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Preoperative risk assessment is important in older patients because they often have comorbidities and impaired organ function. We performed preoperative comprehensive geriatric assessment (CGA) for older patients with esophageal cancer.A total of 217 patients over 75 years old who underwent esophagectomy for thoracic esophageal cancer were analyzed. The CGA was performed preoperatively and included the Mini-Mental State Examination (MMSE), Geriatric Depression Score (GDS), vitality index, Barthel index, and instrumental activities of daily living (IADL). We defined the robust group as patients with normal function on every instrument, and the pre-frail and frail groups as those with functional impairment on one instrument or two or more instruments, respectively. We assessed how the CGA correlated with postoperative complications and prognosis.Of the 217 patients, 86 (39.6%) were in the robust group, 68 (31.3%) in the pre-frail group, and 63 (29.0%) in the frail group. Postoperative pneumonia (P = 0.026) and anastomotic leakage (P = 0.032) were significantly more common in the frail group. The frail group had a significantly longer postoperative hospitalization period (P = 0.016) and significantly lower rate of discharge to home (P = 0.016). Overall survival (OS) was significantly worse in the frail group (5-year overall survival rate, frail group versus others, 37.8% versus 52.0%, P = 0.046), but it was not significant on multivariate analysis.The preoperative CGA in older patients with esophageal cancer was associated with risk of postoperative complications.

Surgery for esophageal cancer (EC) causes morphological and functional changes in the upper gastrointestinal tract, resulting in postoperative weight loss (PWL). PWL has been shown to lead to poor nutritional status and immunocompetence, which may worsen the prognosis for several types of cancer. However, few reports have examined the relationship between weight loss (WL) in the early postoperative period and cancer prognosis.A total of 421 esophageal cancer patients underwent curative esophagectomy at Osaka University Hospital from 2010 to 2016. Based on the patients' body weight 1.5 months after surgery, they were classified into severe WL (n = 50) and slight-moderate WL (n = 371) groups.The 5-year overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) were significantly lower in the severe WL group than the slight-moderate WL group (p = 0.0002, p 0.0001, and p = 0.0004, respectively). In the multivariate analysis, tumor invasion depth (pT3, 4), lymph node metastasis (pN2, 3), preoperative Prognostic Nutrition Index ( 45), postoperative complications (≥ G3), and severe WL were independent prognostic factors for CSS (hazard ratio [HR] 2.5, 95% confidence interval [CI] 1.7-3.7; HR 1.6, 95% CI 1.1-2.4; HR 1.9, 95% CI 1.3-2.8; HR 1.6, 95% CI 1.1-2.4; and HR 2.7, 95% CI 1.7-4.2, respectively). In a multivariate analysis of risk factors leading to severe WL, thoracotomy (VATS) and postoperative MAX CRP (high) were independent risk factors (odds ratio [OR 0.48, 95% CI 0.24-0.97; OR 1.9, 95% CI 1.0-3.5).Early PWL would be a useful marker of poor cancer prognosis in EC patients. Highly inflammatory conditions due to surgical invasion and postoperative complications may contribute to early PWL.

To investigate short-term treatment outcomes of intravitreal brolucizumab (IVBr) for treatment-naïve neovascular age-related macular degeneration (AMD) in a Japanese multicenter study.Retrospective case control study METHODS: The subjects were 58 eyes of 57 patients with neovascular AMD (43 men and 14 women, mean age 74.6 years) of whom 43 eyes of 42 patients completed initial loading of 3 monthly IVBr injections and were followed for more than 3 months. Best-corrected visual acuity (BCVA) changes, anatomical outcomes, and complications were investigated.Of the 43 eyes that completed loading doses, the AMD subtype was type 1 and type 2 macular neovascularization (MNV) in 51%, polypoidal choroidal vasculopathy (PCV) in 42%, and type 3 MNV in 7%. At 3 months after initiating treatment, BCVA significantly improved (P = 0.002) and central retinal thickness significantly decreased (P 0.0001). At 3 months, complete retinal and subretinal fluid resolution was achieved in 91% of all eyes and complete regression of polypoidal lesions was achieved in 82% of PCV eyes. Iritis occurred in 8 eyes of 8 patients (14%), but resolved using topical or subtenon corticosteroid injection without visual loss in all cases.IVBr for treatment-naïve neovascular AMD was effective in the short-term, achieving significantly improved BCVA, good retinal fluid resolution, and a high rate of polypoidal lesion regression. However, iritis was noted in 14% of patients which may limit use of this drug.

Outcomes of salvage surgery after failed definitive chemoradiation (CRT) for esophageal cancer have been well defined. However, only a few studies have focused on salvage esophagectomy for recurrent disease after CRT.In 227 patients with esophageal cancer who underwent salvage esophagectomy after definitive CRT, consisting of 116 patients who underwent esophagectomy for persistent disease (the persistent group) and 111 patients who underwent esophagectomy for recurrent disease (the recurrent group), the short- and long-term outcomes were investigated.The rates of any postoperative complication were similar between the groups (49.1% in the persistent group vs. 49.5% in the recurrent group, p = 0.951), although there was a higher rate of anastomotic leakage in the recurrent group (p = 0.027). Thirty-day mortality was also similar between the groups (1.7% in the persistent group vs. 0.9% in the recurrent group, p = 0.587). The 3-year and 5-year overall survival rates were 33.7% and 28.0% in the persistent group and 48.7% and 41.7% in the recurrent group, respectively (p = 0.0175). In the recurrent group, clinically nodal status before CRT as well as pathologically nodal status and time to relapse were identified as independent prognostic factors. In the persistent group, pT and resection margin were identified as independent factors associated with survival.The present study showed that salvage surgery for recurrent disease can provide acceptable short- and long-term outcomes. Considering clinically and pathologically nodal status and time to relapse, adjuvant therapy might be offered for patients who underwent salvage esophagectomy for recurrent disease after definitive CRT.

Established supportive care to reduce the toxicity of neoadjuvant chemotherapy (NAC) is lacking. This multicenter randomized study compared the administration of synbiotics combined with enteral nutrition (EN) versus that of prophylactic antibiotics as supportive care treatment for patients with esophageal cancer undergoing NAC.Patients with advanced esophageal cancer scheduled to receive NAC were randomly administered either prophylactic antibiotics (antibiotic group) or synbiotics combined with EN (Syn + EN group). The primary endpoint was the febrile neutropenia (FN) incidence during the first course, and the secondary endpoints were other adverse events, changes in intestinal environment, including fecal microbiota, organic acid concentrations, pH, and chemotherapy tolerability.Eighty-one patients were enrolled. The FN incidence was nonsignificantly lower (P = 0.088) in the Syn + EN group. The incidences of grade 4 neutropenia and grades 2-4 diarrhea were significantly lower in the Syn + EN group (P = 0.014 and 0.033, respectively). Relative dose intensity was significantly higher in the Syn + EN group (92.0 ± 10.9%) than in the antibiotic group (83.2 ± 18.2%) (P = 0.01). Alpfa diversity was significantly higher in the Syn + EN group than in the antibiotic after chemotherapy (P = 0.002). The numbers of Bifidobacterium (P 0.05), Lacticaseibacillus (P 0.001), and Enterobacteriaceae (P 0.001) and the concentration of acetic acid (P 0.001) were significantly higher in the Syn + EN group than in the antibiotic group after chemotherapy. The severity of diarrhea and occurrence of FN were significantly correlated with Clostridioides difficile abundance and were significantly inversely correlated with acetic acid concentration after chemotherapy.Synbiotics combined with EN may be an alternative supportive care treatment to prophylactic antibiotics in patients with cancer undergoing toxic chemotherapy (https://jrct.niph.go.jp; jRCTs051180153).

