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Endoscopic submucosal dissection (ESD) is a promising procedure that enables en bloc resection of large superficial tumors in the upper gastrointestinal tract. On the other hand, ESD in the colon and rectum is technically difficult to perform because of its anatomical features. At our institution, 137 consecutive superficial colorectal tumors larger than 20 mm in diameter in 137 patients were treated by ESD between April 2007 and October 2010, and 132 lesions were successfully resected. The average procedure time was 79.2 minutes, and the rate of en bloc resection was 89.1% (122/137). The rate of complete resection, defined as en bloc resection with tumor-free lateral and vertical margins, was 85.4% (117/137). The rate of perforation was 3.6% (5/137). Colorectal ESD achieved a high rate of en bloc resection and complete resection and is applicable in the colorectum.

Background/aims: This study aimed to examine the synergistic effect of independent risk factors on post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP)., Methods: This multicenter retrospective study included 1,273 patients with native papillae who underwent ERCP for bile duct stones in Japan. Independent PEP risk factors were identified using univariate and multivariate analyses. Significant risk factors for PEP in the multivariate analysis were included in the final analysis to examine the synergistic effect of independent risk factors for PEP., Results: PEP occurred in 45 of 1,273 patients (3.5%). Three factors including difficult cannulation ≥10 minutes, pancreatic injection, and normal serum bilirubin level were included in the final analysis. The incidences of PEP in patients with zero, one, two, and three factors were 0.5% (2/388), 1.9% (9/465), 6.0% (17/285), and 12.6% (17/135), respectively. With increasing risk factors for PEP, the incidence of PEP significantly increased (1 factor vs. 2 factors, p=0.006; 2 factors vs. 3 factors, p=0.033)., Conclusions: As the number of risk factors for PEP increases, the risk of PEP may not be additive; however, it may multiply. Thus, aggressive prophylaxis for PEP is strongly recommended in patients with multiple risk factors.

Background & Aims: Reported rates of delayed bleeding (DB) after endoscopic resection using direct oral anticoagulants (DOACs) are high and heterogeneous. This large-scale multicenter study analyzed cases of DB after colorectal endoscopic submucosal dissection related to various types of DOACs in Japan (the ABCD-J study) with those associated with warfarin., Methods: We retrospectively reviewed 1019 lesions in patients treated with DOACs and 459 lesions in patients treated with warfarin among 34,455 endoscopic submucosal dissection cases from 47 Japanese institutions between 2012 and 2021. The DB rate (DBR) with each DOAC was compared with that with warfarin. Risk factors for DB in patients treated with DOACs or warfarin were also investigated., Results: The mean tumor sizes in the DOAC and warfarin groups were 29.6 ± 14.0 and 30.3 ± 16.4 mm, respectively. In the DOAC group, the DBR with dabigatran (18.26%) was significantly higher than that with apixaban (10.08%, P = .029), edoxaban (7.73%, P = .001), and rivaroxaban (7.21%, P < .001). Only rivaroxaban showed a significantly lower DBR than warfarin (11.76%, P = .033). In the multivariate analysis, heparin bridging therapy (odds ratio [OR], 2.18; 95% confidence interval [CI], 1.27-3.73, P = .005), rectal location (2.01, 1.28-3.16, P = .002), and procedure time ≥55 minutes (2.43, 1.49-3.95, P < .001) were significant risk factors for DB in the DOAC group. The DB risk in the DOAC group (OR, (95% CI)) was 2.13 (1.30-3.50) and 4.53 (2.52-8.15) for 1 and 2 significant risk factors, respectively., Conclusions: Dabigatran was associated with a higher DBR than other DOACs, and only rivaroxaban was associated with a significantly lower DBR than warfarin., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Introduction: Endoscopic retrograde cholangiopancreatography (ERCP) for asymptomatic common bile duct stones (CBDS) has been associated with an increased risk of post-ERCP pancreatitis (PEP). Patients with asymptomatic CBDS at the time of ERCP include those with incidentally discovered CBDS (group A) and previously symptomatic patients with CBDS who became asymptomatic after conservative treatment for symptomatic CBDS, including obstructive jaundice or acute cholangitis (group B). In this study, we aimed to examine PEP risk in group B by comparing PEP risks between groups A, B, and currently symptomatic patients (group C)., Methods: In this multicenter retrospective study, we examined 77 patients in group A, 41 patients in group B, and 1225 patients in group C who had native papillae. PEP incidence rates between asymptomatic patients at the time of ERCP (groups A and B) and symptomatic patients (group C) were compared using one-to-one propensity score matching. Bonferroni's correction analysis was also performed to compare PEP incidence rates among the three groups., Results: As per our findings, PEP incidence rate in propensity score-matched groups A and B was significantly higher than that of propensity score-matched group C (13.2% [15/114] versus 4.4% [5/114], respectively, P = 0.033). In groups A and B, PEP incidence rates were 11.7% (9/77) and 14.6% (6/41), respectively. PEP risk in group B was similar to that in group A (P = 1.0). PEP incidence in group B was significantly higher than PEP incidence in group C (14.6% (6/41)) vs. 2.9% (35/1225)) (P = 0.005))., Conclusions: ERCP for previously symptomatic patients with CBDS who became asymptomatic after conservative treatment for symptomatic CBDS may increase the risk of PEP compared with ERCP for currently symptomatic patients. Thus, ERCP should be performed before patients become asymptomatic using conservative treatments if patients can tolerate ERCP procedures., Competing Interests: None, (Copyright © Japan Medical Association.)

