consensus based on a modified Delphi process.

Delayed gastric conduit emptying (DGCE) after esophagectomy for cancer is associated with adverse outcomes and troubling symptoms. Widely accepted diagnostic criteria and a symptom grading tool for DGCE are missing. This hampers the interpretation and comparison of studies. A modified Delphi process, using repeated web-based questionnaires, combined with live interim group discussions was conducted by 33 experts within the field, from Europe, North America, and Asia. DGCE was divided into early DGCE if present within 14 days of surgery and late if present later than 14 days after surgery. The final criteria for early DGCE, accepted by 25 of 27 (93%) experts, were as follows: >500 mL diurnal nasogastric tube output measured on the morning of postoperative day 5 or later or >100% increased gastric tube width on frontal chest x-ray projection together with the presence of an air-fluid level. The final criteria for late DGCE accepted by 89% of the experts were as follows: the patient should have 'quite a bit' or 'very much' of at least two of the following symptoms; early satiety/fullness, vomiting, nausea, regurgitation or inability to meet caloric need by oral intake and delayed contrast passage on upper gastrointestinal water-soluble contrast radiogram or on timed barium swallow. A symptom grading tool for late DGCE was constructed grading each symptom as: 'not at all', 'a little', 'quite a bit', or 'very much', generating 0, 1, 2, or 3 points, respectively. For the five symptoms retained in the diagnostic criteria for late DGCE, the minimum score would be 0, and the maximum score would be 15. The final symptom grading tool for late DGCE was accepted by 27 of 31 (87%) experts. For the first time, diagnostic criteria for early and late DGCE and a symptom grading tool for late DGCE are available, based on an international expert consensus process.

Size of recurrent laryngeal nerve as a new risk factor for postoperative vocal cord paralysis.

Recurrent laryngeal nerve paralysis (RLNP) is a frequent and serious complication following esophageal cancer surgery. Therefore, this study aims to evaluate the correlation between recurrent laryngeal nerve (RLN) size and RLNP. This was a retrospective study of esophageal cancer patients who underwent thoracoscopic esophagectomy from January 2012 to December 2014. Eighty-four patients were included in the primary analysis. Diameter of the RLN was measured using the digital video recording of surgical procedures by the ratio between scissor and RLN. For evaluation of vocal cord paralysis or paresis, indirect laryngoscopy was performed. Because RLNP more frequently occurs on the left side than the right, we evaluated the correlation between size of the left RLN and left RLNP. The median size of the left RLN was 1.51 mm. We found that the incidence of postoperative left RLNP (Clavien-Dindo classification ≥1) was significantly higher (71% vs. 24%; P < 0.001) in thin RLNs (≤1.5 mm) than in thick RLNs (>1.5 mm). Thin RLN (P < 0.001), female sex (P = 0.025), and being overweight (P = 0.034) were identified as significant independent risk factors for postoperative RLNP. RLNP more easily occurred when the RLN was thin. It is difficult to confirm occurrence of postoperative RLNP before and at extubation. Therefore, it is helpful to know its risk factors including size of RLN.

Long-term results of concurrent chemoradiotherapy with daily-low-dose continuous infusion of 5-fluorouracil and cisplatin (LDFP) for Stage I-II esophageal carcinoma.

