Efficacy and safety of endoscopic ultrasound-guided gallbladder drainage without dilation by using a 0.035-inch stiff guidewire.

Endoscopic ultrasound-guided gallbladder drainage for patients with cholecystitis and high surgical risk is commonly performed by dilating the fistula before inserting the delivery sheath; however, this carries an increased risk of peritonitis. To overcome this problem, we developed a new technique that did not require dilation, using a 0.035-inch stiff guidewire, and retrospectively evaluated the efficacy and safety of this technique. This retrospective case series report collected data on non-surgical patients who underwent endoscopic ultrasound-guided gallbladder drainage for various indications at Steel Memorial Muroran Hospital between November 2020 and October 2022. A total of 71 patients were included (mean age 83 ± 7.6 years; 33 women and 38 men). Breakthrough of the delivery sheath without dilation of the fistula was successful in 97.2% (n = 69) of patients. The success rate of stent placement was 98.6% (n = 70), as was the clinical success rate. Complications occurred in 2.8% (n = 2) of patients. Early and late adverse events occurred in 2.8% (n = 2) and 12.7% (n = 9) of patients, respectively. The mean procedure time was 24.8 ± 9.3 min. If a 0.035-inch stiff guidewire is used, the dilation procedure can be omitted in the endoscopic ultrasound-guided gallbladder drainage using self-expandable metal stents.

Tissue acquisition for comprehensive genomic profiling of gallbladder cancer using a forward-viewing echoendoscope in a patient who underwent Roux-en-Y reconstruction.

A 50-year-old man with a history of total gastrectomy, distal pancreatectomy, splenectomy, and Roux-en-Y reconstruction was admitted to our hospital with a gallbladder tumor that had infiltrated the liver and abdominal wall. Because malignant cells were not collected during the percutaneous biopsy, we planned to perform an endoscopic ultrasound-guided fine-needle biopsy with a 22-G Franseen needle using a forward-viewing echoendoscope. Using intermittent manual compression, the forward-viewing echoendoscope reached the duodenum under fluoroscopic guidance. Endoscopic ultrasound-guided fine-needle biopsy was performed using a 22-G needle and 20-mL syringe and yielded a sufficient specimen with a single puncture. Malignant cells were promptly identified during on-site evaluation. The composition of the specimen (> 20% cancer cells and tissue area exceeding 25 mm2) enabled comprehensive genomic profiling. Subsequently, high-tumor mutational burden was diagnosed based on comprehensive genomic profiling, and pembrolizumab was initiated as a second-line therapy. Even in cases involving Roux-en-Y reconstruction, endoscopic ultrasound-guided fine-needle biopsy using a forward-viewing echoendoscope can result in collection of a high-quality specimen.

Detailed Clinical Characteristics, Interventions, and Long-Term Outcomes of Patients With Gastric Cancer Who Received the Best Supportive Care Without Any Anticancer Treatment.

Background: Due to the lack of studies, the long-term prognoses of unfit patients with gastric cancer (GC) who did not receive any aggressive cancer treatment (best supportive care [BSC] cases) remain unclear, especially for those with potentially curable GC. We conducted this observational study to capture the real-world data of characteristics and outcomes for BSC cases. Method: Consecutive clinical records of patients with GC diagnosed at Steel Memorial Muroran Hospital from January 2017 to December 2021 were analyzed. Result: Of 481 patients diagnosed with GC, 91 (18.9%) were BSC cases. The median overall survival (OS) was 12.4, 8.3, and 2.5 months for clinical stage (cStage) I, II-III, and IV, respectively. Patients with potentially curable GC (cStage I-III) had significantly longer OS than those with incurable disease (cStage IV), with a hazard ratio for death of 0.29 (95% confidence interval: 0.18-0.47). Conclusion: Our report provides useful information for decision-making for unfit patients with GC in daily clinical practice.

Clinical factors associated with acute abdominal symptoms induced by gastric anisakiasis: a multicenter retrospective cohort study.