Regorafenib is an oral multi-kinase inhibitor that has been established as third-line treatment for patients after the failure of imatinib and sunitinib. However, since clinical data of regorafenib in the Japanese population are still lacking, the management of regorafenib is mainly based on the clinical experience of each oncologist. The aim of this study was to evaluate the efficacy and safety of regorafenib in a Japanese population.Thirty-three patients treated with regorafenib for metastatic and recurrent gastrointestinal stromal tumors were retrospectively enrolled. This study investigated the anti-tumor effect, including overall survival, progression-free survival, and safety, which was evaluated based on the incidence of adverse events.The median overall survival of patients treated with regorafenib was 23.8 months and the 1-year overall survival rate was 80.0%, the median progression-free survival was 7.1 months and the 1-year progression-free survival rate was 40.2%. The responses to regorafenib were partial response in 3 cases (9.1%), stable disease in 17 (51.5%), progressive disease in 10 (30.3%), and non-evaluable in 3 (9.1%). The disease control rate was 54.0%. Treatment-related adverse events were reported in all patients, with the most common being hand-foot syndrome (72.7%), followed by liver damage (36.4%) and diarrhea (27.3%), and six patients (20.0%) were discontinued due to adverse events.This is the first report of Japanese patients with gastrointestinal stromal tumors treated with regorafenib. Regorafenib showed efficacy and a manageable safety profile in Japanese patients with advanced gastrointestinal stromal tumors, which was comparable with previous studies.

Ghrelin has been reported to reduce postoperative weight loss by improving appetite and food intake in patients undergoing upper gastrointestinal surgery.We aimed to investigate whether growth hormone induction, another essential effect of ghrelin, may attenuate skeletal muscle loss in patients during postoperative starvation.Esophageal cancer patients were randomized to receive a continuous intravenous infusion of high-dose ghrelin (HD; 0.5 µg/kg/h), low-dose ghrelin (LD; 0.25 µg/kg/h), or placebo for 7 days after surgery. During this period, oral feeding was not introduced but the patients received the same parenteral and enteral nutrition. We investigated the effects of ghrelin on body weight, skeletal muscle mass, nutritional status, and hormone levels.Overall, 73 patients were enrolled in this study. The rate of weight loss on postoperative day (POD) 7 relative to that before surgery was significantly lower in the HD group than in the placebo group (HD vs. placebo: -0.61% vs. 1.8%, p = 0.030). The rate of muscle loss in the erector spinae muscle on POD 7 in the HD and LD groups was significantly lower than that in the placebo group (HD vs. placebo: 2.8% vs. 8.5%, p 0.001; LD vs. placebo: 4.9% vs. 8.5%, p = 0.028). The levels of growth hormone on PODs 1, 3, and 7, and insulin-like growth factor 1 on PODs 3, 7, and 14 were significantly higher in patients who received ghrelin.Continuous ghrelin administration could attenuate skeletal muscle loss in esophageal cancer patients during postoperative starvation.

To describe the clinical and genetic findings of patients in the second Japanese family with Malattia Leventinese/Doyne honeycomb retinal dystrophy (ML/DHRD). Two patients (a 41-year-old male proband and his third son) underwent comprehensive ophthalmic examinations, including full-field and multifocal electroretinography (ERG). Sanger sequencing was performed to detect an EFEMP1 gene variant (p.Arg345Trp), which was identified as the only causative pathogenic variant. Genetic analysis revealed that both patients carried the heterozygous variant, but the other unaffected family members did not. Although the proband exhibited innumerable radially distributed drusen in both the posterior poles and good visual acuity at initial presentation, bilateral choroidal neovascularization (CNV) developed during the 15-year follow-up. The proband received 15 intravitreal anti-vascular endothelial growth factor (VEGF) injections in the left eye (LE) and two injections in the right eye (RE). At 56 years of age, his decimal best-corrected visual acuity was 0.1 and 1.2 in the LE and RE, respectively. Full-field ERG showed that while the rod and combined responses were within normal amplitudes, the cone and 30-Hz flicker responses had slightly decreased amplitudes. Multifocal ERG revealed attenuated central responses in the LE and decreased temporal responses in the RE. In the 20-year-old son, multifocal ERG showed normal responses in both eyes. This is the first report of ML/DHRD in a patient who developed bilateral CNV and received anti-VEGF treatment in both eyes. Although multifocal ERG exhibited worsening of macular function, the generalized photoreceptor function was preserved until middle age.

Introduction: Diagnosing functional dyspepsia requires excluding organic disease and gastrointestinal function evaluation; however, there are no modalities to evaluate these simultaneously. This preclinical study examined the possibility of an endoscopic barostat. Methods: Ultrathin endoscopy and our newly developed pressure-regulated endoscopic insufflator, which insufflates the gastrointestinal tract until the preset pressure is achieved, were used. The actual intragastric pressure was measured using an optical fiber manometer placed in the stomach. Experiment-1: in an ex vivo experiment, we insufflated the isolated stomach and verified whether the intragastric pressure reached the preset pressure. Experiment-2: we inserted the endoscope orally in a porcine stomach, insufflated the stomach, and verified whether the intragastric pressure reached the preset pressure. Finally, we insufflated the stomach at a random pressure to verify the functional tests for proof-of-concept. Results: Experiment-1: the intragastric pressure reached the preset pressure. After reaching the plateau, the pressure remained stable at the preset pressure (Huber M value: 1.015, regression line: 0.988, 95% confidence interval [CI]: 0.994–0.994). Experiment-2: the intragastric pressure reached the preset pressure. After reaching the plateau, the pressure remained stable at the preset pressure (Huber M value: 1.018, regression line: 0.971, 95% CI: 0.985–0.986). At randomly preset pressures, the transendoscopic theoretical intragastric pressure detected by using the insufflator was correlated with the actual pressure measured by using the pressure manometer. Conclusions: This proof-of-concept study shows that a pressure-regulated endoscopic insufflator provides stable intragastric pressure at the preset level, with the potential of an endoscopic barostat to assess the visceral hypersensitivity related to functional dyspepsia.

Microfocus computed tomography (micro-CT) has not been widely used at high radiation intensity (industrial micro-CT) in life science fields. In this preliminary study, we investigated its potential value in the detection of micro-hepatic tumors in a mouse model. The liver with micro-hepatic tumors was surgically resected en-bloc from mice, and examined with industrial micro-CT and lower intensity micro-CT (small animal micro-CT). The number of hepatic tumors was manually counted on serial images. Then, the accuracy of each technique was determined by preparing matching liver sections and comparing the number of tumors identified in a conventional pathological examination. The number of hepatic tumors evaluated with industrial micro-CT showed high concordance with the results of the pathological examinations (intraclass correlation coefficient [ICC]: 0.984; 95% confidence interval [CI] 0.959–0.994). On the other hand, the number of hepatic tumors evaluated with the small animal micro-CT showed low concordance with the number identified in the pathological examinations (ICC: 0.533; 95% CI 0.181–0.815). Industrial micro-CT improved the detection of small structures in resected specimens, and might be a promising solution for life science research.

Background Mutations in p53, identified in 90% of oesophageal squamous cell carcinoma (ESCC), are associated with unfavourable prognosis and chemo-resistance. APR-246 induces apoptosis by restoring transcriptional ability of mutant p53, and may be a promising therapeutic agent to overcome chemo-resistance in ESCC. Methods In ESCC cell lines differing in p53 status, we performed in vitro cell viability and apoptosis assays, evaluated reactive oxygen species (ROS) generation, and assessed signal changes by western blot after APR-246 administration with/without chemo-agent. Antitumour effects and signal changes were evaluated in in vivo experiments using xenograft and patient-derived xenograft (PDX) mouse models. Results APR-246 administration induced significant apoptosis by upregulating p73 and Noxa via ROS induction in ESCC cell lines harbouring p53 missense mutations. Moreover, APR-246 plus chemotherapy exerted combined antitumour effects in ESCC with p53 missense mutations. This effect was also mediated through enhanced ROS activity, leading to massive apoptosis via upregulation of p73 and Noxa. These findings were confirmed by xenograft and PDX models with p53 mutant ESCC. Conclusion APR-246 strongly induced apoptosis by inducing ROS activity and p73-Noxa signalling, specifically in ESCC with p53 missense mutation. This antitumour effect was further enhanced by combination with 5-FU, which we first confirmed in ESCC preclinical model.

