[A Case of Distal Gastrectomy and Left Segmentectomy for Hepatic Invasion of Gastric Cancer].

A 66-year-old male came to our hospital because of occult blood in stool and anemia. The patient was diagnosed as unresectable advanced gastric cancer,( ML/Less, type 2, tub2, cT4b[liver], cN+, cM0, cStage Ⅳ, HER2 negative). He was given oxaliplatin plus S-1 therapy. In the 3rd course of chemotherapy, he had severe anemia, and active bleeding from the tumor. To control the bleeding he underwent distal gastrectomy, lateral segmentectomy of the liver, and S4 partial hepatectomy. The patient underwent adjuvant chemotherapy with docetaxel plus S-1. Three months after surgery, lymph nodes recurrence was observed. He underwent second-line therapy with paclitaxel and ramucirumab. Seven months after surgery, lymph nodes recurrence was increased. He was switched to third-line therapy with nivolumab. He is currently arrive 12 months after surgery.

[A Case of Colon Metastasis after Surgery for Left Renal Pelvis Cancer].

The patient was a 73-year-old man. He was diagnosed with left renal pelvic carcinoma(papillary urothelial carcinoma, pT3aN0M0, Stage Ⅱ)at the age of 69. Left nephroureterectomy and partial cystectomy were performed at our hospital. At the age of 71, he was diagnosed with a recurrent bladder tumor and underwent radical cystectomy and ureteroenterostomy at a different hospital. At the age of 73, he visited our hospital with abdominal pain. Computed tomography(CT)revealed wall thickening of the descending colon and dilation of the oral tract. Emergency colonoscopy was performed. He was diagnosed with intestinal obstruction due to descending colon cancer. Colonoscopy revealed a circumferential type 2 lesion in the descending colon that was completely stenosed. Colonic stent placement was performed. A tumor biopsy confirmed the diagnosis of micropapillary adenocarcinoma. The preoperative diagnosis was descending colon cancer cT4aN2aM0, cStage Ⅲc. One month after stent placement, an open segmental resection of the descending colon with D2 dissection was performed. Immunostaining of the specimen showed CK7(+)and CK20(-), and the postoperative diagnosis was a recurrence of left renal pelvic carcinoma in the descending colon. We report a rare case of renal pelvic carcinoma that recurred in the descending colon 4 years after initial surgery.

Impaired humoral immunity following COVID-19 vaccination in HTLV-1 carriers.

BACKGROUND: Whether human T-lymphotropic virus type 1 (HTLV-1) carriers can develop sufficient humoral immunity after coronavirus disease 2019 (COVID-19) vaccination is unknown. METHODS: To investigate humoral immunity after COVID-19 vaccination in HTLV-1 carriers, a multicenter, prospective observational cohort study was conducted at five institutions in southwestern Japan, an endemic area for HTLV-1. HTLV-1 carriers and HTLV-1-negative controls were enrolled for this study from January to December 2022. During this period, the third dose of the COVID-19 vaccine was actively administered. HTLV-1 carriers were enrolled during outpatient visits, while HTLV-1-negative controls included health care workers and patients treated by participating institutions for diabetes, hypertension, or dyslipidemia. The main outcome was the effect of HTLV-1 infection on the plasma anti-COVID-19 spike IgG (IgG-S) titers after the third dose, assessed by multivariate linear regression with other clinical factors. RESULTS: We analyzed 181 cases (90 HTLV-1 carriers, 91 HTLV-1-negative controls) after receiving the third dose. HTLV-1 carriers were older (median age 67.0 vs. 45.0 years, p < 0.001) and more frequently had diabetes, hypertension, or dyslipidemia than did HTLV-1-negative controls (60.0% vs. 27.5%, p < 0.001). After the third dose, the IgG-S titers decreased over time in both carriers and controls. Multivariate linear regression in the entire cohort showed that time since the third dose, age, and HTLV-1 infection negatively influenced IgG-S titers. After adjusting for confounders such as age, or presence of diabetes, hypertension, or dyslipidemia between carriers and controls using the overlap weighting propensity score method, and performing weighted regression analysis in the entire cohort, both time since the third dose and HTLV-1 infection negatively influenced IgG-S titers. CONCLUSIONS: The humoral immunity after the third vaccination dose is impaired in HTLV-1 carriers; thus, customized vaccination schedules may be necessary for them.

