A role for astrocytic insulin-like growth factor I receptors in the response to ischemic insult.

Increased neurotrophic support, including insulin-like growth factor I (IGF-I), is an important aspect of the adaptive response to ischemic insult. However, recent findings indicate that the IGF-I receptor (IGF-IR) in neurons plays a detrimental role in the response to stroke. Thus, we investigated the role of astrocytic IGF-IR on ischemic insults using tamoxifen-regulated Cre deletion of IGF-IR in glial fibrillary acidic protein (GFAP) astrocytes, a major cellular component in the response to injury. Ablation of IGF-IR in astrocytes (GFAP-IGF-IR KO mice) resulted in larger ischemic lesions, greater blood-brain-barrier disruption and more deteriorated sensorimotor coordination. RNAseq detected increases in inflammatory, cell adhesion and angiogenic pathways, while the expression of various classical biomarkers of response to ischemic lesion were significantly increased at the lesion site compared to control littermates. While serum IGF-I levels after injury were decreased in both control and GFAP-IR KO mice, brain IGF-I mRNA expression show larger increases in the latter. Further, greater damage was also accompanied by altered glial reactivity as reflected by changes in the morphology of GFAP astrocytes, and relative abundance of ionized calcium binding adaptor molecule 1 (Iba 1) microglia. These results suggest a protective role for astrocytic IGF-IR in the response to ischemic injury.

Usefulness of Intraductal Placement of a Dumbbell-Shaped Fully Covered Self-Expandable Metal Stent for Post-Cholecystectomy Bile Leaks.

Background and aims: In the treatment of post-cholecystectomy bile leaks, endoscopic naso-biliary drainage (ENBD) or biliary stenting using plastic stents is the standard of care. Fully covered self-expandable metal stent (FCSEMS) placement across the sphincter of Oddi is considered a salvage therapy for refractory cases, but pancreatitis and migration are the major concerns. Intraductal placement of a dumbbell-shaped FCSEMS (D-SEMS) could avoid these drawbacks of FCMSESs. In this retrospective study, we investigated the usefulness of intraductal placement of the D-SEMS for post-cholecystectomy bile leaks. Methods: Six patients who underwent intraductal placement of the D-SEMS for post-cholecystectomy bile leaks were enrolled. This method was performed as initial treatment in three patients and as salvage treatment in three ENBD refractory cases. Results: Technical and clinical successes were obtained in 6 (100%) patients and 5 (83%) patients, respectively. One clinically unsuccessful patient required laparoscopic peritoneal lavage. The early adverse event was one case of mild pancreatitis (17%). The median duration of the D-SEMS indwelling was 61 days (42-606 days) with no migration cases, all of which were successfully removed. The median follow-up after index ERCP was 761 (range: 161-1392) days with no cases of recurrent bile leaks. Conclusions: Intraductal placement of the D-SEMS for post-cholecystectomy bile leaks might be safe and effective even in refractory cases.

Endoscopic Ultrasound-Guided Gastrojejunostomy for Malignant Afferent Loop Syndrome Using a Fully Covered Metal Stent: A Multicenter Experience.

BACKGROUND: Endoscopic-ultrasound-guided gastrojejunostomy (EUS-GJ) can be a new alternative for patients with malignant afferent loop syndrome (MALS). However, a fully covered self-expandable metal stent (FCSEMS) has not been well investigated in this setting. METHODS: This is a multicenter retrospective cohort study. Consecutive patients that underwent EUS-GJ using a FCSEMS for MALS between April 2017 and November 2022 were enrolled. Primary outcomes were technical and clinical success rates. Secondary outcomes were adverse events, recurrent symptoms, and overall survival. RESULTS: Twelve patients (median age: 67.5 years (interquartile range: 58-74.8); 50% male) were included. The most common primary disease and type of previous surgery were pancreatic cancer (67%) and pancreatoduodenectomy (75%), respectively. Technical success and clinical success were achieved in all patients. Procedure-related adverse events occurred in one patient (8%) with mild peritonitis. During a median follow-up of 96.5 days, one patient (8%) had recurrent symptoms due to the EUS-GJ stent dysfunction; including biliary events unrelated to the EUS-GJ stent, five patients (42%) had recurrent events. The median overall survival was 137 days. Nine patients (75%) died due to disease progression. CONCLUSIONS: EUS-GJ with a FCSEMS seems safe and effective for MALS with high technical and clinical success rates and an acceptable recurrence rate.

The Feasibility of Whole-Liver Drainage with a Novel 8 mm Fully Covered Self-Expandable Metal Stent Possessing an Ultra-Slim Introducer for Malignant Hilar Biliary Obstructions.