Background: Patients with chronic kidney disease frequently develop neurological complications including confusion and altered consciousness. Non-convulsive status epilepticus, which is characterized by a change in behavior and/or mental process accompanied by epileptiform discharges on electroencephalogram in the absence of convulsive seizures, is one of the overlooked causes of altered consciousness. The incidence and precise pathophysiological mechanism of non-convulsive status epilepticus in patients with kidney disease, and especially in patients with electrolyte disturbances, remains unknown. We recently treated an older patient with chronic kidney disease and severe hyperkalemia in whom non-convulsive status epilepticus developed following a correction of severe hyperkalemia., Case Presentation: An 82-year-old male was admitted to our hospital at midnight because of weakness of all four limbs (Day 1). He underwent urgent hemodialysis for severe hyperkalemia (9.84 mEq/L) and his serum potassium concentration decreased to 4.97 mEq/L. He regained full consciousness and his limb weakness improved on the morning of Day 2, but he became confused in the evening. Electroencephalogram revealed repeated low-voltage ictal discharges in the right occipital region and a diagnosis of non-convulsive status epilepticus was made. Following medication with fosphenytoin and phenytoin, the patient became fully alert and orientated on Day 8., Conclusion: We speculate that a rapid correction of hyperkalemia was the possible cause of non-convulsive status epilepticus development. To our knowledge, this is the first report of non-convulsive status epilepticus from a potassium abnormality. We described a case of this condition in detail and summarized 78 previous case reports of non-convulsive status epilepticus with kidney disease or electrolyte disturbances., (© 2023. The Author(s).)

Background: Our recent report showed that 1.5-T pulsed arterial spin labeling (ASL) magnetic resonance (MR) perfusion imaging (1.5-T Pulsed ASL [PASL]), which is widely available in the field of neuroemergency, is useful for detecting ictal hyperperfusion. However, the visualization of intravascular ASL signals, namely, arterial transit artifact (ATA), is more remarkable than that of 3-T pseudocontinuous ASL and is easily confused with focal hyperperfusion. To eliminate ATA and enhance the detectability of (peri) ictal hyperperfusion, we developed the subtraction of ictal-interictal 1.5-T PASL images co-registered to conventional MR images (SIACOM)., Methods: We retrospectively analyzed the SIACOM findings in four patients who underwent ASL during both (peri) ictal and interictal states and examined the detectability for (peri) ictal hyperperfusion., Results: In all patients, the ATA of the major arteries was almost eliminated from the subtraction image of the ictal-interictal ASL. In patients 1 and 2 with focal epilepsy, SIACOM revealed a tight anatomical relationship between the epileptogenic lesion and the hyperperfusion area compared with the original ASL image. In patient 3 with situation-related seizures, SIACOM detected minute hyperperfusion at the site coinciding with the abnormal electroencephalogram area. SIACOM of patient 4 with generalized epilepsy diagnosed ATA of the right middle cerebral artery, which was initially thought to be focal hyperperfusion on the original ASL image., Conclusion: Although it is necessary to examine several patients, SIACOM can eliminate most of the depiction of ATA and clearly demonstrate the pathophysiology of each epileptic seizure., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Surgical Neurology International.)

Objectives: Endoscopic submucosal resection with band ligation (ESMR-L) and endoscopic submucosal dissection (ESD) are both standard endoscopic resection methods for rectal neuroendocrine tumors (NETs) <10 mm in size. However, there is no definitive consensus on which is better. Here, we compared the efficacy of ESMR-L and ESD for small rectal NETs., Methods: This was a multicenter retrospective cohort study including 205 patients with rectal NETs who underwent ESMR-L or ESD. Treatment outcomes were compared by univariate analysis, multivariate analysis, and inverse probability treatment weighting (IPTW) using propensity scores. Subgroup analysis evaluated the impact of the endoscopist's experience on the technical outcome., Results: Eighty-nine patients were treated by ESMR-L and 116 by ESD. The R0 resection rate was not significantly different between the two (90% vs. 92%, p = 0.73). The procedure time of ESMR-L was significantly shorter than for ESD (17 min vs. 52 min, p < 0.01) and the hospitalization period was also significantly shorter (3 days vs. 5 days, p < 0.01). These results were confirmed by multivariate analysis and also after IPTW adjustment. The procedure time of ESD was significantly prolonged by a less-experienced endoscopist (49 min vs. 70 min, p = 0.02), but that of ESMR-L was not affected (17 min vs. 17 min, p = 0.27)., Conclusions: For small rectal NETs, both ESMR-L and ESD showed similar high complete resection rates. However, considering the shorter procedure time and shorter hospitalization period, ESMR-L is the more efficient treatment method, especially for less-experienced endoscopists., Competing Interests: None., (© 2022 The Authors. DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Background: As the aging population grows worldwide, the rates of endoscopic retrograde cholangiopancreatography (ERCP) for common bile duct stones (CBDS) in older patients with a poor performance status (PS) have been increasing. However, the data on the safety and efficacy of ERCP for CBDS in patients with a PS score of 3 or 4 are lacking, with only a few studies having investigated this issue among patients with poor PS., Aim: To examine the safety and efficacy of ERCP for CBDS in patients with a PS score of 3 or 4., Methods: This study utilized a retrospective multi-centered design of three institutions in Japan for 8 years to identify a total of 1343 patients with CBDS having native papillae who underwent therapeutic ERCP. As a result, 1113 patients with a PS 0-2 and 230 patients with a PS 3-4 were included. One-to-one propensity-score matching was performed to compare the safety and efficacy of ERCP for CBDS between patients with a PS 0-2 and those with a PS 3-4., Results: The overall ERCP-related complication rates in all patients and propensity score-matched patients with a PS 0-2 and 3-4 were 9.0% (100/1113) and 7.0% (16/230; P = 0.37), and 4.6% (9/196) and 6.6% (13/196; P = 0.51), respectively. In the propensity score-matched patients, complications were significantly more severe in the group with a PS 3-4 than in the group with a PS 0-2 group ( P = 0.042). Risk factors for complications were indications of ERCP and absence of antibiotics in the multivariate analysis. Therapeutic success rates, including complete CBDS removal and permanent biliary stent placement, in propensity score-matched patients with a PS 0-2 and 3-4 were 97.4% (191/196) and 97.4% (191/196), respectively ( P = 1.0)., Conclusion: ERCP for CBDS can be effectively performed in patients with a PS 3 or 4. Nevertheless, the indication for ERCP in such patients should be carefully considered with prophylactic antibiotics., Competing Interests: Conflict-of-interest statement: The authors declare that there are no conflicts of interest in relation to this article., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Recent our reports showed that 3-T pseudocontinuous arterial spin labeling (3-T pCASL) magnetic resonance perfusion imaging with dual post labeling delay (PLD) of 1.5 and 2.5 s clearly demonstrated the hemodynamics of ictal hyperperfusion associated with non-convulsive status epilepticus (NCSE). We aimed to examine the utility of 1.5-T pulsed arterial spin labeling (1.5-T PASL), which is more widely available for daily clinical use, for detecting ictal hyperperfusion., Methods: We retrospectively analyzed the findings of 1.5-T PASL with dual PLD of 1.5 s and 2.0 s in six patients and compared the findings with ictal electroencephalographic (EEG) findings., Results: In patients 1 and 2, we observed the repeated occurrence of ictal discharges (RID) on EEG. In patient 1, with PLDs of 1.5 s and 2.0 s, ictal ASL hyperperfusion was observed at the site that matched the RID localization. In patient 2, the RID amplitude was extremely low, with no ictal ASL hyperperfusion. In patient 3 with lateralized periodic discharges (LPD), we observed ictal ASL hyperperfusion at the site of maximal LPD amplitude, which was apparent at a PLD of 2.0 s but not 1.5 sec. Among three patients with rhythmic delta activity (RDA) of frequencies <2.5 Hz (Patients 4-6), we observed obvious and slight increases in ASL signals in patients 4 and 5 with NCSE, respectively. However, there was no apparent change in ASL signals in patient 6 with possible NCSE., Conclusion: The detection of ictal hyperperfusion on 1.5-T PASL might depend on the electrophysiological intensity of the epileptic ictus, which seemed to be more prominent on 1.5-T PASL than on 3-T pCASL. The 1.5-T PASL with dual PLDs showed the hemodynamics of ictal hyperperfusion in patients with RID and LPD. However, it may not be visualized in patients with extremely low amplitude RID or RDA (frequencies <2.5 Hz)., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Surgical Neurology International.)