The NERP-4-SNAT2 axis regulates pancreatic ß-cell maintenance and function.

Insulin secretion from pancreatic ß cells is regulated by multiple stimuli, including nutrients, hormones, neuronal inputs, and local signalling. Amino acids modulate insulin secretion via amino acid transporters expressed on ß cells. The granin protein VGF has dual roles in ß cells: regulating secretory granule formation and functioning as a multiple peptide precursor. A VGF-derived peptide, neuroendocrine regulatory peptide-4 (NERP-4), increases Ca2+ influx in the pancreata of transgenic mice expressing apoaequorin, a Ca2+-induced bioluminescent protein complex. NERP-4 enhances glucose-stimulated insulin secretion from isolated human and mouse islets and ß-cell-derived MIN6-K8 cells. NERP-4 administration reverses the impairment of ß-cell maintenance and function in db/db mice by enhancing mitochondrial function and reducing metabolic stress. NERP-4 acts on sodium-coupled neutral amino acid transporter 2 (SNAT2), thereby increasing glutamine, alanine, and proline uptake into ß cells and stimulating insulin secretion. SNAT2 deletion and inhibition abolish the protective effects of NERP-4 on ß-cell maintenance. These findings demonstrate a novel autocrine mechanism of ß-cell maintenance and function that is mediated by the peptide-amino acid transporter axis.

Association between personality traits and glycemic control after inpatient diabetes education.

Aims: The longitudinal effect of personality traits on glycemic control is unclear. This prospective observational study explored the relationship between personality traits and glycemic control in patients with uncontrolled diabetes after inpatient diabetes education. Methods: Patients with diabetes mellitus (HbA1c ≥ 7.5%, measured by high-performance liquid chromatography) who received inpatient diabetes education were scored on the Big Five personality traits: neuroticism, extraversion, openness, agreeableness, and conscientiousness. Multiple linear analysis was used to determine whether any personality traits were independently associated with HbA1c on admission and HbA1c change from admission to 1, 3, and 6 months after discharge. Results: One hundred seventeen participants (mean age 60.4 ± 14.5 years; 59.0% male) were enrolled. HbA1c values on admission and 1, 3, and 6 months after discharge were 10.2 ± 2.1%, 8.3 ± 1.4%, 7.6 ± 1.4%, and 7.7 ± 1.5%, respectively. Multiple linear analysis showed that no personality traits were associated with HbA1c on admission. Neuroticism was negatively associated with the HbA1c change from admission to 3 months (ß = -0.192, P = 0.025) and 6 months after discharge (ß = -0.164, P = 0.043). Conclusions: Neuroticism was associated with good long-term glycemic control after inpatient diabetes education.

[A Case of Thoracoscopic Tumor Enucleation of Esophageal Leiomyoma].

We present a case of benign esophageal leiomyoma with video-assisted thoracic enucleation. A 39-year-old woman was found to have an abnormal shadow in the mediastinum on a chest X-ray on a medical check-up. Chest CT performed for the purpose of close examination revealed a tumor with a size of 62×33 mm from the middle intrathoracic esophagus to the lower esophagus. Upper gastrointestinal endoscopy revealed a left half-circumferential elastic soft submucosal bulge in the thoracic middle-lower esophagus. Endoscopic ultrasonographic fine-needle aspiration biopsy(EUS-FNA)was performed, and immunostaining showed positive muscular markers SMA, but negative for CD34, c-kit, and S-100, and the diagnosis was esophageal leiomyoma. Therefore, thoracoscopic-assisted esophageal leiomyoma resection was performed. Postoperative immunohistological examination showed positive for SMA and Desmin, and the diagnosis was leiomyoma.