BACKGROUND: In the case of an unresectable malignant hilar biliary obstruction (MHBO), the optimal drainage method has not yet been established. Recently, an 8 mm, fully covered, self-expandable metal stent (FCSEMS) with an ultra-slim introducer has become available. In this article, the results of whole-liver drainage tests using this novel FCSEMS for MHBO are reported. METHODS: Unresectable MHBOs up to Bismuth IIIa with strictures limited to the secondary branches were eligible. The proximal end of the stent was placed in such a way as to avoid blocking the side branches, and the distal end was placed above the papilla when possible. Consecutive patients treated between April 2017 and January 2021 were retrospectively analyzed. The technical and functional success rates, rates and causes of recurrent biliary obstruction (RBO), time to RBO (TRBO), revision for RBO, and adverse events (AEs) were evaluated. RESULTS: Eleven patients (Bismuth I/II/IIIa: 1/7/3) were enrolled. Two stents were placed in nine patients and three were placed in two patients. Both the technical and functional success rates were 100%. RBO occurred in four (36%) patients due to sludge formation. Revision was performed for three patients, with the successful removal of all stents. The median TRBO was 187 days, and no late AEs other than the RBO occurred. Regarding the distal position of the stent, the RBO rate was significantly lower (14.3% vs. 75%, p = 0.041) and the cumulative TRBO was significantly longer (median TRBO: not reached vs. 80 days, p = 0.031) in the case of the placement above the papilla than the placement across the papilla. CONCLUSION: For unresectable MHBOs of Bismuth I, II, and IIIa, whole-liver drainage with a novel 8 mm FCSEMS possessing an ultra-slim introducer was feasible and potentially safe, with favorable stent patency. Placement above the papilla might be preferrable to placement across the papilla.

Insulin-like growth factor I sensitization rejuvenates sleep patterns in old mice.

Sleep disturbances are common during aging. Compared to young animals, old mice show altered sleep structure, with changes in both slow and fast electrocorticographic (ECoG) activity and fewer transitions between sleep and wake stages. Insulin-like growth factor I (IGF-I), which is involved in adaptive changes during aging, was previously shown to increase ECoG activity in young mice and monkeys. Furthermore, IGF-I shapes sleep architecture by modulating the activity of mouse orexin neurons in the lateral hypothalamus (LH). We now report that both ECoG activation and excitation of orexin neurons by systemic IGF-I are abrogated in old mice. Moreover, orthodromical responses of LH neurons are facilitated by either systemic or local IGF-I in young mice, but not in old ones. As orexin neurons of old mice show dysregulated IGF-I receptor (IGF-IR) expression, suggesting disturbed IGF-I sensitivity, we treated old mice with AIK3a305, a novel IGF-IR sensitizer, and observed restored responses to IGF-I and rejuvenation of sleep patterns. Thus, disturbed sleep structure in aging mice may be related to impaired IGF-I signaling onto orexin neurons, reflecting a broader loss of IGF-I activity in the aged mouse brain.

Practical Tips for Safe and Successful Endoscopic Ultrasound-Guided Hepaticogastrostomy: A State-of-the-Art Technical Review.

Currently, endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) is widely performed worldwide for various benign and malignant biliary diseases in cases of difficult or unsuccessful endoscopic transpapillary cholangiopancreatography (ERCP). Furthermore, its applicability as primary drainage has also been reported. Although recent advances in EUS systems and equipment have made EUS-HGS easier and safer, the risk of serious adverse events such as bile leak and stent migration still exists. Physicians and assistants need not only sufficient skills and experience in ERCP-related procedures and basic EUS-related procedures such as fine needle aspiration and pancreatic fluid collection drainage, but also knowledge and techniques specific to EUS-HGS. This technical review mainly focuses on EUS-HGS with self-expandable metal stents for unresectable malignant biliary obstruction and presents the latest and detailed tips for safe and successful performance of the technique.

Radiofrequency ablation of hyperplasia at an uncovered portion of a partially covered metal stent in endoscopic ultrasound-guided hepaticogastrostomy (with video).

Highlight Endoscopic ultrasound-guided hepaticogastrostomy with a partially covered metal stent has a potential risk of stent occlusion due to hyperplasia at an uncovered portion of the stent. Matsubara and colleagues report that radiofrequency ablation of hyperplasia with additional placement of an uncovered metal stent is useful for preventing recurrent stent occlusion.

Mechanistic insights into immune checkpoint inhibitor-related hypophysitis: a form of paraneoplastic syndrome.