Background/aims: Difficult biliary cannulation is an important risk factor for post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). Therefore, this study aimed to identify the factors that predict difficult cannulation for common bile duct stones (CBDS) to reduce the risk for PEP., Methods: This multicenter retrospective study included 1,406 consecutive patients with native papillae who underwent ERCP for CBDS. Factors predicting difficult cannulation for CBDS were identified using univariate and multivariate analyses., Results: Univariate analysis showed that six factors significantly predicted difficult cannulation: ERCP performed by non-expert endoscopists, low-volume center, absence of acute cholangitis, normal serum bilirubin, intradiverticular papilla, and type of major duodenal papilla. Multivariate analysis identified ERCP performed by non-expert endoscopists (odds ratio [OR], 2.5; p<0.001), low-volume center (OR, 1.6; p<0.001), intradiverticular papilla (OR, 1.3; p=0.007), normal serum bilirubin (OR, 1.3; p=0.038), and absence of acute cholangitis (OR, 1.3; p=0.049) as factors significantly predicting difficult cannulation for CBDS., Conclusion: Initial cannulation by an experienced endoscopist, early rescue cannulation, or early takeover by an experienced endoscopist should be considered when performing ERCP for CBDS in the presence of factors predicting difficult cannulation.

Background and Aim: Current guidelines recommend the removal of common bile duct (CBD) stones by endoscopic retrograde cholangiopancreatography (ERCP) for both asymptomatic and symptomatic patients. We conducted this study because of the limited research comparing the risks of ERCP-related complications between these two groups., Methods: This retrospective study involved 1491 patients with native major duodenal papilla diagnosed with choledocholithiasis at three institutions in Japan. The rates of ERCP-related complications, including post-ERCP pancreatitis (PEP), cholangitis, bleeding, and perforation, were compared using one-to-one propensity score matching between the asymptomatic and symptomatic patients., Results: Complications were observed in 112 (7.5%) of the 1491 patients (asymptomatic group: 31/172 [18.0%] vs symptomatic group: 81/1319 [6.1%], P  < 0.001). The rate of severe complications was higher in the asymptomatic group than that in the symptomatic group (asymptomatic group: 5/31 [16.1%] vs symptomatic group: 3/81 [3.7%], P  = 0.036). In the propensity-matched asymptomatic and symptomatic patients, the incidences of PEP, cholangitis, bleeding, and perforation were 18/143 (12.6%) vs 4/143 (2.8%) ( P  = 0.003); 4/107 (3.7%) vs 6/107 (5.6%) ( P  = 0.75); 1/140 (0.7%) vs 3/140 (2.1%) ( P  = 0.62); and 2/140 (1.4%) vs 2/140 (1.4%) ( P  = 1.0)., Conclusions: ERCP for asymptomatic patients with CBD stones is associated with a higher risk of overall and severe complications than that for symptomatic patients with CBD stones; the overall rate is influenced by the high incidence of PEP in the asymptomatic group. Endoscopists should explain the risk of ERCP-related complications for asymptomatic patients before performing the procedure., (© 2021 The Authors. JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Acromegaly is a chronic systemic disease characterized by facial and peripheral changes caused by soft tissue overgrowth and is associated with multiple comorbidities. Despite available surgical and medical therapies, suitable treatments for acromegaly are still lacking. Efficient drug development requires an understanding of the exposure-response (E-R) relationship based on nonclinical and early clinical studies. We aimed to establish a platform to facilitate the development of novel drugs to treat acromegaly. We evaluated the E-R relationship of the growth hormone (GH)-inhibitory effect of the somatostatin analog octreotide under growth hormone-releasing hormone + arginine stimulation in healthy participants and compared the results with historical data for patients with acromegaly. This randomized five-way crossover study included two placebo and three active-treatment periods with different doses of octreotide acetate. GH secretion in the two placebo periods was comparable, which confirmed the reproducibility of the response with no carryover effect. GH secretion was inhibited by low-, medium-, and high-dose octreotide acetate in a dose-dependent manner. We also examined the E-R relationship in monkeys as a preclinical drug evaluation study and in rats as a more convenient and simple system for screening candidate drugs. The E-R relationships and EC 50 values were similar among animals, healthy participants, and patients with acromegaly, which suggests that GH stimulation studies in early research and development allowed simulation of the drug response in patients with acromegaly. SIGNIFICANCE STATEMENT: This study demonstrated similar exposure-response relationships in terms of the growth hormone-inhibitory effect of octreotide after growth hormone-releasing hormone stimulation among healthy participants, monkeys, and rats. The research methods and analyses utilized in this study will be useful for simulating the dosages and therapeutic effects of drugs for acromegaly and will facilitate the research and development of novel therapeutic agents with similar modes of action., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: In recent years, with the growing availability of image-enhanced gastrointestinal endoscopy, gastroenterologists have contributed to the early detection of pharyngeal squamous cell carcinomas (SCC)., Aim: To clarify the clinical characteristics of pharyngeal SCCs detected by gastrointestinal endoscopy., Methods: This is a retrospective cohort study conducted in a single-center, a university hospital in Japan. We retrospectively assessed the clinical records of 522 consecutive patients with oropharyngeal or hypopharyngeal SCC who were examined in our hospital between 2011 and 2018. The lesions were classified into two groups: Group GE (detected by gastrointestinal endoscopy) and Group non-GE (detected by means other than gastrointestinal endoscopy). The clinical characteristics were compared between the two groups. Continuous data were compared using the Mann-Whitney U test. Pearson's χ 2 test or Fisher's exact