Background The registration committee for esophageal cancer in the Japan Esophageal Society (JES) has collected the patients' characteristics, treatment, and outcomes annually. Methods We analyzed the data of patients who had visited the participating hospitals in 2014. We collected the data with a web-based data collection system using the National Clinical Database. We used the Japanese Classification of Esophageal Cancer 10th edition by JES and the TNM classification 7th edition by the Union of International Cancer Control (UICC) for cancer staging. Results A total of 9026 cases were registered from 344 institutions in Japan. Squamous cell carcinoma and adenocarcinoma accounted for 87.9% and 7.1%, respectively. The 5-year survival rates of patients treated using endoscopic resection, concurrent chemoradiotherapy, radiotherapy alone, and esophagectomy were 87.1%, 33.7%, 25.3%, and 59.3%, respectively. Esophagectomy was performed in 5204 cases. Concerning the approach used for esophagectomy, 48.1% of the cases were treated thoracoscopically. The operative mortality (within 30 days after surgery) was 0.75%, and the hospital mortality was 2.0%. The survival curves showed an excellent discriminatory ability both in the clinical and pathologic stages by the JES system. The survival of pStage IV was better than IIIC in the UICC system, because pStage IV included the patients with supraclavicular lymph-node metastasis (M1 LYM). Conclusion We hope that this report contributes to improving all aspects of diagnosing and treating esophageal cancer in Japan.

Background: Age and infarct volume are strong predictors of outcome in patients with ischemic stroke who underwent endovascular therapy (EVT). We aimed to investigate the impact of ischemic core volume (ICV) on stroke outcome after EVT in elderly. Methods: Using the HERMES (Highly Effective Reperfusion Using Multiple Endovascular Devices) collaboration, a patient-level meta-analysis of 7 randomized trials in which patients were enrolled from December 2010 to April 2015) dataset, we categorized patients into those aged Results: A total of 899 patients who had baseline ICV data, 247 patients aged ≥75 years, of which 118 were randomized in the EVT arm. Patients aged ≥75 years required smaller ICV to achieve mRS score ≤3 than those aged P Conclusions: Baseline ICV has an impact on stroke outcome after EVT in the elderly, but elderly patients with large ICV may still benefit from EVT if near-complete or complete reperfusion is achieved. Young patients seem to benefit from EVT regardless of ICV status.

Left atrial (LA) function can help predict various cardiovascular events. Catheter ablation for atrial fibrillation (AF) modifies baseline LA function through the maintenance of sinus rhythm and myocardial injury. We investigated the impact of post-ablation LA function on recurrence of AF after ablation and identified the predictors of reduced post-ablation LA function. A total of 616 patients who underwent AF ablation (paroxysmal, N = 310; non-paroxysmal, N = 306) were retrospectively examined with cardiac computed tomography at baseline and 3 months after the final ablation procedure. Post-ablation LA emptying fraction (LAEFpost) was calculated. We evaluated the association between LAEFpost and recurrence of AF after the final ablation procedure. Further, we assessed the predictors of reduced LAEFpost. The recurrence rate of AF was 72.7% after the final ablation procedure [median follow-up 48 months (48.0, 48.0), total number of ablation sessions: 1.4 ± 0.7]. Multivariate analysis revealed that LAEFpost was associated with the recurrence of AF (hazard ratio/10% increase: 0.62, 95% confidence interval: 0.51–0.75, P

The impact of pneumonia on prognosis is controversial, and no report has focused on its onset. This study aimed to examine the impact of pneumonia according to its onset on prognosis and its associated risk factors after esophagectomy.In total, 484 patients who underwent curative resection for esophageal squamous cell carcinoma were retrospectively reviewed. Patients with pneumonia were divided into two groups by the date of onset: pneumonia in the acute phase within 7 days after surgery (n = 59) and pneumonia in the subacute phase 8 days after surgery (n = 49).The disease-free survival of patients with acute pneumonia was significantly lower than that of those without pneumonia (P = .0002), whereas the disease-free survival of patients with subacute pneumonia was similar to that of patients without pneumonia (P = .5363). In multivariate analysis for disease-free survival, P-stage III to IV (hazard ratio [HR], 3.344; P.0001), transfusion (HR, 1.4078; P = .0291), and acute pneumonia (HR, 1.8463; P = .0009) were independent prognostic factors. Multivariate analysis revealed that age75 years (odds ratio [OR], 2.1746; P = .0232), respiratory disease comorbidity (OR, 4.3869; P = .0002), cT3-4 (OR, 2.0143; P = .0477), extended surgery duration (OR, 2.3406; P = .0152), and posterior mediastinal reconstruction (OR, 0.1432; P = .0439) were independent risk factors for acute pneumonia.Post-esophagectomy pneumonia in the acute phase was an independent prognostic factor, whereas advanced age, respiratory disease comorbidity, and extended surgery duration were risk factors for acute pneumonia.

Background After the revised organ transplant law came into effect in Japan, donations of organs under brain death have been increasing; however, because of the expansion of donor indications, donations from expanded criteria donors and cardiac arrest donors (donation after cardiac death) have also increased. In kidney transplantation, ischemia-reperfusion injury results in a high rate of delayed graft function, which adversely affects patients’ long-term prognoses. Hypothermic machine perfusion preservation results in superior postoperative function and survival rates compared with cold storage preservation. We used an organ preservation device for kidneys and performed a graft viability evaluation before to kidney transplantation. Methods We used the CMP-X08 perfusion device (Chuo-Seiko Co, Ltd, Asahikawa, Hokkaido, Japan) and Belzer MPS solution to preserve the donated organ. The perfusion pressure and temperature were monitored during cold storage with continuous perfusion. Standard renal transplantation protocols were followed. A renal biopsy was performed 1 hour after transplantation and the renal function was evaluated. This study followed the principles of the Declaration of Helsinki. Results The first presented case is of a 63-year-old woman who received a kidney from a middle-aged man with brain death due to hypoxic encephalopathy. The creatinine at the time of admission was 0.9 mg/dL and at the time of excision was 2.86 mg/dL. The total perfusion time was 120 minutes. The total ischemia time was 7 hours and 15 minutes. The recipient urinated 115 minutes postoperatively, and no dialysis was required. The second presented case is of a 47-year-old man with a 15-year history of dialysis who received a kidney from a middle-aged woman with brain death due to subarachnoid hemorrhage. The creatinine at the time of admission was 0.8 mg/dL and at the time of excision was 0.77 mg/dL. The total perfusion time was 240 minutes. The total ischemia time was 13 hours and 14 minutes. The recipient urinated 38 minutes postoperatively, and no dialysis was required. Conclusions Mechanical perfusion storage performed for 2 to 4 hours resulted in a viable organ that was successfully transplanted in both cases.

Summary Background & aims Reductions in skeletal muscle mass during neoadjuvant therapy can have a negative effect on short- and long-term outcomes in patients with esophageal cancer. However, effective treatment for suppressing reductions in skeletal muscle mass during neoadjuvant therapy has not been established. Methods Eighty-seven patients were included in this study who were enrolled in a previous randomized study comparing the effects of enteral nutrition (EN) and parenteral nutrition (PN) on chemotherapy-related toxicities during neoadjuvant chemotherapy in esophageal cancer patients. Changes in skeletal muscle mass during neoadjuvant therapy were compared between the two groups. Results Skeletal muscle mass index (SMI) decreased from 45.8 cm2/m2 before treatment to 43.7 cm2/m2 after neoadjuvant chemotherapy in 87 patients (p = 0.092). The total calorie intake during neoadjuvant therapy was equal between the two groups. SMI reduction was significantly smaller in the EN group than in the PN group (−1.4 cm2/m2 vs −3.0 cm2/m (Gebski et al., 2007) [2], p Conclusions Compared with PN support, EN support during neoadjuvant chemotherapy suppressed reductions in skeletal muscle mass in patients with esophageal cancer.