BACKGROUND: Immune checkpoint inhibitors (ICIs) as a cancer immunotherapy have emerged as a treatment for multiple advanced cancer types. Because of enhanced immune responses, immune-related adverse events (irAEs), including endocrinopathies such as hypophysitis, have been associated with the use of ICIs. Most underlying mechanisms of ICI-related hypophysitis remain unclear, especially for programmed cell death-1 (PD-1)/PD-1 ligand 1 (PD-L1) inhibitors. We hypothesized that ICI-related hypophysitis is associated with paraneoplastic syndrome caused by ectopic expression of pituitary-specific antigens. METHODS: Twenty consecutive patients with ICI-related hypophysitis between 2017 and 2019 at Kobe University Hospital were retrospectively analyzed. Circulating anti-pituitary antibodies were detected using immunofluorescence staining and immunoblotting. Ectopic expression of pituitary autoantigens in tumor specimens was also examined. RESULTS: Eighteen patients were treated with PD-1/PD-L1 inhibitors, and two were treated with a combination of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and PD-1 inhibitors. All patients showed adrenocorticotropic hormone (ACTH) deficiency and additionally, three showed thyroid-stimulating hormone (TSH) deficiency, and one showed gonadotropin-releasing hormone (GnRH) deficiency. Among these patients, three exhibited anti-pituitary antibodies, two with anti-corticotroph antibody and one with anti-somatotroph antibody. Interestingly, the anti-corticotroph antibody recognized proopiomelanocortin (POMC) and those two patients exhibited ectopic ACTH expression in the tumor, while the patients without anti-corticotroph antibody did not. CONCLUSIONS: We demonstrated 10% of PD-1/PD-L1 inhibitors-related hypophysitis were associated with the autoimmunity against corticotrophs and maybe caused as a form of paraneoplastic syndrome, in which ectopic expression of ACTH in the tumor was observed. It is also suggested that the pathophysiology is heterogenous in ICI-related hypophysitis.

Clinical Heterogeneity of Acquired Idiopathic Isolated Adrenocorticotropic Hormone Deficiency.

Objective: Heterogeneous clinical characteristics are observed in acquired isolated adrenocorticotropic hormone (ACTH) deficiency (IAD); however, its classification remains to be established because of its largely unknown pathophysiology. In IAD, anti-pituitary antibodies have been detected in some patients, although their significance remains unclear. Therefore, this study aimed to classify patients with IAD and to clarify the significance of anti-pituitary antibodies. Design and Methods: We analyzed 46 consecutive patients with IAD. Serum anti-pituitary antibodies were analyzed via immunofluorescence staining using a mouse pituitary tissue. Principal component and cluster analyses were performed to classify IAD patients based on clinical characteristics and autoantibodies. Results: Immunofluorescence analysis using the sera revealed that 58% of patients showed anti-corticotroph antibodies and 6% of patients showed anti-follicular stellate cell (FSC) antibodies. Principal component analysis demonstrated that three parameters could explain 70% of the patients. Hierarchical cluster analysis showed three clusters: Groups A and B comprised patients who were positive for anti-corticotroph antibodies, and plasma ACTH levels were extremely low. Groups A and B comprised middle-aged or elderly men and middle-aged women, respectively. Group C comprised patients who were positive for the anti-FSC antibody and elderly men; plasma ACTH levels were relatively high. Conclusions: Patients with IAD were classified into three groups based on clinical characteristics and autoantibodies. The presence of anti-corticotroph antibody suggested severe injury to corticotrophs. This new classification clearly demonstrated the heterogeneity in the pathogenesis of IAD.

Two Cases of anti-PIT-1 Hypophysitis Exhibited as a Form of Paraneoplastic Syndrome not Associated With Thymoma.