test was used to analyze the categorical data and compare proportions. The Kaplan-Meier method was used to estimate the cumulative patient survival rates., Results: In our study group, the median age was 65 years and 474 patients (90.8%) were male. One hundred and ninety-six cases (37.5%) involved the oropharynx and 326 cases (62.5%) involved the hypopharynx. Three hundred and ninety-five cases (75.7%) had some symptoms at the time of diagnosis. One hundred and forty-five (27.8%) cases had concurrent ESCC or a history of ESCC. One hundred and sixty-four (31.4%) cases were detected by gastrointestinal endoscopy and classified as Group GE. The proportions of asymptomatic cases, cTis-1 cases and cases with no lymph node metastasis were significantly higher in Group GE than Group non-GE (61.6% vs 7.3%, P < 0.001, 32.9% vs 12.0%, P < 0.001 and 69.5% vs 19.0%, P < 0.001). Endoscopic laryngo-pharyngeal surgery or endoscopic submucosal dissection were performed in only 0.6% of the lesions in Group non-GE but in 21.3% of the lesions in Group GE ( P < 0.001). Overall survival was significantly longer in Group GE than in Group non-GE ( P = 0.018). The 2-year and 4-year survival rates were 82.5% and 70.7% in Group GE, and 71.5% and 59.0% in Group non-GE, respectively., Conclusion: Gastrointestinal endoscopy plays an important role in the early detection and improving the prognosis of pharyngeal SCCs., Competing Interests: Conflict-of-interest statement: The authors declare no conflicts of interest associated with this manuscript., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Closed spinal dysraphism of primary neurulation failure could be associated with filar anomalies, such as filar lipoma or thickened and tight filum terminale (TFT), resulting from impaired secondary neurulation. Retained medullary cord (RMC) is a remnant of the cavitary medullary cord originating from the secondary neurulation failure. Some filar lipomas are known to contain a central canal-like ependyma-lined lumen with surrounding neuroglial tissues (E-LC w/NGT), that is, a characteristic histopathology of RMC. To clarify the embryological background of these filar anomalies, we evaluated the histopathological findings., Methods: Among 41 patients with lesions of primary neurulation failure who underwent initial untethering surgery, the filum including cord-like structure (C-LS) was additionally resected in 10 patients (five dorsal and transitional lipomas; five limited dorsal myeloschisis). We retrospectively analyzed the clinical, neuroradiological, intraoperative, and histopathological findings., Results: Among 10 patients, two patients were diagnosed with RMC based on morphological features and intraoperative neurophysiological monitoring. The diagnosis of filar lipoma was made in six patients, since various amounts of fibroadipose tissue were histopathologically noted in the filum. Two patients were diagnosed with TFT, since the filum was composed solely of fibrocollagenous tissue. E-LC w/NGT was noted not only in both C-LSs of RMCs but also in two out of six fila both with filar lipomas and fila with TFTs., Conclusion: These findings provide further evidence for the idea that entities, such as filar lipoma, TFT, and RMC, can be considered consequences of a continuum of regression failure occurring during late secondary neurulation., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Surgical Neurology International.)

Current guidelines for treating asymptomatic common bile duct stones (CBDS) recommend stone removal, with endoscopic retrograde cholangiopancreatography (ERCP) being the first treatment choice. When deciding on ERCP treatment for asymptomatic CBDS, the risk of ERCP-related complications and outcome of natural history of asymptomatic CBDS should be compared. The incidence rate of ERCP-related complications, particularly of post-ERCP pancreatitis for asymptomatic CBDS, was reportedly higher than that of symptomatic CBDS, increasing the risk of ERCP-related complications for asymptomatic CBDS compared with that previously reported for biliopancreatic diseases. Although studies have reported short- to middle-term outcomes of natural history of asymptomatic CBDS, its long-term natural history is not well known. Till date, there are no prospective studies that determined whether ERCP has a better outcome than no treatment in patients with asymptomatic CBDS or not. No randomized controlled trial has evaluated the risk of early and late ERCP-related complications vs the risk of biliary complications in the wait-and-see approach, suggesting that a change is needed in our perspective on endoscopic treatment for asymptomatic CBDS. Further studies examining long-term complication risks of ERCP and wait-and-see groups for asymptomatic CBDS are warranted to discuss whether routine endoscopic treatment for asymptomatic CBDS is justified or not., Competing Interests: Conflict-of-interest statement: There are no conflicts of interest to declare in relation to this article., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: The PD-1/PD-L1 pathway plays critical roles in tumour immunology, and serves as an immune-based therapeutic target. Less is known regarding PD-L2, another ligand of PD-1, and its relation to clinical outcome in human cancers., Methods: We used a database of 437 surgically and 100 endoscopically resected oesophageal cancers (squamous cell carcinoma, n = 483; adenocarcinoma, n = 36; others, n = 18) to evaluate PD-L2 and PD-L1 expression by immunohistochemistry., Results: Compared with PD-L2-negative cases (n = 366, 83.8%), PD-L2-positive cases (n = 71, 16.2%) had worse overall survival (P = 0.011, log-rank test). There was not a significant correlation between PD-L2 and PD-L1 expression. Multiplex immunofluorescence revealed that there was variability in the expression pattern of PD-L2 and PD-L1. In early-stage tumours, PD-L2 expression was more frequently observed compared with PD-L1., Conclusions: PD-L2 as well as PD-L1 were associated with an unfavourable prognosis in oesophageal cancer, supporting the role of PD-L2 as a prognostic biomarker. Considering that PD-L2 and PD-L1 had different features in terms of expression timing and responses to chemotherapeutic drugs, evaluation of both PD-L2 and PD-L1 expression may be clinically important.