We investigated long-term treatment outcomes and the feasibility of chemoradiotherapy consisting of daily-low-dose 5-fluorouracil and cisplatin (LDFP) chemotherapy plus radiotherapy for Stage I-II squamous cell esophageal cancer. Treatment records from the 2000 through 2008 period were reviewed retrospectively. Fractionated radiotherapy was performed with a total dose of 60 Gy delivered in 2 Gy per fraction. LDFP chemotherapy, as continuous infusion of 200 mg/m2 5-fluorouracil combined with one hour infusion of 4 mg/m2 cisplatin, was administered on the same days as radiotherapy. Survival was calculated by the Kaplan-Meier method. Survival, responses, failure patterns, and toxicities were evaluated. Seventy-six (47 stage I and 29 stage II) patients were analyzed with a median follow-up of 93.6 months. The 8-year overall survival (OS), progression-free survival (PFS) and cause-specific survival (CSS) rates were 63.4%, 49.8%, and 76.7%, respectively. The 8-year OS, PFS, and CSS for stage I and stage II patients were 71.0%/56.1%/82.9% and 45.2%/40.2%/66.6%, respectively. Sixty-eight patients (89.5%) completed the treatment regimen. A complete response (CR) was achieved in 68 patients (89.5%). Twenty-five patients (36.8%) experienced recurrence after CR. The failure patterns were (overlap included): local failure (n = 12), nodal metastasis (n = 12), distant metastasis (n = 3), details unknown (n = 2). Salvage therapy was performed for local failure; endoscopic therapy (n = 7) or surgery (n = 2). Six patients remain alive without relapse after salvage endoscopic therapy. Major Grade 3 or higher acute adverse events were leukopenia (22%), anorexia (17%), and esophagitis (11%). Major late toxicities (Grade 3 or 4) involved pericardial effusion (12%), pleural effusion (4%), and esophageal stenosis (3%). Chemoradiotherapy with LDFP provided favorable long-term survival with acceptable toxicity for Stage I-II squamous cell esophageal cancer. The tumor response was excellent, but close endoscopic follow-up is essential for detecting and treating local recurrence.

Effects of testosterone replacement therapy on metabolic syndrome among Japanese hypogonadal men: A subanalysis of a prospective randomised controlled trial (EARTH study).

We investigated the effects of testosterone replacement therapy (TRT) on metabolic factors among hypogonadal men with a metabolic syndrome. From the study population of the EARTH study, which was a randomised controlled study in Japan, 65 hypogonadal patients with a metabolic syndrome, comprising the TRT group (n = 32) and controls (n = 33), were included in this study analysis. The TRT group was administered 250 mg of testosterone enanthate as an intramuscular injection every 4 weeks for 12 months. Waist circumference, body mass index, body fat volume and blood pressure were measured in all patients at baseline and at 12 months. In addition, blood biochemical data, including total cholesterol, triglyceride (TG), HDL cholesterol, fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c) levels, were also evaluated. Changes in these categories from baseline to 12 months were compared between the TRT and control groups, with significant differences observed in waist circumference, body fat percentage, FPG, TG and HbA1c levels. No significant differences were observed in other parameters. TRT for 1 year was associated with improvements in some metabolic factors among Japanese men with hypogonadism and metabolic syndrome.

Smoking is a risk factor for pulmonary metastasis in colorectal cancer.

AIM: The hepatic microenvironment, which may include chronic inflammation and fibrosis, is considered to contribute to the pathogenesis of liver metastases of colorectal cancer. A similar mechanism is anticipated for pulmonary metastases, although no reports are available. Smoking causes pulmonary inflammation and fibrosis. Thus, we hypothesized that smokers would be especially affected by pulmonary metastases of colorectal cancer. In this study, we attempted to clarify the impact of smoking on pulmonary metastasis of colorectal cancer. METHOD: Between September 2005 and December 2010 we reviewed 567 patients with pathological Stage I, II or III colorectal cancer, whose clinicopathological background included a preoperative smoking history, pack-year history from medical records. Univariate and multivariate analyses using the Cox proportional hazard model were performed to determine the independent prognostic factors for pulmonary metastasis-free survival. RESULTS: Pulmonary metastases occurred in 39 (6.9%) patients. The smoking histories revealed 355 never smokers, 119 former smokers and 93 current smokers among the subjects. Multivariate analysis revealed that being a current smoker (hazard ratio = 2.72, 95% CI 1.18-6.25; P = 0.02) was an independent risk factor for pulmonary metastases. CONCLUSION: Smoking may be a risk factor for pulmonary metastasis of colorectal cancer. Cessation of smoking should be recommended to prevent pulmonary metastasis, although further basic and clinical studies are required.

Comparison of neoadjuvant chemotherapy versus upfront surgery with or without chemotherapy for patients with clinical stage III esophageal squamous cell carcinoma.