Background Esophageal squamous cell carcinoma (ESCC) is the deadliest of all human squamous cell carcinomas and is characterized by chemotherapy resistance and poor prognosis associated with the epithelial–mesenchymal transition (EMT). A subset of ESCC displays loss‐of‐function mutations in genes encoding Notch receptor family members, including NOTCH3. Although Notch signaling regulates EMT in ESCC cells, the role of NOTCH3 in EMT and chemotherapy resistance remains elusive. This study aimed to examine the role of NOTCH3 in EMT and chemotherapy resistance, and determine whether NOTCH3 expression can be used to predict the response to chemotherapy. Methods In vitro and in vivo assays were conducted to clarify the contribution of NOTCH3 to chemotherapy resistance. Using specimens from 120 ESCC patients treated with neoadjuvant chemotherapy, we compared the expression levels of NOTCH3 and genes involved in EMT according to the degree of chemotherapy sensitivity. Results In ESCC cells, chemotherapy resistance was associated with NOTCH3 downregulation and concurrent activation of EMT. RNA interference to silence NOTCH3 resulted in induction of the EMT marker Vimentin (VIM), leading to chemotherapy resistance in ESCC cells. Conversely, ectopic expression of the activated form of NOTCH3 suppressed EMT and sensitized cells to chemotherapy. Results of chromatin immunoprecipitation assays suggested that NOTCH3 may repress transcription of the VIM. Conclusions Our findings suggest that NOTCH3 may control chemotherapy sensitivity by regulating EMT. NOTCH3 may serve as a novel biomarker to predict better clinical outcomes in ESCC patients., Notch3 may control chemotherapy sensitivity by regulating the epithelial‐mesenchymal transition. Notch3 may predict better clinical outcomes in esophageal squamous cell carcinoma patients.

Background Modification of arrhythmogenic substrates with extensive ablation comprising linear and/or complex fractional atrial electrogram ablation in addition to pulmonary vein isolation (PVI‐plus) can theoretically reduce the recurrence of atrial fibrillation. The DR‐FLASH score (score based on diabetes mellitus, renal dysfunction, persistent form of atrial fibrillation, left atrialdiameter >45 mm, age >65 years, female sex, and hypertension) is reportedly useful for identifying patients with arrhythmogenic substrates. We hypothesized that, in patients with persistent atrial fibrillation, the DR‐FLASH score can be used to classify patients into those who require PVI‐plus and those for whom a PVI‐only strategy is sufficient. Methods and Results This study is a post hoc subanalysis of the a multicenter, randomized controlled, noninferiority trial investigating efficacy and safety of pulmonary vein isolation alone for recurrence prevention compared with extensive ablation in patients with persistent atrial fibrillation (EARNEST‐PVI trial). This analysis focuses on the relationship between DR‐FLASH score and the efficacy of different ablation strategies. We divided the population into 2 groups based on a DR‐FLASH score of 3 points. A total of 469 patients were analyzed. Among those with a DR‐FLASH score >3 (N=279), the event rate of atrial arrhythmia recurrence was significantly lower in the PVI‐plus arm than in the PVI‐only arm (hazard ratio [HR], 0.45 [95% CI, 0.28–0.72]; P P =0.795). There was significant interaction between patients with a DR‐FLASH score >3 and DR‐FLASH score ≤3 ( P value for interaction=0.020). Conclusions The DR‐FLASH score is a useful tool for deciding the catheter ablation strategy for patients with persistent atrial fibrillation. Registration URL: https://clinicaltrials.gov ; Unique identifier: NCT03514693.

Left ventricular (LV) reverse remodeling (LVRR) after catheter ablation of atrial fibrillation (AFCA) has not been fully described. This study investigated the predictors and clinical outcomes of LVRR after AFCA in patients with LV systolic dysfunction.Of 3319 consecutive patients who underwent first-time AFCA between January 2012 and October 2019, 376 with a baseline LV ejection fraction of50% were retrospectively evaluated. They were subjected to 256-slice multidetector computed tomography (MDCT) scanning at baseline and 3 months after AFCA. The LVRR was defined as a decrease in the LV end-systolic volume of ≥15%.The prevalence of LVRR was 83% (n = 306). Multivariate logistic regression analysis including age, body mass index, diabetic status, beta-blocker use, and LV diastolic diameter revealed that the predictors of LVRR were non-paroxysmal atrial fibrillation (AF) (odds ratio, 2.68; 95% confidence interval, 1.42-5.05; p = 0.002) and absence of apparent underlying structural heart disease (4.81; 2.31-10.0; p0.001). The prevalence of LVRR differed depending on AF recurrence pattern prior to the post-MDCT [no episode vs. paroxysmal episode (lasting7 days) vs. persistent episode (lasting ≥7 days), 84% vs. 81% vs. 63%, respectively, p = 0.023]. During a median follow-up of 32 months, the incidence of paroxysmal form of AF recurrence was similar, whereas persistent form of AF recurrence was less frequent in patients with LVRR (10.5% vs. 18.6%, p = 0.018). Heart failure hospitalizations (2.3% vs. 15.7%, p0.001), cardiovascular deaths (0.7% vs. 4.3%, p = 0.015), and all-cause deaths (1.3% vs. 5.7%, p = 0.018) were similarly less frequent in those with LVRR.LVRR after AFCA, which was predicted by non-paroxysmal AF without any apparent structural heart disease at baseline, was associated with persistent form of AF recurrence prior to the evaluation. LVRR was associated with favorable clinical outcomes.

INTRODUCTION: The pancreas often interferes with the surgical field during laparoscopic gastrectomy (LG) and its disorders cause severe postoperative complications. This study aimed to evaluate the association between the anatomical location of the pancreas and surgical outcome and to investigate the optimal surgical position in LG. METHODS: We newly defined the angle formed between the supra-pancreatic region and the root of the left gastric artery (LGA) as the pancreas-LGA angle (PLA). The association between PLA and surgical outcomes in 107 consecutive patients who underwent laparoscopic distal gastrectomy (LDG) was investigated. Then, the change in PLA before and after insertion of the back pillow in 30 patients with gastric cancer was examined. RESULTS: The median PLA was 62° (range, 2°-157°). No differences were found in the patient background between patients with small PLA (PLA < 62°; n = 53) and those with large PLA (PLA ≧ 62°; n = 54). The postoperative inflammation response (white blood cells, neutrophils, and C-reactive protein) and amylase concentration in the drainage fluid (D-AMY) were significantly higher in the small PLA group than large PLA group. Multivariable analyses demonstrated that small PLA was an independent risk factor for high D-AMY. After insertion of a back pillow, PLA was noninvasively increased in all patients, and the median PLA was changed to 92° (range, 8°-151°) from 61° (range, 2°-140°). Of 17 patients with small PLA, nine developed large PLA. CONCLUSIONS: These results suggest that PLA can become one of the indicators of postoperative complications related to anatomical patient factors in LDG.

The impact of thoracic duct (TD) resection on prognosis is controversial. This study aimed to examine the impact of TD resection. In this six-institution, matched-cohort study, 2269 consecutive patients with esophageal squamous cell carcinoma who underwent esophagectomy between 2000 and 2017 were enrolled for analysis of long-term outcomes, including overall survival (OS), disease-free survival (DFS), cause-specific survival (CSS), and recurrence patterns. Based on a propensity score, 642 TD-resected and 642 TD-preserved patients with all stages of disease were selected. At 5 years, the TD-resected group had an OS of 57.7%, a DFS of 50.9%, and a CSS of 62.2%. These rates were significantly higher than the corresponding rates of 48.7% (p = 0.0078), 41.0% (p = 0.0297), and 55.3% (p = 0.0473) in the TD-preserved group. The OS in the TD-preserved and TD-resected groups was similar for the patients with cStage 1 or 2 (p = 0.6265), but it was significantly higher in the TD-resected group for the patients with cStage 3 or 4 (p = 0.0052). The incidence of total recurrence did not differ between the two groups. However, the incidence of hematogenous recurrence in the TD-resected group (19.0%) was significantly lower than in the TD-preserved group (26.2%) (p = 0.0021). For cT4a tumors, the incidence of local recurrence in the TD-resected group (2.4%) was significantly lower than in the TD-preserved group (18.4%) (p = 0.0183). Performance of TD resection may help to improve prognosis, especially for patients with advanced esophageal squamous cell carcinoma, by reducing hematogenous and local recurrence. Prospective trials are needed to determine whether prophylactic TD resection has a positive impact on the prognosis of patients with esophageal cancer.