Improving the Effects of Imeglimin on Endothelial Function: A Prospective, Single-Center, Observational Study.

INTRODUCTION: Endothelial dysfunction is a risk factor for cardiovascular disease in patients with diabetes. We hypothesized that imeglimin, a novel oral hypoglycemic agent, would improve endothelial function. METHODS: In this study, imeglimin was administered to patients with type 2 diabetes and HbA1c ≥ 6.5% who were not receiving insulin therapy. A meal tolerance test (592 kcal, glucose 75.0 g, fat 28.5 g) was performed before and 3 months after administration, and endothelial function, blood glucose, insulin, glucagon, and triglycerides were evaluated. Endothelial function was assessed by flow-mediated dilation (FMD). RESULTS: Twelve patients (50% male) with a median age of 55.5 years old (interquartile range [IQR] 51.3-66.0) were enrolled. Fasting FMD did not differ before or 3 months after imeglimin administration (from 6.1 [3.9-8.5] to 6.6 [3.9-9.0], p = 0.092), but 2 h postprandial FMD was significantly improved 3 months after imeglimin administration (from 2.3 [1.9-3.4] to 2.9 [2.4-4.7], p = 0.013). In terms of the glucose profile, imeglimin administration significantly improved HbA1c (from 7.2 ± 0.6% to 6.9 ± 0.6%, p = 0.007), fasting glucose (from 138 ± 19 mg/dL to 128 ± 20 mg/dL, p = 0.020), and 2 h postprandial glucose (from 251 ± 47 mg/dL to 215 ± 68 mg/dL, p = 0.035). The change in 2 h postprandial FMD between before and 3 months after imeglimin administration (Δ2 h postprandial FMD) was negatively correlated with Δ2 h postprandial glucose (r = - 0.653, p = 0.021) in a univariate correlation coefficient analysis. Both patients with and without decreased postprandial glucose 3 months after imeglimin administration had improved postprandial FMD. CONCLUSION: In this small study, imeglimin administration improved 2 h postprandial FMD. Both glycemic control-dependent and -independent mechanisms might contribute to improved endothelial function. TRIAL REGISTRATION: This research was registered in the University Hospital Medical Information Network (UMIN, UMIN000046311).

[A Case of HER2-Positive Advanced Gastric Cancer with Liver Metastasis Treated by Laparoscopic Surgery after Chemotherapy and Achieved Pathological Complete Response].

A 77-year-old man presented to our hospital with diarrhea and weight loss. Upper gastrointestinal endoscopy revealed advanced Type 3 gastric cancer measuring 40 mm in the lower greater curvature of the stomach. Biopsy from a gastric tumor revealed moderately differentiated tubular adenocarcinoma overexpressing HER2. Abdominal contrast-enhanced computed tomography(CT)showed multiple liver metastases in S3 and S5. We diagnosed HER2-positive gastric cancer with liver metastasis. Systemic chemotherapy was administrated, with a total of 13 courses of combination therapy with S-1, oxaliplatin and trastuzumab. After chemotherapy, the primary tumor was significantly reduced and liver metastases were almost undetectable. Laparoscopic distal gastrectomy and partial hepatectomy were performed as conversion surgery. The patient was discharged on the 9th day without any postoperative complications. Postoperative pathological findings showed no residual tumor in either gastric and hepatic specimens, and the therapeutic effect of chemotherapy was diagnosed as pathological complete response. We report a case of HER2-positive advanced gastric cancer with multiple liver metastases that achieved a pathologically complete response to chemotherapy followed by conversion surgery. Laparoscopic surgery would be one of an effective option for conversion surgery.

[A Case of Local Recurrence of Esophageal Cancer after Chemoradiation Therapy Successfully Treated with Nivolumab].