Neoadjuvant chemotherapy (NAC) and chemoradiotherapy have been shown to extend postoperative survival, and preoperative therapy followed by esophagectomy has become the standard treatment worldwide for patients with esophageal squamous cell carcinoma (ESCC). The Japan Clinical Oncology Group 9907 study showed that NAC significantly extended survival in advanced ESCC, but the survival benefit for patients with clinical stage III disease remains to be elucidated. We compared the survival rates of NAC and upfront surgery in patients with clinical stage III ESCC. Consecutive patients histologically diagnosed as clinical stage III (excluding cT4) ESCC were eligible for this retrospective study. Between September 2002 and April 2007, upfront transthoracic esophagectomy was performed initially and, for patients with positive lymph node (LN) metastasis in a resected specimen, adjuvant chemotherapy using cisplatin and 5-fluororouracil every 3 weeks for two cycles was administered (Upfront surgery group). Since May 2007, a NAC regimen used as adjuvant chemotherapy followed by transthoracic esophagectomy has been administered as the standard treatment in our institution (NAC group). Patient characteristics, clinicopathological factors, treatment outcomes, post-treatment recurrence, and overall survival (OS) were compared between the NAC and upfront surgery groups. Fifty-one and 55 patients were included in the NAC and upfront surgery groups, respectively. The R0 resection rate was significantly lower in the NAC group than in the upfront surgery group (upfront surgery, 98%; NAC, 76%; P = 0.003). In the upfront surgery group, of 49 patients who underwent R0 resection and pathologically positive for LN metastasis, 22 (45%) received adjuvant chemotherapy. In the NAC group, 49 (96%) of 51 patients completed two cycles of NAC. In survival analysis, no significant difference in OS was observed between the NAC and upfront surgery groups (NAC: 5-year OS, 43.8%; upfront surgery: 5-year overall surgery, 57.5%; P = 0.167). Patients who underwent R0 resection showed significantly longer OS than did those who underwent R1, R2, or no resection (P = 0.001). In multivariate analysis using age, perioperative chemotherapy, depth of invasion, LN metastasis, surgical radicality, postoperative pneumonia, and anastomotic leakage as covariates, LN metastasis [cN2: hazard ratio (HR), 1.389; P = 0.309; cN3: HR, 16.019; P = 0.012] and surgical radicality (R1: HR, 3.949; P = 0.009; R2 or no resection: HR, 2.912; P = 0.022) were shown to be significant independent prognostic factors. In clinical stage III ESCC patients, no significant difference in OS was observed between NAC and upfront surgery. Although potential patient selection bias might be a factor in this retrospective analysis, the noncurative resection rate was higher after NAC than after upfront surgery. The survival benefit of more intensive NAC needs to be further evaluated.

Meta-analysis of the risk of small bowel obstruction following open or laparoscopic colorectal surgery.

BACKGROUND: One of the potential advantages of laparoscopic compared with open colorectal surgery is a reduction in postoperative bowel obstruction events. Early reports support this proposal, but accumulated evidence is lacking. METHODS: A systematic review and meta-analysis was performed of randomized clinical trials and observational studies by searching the PubMed and Cochrane Library databases from 1990 to August 2015. The primary outcomes were early and late postoperative bowel obstruction following laparoscopic and open colorectal surgery. Both ileus and bowel obstruction were defined as a postoperative bowel obstruction. Subgroup and sensitivity analyses were performed, and a random-effects model was used to account for the heterogeneity among the studies. RESULTS: Twenty-four randomized clinical trials and 88 observational studies were included in the meta-analysis; 106 studies reported early outcome and 12 late outcome. Collectively, these studies reported on the outcomes of 148 392 patients, of whom 58 133 had laparoscopic surgery and 90 259 open surgery. Compared with open surgery, laparoscopic surgery was associated with reduced rates of early (odds ratio 0·62, 95 per cent c.i. 0·54 to 0·72; P < 0·001) and late (odds ratio 0·61, 0·41 to 0·92; P = 0·019) postoperative bowel obstruction. Weighted mean values for early postoperative bowel obstruction were 8 (95 per cent c.i. 6 to 10) and 5 (3 to 7) per cent for open and laparoscopic surgery respectively, and for late bowel obstruction were 4 (2 to 6) and 3 (1 to 5) per cent respectively. CONCLUSION: The reduction in postoperative bowel obstruction demonstrates an advantage of laparoscopic surgery in patients with colorectal disease.