Aims: Although the bacterial virulent factor of cytotoxin-associated gene-A (CagA)-seropositivity and the host genetic factors of interleukin (IL)-1 polymorphisms have been suggested to influence Helicobacter pylori (HP) -related diseases, the underlying mechanisms of the association between HP infection and acute coronary syndrome (ACS) remain unknown., Methods and Results: Among 341 consecutive ACS patients, the clinical outcomes after ACS included composite cardiovascular events within the 2-year follow-up period.A significantly higher probability of primary outcomes was observed in HP positive patients than in HP negative patients. There were no significant differences in the rate of cardiovascular events between HP positive and HP negative patients in the absence of an IL -polymorphism, while there were significant differences in the presence of an IL -polymorphism. There were significant differences in the rate of cardiovascular events among CagA positive, CagA negative/ HP positive and CagA negative/ HP negative patients. Moreover, via immunohistochemical staining, aortic CagA positive cells were confirmed in the vasa vasorum in CagA positive patients, whereas they could not be identified in CagA negative patients., Conclusions: The bacterial virulence factor CagA and host genetic IL-1 polymorphisms influence the incidence of adverse cardiovascular events, possibly through infection of atherosclerotic lesions. Registration: University Hospital Medical Information Network (UMIN)-CTR (http://www.umin.ac.jp/ctr/). Identifier: UMIN000035696., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Authors.)

Background: Congenital hyperinsulinism (CH) is a rare disease, characterized by severe hypoglycemia induced by inappropriate insulin secretion from pancreatic beta-cells in neonate and infant. Hirschsprung's disease (HD) is also a rare disease in which infants show severe bowel movement disorder. We herein report an extremely rare case of combined CH and HD., Case Presentation: The patient was a full-term male infant who showed poor feeding, vomiting, and hypotonia with lethargy on the day of birth. He was transferred to tertiary hospital after a laboratory analysis revealed hyperinsulinemic hypoglycemia. The patient showed remarkable abdominal distension without meconium defecation. An abdominal X-ray showed marked dilatation of the large bowel. He was diagnosed with CH (nesidioblastosis) associated with suspected HD. He was initially treated with an intravenous infusion of high-dose glucose with the intermittent injection of glucagon. This was successfully followed by treatment with diazoxide and octreotide (a somatostatin analog). At 8 months of age, HD was confirmed by the acetylcholinesterase staining of a rectal mucosal biopsy specimen, and a transanal pull-through operation was performed to treat HD. At 14 months of age, subtotal pancreatectomy was performed for the treatment of focal CH located in the pancreatic body. His postoperative course over the past 12 years has been uneventful without any neurologic or bowel movement disorders., Conclusions: Although it is extremely rare for CH to be associated with HD, associated HD should be considered when a patient with CH presents severe constipation.

Objective The measurement of C-peptide immunoreactivity (CPR) is essential for evaluating the pancreatic β-cell function and selecting appropriate therapeutic agents in patients with diabetes mellitus. The meal tolerance test (MTT) is simple to administer physiological insulin-stimulating test. Previous studies have reported that several CPR-related indices are useful markers for predicting insulin requirement in type 2 diabetes. In the present study, we investigated the serum CPR response during the MTT in hospitalized patients with type 2 diabetes mellitus in order to clarify the clinical utility of the MTT. Methods We performed the MTT using a test meal with timed measurements of the serum CPR level based on the oral glucose tolerance test over 180 minutes and tested the correlation of various CPR-related indices and clinical factors in patients with type 2 diabetes mellitus. Patients The subjects were patients with type 2 diabetes mellitus who had been admitted to our hospital for diabetes management and education. The final study population consisted of 68 patients. Results The fasting CPR level was correlated with the 24-hour urinary CPR excretion and body mass index. The serum CPR level at 120 minutes in the MTT was strongly correlated with the area under the curve of CPR during the MTT. The patients who needed insulin therapy at 6 months after hospitalization showed a significant lower incremental CPR value from 0 to 120 minutes in the MTT than those who did not need insulin therapy. Conclusion The plasma C-peptide levels at 0 and 120 minutes in the MTT provide essential information for the clinical management of patients with type 2 diabetes mellitus.

Background: Spontaneously ruptured large splenic cyst is a rare in children, and traditionally total or partial splenectomy has been performed for treating an emergent case. We herein present a first case with spontaneously ruptured pediatric splenic cyst treated with emergent laparoscopic dome resection with omental suturing to the parenchymal edge of the spleen., Case Presentation: A 12-year-old girl with a spontaneously ruptured large non-parasitic splenic cyst (SC) was successfully treated by emergent laparoscopic dome resection with omental suturing to the edge of the splenic parenchyma. The patient presented with acute abdominal pain and was diagnosed with a ruptured non-parasitic SC and peritonitis by contrast-enhanced computed tomography (CT). Emergent laparoscopic dome resection of the SC and omental suturing to the splenic parenchymal edge were then performed. The protruding part of the cyst wall was completely resected using an ultrasonically activated device (USAD), and the greater omentum was then sutured to the anterior edge of the splenic parenchyma under a laparoscopic view. No complications were observed during the operation. A histological examination revealed a congenital splenic cyst lined by epithelial cells. The postoperative course was uneventful, and an ultrasound scan showed no evidence of cyst recurrence at 3 years after the operation., Conclusions: This minimally invasive laparoscopic procedure was feasible and effective for treating a ruptured large splenic cyst in an emergent pediatric patient.

