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Competing Interests: Conflict of Interest The authors declare that they have no conflict of interest.

A 54-year-old woman presented with an elevated esophageal lesion. Computed tomography (CT) and magnetic resonance imaging revealed a mass in the pancreatic head. Endoscopic ultrasound (EUS) showed a well-defined, round, hypoechoic mass, which was considered lymph node enlargement. An EUS-guided fine-needle aspiration biopsy (FNAB) was performed on the esophagus and the mass above the pancreatic head. The pathologically confirmed epithelial cells and multinucleated giant cells were positive for T-SPOT. Clinically, tuberculous lymphadenitis and esophageal tuberculosis were suspected, with successful treatment with anti-tuberculosis therapy resulting in a good response. Our findings suggest that an EUS-FNAB is useful for diagnosing esophageal tuberculosis.

Background/purpose: Endoscopic biliary stenting (EBS) is commonly used for preoperative drainage of localized perihilar cholangiocarcinoma (LPHC). This study retrospectively compared the utility of inside stent (IS) and conventional stent (CS) for preoperative EBS in patients with LPHC., Methods: EBS was performed in 56 patients with LPHC. EBS involved the placement of a CS (n = 32) or IS (n = 24). Treatment outcomes were compared between these two groups., Results: Preoperative recurrent biliary obstruction (RBO) occurred in 23 patients (71.9%) in the CS group and 7 (29.2%) in the IS group, with a significant difference (p = 0.002). The time to RBO (TRBO) was significantly longer in IS than in CS (log-rank: p < 0.001). The number of stent replacements was significantly lower in IS than CS [0.38 (0-3) vs. 1.88 (0-8), respectively; p < 0.001]. Gemcitabine-based neoadjuvant chemotherapy (NAC) was administered to 26 patients (46.4%). Among patients who received NAC, TRBO was longer in IS than in CS group (log-rank: p < 0.001). The IS group had a significantly shorter preoperative and postoperative hospital stay than the CS group (20.0 vs. 37.0 days; p = 0.024, and 33.5 vs. 41.5 days; p = 0.016).　 Both the preoperative and the postoperative costs were significantly lower in the IS group than in the CS group (p = 0.049 and p = 0.0034, respectively)., Conclusion: Compared with CS, IS for preoperative EBS in LPHC patients resulted in fewer complications and lower re-intervention rates. The fact that the IS group had shorter preoperative and postoperative hospital stays and lower costs both preoperatively and postoperatively compared to the CS group may suggest that the use of IS has the potential to benefit not only the patient but also the healthcare system., (© 2024. The Author(s).)

Familial neurohypophyseal diabetes insipidus (FNDI) is a degenerative disorder in which vasopressin-secreting neurons degenerate over time due to the production of mutant proteins. We have demonstrated therapeutic effects of chemical chaperones in an FNDI mouse model, but the complexity and length of this evaluation were problematic. In this study, we established disease-specific mouse induced pluripotent stem cells (iPSCs) from FNDI-model mice and differentiated vasopressin neurons that produced mutant proteins. Fluorescence immunostaining showed that chemical chaperones appeared to protect vasopressin neurons generated from iPSCs derived from FNDI-model mice. Although KCL stimulation released vasopressin hormone from vasopressin neurons generated from FNDI-derived iPSCs, vasopressin hormone levels did not differ significantly between baseline and chaperone-added culture. Semi-quantification of vasopressin carrier protein and mutant protein volumes in vasopressin neurons confirmed that chaperones exerted a therapeutic effect. This research provides fundamental technology for creating in vitro disease models using human iPSCs and can be applied to therapeutic evaluation of various degenerative diseases that produce abnormal proteins., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Competing Interests: The authors declare that they have no conflict of interest.

A 66-year-old man diagnosed with immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) with diffuse intrahepatic bile duct stenosis and elevated serum IgG4 levels was referred for a further examination because of elevated serum carbohydrate antigen 19-9 levels despite treatment with corticosteroids. An umbilical nodule was found on a physical examination and a biopsy showed adenocarcinoma. Although several imaging studies revealed no changes from prior studies, bile cytology collected by endoscopic retrograde cholangiopancreatography showed adenocarcinoma. Consequently, the patient was diagnosed with cholangiocarcinoma resembling IgG4-SC after detecting an umbilical metastasis, also known as Sister Mary Joseph's nodule.