Fast Heating of Imploded Core with Counterbeam Configuration.

A tailored-pulse-imploded core with a diameter of 70 µm is flashed by counterirradiating 110 fs, 7 TW laser pulses. Photon emission (>40 eV) from the core exceeds the emission from the imploded core by 6 times, even though the heating pulse energies are only one seventh of the implosion energy. The coupling efficiency from the heating laser to the core using counterirradiation is 14% from the enhancement of photon emission. Neutrons are also produced by counterpropagating fast deuterons accelerated by the photon pressure of the heating pulses. A collisional two-dimensional particle-in-cell simulation reveals that the collisionless two counterpropagating fast-electron currents induce mega-Gauss magnetic filaments in the center of the core due to the Weibel instability. The counterpropagating fast-electron currents are absolutely unstable and independent of the core density and resistivity. Fast electrons with energy below a few MeV are trapped by these filaments in the core region, inducing an additional coupling. This might lead to the observed bright photon emissions.

Visible luminescent lanthanide ions and a large π-conjugated ligand system shake hands.

Visible luminescence europium(iii) complexes with large π-conjugated systems were theoretically and experimentally studied. A strategy for extending the π-conjugation of a ligand for use with europium(iii) ions was found on the basis of fragment molecular orbital and density functional theory calculations. Using this method, a novel europium complex was designed and synthesized. Its excited state properties were assessed from the luminescence spectrum, excitation spectrum, luminescence lifetime, and luminescence quantum yield. In this study, the novel photophysics induced by the combination of visible luminescent europium(iii) ions and large π-conjugated systems are described.

A DFT and multi-configurational perturbation theory study on O2 binding to a model heme compound via the spin-change barrier.

Dioxygen binding to a model heme compound via intersystem crossing (ISC) was investigated with a multi-state multi-configurational self-consistent field method with second-order perturbation theory (MS-CASPT2) and density functional theory (DFT) calculations. In elongated Fe-O distances, the energy levels of the S0 and T1 states are separated, which decreases the probability of intersystem crossing in these structures. At the DFT(B97D) level of calculation, the Fe-O distances of the S0 and T1 states were 1.91 and 2.92 Å, respectively. The minimum energy intersystem crossing point (MEISCP) was located as a transition state at a Fe-O distance of 2.17 Å with an energy barrier of 1.0 kcal mol(-1) from the T1 minimum. The result was verified with MS-CASPT2 calculations including the spin-orbit interaction which also showed the intersystem crossing point at a Fe-O distance of 2.05 Å. An energy decomposition analysis on the reaction coordinate showed the important contribution of the ring-shrinking mode of the porphyrin ring, indicating that the reaction coordinates which control the relative energy level of the spin-states play a key role in intersystem crossing.

Peripheral nerve crushing to relieve chronic pain in diabetic and ischaemic foot ulcers.