Anti-pituitary-specific transcription factor 1 (PIT-1) hypophysitis (anti-PIT-1 antibody syndrome) is a thymoma-associated autoimmune disease characterized by acquired growth hormone (GH), prolactin (PRL), and thyrotropin (TSH) deficiencies due to autoimmunity against PIT-1. Ectopic expression of PIT-1 in the thymoma plays a causal role in development of the disease. Here, we report 2 cases of anti-PIT-1 hypophysitis exhibiting as a form of paraneoplastic syndrome with conditions other than thymoma. A 79-year-old woman (case 1) and an 86-year-old man (case 2) were referred with a suspicion of anti-PIT-1 hypophysitis because of acquired GH, PRL, and TSH deficiencies. Case 1 was complicated by diffuse large B-cell lymphoma (DLBCL) of the bladder and case 2 was diagnosed with malignancy with multiple metastases of unknown origin. Because circulating anti-PIT-1 antibody was detected, both patients were diagnosed with anti-PIT-1 hypophysitis. Circulating PIT-1-reactive T cells were detected in case 1 via enzyme-linked immunospot (ELISPOT) assay. Interestingly, the PIT-1 protein was ectopically expressed in the DLBCL cells of case 1, whereas DLBCL tissues derived from patients without anti-PIT-1 hypophysitis were negative for PIT-1. In case 2, the materials were not available because of best supportive care was under way. These data show that anti-PIT-1 hypophysitis is associated not only with thymoma but also with other malignancies. Additionally, the ectopic expression of PIT-1 in the DLBCL tissues and presence of PIT-1-reactive T cells suggested that the underlying mechanisms were similar to those observed in thymoma. Thus, anti-PIT-1 hypophysitis is defined as a form of paraneoplastic syndrome.

A Case of Luscan-Lumish Syndrome: Possible Involvement of Enhanced GH Signaling.

CONTEXT: Luscan-Lumish syndrome (LLS) is characterized by postnatal overgrowth, obesity, Chiari I malformation, seizures, and intellectual disability. SET domain-containing protein 2 (SETD2) is a histone methyltransferase, where mutations in the gene are associated with the development of LLS. However, mechanisms underlying LLS remain unclear. CASE DESCRIPTION: A 20-year-old man was referred to our hospital because of tall stature. His body height was 188.2 cm (+3.18 SD) and he showed obesity with a body mass index of 28.4 kg/m2. He exhibited acral overgrowth, jaw malocclusion, and prognathism, but no history of seizures, intellectual disability, or speech delay. Serum growth hormone (GH), insulin-like growth factor 1 (IGF-1), and nadir GH levels after administration of 75 g oral glucose were within normal range. Pituitary magnetic resonance imaging showed no pituitary adenoma, but Chiari I malformation. Whole exome sequencing analysis of the proband revealed a de novo heterozygous germline mutation in SETD2 (c.236T>A, p.L79H). Skin fibroblasts derived from the patient grew faster than those from his father and the control subject. In addition, these cells showed enhanced tyrosine phosphorylation and transcriptional activity of signal transducer and activator of transcription 5b (STAT5b) and increased IGF-1 expression induced by GH. CONCLUSION: This is a mild case of LLS with a novel mutation in SETD2 without neurological symptoms. LLS should be differentiated in a patient with gigantism without pituitary tumors. Although further investigation is necessary, this is the first study to suggest the involvement of aberrant GH signaling in the development of LLS.

A Proposed Algorithm for Endoscopic Ultrasound-Guided Rendezvous Technique in Failed Biliary Cannulation.

BACKGROUND: The selection of an approach route in endoscopic ultrasound-guided rendezvous (EUS-RV) for failed biliary cannulation is complicated. We proposed an algorithm for EUS-RV. METHODS: We retrospectively evaluated consecutive EUS-RV cases between April 2017 and July 2020. Puncturing the distal extrahepatic bile duct (EHBD) from the duodenal second part (D2) (DEHBD/D2 route) was attempted first. If necessary, puncturing the proximal EHBD from the duodenal bulb (D1) (PEHBD/D1 route), puncturing the left intrahepatic bile duct (IHBD) from the stomach (LIHBD/S route), or puncturing the right IHBD from the D1 (RIHBD/D1 route) were attempted in this order. RESULTS: A total of 16 patients were included. The DEHBD/D2 route was used in 10 (62.5%) patients. The PEHBD/D1 route was attempted in five (31.3%) patients, and the biliary puncture failed in one patient in whom the RIHBD/D1 route was used because of tumor invasion to the left hepatic lobe. The LIHBD/S route was applied in one (6.3%) patient. Successful biliary cannulation was achieved in all patients eventually. The time from the puncture to the guidewire placement in the DEHBD/D2 route (3.5 min) was shorter than that in other methods (14.0 min) (p = 0.014). Adverse events occurred in one (6.3%) patient with moderate pancreatitis. CONCLUSIONS: The proposed algorithm might be useful for the selection of an appropriate approach route in EUS-RV.

Adrenal Corticomedullary Mixed Tumor Associated With the FGFR4-G388R Variant.