Despite improvements in gastric cancer treatment, the mortality associated with advanced gastric cancer is still high. The activation of β-adrenergic receptors by stress has been shown to accelerate the progression of several cancers. Accordingly, increasing evidence suggests that the blockade of β-adrenergic signaling can inhibit tumor growth. However, the effect of β-blockers, which target several signaling pathways, on gastric cancer remains to be elucidated. This study aimed to investigate the anti-tumor effects of propranolol, a non-selective β-blocker, on gastric cancer. We explored the effect of propranolol on the MKN45 and NUGC3 gastric cancer cell lines. Its efficacy and the mechanism by which it exerts anti-tumor effects were examined using several assays (e.g., cell proliferation, cell cycle, apoptosis, and wound healing) and a xenograft mouse model. We found that propranolol inhibited tumor growth and induced G1-phase cell cycle arrest and apoptosis in both cell lines. Propranolol also decreased the expression of phosphorylated CREB-ATF and MEK-ERK pathways; suppressed the expression of matrix metalloproteinase-2, 9 and vascular endothelial growth factor; and inhibited gastric cancer cell migration. In the xenograft mouse model, propranolol treatment significantly inhibited tumor growth, and immunohistochemistry revealed that propranolol led to the suppression of proliferation and induction of apoptosis. Propranolol inhibits the proliferation of gastric cancer cells by inducing G1-phase cell cycle arrest and apoptosis. These findings indicate that propranolol might have an opportunity as a new drug for gastric cancer.

To compare short-term outcomes between two- vs. three courses of neoadjuvant chemotherapy (NAC) to clarify the optimal treatment for esophageal squamous cell cancer (ESCC) in a multicenter, randomized, phase II trial. An optimal number of NAC cycles remains to be established for locally advanced ESCC. Patients with locally advanced ESCC were randomly assigned to either two (N = 91) or three (N = 89) courses of DCF (70 mg/m2 intravenous docetaxel and 70 mg/m2 intravenous cisplatin on day 1, and a continuous 700 mg/m2 fluorouracil infusion for 5 days) every 3 weeks followed by surgery. We compared the two groups for perioperative parameters, adverse events, and the response to NAC. The two- and three-course groups showed similar completion rates and overall NAC dose reductions. Although the two-course group showed significantly lower overall grades 3–4 leukopenia and anemia compared to the three-course group, the two groups had similar overall toxicity rates. Postoperative complications were not significantly different between the two groups, except arrhythmia (13 vs. 0%, P = 0.0007). Only two postoperative in-hospital deaths occurred in the three-course group, due to sepsis following severe pneumonia. Compared to the two-course group, the three-course group was associated with a significantly better clinical response (42.9 vs. 65.2%, P = 0.0027) and a relatively higher rate of pathological complete response (9.1 vs. 15.3%, P = 0.212). Both two- and three-course DCF regimens in the NAC setting seemed to be equally feasible in locally advanced ESCC patients. Additional DCF courses led to a better NAC response without increasing the incidence of adverse events or postoperative morbidity. University Hospital Medical Information Network Clinical Trials Registry of Japan (Identification Number UMIN 000015788).

Esophageal squamous cell carcinoma (ESCC) is the predominant subtype of esophageal cancer with a particularly high prevalence in certain geographical regions and a poor prognosis with a 5-year survival rate of 15–25%. Despite numerous studies characterizing the genetic and transcriptomic landscape of ESCC, there are currently no effective targeted therapies. In this study, we used an unbiased screening approach to uncover novel molecular precision oncology targets for ESCC and identified the bromodomain and extraterminal (BET) family member bromodomain testis-specific protein (BRDT) to be uniquely expressed in a subgroup of ESCC. Experimental studies revealed that BRDT expression promotes migration but is dispensable for cell proliferation. Further mechanistic insight was gained through transcriptome analyses, which revealed that BRDT controls the expression of a subset of ΔNp63 target genes. Epigenome and genome-wide occupancy studies, combined with genome-wide chromatin interaction studies, revealed that BRDT colocalizes and interacts with ΔNp63 to drive a unique transcriptional program and modulate cell phenotype. Our data demonstrate that these genomic regions are enriched for super-enhancers that loop to critical ΔNp63 target genes related to the squamous phenotype such as KRT14, FAT2, and PTHLH. Interestingly, BET proteolysis-targeting chimera, MZ1, reversed the activation of these genes. Importantly, we observed a preferential degradation of BRDT by MZ1 compared with BRD2, BRD3, and BRD4. Taken together, these findings reveal a previously unknown function of BRDT in ESCC and provide a proof-of-concept that BRDT may represent a novel therapeutic target in cancer.

BACKGROUND Whether all atrial fibrillation (AF) patients should be evaluated for sleep apnea before catheter ablation (CA) remains controversial. Watch-type peripheral arterial tonometry (W-PAT) is a home sleep testing device and an easier tool for diagnosing sleep apnea than polysomnography. We investigated the prevalence and predictors of sleep apnea using W-PAT in unscreened sleep apnea patients with AF before CA.Methods and Results:The study was conducted under a retrospective, single-center, observational design. We included 776 consecutive patients who underwent both W-PAT and AF ablation. Sleep apnea assessments were successfully performed in 774 patients (99.7%; age 65±11 years, 73.3% male; body mass index [BMI] 24.1±3.5, 56.8% paroxysmal AF). The mean apnea-hypopnea index (AHI) was 20.1±15.6. Although 81.7% of the patients had normal Epworth sleepiness scores (mean 6.5), only 88 (11.4%) had a normal AHI (AHI

Esophageal cancer typically has a poor prognosis. While neoadjuvant chemotherapy (NAC) is reported to be effective for esophageal cancer patients, the prognosis of patients for whom NAC is ineffective remains poor. In total, 113 patients with thoracic esophageal squamous cell carcinoma who were treated between January 2006 and December 2015 were enrolled. These patients received NAC followed by radical surgery and had three or more pathologic positive lymph nodes. The effectiveness and feasibility of adjuvant chemotherapy (AC) were evaluated. Forty patients received AC (AC(+) group) and 73 patients did not (AC(−) group). Two-year relapse-free survival (RFS) rates of the AC(+) and AC(−) groups were 30.0% and 28.8%, respectively (p = 0.47). These patients were further divided into two subgroups, i.e., those with 3–6 positive lymph nodes (3–6 subgroup) and those with ≥ 7 positive lymph nodes (≥ 7 subgroup). Within the 3–6 subgroup (72 patients), 2-year RFS rates of the AC(+) and AC(−) groups were 38.5% and 33.9%, respectively (p = 0.31). Within the ≥ 7 subgroup (41 patients), 2-year RFS rates of the AC(+) and AC(−) groups were 25.9% and 7.1%, respectively (p = 0.04). AC may offer a significant additional benefit to the prognosis of esophageal cancer patients who have many positive lymph nodes even after NAC.

Imatinib is the standard treatment for unresectable and metastatic GIST. In the late stages, patients undergoing imatinib show drug resistance. Surgical intervention has been occasionally performed for resistant lesions. However, the clinical significance of such intervention remains unclear. Between 2006 and 2015, 37 patients were diagnosed with imatinib-resistant GISTs. We performed surgical intervention only for localized resistant lesions. We retrospectively investigated the background characteristics, data on surgical intervention and subsequent treatment, progression-free survival (PFS), and overall survival (OS). Eighteen patients diagnosed with localized resistance received surgical intervention (S-group) and 19 patients diagnosed with generalized resistance were received other TKIs (M-group). In S-group, no serious complications occurred, and all patients restarted imatinib after resection. The median PFS was 14.5 months. Five patients underwent surgical intervention multiple times followed by the continuation of imatinib, and the median duration of imatinib continuation was 22.2 months. Second-line TKIs were administered to 93% of the patients and the dose-intensity and outcome were similar in both groups. The median OS was 47.2 months after surgery. Surgical intervention could be performed safely and therefore could be followed by the continuation of TKI therapy. Surgical intervention based on the appropriate criteria of resistance might thus be useful for imatinib-resistant GISTs.