Pituitary organoids are promising graft sources for transplantation in treatment of hypopituitarism. Building on development of self-organizing culture to generate pituitary-hypothalamic organoids (PHOs) using human pluripotent stem cells (hPSCs), we established techniques to generate PHOs using feeder-free hPSCs and to purify pituitary cells. The PHOs were uniformly and reliably generated through preconditioning of undifferentiated hPSCs and modulation of Wnt and TGF-β signaling after differentiation. Cell sorting using EpCAM, a pituitary cell-surface marker, successfully purified pituitary cells, reducing off-target cell numbers. EpCAM-expressing purified pituitary cells reaggregated to form three-dimensional pituitary spheres (3D-pituitaries). These exhibited high adrenocorticotropic hormone (ACTH) secretory capacity and responded to both positive and negative regulators. When transplanted into hypopituitary mice, the 3D-pituitaries engrafted, improved ACTH levels, and responded to in vivo stimuli. This method of generating purified pituitary tissue opens new avenues of research for pituitary regenerative medicine., Competing Interests: Conflicts of interest Sumitomo Pharma employs S.T., A.K., K.W., A.I., and M.Y. T. Kimura is a board member of Sumitomo Pharma. Sumitomo Chemical employs T.N., Y. Takahashi, S.K., and Y. Tomigahara. H.S. and H.A. have received research funding from Sumitomo Pharma and Sumitomo Chemical. S.T., H.S., T.N., and A.K. are co-inventors in patent applications related to this study., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

When damaged, restoring the function of the hypothalamus is currently impossible. It is unclear whether neural stem cells exist in the hypothalamus. Studies have reported that adult rodent tanycytes around the third ventricle function as hypothalamic neural stem cell-like cells. However, it is currently impossible to collect periventricular cells from humans. We attempted to generate hypothalamic neural stem cell-like cells from human embryonic stem cells (ESCs). We focused on retina and anterior neural fold homeobox (RAX) because its expression is gradually restricted to tanycytes during the late embryonic stage. We differentiated RAX::VENUS knockin human ESCs (hESCs) into hypothalamic organoids and sorted RAX + cells from mature organoids. The isolated RAX + cells formed neurospheres and exhibited self-renewal and multipotency. Neurogenesis was observed when neurospheres were transplanted into the mouse hypothalamus. We isolated RAX + hypothalamic neural stem cell-like cells from wild-type human ES organoids. This is the first study to differentiate human hypothalamic neural stem cell-like cells from pluripotent stem cells., Competing Interests: Conflict of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The pituitary gland, regulating various hormones, is central in the endocrine system. As spontaneous recovery from hypopituitarism is rare, and exogenous-hormone substitution is clumsy, pituitary replacement via regenerative medicine, using pluripotent stem cells, is desirable. We have developed a differentiation method that in mice yields pituitary organoids (POs) derived from human embryonic stem cells (hESC). Efficacy of these POs, transplanted subcutaneously into hypopituitary mice, in reversing hypopituitarism was studied., Methods: hESC-derived POs were transplanted into inguinal subcutaneous white adipose tissue (ISWAT) and beneath dorsal skin, a relatively avascular region (AR), of hypophysectomized severe combined immunodeficient (SCID) mice. Pituitary function was evaluated thereafter for ¾ 6mo, assaying basal plasma ACTH and ACTH response to corticotropin-releasing hormone (CRH) stimulation. Histopathologic examination of organoids 150d after transplantation assessed engraftment. Some mice received an inhibitor of vascular endothelial growth factor (VEGF) to permit assessment of how angiogenesis contributed to subcutaneous engraftment., Results: During follow-up, both basal and CRH-stimulated plasma ACTH levels were significantly higher in the ISWAT group ( p < 0.001 - 0.05 and 0.001 - 0.005, respectively) than in a sham-operated group. ACTH secretion also was higher in the ISWAT group than in the AR group. Histopathologic study found ACTH-producing human pituitary-cell clusters in both groups of allografts, which had acquired a microvasculature. POs qPCR showed expression of angiogenetic factors. Plasma ACTH levels decreased with VEGF-inhibitor administration., Conclusions: Subcutaneous transplantation of hESC-derived POs into hypopituitary SCID mice efficaciously renders recipients ACTH-sufficient., Competing Interests: ST and AK are employed by Sumitomo Pharma. TN is employed by Sumitomo Chemical. HSu has received research funding from Sumitomo Pharma and Sumitomo Chemical. Authors are co-inventors on patent applications related to the study presented in this article. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2023 Sasaki, Suga, Takeuchi, Nagata, Harada, Kondo, Ito, Maeda, Sakakibara, Soen, Miwata, Asano, Ozaki, Taga, Kuwahara, Nakano, Arima and Saito.)