Teleost fishes develop remarkable varieties of skin ornaments. The developmental basis of these structures is poorly understood. The order Tetraodontiformes includes diverse fishes such as the ocean sunfishes, triggerfishes, and pufferfishes, which exhibit a vast assortment of scale derivatives. Pufferfishes possess some of the most extreme scale derivatives, dermal spines, erected during their characteristic puffing behavior. We demonstrate that pufferfish scale-less spines develop through conserved gene interactions that underlie general vertebrate skin appendage formation, including feathers and hair. Spine development retains conservation of the EDA (ectodysplasin) signaling pathway, important for the development of diverse vertebrate skin appendages, including these modified scale-less spines of pufferfish. Further modification of genetic signaling from both CRISPR-Cas9 and small molecule inhibition leads to loss or reduction of spine coverage, providing a mechanism for skin appendage diversification observed throughout the pufferfishes. Pufferfish spines have evolved broad variations in body coverage, enabling adaptation to diverse ecological niches., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Esophageal injury (EI) is a serious complication that occurs after catheter ablation of atrial fibrillation (AF), however predictable factor of EI is unclear., Methods: Among 308 patients who underwent AF ablation, upper gastrointestinal tract endoscopy was performed the next day after ablation to examine for EI. To define the primary factor that predicts EI, patients' characteristics, number and amount of radiofrequency energy applied to the posterior wall, ablation procedure, and the shortest distance between esophagus and posterior left atrium measured on contrast computed tomography (SD-CT) were analyzed., Results: EI was found in 27 patients (8.8%). There were no significant differences in the patient characteristics, number and amount of radiofrequency energy applied to posterior wall or ablation procedure between patients with (Injury Group) and without EI (Non-Injury Group). However, SD-CT in the Injury Group was significantly shorter than that in Non-Injury Group (2.3±0.6mm vs 4.1±0.9mm, p<0.001). The area under a receiver operating characteristic curve using SD-CT as a predictive marker in EI patients was 0.988 (p<0.001). When the cut-off value of SD-CT was set at 2.9mm, the sensitivity and specificity for EI diagnosis were 92.3% and 96.8%, and the positive predictive value and negative predictive value were 0.75 and 0.99, respectively., Conclusions: EI observed after catheter ablation of AF was closely associated with the SD-CT. Patients with SD-CT below 2.9mm have a potential risk of EI and thus must be strictly followed., (Copyright © 2018 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Aim: Our study sought to identify dosimetric predictors of treatment-related lymphopenia during chemoradiotherapy for esophageal cancer., Materials and Methods: Patients with esophageal cancer who had received definitive chemoradiotherapy at our Institution were retrospectively assessed. The absolute volume of the spleen, body, and bone marrow that had received 5, 10, 20, and 30 Gy and the mean splenic dose were recorded., Results: Multivariate linear regression analysis revealed that docetaxel use and spleen dose-volume parameters (V5, V10, V20, V30, and mean splenic dose) were significant independent factors negatively influencing the absolute lymphocyte count at nadir. An increase of 1 Gy in mean splenic dose predicted a 2.9% decrease in nadir absolute lymphocyte count. Univariable logistic regression analysis showed that the mean splenic dose was a significant predictor of grade 4 lymphopenia. None of the body or bone marrow dose-volume parameters significantly predicted lymphopenia., Conclusion: Higher spleen dose-volume parameters were associated with severe lymphopenia during chemoradiotherapy., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The adenoma-carcinoma sequence, the sequential mutation and deletion of various genes by which colorectal cancer progresses, is a well-established and accepted concept of colorectal cancer carcinogenesis. Proteins of the polycomb repressive complex 2 (PRC2) function as transcriptional repressors by trimethylating histone H3 at lysine 27; the activity of this complex is essential for cell proliferation and differentiation. The histone methyltransferase enhancer of zeste homolog 2 (EZH2), an essential component of PRC2, is associated with the transcriptional repression of tumor suppressor genes. EZH2 expression has previously been reported to increase with the progression of pancreatic intraductal papillary mucinous neoplasm. Thus, we hypothesized that EZH2 expression also increases during the adenoma-carcinoma sequence of colorectal cancer. The present study investigated changes in EZH2 expression during the colorectal adenoma-carcinoma sequence. A total of 47 patients with colorectal adenoma, 20 patients with carcinoma in adenoma and 43 patients with colorectal carcinoma who underwent surgical or endoscopic resection were enrolled in this study. Non-cancerous tissue from the clinical specimens was also examined. The association between EZH2 expression, pathology and expression of tumor suppressor genes during colorectal carcinogenesis were analyzed. Each specimen was immunohistochemically stained for EZH2, proliferation marker protein Ki-67 (Ki-67), cyclin-dependent kinase inhibitor (CDKN) 1A (p21), CDKN1B (p27) and CDKN2A (p16). Total RNA was extracted from formalin-fixed paraffin-embedded blocks and reverse transcription-quantitative polymerase chain reaction analysis of these genes was performed. Ki-67 and EZH2 expression scores increased significantly during the progression of normal mucosa to adenoma and carcinoma (P=0.009), and EZH2 expression score was positively associated with Ki-67 expression score (P=0.02). Conversely, p21 mRNA and protein expression decreased significantly, whereas expression of p27 and p16 did not change significantly. During the carcinogenesis sequence from normal mucosa to adenoma and carcinoma, EZH2 expression increased and p21 expression decreased significantly. EZH2 may therefore contribute to the development of colorectal cancer from adenoma via suppression of p21.