Purpose: Esophageal cancer patients may simultaneously have resectable esophageal cancer and undiagnosable incidental minute solid pulmonary nodules. While the latter is rarely metastatic, only a few studies have reported on the outcomes of such nodules after surgery. In this retrospective study, we assessed the incidence of such nodules, the probability that they are ultimately metastatic nodules, and the prognosis of patients after esophagectomy according to the metastatic status of the nodules. Methods: Data of 398 patients who underwent esophagectomy for resectable esophageal cancer between January 2012 and December 2016 were collected. We reviewed computed tomography (CT) images from the first visit and searched for incidental minute pulmonary nodules Results: Among the patients who underwent esophagectomy, 149 (37.4%) had one or more minute pulmonary nodules, with a total of 285 nodules. Thirteen (4.6%) of these nodules in 12 (8.1%) patients were ultimately diagnosed as being metastatic. Thirteen (8.7%) patients experienced recurrence at a different location from where the nodules were originally identified. Characteristics of the metastatic nodules were not unique in terms of size, SUVmax, or location in the lungs. Two-year and 5-year overall survival rates of patients whose nodules were metastatic were 64.2 and 32.1%, respectively. Conclusion: The rate of minute pulmonary nodules which were ultimately metastatic was 4.6%. Our findings suggest that esophagectomy followed by the identification of minute pulmonary nodules is an acceptable strategy even if the nodules cannot be diagnosed as being metastatic on the first visit CT due to their small size.

A 44-year-old male was admitted to our hospital because of sudden weakness and sensory loss in both legs following left scapular pain. He had a history of lower back pain but no vascular risk factors. Neurological examination on admission revealed flaccid paraplegia, a loss of both pinprick and vibratory sensations below the Th6 level, and bladder and rectal disturbances. Tendon reflexes were absent in both lower limbs. Diffusion-weighted imaging performed 5 hours after onset revealed an extensive high-intensity lesion at the Th2-6 spine levels, accompanied by a vague high intensity on T2-weighted images. CT angiography showed no abnormalities of the aorta or the artery of Adamkiewicz. Laboratory test results were normal and there was no evidence of coagulopathy. Autoantibodies, including anti-aquaporin-4 and anti-myelin oligodendrocyte glycoprotein antibodies, were negative. The cerebrospinal fluid test was normal. The lesion had expanded to the whole thoracic cord and was markedly swollen on T2-weighted imaging at 5 days after onset. Immunotherapies, including intravenous methylprednisolone pulse therapy and plasma exchange, were ineffective. Although there was no evidence of any source of embolism, we found degenerative calcified changes in the fibrocartilage of the intervertebral discs, with Schmorl's nodes in the thoracic spines. We clinically diagnosed the patient with spinal cord infarction caused by fibrocartilaginous embolism. He developed deep vein thrombosis and was treated with edoxaban. His neurological symptoms did not improve during 55 days of hospitalization. In a case with sudden-onset myelopathy, fibrocartilaginous embolism should be considered.

Background Esophageal squamous cell carcinoma (ESCC) is one of the most severe cancers and is characterized by chemotherapy resistance and poor prognosis associated with epithelial-mesenchymal transition (EMT). In a previous study, a low mitochondrial DNA (mtDNA) copy number was associated with poorer prognosis and induced EMT in ESCC. However, the detailed mechanism related to mtDNA copy number and EMT is unclear. The aim of this study was to clarify the mechanism by which a change in mtDNA copy number contributes to EMT and to examine treatment of chemotherapy resistance in ESCC. Methods The association between low mtDNA copy number and chemotherapy resistance was investigated using specimens from 88 patients who underwent surgery after neoadjuvant chemotherapy. Then, the mtDNA content of human ESCC cell lines, TE8 and TE11, was depleted by knockdown of mitochondrial transcription factor A expression. The present study focused on modulation of mitochondrial membrane potential (MMP) and DNA methylation as the mechanisms by which mtDNA copy number affects EMT. mRNA and protein expression, chemotherapy sensitivity, proliferation, MMP and DNA methylation were evaluated, and in vitro and in vivo assays were conducted to clarify these mechanisms. Results ESCC patients with decreased mtDNA copy number who underwent R0 resection after neoadjuvant chemotherapy had significantly worse pathological response and recurrence-free survival. Additionally, low mtDNA copy number was associated with resistance to chemotherapy in vitro and in vivo. mtDNA controlled MMP, and MMP depolarization induced EMT. Depletion of mtDNA and low MMP induced DNA methylation via a DNA methylation transcription factor (DNMT), and a DNMT inhibitor suppressed EMT and improved chemotherapy sensitivity in mtDNA-depleted ESCC cells, as shown by in vitro and in vivo assays. Conclusion This study showed that decreased mtDNA copy number induced EMT via modulation of MMP and DNA methylation in ESCC. Therapeutic strategies increasing mtDNA copy number and DNMT inhibitors may be effective in preventing EMT and chemosensitivity resistance.

In flexible gastrointestinal (GI) endoscopy, endoscopic insufflation is crucial and directly affects visualization. Optimal visualization enables endoscopists to conduct better examinations and administer optimal treatments. However, endoscopic insufflation is typically performed manually and is subjective. We aimed to measure the GI endoluminal pressure during flexible GI endoscopy. Participants underwent esophagogastroduodenoscopy (EGD) at our endoscopy center. Pressure measurement was conducted after completing diagnostic or follow-up EGD. The endoluminal pressure in the esophagus and stomach was measured at 1-s intervals for 1 min while performing EGD for observational and diagnostic purposes. During the measurements, the endoscopists maintained what they subjectively considered to be adequate exposure for screening for lesions by dilating the lumen. Eighty patients were enrolled in this study. The upper GI endoluminal pressure was assessed during EGD without adverse events. The esophageal endoluminal pressure averaged 8.9 (− 3.0 to 20.7) mmHg, and the gastric endoluminal pressure averaged 10.0 (3.0–17.9) mmHg; the upper GI endoluminal pressures were not affected by patient-related factors or the number of endoscopists’ postgraduate years. We have successfully obtained the GI endoluminal pressures during EGD. Further accumulation of these data may lead to more stable and reproducible flexible endoscopic diagnosis and intervention.

Background and purpose A transient ischemic attack (TIA) can occur without self‐awareness of symptoms. We aimed to investigate characteristics of patients with a tissue‐based diagnosis of TIA but having no self‐awareness of their symptoms and whose symptoms were witnessed by bystanders. Methods We used data from the multicenter registry of 1414 patients with a clinical diagnosis of TIA. For patients without evidence of ischemic lesions on imaging, clinical characteristics were compared between patients with and without self‐awareness of their TIA symptoms. Results Among 896 patients (559 men, median age of 70 years), 59 (6.6%) were unaware of their TIA symptoms, but had those symptoms witnessed by bystanders. Patients without self‐awareness of symptoms were older and more frequently female, and more likely to have previous history of stroke, premorbid disability, and atrial fibrillation, but less likely to have dyslipidemia than those with self‐awareness. Patients without self‐awareness of symptoms arrive at hospitals earlier than those with self‐awareness (P, Graphical Table of Contents Among 896 patients (559 men, median age of 70 years) with diagnosis of a tissue‐based transient ischemic attack (TIA), 59 (6.6%) were unaware of their symptoms but had their symptoms witnessed by bystanders. The cumulative incidence rate of occurrence of ischemic stroke after 1 year from TIA was higher in patients without self‐awareness than those with self‐awareness (16.3% vs. 6.9%, log‐rank; P = 0.010).

Dementia that occurs before age 65 years is defined as young-onset dementia (YOD). YOD develops during the prime of a person's working life and has a major impact on not only work but life in general. Therefore, Japan is promoting measures to support work and social participation, taking into account the characteristics of people living with YOD. Given the rarity of YOD, few studies have examined the difficulties faced by people living with YOD during this life stage or the kinds of support they require. We believe that studying these difficulties and support requirements will contribute to prolonging the careers of people living with YOD and to providing them support during social, emotional and economic crises. This qualitative study aims to clarify the experiences of working-age Japanese people living with YOD to examine, from their perspective, possibilities for employment support. For this study, people living with YOD who were currently working were recruited by snowball sampling. This study was conducted in Japan between September 2018 and February 2019. A semi-structured interview was conducted, and the contents were transcribed and analysed using Colaizzi's qualitative methodology. Four categories were derived: (a) crisis from continuing to work, (b) seeking support, (c) overcoming challenges to work and (d) reaffirming a sense of purpose by resuming work and social participation. Participants were able to continue working and socialising by letting others know about their illness and seeking support. In the process of reaffirming a sense of purpose by resuming work and social participation, participants continued working or transitioned to socially active lives after leaving their job thanks to the support of work colleagues and medical and healthcare/welfare professionals who understand YOD. The results indicate a need for awareness raising in the workplace to promote understanding of such professional support and its significance.