Generation of a variety of organs and tissues from human pluripotent stem cells (hPSCs) has been attempted in vitro . We here present a simple and efficient method for induction of hypothalamic and pituitary tissues from hPSCs. On provision of exogenous agents important for early hypothalamus-pituitary organogenesis, including bone morphogenetic protein 4 and activators of sonic hedgehog, in three-dimensional culture, hPSCs spontaneously form spherical organoids with two distinct tissues, hypothalamus and adenohypophysis. The pituitary tissues derived from hPSCs not only secrete adenocorticotropic hormone, but also retain both positive and negative feedback mechanisms, recapitulating mature endocrine organs in vivo . Furthermore, the results of ectopic transplantation with mouse models of hypopituitarism suggest that these hypothalamus-pituitary organoids have potential as engraftment organs. In addition to their use in transplantation for patients with hypopituitarism they will allow establishment of disease models in vitro and enable research impossible in humans. Hypothalamus-pituitary organoids promise to be a powerful tool in regenerative medicine, drug discovery, and basic research into pituitary development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kano, Sasaki, Miwata and Suga.)

Competing Interests: The authors declare that they have no conflict of interest.

Familial neurohypophyseal diabetes insipidus (FNDI) is a degenerative disease of vasopressin (AVP) neurons. Studies in mouse in vivo models indicate that accumulation of mutant AVP prehormone is associated with FNDI pathology. However, studying human FNDI pathology in vivo is technically challenging. Therefore, an in vitro human model needs to be developed. When exogenous signals are minimized in the early phase of differentiation in vitro, mouse embryonic stem cells (ESCs)/induced pluripotent stem cells (iPSCs) differentiate into AVP neurons, whereas human ESCs/iPSCs die. Human ESCs/iPSCs are generally more similar to mouse epiblast stem cells (mEpiSCs) compared to mouse ESCs. In this study, we converted human FNDI-specific iPSCs by the naive conversion kit. Although the conversion was partial, we found improved cell survival under minimal exogenous signals and differentiation into rostral hypothalamic organoids. Overall, this method provides a simple and straightforward differentiation direction, which may improve the efficiency of hypothalamic differentiation., (© 2022. The Author(s).)

Background: Endoscopic submucosal dissection (ESD) has become a widely accepted treatment method for colorectal tumors; however, there are some persistent problems. This multi-center study aimed to characterize the risk factors for incomplete resection and perforation in standardized colorectal ESD procedures., Methods: This study included 2423 consecutive patients who underwent ESD for 2592 colorectal tumors between August 2013 and December 2018 at 11 institutions (1 academic hospital and 10 affiliated hospitals) from the Hiroshima GI Endoscopy Research Group. We evaluated the risk factors for interruption, piecemeal resection, and perforation of standardized colorectal ESD in relation to clinicopathologic and endoscopic characteristics., Results: The incidences of interruption, piecemeal resection, and perforation were 0.7%, 2.9%, and 3.0%, respectively. Multivariate analysis identified the following risk factors for interruption: perforation during the procedure, deep submucosal invasion (> 1000 μm), poor scope operability, and severe submucosal fibrosis. The risk factors for piecemeal resection included poor scope operability, severe submucosal fibrosis, and procedure time (≥ 85 min). The risk factors for perforation during the procedure were severe submucosal fibrosis, poor scope operability, procedure time (≥ 85 min), and tumor size (≥ 40 mm). Independent risk factors for severe submucosal fibrosis included a history of biopsy and lesions located on the fold or flexure., Conclusions: Severe submucosal fibrosis and poor scope operability are the common risk factors for interruption, piecemeal resection, and perforation in standardized colorectal ESD., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Aims: Many knives have been developed to improve the efficacy and safety of endoscopic submucosal dissection (ESD). We aimed to evaluate the efficacy and safety of scissor-type knives for colorectal ESD compared with needle-type knives., Methods: We performed a post-hoc propensity score-matched analysis in an 11-facility study between August 2013 and December 2018. A total of 2330 patients (2498 lesions) who underwent colorectal ESD were divided into needle-type (1923 patients, 2067 lesions) and scissor-type (407 patients, 431 lesions) knife groups. Short-term outcomes were compared between the 2 groups., Results: Two-to-one propensity score-matched analysis identified 814 (709 patients) and 407 (386 patients) lesions in the needle- and scissor-type knife groups, respectively. The median resection speed was significantly faster in the needle-type group (18.3 mm 2 /min) than in the scissor-type group (13.2 mm 2 /min, P < .0001), whereas en-bloc and histologic complete resection rates were not significantly different between the needle- and scissor-type groups (96.8% [788/814] vs 98.3% [400/407], P = .1888 and 95.1% [774/814] vs 95.6% [389/407], P = .7763, respectively). The rate of lesions resected using a single knife was significantly higher in the scissor-type group (98.5% [401/407]) than in the needle-type group (43.9% [357/814], P < .0001). Rates of intraoperative perforation and delayed bleeding were significantly lower in the scissor-type group than in the needle-type group (.7% [3/407] vs 2.5% [20/814], P = .0431 for each)., Conclusions: Scissor-type knives are safer for colorectal ESD. However, they are associated with slower resection speeds compared with needle-type knives. (Clinical trial registration number: UMIN000016197.)., (Copyright © 2022 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Endoscopic ultrasound can be useful for obtaining detailed diagnostic images for pancreatic disease. Contrast-enhanced harmonic endoscopic ultrasound has allowed to demonstrate not only microvasculature but also real perfusion imaging using second-generation contrast agents. Furthermore, endoscopic ultrasound fine-needle aspiration cytology and histology have become more ubiquitous; however, the risk of dissemination caused by paracentesis has yet to be resolved, and the application of less invasive contrast-enhanced endoscopic ultrasound for the differential diagnosis of pancreatic tumors has been anticipated. Contrast-enhanced harmonic endoscopic ultrasound can contribute to the differential diagnosis of pancreatic tumors.