OBJECTIVE: We retrospectively assessed the effectiveness of peripheral nerve crushing (Smithwick operation) in relieving intractable chronic pain associated with foot ulcers caused by diabetes mellitus (DM) or atherosclerosis. METHOD: From April 2009 to April 2012, patients underwent peripheral nerve crushing in the leg affected by foot ulceration. The cause of ulceration was either DM alone, atherosclerosis alone, or both DM and atherosclerosis. Because sensation in the foot is associated with five nerves: the tibial, deep peroneal, superficial peroneal, sural, and saphenous, one or more of these nerves were crushed over a length of 1.5cm by using a 'pean' in the distal third of leg the where there are no major motor nerves. RESULTS: There were 36 patients recruited with ulcers grade 3-5 according to the Wagner ulcer classification system that affected the toes, dorsum pedis, or any part of the plantar surface or the heel. The mean duration of foot ulcerations before the nerve crushing was 22.3±9.7 weeks. In all 36 patients, the nerve crushing was performed successfully without any perioperative surgical complication. Of the 36 patients, 34 (94.4%) had substantial pain relief immediately after nerve crushing. While the mean pain level before the procedure was 86.6±0.51mm on visual analogue scale (VAS), pain level dropped significantly after the operation to 18.6 ± 5.4mm at one week, 14.8±4.8mm at one month, 13.7±4.1mm at two months, 9.8±4.1mm at three months, 11.8±5.7mm at four months, 10.1±4.7mm at five months and 8.8±3.3mm at six months. The time to regeneration of the sensory nerves was 121±6.5 days (range: 80-181 days). The surgical complications were wound infection (6 patients) and temporary toe paralysis (three patients). The foot ulcers in 20 of the 36 patients (55.6%) were resolved by debridement or minor amputation. In seven patients (19.4%), a major amputation (five below and two above the knee) was required because of ischemia or infection. No patient died within 30 days of the operation, while nine patients died during the observation period because of comorbid conditions. CONCLUSION: Peripheral nerve crushing could be the alternative procedure for achieving analgesia in patients with intractable chronic pain from foot ulcers caused by DM or atherosclerosis.

Blood oxygenation of masseter muscle during sustained elevated muscle activity in healthy participants.

Myofascial pain associated with temporomandibular disorders has often been linked to pathological muscle hyperactivity. As a result, localised disturbances of intramuscular blood flow could lead to a lower level of oxygen distribution, hypoxia and microcirculatory changes. To assess haemodynamic changes in the masseter muscle during sustained elevated muscle activity (SEMA). Sixteen healthy participants performed thirty 1-min bouts of SEMA with intervals of 1-min 'rest' periods between the bouts on a bite force transducer device. The participants completed three sessions with different percentage of their maximal voluntary occlusal bite force (MVOBF): 0% (no task), 10% or 40% MVOBF tasks. The order of the sessions was randomised with 1- to 2-week intervals. Haemodynamic characteristics of the masseter muscle were estimated with use of a laser blood oxygenation monitor. Tissue blood oxygen saturation (StO2 ) during SEMA was lower than during rest (P < 0·001). The relative changes in total haemoglobin (Total-Hb) and StO2 were influenced by condition (SEMA and rest) and with interactions between condition and session (0%, 10% and 40% MVOBF tasks). These results suggest that SEMA may lead to hypoxia in the masseter muscle and that the haemodynamic characteristics and muscle symptoms depend on the magnitude of muscle contractions. Overall, the present findings may help to provide better insights into relationships between jaw muscle activity, haemodynamic changes and symptom developments with implications for clinical conditions such as bruxism characterised by different levels of tooth-grinding and tooth-clenching muscle activity.

Upregulation of integrin ß4 promotes epithelial-mesenchymal transition and is a novel prognostic marker in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive and often lethal malignant tumor. Several studies have shown that epithelial-mesenchymal transition (EMT) is frequently observed in clinical samples of PDA and is related to high metastatic rates and poor outcomes. To identify candidate molecules regulating EMT in PDA, we previously used cDNA microarray analysis and identified integrin ß4 (ITGB4) as one of the genes upregulated in high-EMT xenografts derived from PDA patients. The aim of the current study was to clarify the clinicopathological and functional significance of ITGB4 overexpression in PDA. ITGB4 upregulation in high-EMT xenografts was confirmed by immunohistochemistry. Immunohistochemical analyses of 134 surgically resected PDA cases revealed intratumoral heterogeneity with respect to ITGB4 expression and showed that cancer cells undergoing EMT often display strong diffuse ITGB4 expression. High levels of ITGB4 expression were significantly correlated with the hallmarks of EMT (solitary cell infiltration, reduced E-cadherin expression, and increased vimentin expression), with high tumor grade, and with the presence of lymph node metastasis, and showed an independent prognostic effect. Immunocytochemical analyses of PDA cell lines revealed that localization of ITGB4 changed from regions of cell-cell contact to diffuse cytoplasm and cell edges with occasional localization in filopodia during EMT. Knockdown of ITGB4 reduced the migratory and invasive ability of PDA cells. Overexpression of ITGB4 promoted cell scattering and cell motility in combination with downregulation of E-cadherin and upregulation of vimentin expression. In conclusion, we elucidated the prognostic and clinicopathological significance of ITGB4 overexpression in PDA and also the potential role for ITGB4 in the regulation of cancer invasion and EMT.