Lymph node (LN) recurrence is frequently encountered in esophageal cancer. The aim of this study was to determine the effects of various factors, including loco-regional treatment of LN-only recurrence, on the survival rate. Among 941 patients who underwent curative resection for esophageal squamous cell carcinoma in 2003–2016, we retrospectively reviewed 117 patients (12.4%) who developed LN-only recurrence. One, 2, 3, and 4 or more metastatic LNs were found in 72, 22, 6, and 17 patients, respectively, after a median disease-free interval of 8.4 months (range 1.1–62.0). Among all cases, recurrence was out of the surgical field in 53 cases (45.3%). Recurrent LNs were controlled by loco-regional treatment in 29 (43.9%) and by chemotherapy alone in 3 patients (7.0%). The 3-year survival rates of patients who did and did not achieve local control were 53.2% and 5.2%, respectively. Univariate analysis showed significant relationships between post-recurrence survival rate and pStage I–II at initial surgery, no history of radiotherapy, recurrence in ≤ 2 LN, and loco-regional treatment of LN recurrence. Multivariate analysis identified recurrence in ≤ 2 LN (HR 0.3169, 95% CI 0.1023–0.5314, p = 0.0038) and loco-regional treatment (HR 0.1973, 95% CI 0.0075–0.3871, p = 0.0416) as the only two significant and independent prognostic factors of survival. Recurrence limited to ≤ 2 LN and loco-regional treatment (chemoradiotheapy or surgery) for LN recurrence were associated with favorable survival of patients with history of radical esophagectomy followed by LN recurrence. Our results emphasize the importance of local control of LN recurrence regardless of location.

The aim of this study was to clarify whether ghrelin infusion is useful for suppressing inflammatory responses after esophagectomy. A phase I study of ghrelin administration after esophagectomy was performed in 20 patients with esophageal cancer. The anti-inflammatory effect of ghrelin was compared with 20 consecutive patients who did not receive ghrelin infusion. Additionally, 10 patients with intermittent infusion for 10 days were compared with 10 patients with continuous infusion for 5 days. The primary endpoint was the duration of systemic inflammatory response syndrome (SIRS). Secondary endpoints included postoperative complications, serum C-reactive protein (CRP), interleukin-6 (IL-6), and growth hormone (GH) levels. No adverse events of ghrelin administration occurred. Patients with ghrelin infusion had higher plasma ghrelin levels on postoperative day (POD) 3 (p = 0.003) and shorter SIRS duration (p = 0.007) than patients without ghrelin infusion. Although SIRS duration was similar (p = 0.19), patients with continuous ghrelin infusion had significantly higher plasma ghrelin (p

Malignant invasion of the respiratory tract is a common complication in advanced cases of esophageal carcinoma. Resection and reconstruction can be extremely challenging, particularly when the invasion is intrathoracic. A circumferential tracheal resection with direct tracheal closure or mediastinal tracheostomy is often performed, but the outcome is not always favorable, with high morbidity rates, loss of vocal function, and reduced quality of life. We present our experience in performing an intrathoracic tracheal reconstruction in which a conchal cartilage graft was used in combination with a pectoralis major muscle transposition. This was successfully done following the noncircumferential resection of the intrathoracic trachea due to mural invasion by a metastatic lymph node of esophageal carcinoma. We believe this report will contribute to the growing body of clinical expertise on procedures for intrathoracic tracheal reconstruction.

AimThe impact of sex differences on the clinical outcomes of radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF) is controversial. We investigated the sex differences regarding the efficacy and clinical outcomes of RFCA of AF.Methods and resultsWe conducted a large-scale, prospective, multicentre, observational study (Kansai Plus Atrial Fibrillation Registry). We enrolled 5010 consecutive patients who underwent an initial RFCA of AF at 26 centres (64 ± 10 years; non-paroxysmal AF, 35.7%). The median follow-up duration was 2.9 years. Female patients (n = 1369, 27.3%) were older (female vs. male, 68 ± 9 vs. 63 ± 11 years, P ConclusionsFemales experienced more frequent AF recurrences probably due to non-PV arrhythmogenicity and de novo pacemaker implantations than males during the long-term follow-up after RFCA of AF.

Background Immune checkpoint inhibitors have recently been widely used for advanced cancers and are known to cause ocular complications. We herein report a case developing bilateral serous retinal detachments, without ocular inflammation, after starting nivolumab treatment. Case presentation A 73-year-old man was referred to our hospital, having become aware of metamorphopsia 2 months after starting nivolumab (anti-programmed cell death protein 1 monoclonal antibody) for malignant melanoma of the nasal cavity. The initial corrected visual acuity of the right eye was 20/20, and that of the left eye was 20/16. There were no inflammatory findings in the anterior segment or the vitreous. Vitelliform lesions were found in the macular area of both ocular fundi, consistent with serous retinal detachment and subretinal deposits. Swept source optical coherence tomography showed diffuse thickening of the outer photoreceptor segment and thickening of the choroid. Two months after the initial diagnosis, multiple vitelliform lesions were noted, and the fundus findings had worsened. Indocyanine green fluorescein angiography showed delayed inflow in the peripapillary and posterior pole regions in the early phase of imaging. Fundus autofluorescence showed hyperautofluorescence consistent with most of the vitelliform lesions on color fundus photography. Conclusions Nivolumab may have impaired the pumping and phagocytosis functions of retinal pigment epithelial cells, resulting in bilateral serous retinal detachments and thickening of the photoreceptor outer segment. This is the first case report, to our knowledge, describing multiple bilateral serous retinal detachments and outer segment thickening without inflammation in a patient treated with nivolumab.

Background Left atrial (LA) size is an established predictor of recurrence after catheter ablation for paroxysmal atrial fibrillation (PAF). We investigated the impact of baseline LA function on recurrence after PAF ablation and compared the predictive values of LA function with those of LA size. Methods We retrospectively investigated 292 consecutive patients who underwent PAF ablation (median follow-up: 3.0 years). All patients had their preoperative LA volume (LAV) assessed using cardiac computed tomography under sinus rhythm. We used LA emptying fraction (LAEF) as an indicator of LA function and assessed the association between baseline LAEF and recurrence after initial ablation using a multivariate Cox hazard model. Then, we performed receiver operating characteristic analysis for predicting recurrence after single and multiple procedures and compared the c-statistics of LAEF and indexed maximum and minimum LAV (LAVImax and LAVImin) Results In a multivariate Cox hazard model, LAEF was strongly associated with recurrence after a single procedure [hazard ratio (HR): 0.968, 95% confidence interval (CI): 0.951–0.985, p Conclusions LAEF was associated with recurrence after PAF ablation. LA function is a more useful predictor than LA size.

Laparoscopic gastrectomy (LG) is now practiced widely, but it is unclear whether LG is the appropriate approach for elderly patients with resectable advanced gastric cancer. The aim of this study was to examine whether LG is more or less advantageous for elderly patients than for young patients. We collected data on 571 consecutive patients who underwent gastrectomy for pT2–4 gastric cancer between January 2001 and December 2015. After adjustment with one-to-one propensity score matching, short-term and long-term outcomes were compared between the LG and open gastrectomy (OG) groups among young (age

Cross-sectional research. To objectively evaluate grip force (GF) control while holding a freely movable object in individuals with cervical myelopathy (CM). Harunaso Hospital, Takasaki, Japan. We studied 52 hands from 26 individuals with CM. Participants performed a grip-and-lift task by pulp pinch using the thumb and index finger before surgery. We monitored individual finger GF (N) during the first 3 s while lifting and holding an object. Correlations between the GF and other clinical tests were evaluated. A multiple stepwise regression analysis was used to examine the contribution of the GF to the severity of clinical symptoms. Thumb GF was negatively correlated with the 10-s test (rs = −0.32), and index finger GF was positively correlated with its cutaneous pressure threshold (rs = 0.34). Multiple regression for the severity of upper extremity symptoms revealed that the model including the GF had a larger adjusted R2 and a lower AIC value than that of conventionally used clinical tests. These results suggested that the assessment of individual finger GF control could provide an indicator of the clinical severity of upper extremity in individuals with CM.