Prolactin (PRL), a hormone involved in lactation, is mainly produced and secreted by the lactotrophs of the anterior pituitary (AP) gland. We previously reported a method to generate functional adrenocorticotropic hormone-producing cells by differentiating the AP and hypothalamus simultaneously from human induced pluripotent stem cells (iPSCs). However, PRL-producing cells in the induced AP have not been investigated. Here, we confirmed the presence of PRL-producing cells and evaluated their endocrine functions. We differentiated pituitary cells from human iPSCs using serum-free floating culture of embryoid-like aggregates with quick reaggregation (SFEB-q) method and evaluated the appearance and function of PRL-producing cells. Secretion of PRL from the differentiated aggregates was confirmed, which increased with further culture. Fluorescence immunostaining and immunoelectron microscopy revealed PRL-producing cells and PRL-positive secretory granules, respectively. PRL secretion was promoted by various prolactin secretagogues such as thyrotropin-releasing hormone, vasoactive intestinal peptide, and prolactin-releasing peptide, and inhibited by bromocriptine. Moreover, the presence of tyrosine hydroxylase-positive dopaminergic nerves in the hypothalamic tissue area around the center of the aggregates connecting to PRL-producing cells indicated the possibility of recapitulating PRL regulatory mechanisms through the hypothalamus. In conclusion, we generated pituitary lactotrophs from human iPSCs; these displayed similar secretory responsiveness as human pituitary cells in vivo. In the future, this is expected to be used as a model of human PRL-producing cells for various studies, such as drug discovery, prediction of side effects, and elucidation of tumorigenic mechanisms using disease-specific iPSCs. Furthermore, it may help to develop regenerative medicine for the pituitary gland., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Autoimmune pancreatitis (AIP), which is characterized by pancreatic enlargement and irregular narrowing of the main pancreatic duct, is difficult to differentiate from malignancy. The irregular narrowing of the pancreatic duct, which can be detected via endoscopic retrograde cholangiopancreatography, is a characteristic feature of AIP; however, distinguishing between localized AIP and pancreatic cancer based on pancreatic duct imaging is difficult. This study overviews the efficacy of endoscopic ultrasound (EUS)-guided pancreatic sampling for the histopathological diagnosis of AIP. Recent enhancements in needle biopsy methodologies and technologies have contributed to improvement in the diagnostic efficacy of this technique. The guidance provided in this study for the histological diagnosis of AIP is anticipated to further advance in the histopathological diagnosis of AIP using EUS-guided pancreatic sampling., (© 2021 Japan Gastroenterological Endoscopy Society.)