Background and Aim: Right colon polyps can especially be overlooked when they are located on the backs of haustral folds. Previous studies have reported that repeated forward-view examinations in the right colon were effective in reducing adenoma miss rates. The aim of this study was to clarify the impact of retroflexion in the right colon after repeated forward-view examinations., Methods: This multicenter, prospective, observational study was conducted at three institutions in Kumamoto, Japan, between February 2014 and December 2015. Subjects who were over 40 years old and scheduled for colonoscopy were recruited. For the forward view, after cecal intubation, the colonoscope was withdrawn to the hepatic flexure. The colonoscope was sequentially reinserted to the cecum and then withdrawn to the hepatic flexure. For the retroflexion view (RV), the colonoscope was reinserted to the cecum, retroflexed, and then withdrawn to the hepatic flexure. All polyps were resected at the time of detection. The primary outcome of this study was the adenoma miss rate for the repeated forward-view examinations., Results: Of the 777 enrolled participants, retroflexion was successful in 730 (94.0%). The repeated forward-view withdrawal technique detected 291 adenomas, while the third withdrawal in the RV detected 53. The adenoma miss rate for the repeated forward-view withdrawal was 15.4%. No severe adverse events occurred during retroflexion., Conclusion: Because adenomas located on potential blind spots can be missed when only using forward-view examinations, retroflexion in the right colon after repeated forward-view examinations might improve colonoscopy detection rates.

Background: Adenocarcinoma with enteroblastic differentiation is a subtype of alpha-fetoprotein (AFP) producing adenocarcinoma. This type of tumor is associated with a poor prognosis and is prone to metastasize. Esophageal adenocarcinoma with enteroblastic differentiation is extremely rare., Case Presentation: The patient was a 65-year-old woman who was referred to our hospital with dysphagia. Endoscopic examination revealed an elevated lesion 20mm in diameter at 17cm from the upper incisors. Endoscopic submucosa dissection (ESD) was performed and histopathological examination revealed tubular adenocarcinoma composed of cuboidal cells with clear cell cytoplasm. Immunohistochemical stain was diffusely positive for Sall-like protein 4 (SALL4) and weakly positive for AFP and glypican 3. From this result, we diagnosed esophageal adenocarcinoma with enteroblastic differentiation. The patient is still alive without recurrence of cancer 40 months after ESD., Conclusion: To our knowledge, this is the first report to undergo ESD for esophageal adenocarcinoma with enteroblastic differentiation arising from ectopic gastric mucosa in the esophagus.

Vertebrate dentitions are extraordinarily diverse in both morphology and regenerative capacity. The teleost order Tetraodontiformes exhibits an exceptional array of novel dental morphologies, epitomized by constrained beak-like dentitions in several families, i.e., porcupinefishes, three-toothed pufferfishes, ocean sunfishes, and pufferfishes. Modification of tooth replacement within these groups leads to the progressive accumulation of tooth generations, underlying the structure of their beaks. We focus on the dentition of the pufferfish (Tetraodontidae) because of its distinct dental morphology. This complex dentition develops as a result of ( i ) a reduction in the number of tooth positions from seven to one per quadrant during the transition from first to second tooth generations and ( ii ) a dramatic shift in tooth morphogenesis following the development of the first-generation teeth, leading to the elongation of dental units along the jaw. Gene expression and 1,1'-Dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) lineage tracing reveal a putative dental epithelial progenitor niche, suggesting a highly conserved mechanism for tooth regeneration despite the development of a unique dentition. MicroCT analysis reveals restricted labial openings in the beak, through which the dental epithelium (lamina) invades the cavity of the highly mineralized beak. Reduction in the number of replacement tooth positions coincides with the development of only four labial openings in the pufferfish beak, restricting connection of the oral epithelium to the dental cavity. Our data suggest the spatial restriction of dental regeneration, coupled with the unique extension of the replacement dental units throughout the jaw, are primary contributors to the evolution and development of this unique beak-like dentition., Competing Interests: The authors declare no conflict of interest.

Purpose: The AVAglio trial established the beneficial effect of add-on bevacizumab (BEV) for the treatment of newly diagnosed glioblastomas (nd-GBMs) that led to the approval of BEV for the treatment of these patients in Japan. However, the rationality of using BEV as a first-line treatment for nd-GBMs remains controversial. The purpose of this study was to analyze the outcomes of a case series of nd-GBM patients., Patients and Methods: The outcomes of 69 nd-GBM patients treated after 2006 were retrospectively analyzed. Clinical and genetic analyses were performed, and estimates of progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Since add-on BEV therapy was only used for partially resected GBMs (pr-GBMs) after its approval in 2013, the patients were subdivided into 3 treatment groups: Type I, partial removal with temozolomide (TMZ)/BEV and concurrent radiotherapy (CCRT); Type II, partial removal with TMZ and CCRT; and Type III, gross total removal with TMZ and CCRT., Results: The PFS rate of Type I patients was significantly higher than that of Type II patients ( P =0.014), but comparable to that of Type III patients. Differences in OS rates between Type I and Type II patients were less apparent ( P =0.075), although the median OS of Type I patients was ~8 months higher than that of Type II patients (17.4 vs 9.8 months, respectively). The clinical deterioration rate during initial treatment was significantly ( P =0.024) lower in Type I than in Type II patients (7.7% vs 47.4%, respectively). Differences in OS rates between Type I and Type II patients with a poor performance status (PS) were significant ( P =0.017)., Conclusion: Our findings suggest that add-on BEV can prevent early clinical deterioration of pr-GBM patients and contribute to a prolonged survival, especially for those with a poor PS., Competing Interests: The authors report no conflicts of interest in this work.

Recently updated phase III trials revealed the favorable effect of add-on procarbazine-lomustine-vincristine chemotherapy (CT) to radiotherapy (RT) in treating anaplastic oligodendrogliomas with 1p19q codeletion (codel). However, the underlying rationality of deferring RT and upfront CT administration for these tumors is yet to be elucidated. Here, we retrospectively analyzed the long-term outcome of our case series with oligodendroglial tumors treated with deferred RT and upfront procarbazine+nimustine+vincristine (PAV) in the introduction administration. We enrolled 36 patients with newly diagnosed oligodendroglial tumors (17, grade II and 19, grade III) treated during 1999-2012 and followed up for a median period of 69.0 months. Their clinical and genetic prognostic factors were analyzed, and progression-free survival, overall survival (OS), and deterioration-free survival (DFS) were evaluated. Regardless of the WHO grade, the 25 patients with 1p19q codel tumors never received RT initially, and of these 25, 23 received PAV treatment upfront. The 75% OS of patients with 1p19q codel tumor was 135.3 months (did not reach the median OS), indicating a favorable outcome. Multivariate analysis revealed that IDH mutation and 1p19q, not WHO grade, are independent prognostic factors; furthermore, IDH and 1p19q status stratified the cohort into 3 groups with significantly different OS. The DFS explained the prolonged survival without declining performance in patients with both grade II and III 1p19q codel tumors. Deferred RT and upfront PAV treatment for 1p19q codel oligodendrogliomas were associated with favorable outcomes without compromising performance status, regardless of WHO grade., Competing Interests: The authors report no conflicts of interest in this work.