Variations in survival and perioperative complications between hospitals based on data from two phase III clinical trials for oesophageal cancer.

BACKGROUND: Variations in institutional practice may contribute to different outcomes of cancer treatment. The impact of interinstitutional heterogeneity on outcomes between hospitals after oesophagectomy has not been examined previously using data from surgical clinical trials. METHODS: The data from two phase III trials for oesophageal cancer were used. Japan Clinical Oncology Group (JCOG) 9204 involved oesophagectomy (92-OP) versus oesophagectomy plus postoperative chemotherapy (92-POST), with accrual from 1992 to 1997. JCOG9907 involved postoperative chemotherapy (99-POST) versus preoperative chemotherapy (99-PRE), with accrual from 2000 to 2006. Hospitals contributing fewer than three patients were excluded. The influence of time and preoperative chemotherapy on interinstitutional heterogeneity related to postoperative complications and 5-year overall survival were evaluated by comparisons within and between these trial groups. Heterogeneity was estimated by a mixed-effects model after adjusting for age, sex, performance status, location of the primary tumour and clinical stage. RESULTS: Twelve hospitals in 92-OP (114 patients), 13 in 92-POST (114), 19 in 99-POST (158) and 18 in 99-PRE (154) were eligible. There was considerable heterogeneity in predicted postoperative complications in both groups in JCOG9204 (median 31.3 (range 15.0-68.2) per cent), and in 99-PRE (35.2 (22.6-46.6) per cent) but not in 99-POST (27.7 (27.7-27.7) per cent) from JCOG9907. A similar pattern was seen for predicted overall survival (92-POST: 66.4 (range 64.1-68.9) per cent; 99-PRE: 55.9 (54.0-59.7) per cent; 99-POST: 44.4 (44.4-44.4) per cent). CONCLUSION: Interinstitutional heterogeneity regarding complications and survival after oesophagectomy is a problem that merits wider consideration.

Direct heating of a laser-imploded core by ultraintense laser-driven ions.

A novel direct core heating fusion process is introduced, in which a preimploded core is predominantly heated by energetic ions driven by LFEX, an extremely energetic ultrashort pulse laser. Consequently, we have observed the D(d,n)^{3}He-reacted neutrons (DD beam-fusion neutrons) with the yield of 5×10^{8} n/4π sr. Examination of the beam-fusion neutrons verified that the ions directly collide with the core plasma. While the hot electrons heat the whole core volume, the energetic ions deposit their energies locally in the core, forming hot spots for fuel ignition. As evidenced in the spectrum, the process simultaneously excited thermal neutrons with the yield of 6×10^{7} n/4π sr, raising the local core temperature from 0.8 to 1.8 keV. A one-dimensional hydrocode STAR 1D explains the shell implosion dynamics including the beam fusion and thermal fusion initiated by fast deuterons and carbon ions. A two-dimensional collisional particle-in-cell code predicts the core heating due to resistive processes driven by hot electrons, and also the generation of fast ions, which could be an additional heating source when they reach the core. Since the core density is limited to 2 g/cm^{3} in the current experiment, neither hot electrons nor fast ions can efficiently deposit their energy and the neutron yield remains low. In future work, we will achieve the higher core density (>10 g/cm^{3}); then hot electrons could contribute more to the core heating via drag heating. Together with hot electrons, the ion contribution to fast ignition is indispensable for realizing high-gain fusion. By virtue of its core heating and ignition, the proposed scheme can potentially achieve high gain fusion.