Since the prognosis of patients with adenocarcinoma of the esophagogastric junction (AEG) remains poor, more intensive treatments, including neoadjuvant chemotherapy (NAC), should be developed. We retrospectively examined whether neoadjuvant docetaxel, oxaliplatin, and S‑1 (DOS) combination chemotherapy resulted in a favorable clinical response and acceptable toxicity in patients with AEG.This retrospective cohort study included 36 consecutive patients with cStage IIB-IV AEG (Siewert types I-III). Regarding stage IV disease, patients with resectable distant lymph node metastasis (M1-LYM) were eligible. Patients underwent three 3-week cycles of docetaxel (40 mg/mThree cycles of neoadjuvant DOS were completed in 28 (78%) patients. Grade 3-4 neutropenia, anorexia, and diarrhea were observed in 26 (72%), 7 (19%), and 4 (11%) patients, respectively. Febrile neutropenia occurred in six (17%) patients. There were no treatment-related deaths. R0 resection was achieved in 35 (97%) patients, and postoperative morbidities of Clavien-Dindo grade III or higher were observed in 6 (17%) patients. Pathological complete response was observed in 11 (31%) of 36 patients. Pathological response rates of grade ≥ 2 and grade ≥ 1b were 47 and 72%, respectively. Two-year progression-free and overall survival rates were 60.1 and 81.2%, respectively.Neoadjuvant DOS therapy for AEG produced high pathological response rates with an acceptable safety profile, and may be a promising treatment strategy.

Purpose To investigate the incidence and risk of advanced age-related macular degeneration (AMD), including geographic atrophy (GA) and macular neovascularization (MNV), in eyes with drusenoid pigment epithelial detachment (PED). Methods Eighty-five eyes with drusenoid PED from 85 patients (77.2 ± 7.0 years, male/female:44/41) were included in this study. Patients were followed up every 1–3 months via spectral-domain optical coherence tomography (SD-OCT) and color fundus photography. If exudation was observed on SD-OCT, fluorescein and indocyanine green angiography were performed to confirm the MNV subtype accordingly. The maximum follow-up period was 60 months. Results During the study period, GA developed in 8 eyes while MNV also developed in 8 eyes. The Kaplan-Meier estimator revealed that the cumulative incidence for 60 months was 17.9% and 12.2% for GA and MNV, respectively. In eyes developing MNV, retinal angiomatous proliferation (type 3 neovascularization) was the most common. Cox regression analysis revealed that baseline PED width was the only factor associated with advanced AMD. (p = 0.006, Cox regression analysis). Conclusions The five-year cumulative incidence of advanced AMD, including GA and MNV, was approximately 30% in eyes with drusenoid PED among the Japanese elderly. A larger baseline PED width was the only risk factor for advanced AMD.

Extensive gastrointestinal surgery surveillance data in Japan were analyzed to examine the differences in the risk factors for surgical site infection (SSI) between laparotomy and laparoscopic abdominal procedures. Surgical procedures investigated in the study were gastrectomy, cholecystectomy, colectomy, rectal resection, and appendectomy. A total of 32,629 patients were included in the study. The study participants were divided into two groups according to the year of surgery, 2003–2009 (first study period) and 2010–2015 (second study period), due to the increase in the number of laparoscopic surgeries in the second study period. The incidence of SSI was stratified by three SSI classifications (superficial incisional, deep incisional, and organ/space SSI). Multiple logistic regression analysis was performed to predict the risk factors for SSI. The percentage of laparoscopic surgeries performed has increased linearly since 2010. Patients in the second study period were significantly older and had a higher prevalence of SSI risk factors compared with those in the first study period. In addition, the predictive factors changed substantially in most surgical procedures between the two study periods. Wound class ≥ 3 was a ubiquitous risk factor for superficial incisional SSI (SI-SSI) and organ/space SSI (OS-SSI) in both open (laparotomy) and laparoscopic procedures in the first study period. Meanwhile, in the second study period, operative duration was a ubiquitous risk factor in both procedures. The risk factors for SI-SSI differed from those for OS-SSI in the five abdominal surgeries investigated in the study. Periodic examination of risk factors for SSI is recommended in an aging society.

Background Despite the effectiveness of imatinib mesylate (IM), most gastrointestinal stromal tumours (GISTs) develop IM resistance, mainly due to the additional kinase-domain mutations accompanied by concomitant reactivation of KIT tyrosine kinase. Heat-shock protein 90 (HSP90) is one of the chaperone molecules required for appropriate folding of proteins such as KIT. Methods We used a novel HSP90 inhibitor, TAS-116, which showed specific binding to HSP90α/β with low toxicity in animal models. The efficacy and mechanism of TAS-116 against IM-resistant GIST were evaluated by using IM-naïve and IM-resistant GIST cell lines. We also evaluated the effects of TAS-116 on the other HSP90 client protein, EGFR, by using lung cell lines. Results TAS-116 inhibited growth and induced apoptosis in both IM-naïve and IM-resistant GIST cell lines with KIT activation. We found KIT was activated mainly in intracellular compartments, such as trans-Golgi cisternae, and TAS-116 reduced autophosphorylated KIT in the Golgi apparatus. In IM-resistant GISTs in xenograft mouse models, TAS-116 caused tumour growth inhibition. We found that TAS-116 decreased phosphorylated EGFR levels and inhibited the growth of EGFR-mutated lung cancer cell lines. Conclusion TAS-116 may be a novel promising drug to overcome tyrosine kinase inhibitor-resistance in both GIST and EGFR-mutated lung cancer.

Here, we assess the ability of metabolic tumor volume (MTV) as measured by F-fluorodeoxyglucose-positron emission tomography/computed tomography (F-FDG PET/CT) to evaluate neoadjuvant chemotherapy response for patients with locally advanced esophageal cancer (EC).Optimal methods to evaluate treatment response for EC patients have not yet been established. Although previous studies have reported the value of standardized uptake value (SUV), the accuracy of predicting histological response or long-term survival in EC is limited.In all, 102 EC patients without distant metastasis who underwent F-FDG PET/CT both before and after the preoperative chemotherapy series were analyzed.The median primary tumor MTV values before and after preoperative chemotherapy were 22.55 (range 0.4-183.1) and 2.75 (0-52.9), respectively, and the median MVT reduction rate was 86.5%. We found the most significant difference in survival between PET responders and nonresponders with a cut-off value of 60% MTV reduction, using a 10% stepwise cut-off analysis [2-year progression-free survival (PFS): 79.2 vs 44.4%; hazard ratio (HR) 3.397; P0.0001). With this cut-off value, histological response (P = 0.0091), tumor location (P = 0.0102), pT (P = 0.0011), and pN (P = 0.0110) were significantly associated with PET response. Univariate analysis of PFS indicated a correlation between PFS and tumor size, cT, decrease of primary lesion by CT, SUVmax reduction rate, MTV reduction rate, pT, pN, and pM. Multivariate analysis further identified pM (HR 3.063; P = 0.0279) and MTV reduction rate (HR 2.471; P = 0.0263) to be independent prognostic predictors, but not decrease of primary lesion by CT or SUVmax reduction rate.MTV change is clinically useful in predicting both long-term survival and histological response to preoperative chemotherapy in EC patients, after determining the optimal cut-off value based on survival analysis.

The purpose of this study was to examine aging and bimanual effects on finger spatial stability during precision grip. Twenty-one older and 21 younger adults performed precision grip tasks consisting of a single task (grip and lift an object with the thumb and index finger) and a dual task (the grip-lifting task with one hand and a peg board task with the other hand). The center of pressure (COP) trajectory and the grip force were evaluated using a pressure sensor with a high spatial resolution. In the COP trajectory, the main effects of age for the thumb (F1,140 = 46.17, p < 0.01) and index finger (F1,140 = 22.14, p < 0.01) and task difficulty for the thumb (F1,140 = 6.47, p = 0.01) were significant based on ANCOVA. The COP trajectory was statistically decreased in the older adults. The COP trajectory was also decreased in the dual task, regardless of age. The results suggest the existence of a safety strategy to prioritize the spatial stability in the elderly group and in the dual task. This study provides new insights into the interpretation of the COP trajectory.