Adrenal corticomedullary mixed tumors (CMMTs) are extremely rare; with only 20 cases being reported to date, the pathogenesis has remained elusive. A 31-year-old woman developed gestational hypertension with psychiatric disturbances persistent to postpartum and was diagnosed with pheochromocytoma, for which adrenalectomy was performed. Histological findings showed mixed adrenocortical adenoma and pheochromocytoma. Double immunostaining of inhibin and INSM1 (insulinoma-associated protein 1) showed that the 2 tumor components had distinct functional properties. Exome analysis of peripheral leukocytes and tumor (singular, as anatomically it is only 1 mass) revealed a homozygous germline FGFR4-G388R variant. As a readout of the variant, serine phosphorylation of signal transducer and activator of transcription 3 (STAT3) was detected only in the nucleus of adrenocortical adenoma component but not in the pheochromocytoma component. No tyrosine phosphorylation of STAT3 was detected. We report a case of CMMT with the germline FGFR4-G388R variant. Although additional studies are required, our immunohistochemical analysis suggests that the variant may play a role in the development of the adrenocortical component within the pheochromocytoma, leading to CMMT.

Cardiac Myxoma Caused by Fumarate Hydratase Gene Deletion in Patient With Cortisol-Secreting Adrenocortical Adenoma.

CONTEXT: Germline mutations in fumarate hydratase (FH) gene are known to cause hereditary leiomyomatosis and renal cell carcinoma (HLRCC) and are occasionally accompanied with cutaneous and uterine leiomyoma or cortisol-producing adrenocortical hyperplasia. However, the association between FH mutations and cardiac or adrenocortical tumors has remained unknown. Here, we identified a novel deletion in FH, exhibiting cardiac myxoma and subclinical Cushing syndrome due to adrenocortical tumor. CASE DESCRIPTION: A 44-year-old man was referred to our hospital for cardiac and adrenal tumor evaluation. He had a history of multiple painful, dermal papules and nodules diagnosed as cutaneous leiomyoma. The surgically resected cardiac tumor was diagnosed as myxoma. The adrenal tumor was clinically diagnosed as subclinical Cushing syndrome. Laparoscopically resected adrenal tumor was pathologically diagnosed as adrenocortical adenoma harboring unique histological findings similar to primary pigmented nodular adrenocortical disease (PPNAD). DNA analysis revealed a germline deletion in FH c0.737delT (p. Phe225Leufs*31) and loss of heterozygosity (LOH) in cardiac myxoma. As a functional analysis of FH in cardiac myxoma, low FH protein expression with elevated 2-succinocysteine (2SC), a marker of FH dysfunction, was immunohistochemically detected. However, in adrenocortical tumor, LOH of FH was not detected, and FH or 2SC expression was not altered. CONCLUSIONS: This is the first case of HLRCC complicated by cardiac myxoma. LOH of FH deletion and its dysfunction were identified in cardiac myxoma. The association between FH deletion and adrenocortical lesion, however, needs to be further clarified.

Pathogenesis of Anti-PIT-1 Antibody Syndrome: PIT-1 Presentation by HLA Class I on Anterior Pituitary Cells.

CONTEXT: Anti-pituitary-specific transcriptional factor-1 (anti-PIT-1) antibody syndrome is characterized by acquired and specific deficiencies in growth hormone, prolactin, and thyroid-stimulating hormone. Although PIT-1-reactive cytotoxic T lymphocytes (CTLs) have been speculated to recognize anterior pituitary cells and to cause the injury in the pathogenesis of the syndrome, it remains unclear whether endogenous PIT-1 protein is processed through the proteolytic pathway and presented as an antigen on anterior pituitary cells. OBJECTIVE: To examine how PIT-1 protein is processed and whether its epitope is presented by major histocompatibility complex (MHC)/HLA class I on anterior pituitary cells. MATERIALS AND METHODS: Immunofluorescence staining and proximity ligation assay (PLA) were performed using anti-PIT-1 antibody and patients' sera on PIT-1-expressing cell line GH3 cells and human induced pluripotent stem cell (iPSC)-derived pituitary tissues. RESULTS: PIT-1 was colocalized with MHC class I molecules, calnexin, and GM130 in the cytosol. PLA results showed that PIT-1 epitope was presented by MHC/HLA class I molecules on the cell surface of GH3 cells and iPSC-derived pituitary cells. The number of PIT-1/HLA complexes on the cell surface of pituitary cells in the patient was comparable with that in the control subject. CONCLUSIONS: Our data indicate that PIT-1 protein is processed in the antigen presentation pathway and that its epitopes are presented by in MHC/HLA class I on anterior pituitary cells, supporting the hypothesis that PIT-1-reactive CTLs caused the cell-specific damage. It is also suggested that number of epitope presentation was not associated with the pathogenesis of anti-PIT-1 antibody syndrome.