We report a case of a patient with locally recurrent esophageal cancer after chemoradiation therapy(CRT)who responded to nivolumab. The patient was an 86-year-old man with advanced esophageal cancer. Upper gastrointestinal endoscopy (EGD)revealed a type 2 lesion in the middle thoracic esophagus, and biopsy revealed squamous cell carcinoma(SCC). Contrast- enhanced CT showed invasion of the left main bronchi. The patient was diagnosed as Stage Ⅳa advanced esophageal cancer, and was treated with 5-FU plus cisplatin chemotherapy, and 60 Gy of radiation therapy. The tumor disappeared by CT and EGD, and the patient was followed up for observation. The patient experienced a feeling of tightness again, and EGD revealed an ulcerative lesion in the middle thoracic esophagus, and a biopsy detected SCC. Because of the early recurrence after CRT, the patient was judged to be resistant to 5-FU plus cisplatin chemotherapy, and 8 courses of nivolumab were administered as second-line treatment. Follow-up EGD confirmed disappearance of ulcerative lesions, and no tumors have been observed to date.

Conformational Change in the Ligand-Binding Pocket via a KISS1R Mutation (P147L) Leads to Isolated Gonadotropin-Releasing Hormone Deficiency.

CONTEXT: Kisspeptin receptor (KISS1R) is expressed in hypothalamic gonadotropin-releasing hormone neurons and responsible for pubertal onset and reproductive functions. KISS1R mutations remain a rare cause of congenital hypogonadotropic hypogonadism (CHH). OBJECTIVE: The aim of this study was to identify the genetic cause of CHH in a patient and to functionally characterize a KISS1R mutation. DESIGN: The patient was a 47-year-old Japanese man whose parents were first cousins. He lacked secondary sexual characteristics owing to normosmic CHH. Exon segments for the KISS1R gene in this patient were screened for mutations. Functional analyses were performed using HEK293 cells expressing KISS1R mutants. Molecular dynamics simulations were performed to compare the ligand-KISS1R mutant complex with those of wild-type KISS1R variants. RESULTS: A homozygous mutation (c.440C>T, p.P147L) in KISS1R was identified. The P147L mutation did not affect either receptor expression level or subcellular localization in the recombinant expression system. Intracellular calcium measurements and cellular dielectric spectroscopy demonstrated that the P147L mutation impaired receptor function to an extent more severe than that of a previously reported L148S mutation. A receptor-ligand binding assay showed the P147L mutation causes a substantial loss of ligand-binding affinity. Molecular dynamics simulations revealed the P147L mutation decreases the contact surface area of the ligand-receptor complex in an expanded ligand-binding pocket. CONCLUSION: We identified a loss-of-function mutation in KISS1R associated with CHH. Our results demonstrated that the P147L mutation causes a severe phenotype and functional impairment resulting from the loss of ligand-binding affinity due to an expanded ligand-binding pocket.

Neuromedin U suppresses glucose-stimulated insulin secretion in pancreatic ß cells.

Neuromedin U (NMU), a highly conserved peptide in mammals, is implicated in energy homeostasis and glycemic control, and may also be involved in the regulation of adipoinsular axis function. However, the role of NMU in regulating insulin secretion has not been clearly established. In this study, we investigated the role of NMU in the regulation of insulin secretion both in vitro and in vivo. We found that NMU and NMU receptor (NMUR) 1 were expressed in mouse islets and ß cell-derived MIN6-K8 cells. In mice, NMU suppressed glucose-stimulated insulin secretion (GSIS) both in vitro and in vivo. Additionally, an NMUR1 agonist inhibited GSIS in both MIN6-K8 cells and mice islets. Moreover, NMU attenuated intracellular Ca2+ influx in MIN6-K8 cells, potentially causing a decrease in insulin secretion. siNmu-transfected MIN6-K8 cells showed elevated GSIS. Treatment with anti-NMU IgG increased GSIS in isolated mouse pancreatic islets. These results suggested that NMU can act directly on ß cells through NMUR1 in an autocrine or paracrine fashion to suppress insulin secretion. Collectively, our results highlight the crucial role of NMU in suppressing pancreatic insulin secretion, and may improve our understanding of glucose homeostasis.