Sex determination pathways evolve rapidly, usually because of turnover of master regulatory genes at the top of the developmental pathway. Polygenic sex determination is expected to be a transient state between ancestral and derived conditions. However, polygenic sex determination has been observed in numerous animal species, including the house fly, Musca domestica House fly males carry a male-determining factor (M) that can be located on any chromosome, and an individual male may have multiple M factors. Females lack M and/or have a dominant allele of the Md-tra gene (Md-tra D ) that acts as a female-determining locus even in the presence of multiple copies of M. We found the frequency and linkage of M in house flies collected in Chino, CA (USA) was relatively unchanged between 1982 and 2014. The frequency of females with Md-tra D in the 2014 collection was 33.6% (n = 140). Analysis of these results, plus previously published data, revealed a strong correlation between the frequencies of Md-tra D and multiple M males, and we find that these populations are expected to have balanced sex ratios. We also find that fitness values that allow for the invasion and maintenance of multiple sex determining loci suggest that sexually antagonistic selection could be responsible for maintaining polygenic sex determination in house fly populations. The stability over time and equilibrium frequencies within populations suggest the house fly polygenic sex determination system is not in transition, and provide guidance for future investigations on the factors responsible for the polymorphism., (© The American Genetic Association 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aim: There has been no indicator that allows an early quantitative evaluation of the severity of a mamushi snake ( G loydius blomhoffii ) bite. Because the number of severe mamushi bite cases is much fewer than non-severe cases, a formal case-control study is difficult. Therefore, we tried to generate a preliminary quantitative, real-time index for its severity by referring to published reports of severe mamushi bite cases., Methods: We enrolled patients who presented with a mamushi bite and visited our outpatient clinic. Severe cases were collected from published works. Creatinine kinase levels and white blood cell counts of non-severe and severe cases were compared and analyzed., Results: There was a lag time of 10 h before the creatinine kinase level began to rise. The speed of the increase was higher in severe cases than in non-severe cases, and severe cases were recognized as those showing speeds of above 250 IU/L/h. White blood cell counts increased earlier than creatinine kinase levels without any lag time. Severe cases were recognized as those with the counts of over 1,000 × (h) + 6,000 [/μL] before 5 h and 300 × (h) + 10,000 [/μL] after 5 h., Conclusion: We herein present the creatinine kinase level and white blood cell count trends and demonstrate preliminary cut-off equations. The trends for both parameters serve as quantitative indicators of the severity of a mamushi bite until a large scale case-control study is achieved.

The incidence rate of esophagogastric junction (EGJ) adenocarcinoma has been rapidly increasing worldwide. Carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) are major serum tumor markers in gastrointestinal cancers. However, the role of these markers in EGJ adenocarcinoma has not been thoroughly investigated. A total of 211 patients with EGJ adenocarcinoma who underwent surgery or endoscopic submucosal dissection at two academic institutions, Kumamoto University Hospital or Kyushu University Hospital between January 1996 and March 2014, were eligible for this study. Serum CEA and CA19-9 were examined within 1 month before resection. The cut-off values for CEA and CA19-9 were set at 5.0 ng/mL and 37 U/mL, respectively. The clinicopathological features and prognostic roles of the markers were examined using univariate and multivariate analyses. The positive ratios for preoperative CEA (>5.0 ng/mL) and CA19-9 (>37 U/mL) were 20.3% and 12.9%, respectively. The positive ratio of CEA and CA19-9 was significantly higher in patients with tumors invading muscular or deeper layers (P = 0.002 and <0.001, respectively). Cox proportional hazards model revealed that CA19-9 positivity, but not CEA positivity, was an independent prognostic factor in patients with EGJ adenocarcinoma for cancer-specific survival (multivariate hazard ratio [HR] = 3.89, 95% confidence interval [CI] 1.41-10.33; P = 0.010) and overall survival (multivariate HR = 2.43, 95% CI 1.03-5.35; P = 0.043). Preoperative serum CA19-9 is a useful prognostic marker in patients with EGJ adenocarcinoma., (© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objectives: A nationwide large-scale survey was conducted to identify the prevalence and causal medications of adverse drug events (ADEs) that are caused by potentially inappropriate medications (PIMs) given to homebound elderly patients, factors associated with ADEs, and measures taken by pharmacists to manage ADEs and their effects on ADEs., Settings: A questionnaire was mailed to 3321 pharmacies nationwide. It asked about the details of PIMs and ADEs of up to 5 patients for whom home visits were provided by a pharmacist. Questionnaire forms were filled in by pharmacists who visited the patients., Design and Participants: Between 23 January and 13 February 2013, comprehensive assessment forms were sent to 3321 pharmacies. Data collected from 1890 pharmacies including data of 4815 patients were analysed and 28 patients of unknown sex were excluded. Their average age was 82.7 years. PIMs were identified based on the 2003 Beers Criteria Japan., Results: There were 600 patients who did not provide valid answers regarding the medications. In the remaining 4243 patients, one or more medications that were considered to be PIMs had been prescribed to 48.4% of patients. PIM-induced ADEs were found in 8% of these patients by pharmacists during home visits. The top ADE-inducing medications were strong anticholinergic antihistamines, benzodiazepines, sulpiride and digoxin. The most common ADEs associated with benzodiazepines were frequent lightheadedness, somnolence and sleepiness, which increase the risk of falls and subsequent fractures in elderly patients. The following factors associated with ADEs were identified: sex, pharmacist awareness of prescription issues, frequency of visits and time spent at patients' homes, and the frequency of detailed checks for patient adverse reactions by pharmacists., Conclusions: The PIM prevalence associated with home healthcare in Japan was relatively high, as reported in previous studies. The present study suggests that pharmacists could reduce the incidence of PIMs and consequent ADEs., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)