BACKGROUND: Gastric anisakiasis typically causes severe abdominal symptoms; however, we incidentally detected asymptomatic gastric anisakiasis cases during esophagogastroduodenoscopy. The factors associated with developing acute abdominal symptoms induced by gastric anisakiasis remain unclear. Therefore, this study aimed to investigate the clinical factors associated with abdominal symptoms of gastric anisakiasis by comparing symptomatic and asymptomatic cases. METHODS: This was a retrospective cohort study involving 264 patients diagnosed with gastric anisakiasis at nine hospitals in Japan between October 2015 and October 2021. We analyzed patients' medical records and endoscopic images and compared the clinical factors between the symptomatic and asymptomatic groups. RESULTS: One hundred sixty-five patients (77.8%) were diagnosed with abdominal symptoms, whereas 47 (22.2%) were asymptomatic. Older age, male sex, diabetes mellitus, gastric mucosal atrophy, and gastric mucosal atrophy of the Anisakis penetrating area were significantly more common in the asymptomatic group than in the symptomatic group. Multivariate analysis revealed that age (p = 0.007), sex (p = 0.017), and presence or absence of mucosal atrophy (p = 0.033) were independent factors for the occurrence of acute abdominal symptoms. In addition, cases that were Helicobacter pylori naïve, with an elevation of white blood cells, or without an elevation of eosinophils were more common in the symptomatic group than in the asymptomatic group. CONCLUSIONS: Age, sex, and presence or absence of gastric mucosal atrophy were the clinical factors associated with the occurrence of acute abdominal symptoms. Older and male patients and those with gastric mucosal atrophy were less likely to show abdominal symptoms. The mechanisms of the occurrence of symptoms induced by gastric anisakiasis remain unclear; however, our results will help clarify this issue in the future.

Spore-Forming Lactic Acid-Producing Bacterium Bacillus coagulans Synthesizes and Excretes Spermidine into the Extracellular Space.

The effect of spermidine in extending healthy longevity has attracted attention. As people age, their ability to synthesize putrescine, the precursor of spermidine, declines, and its supplementation from the diet or gut bacteria is needed. Many bacteria synthesize spermidine, but no strains have been reported to excrete de novo synthesized spermidine from the cells. We found that Bacillus coagulans strain YF1, isolated from "nanohana-duke", excreted de novo synthesized spermidine from the cells under anaerobic conditions. This strain synthesizes spermidine from arginine via agmatine, putrescine, and carboxyspermidine in sequential reactions, and the genes encoding the enzymes responsible for these reactions have been identified. B. coagulans is a gastric acid-resistant spore-forming lactic acid-producing bacterium, known for its beneficial effects as a probiotic. It can be used to produce lactic acid fermented foods containing spermidine. The newly discovered ability to excrete de novo synthesized spermidine is the decisive feature of this bacterium.

Targeting apolipoprotein E and N-terminal amyloid ß-protein precursor interaction improves cognition and reduces amyloid pathology in Alzheimer's mice.

Apolipoprotein E (apoE) interaction with amyloid ß-protein precursor (APP) has garnered attention as the therapeutic target for Alzheimer's disease (AD). Having discovered the apoE antagonist (6KApoEp) that blocks apoE binding to N-terminal APP, we tested the therapeutic potential of 6KApoEp on AD-relevant phenotypes in amyloid ß-protein precursor/presenilin 1 (APP/PS1) mice that express each human apoE isoform of apoE2, apoE3, or apoE4 (designated APP/PS1/E2, APP/PS1/E3, or APP/PS1/E4 mice). At 12 months of age, we intraperitoneally administered 6KApoEp (250 µg/kg) or vehicle once daily for 3 months. At 15 months of age, blockage of apoE and N-terminal APP interaction by 6KApoEp treatment improved cognitive impairment in most tests of learning and memory, including novel object recognition and maze tasks in APP/PS1/E2, APP/PS1/E3, and APP/PS1/E4 mice versus each vehicle-treated mouse line and did not alter behavior in nontransgenic littermates. Moreover, 6KApoEp therapy ameliorated brain parenchymal and cerebral vascular ß-amyloid deposits and decreased abundance of amyloid ß-protein (Aß) in APP/PS1/E2, APP/PS1/E3, and APP/PS1/E4 mice versus each vehicle-treated mouse group. Notably, the highest effect in Aß-lowering by 6KApoEp treatment was observed in APP/PS1/E4 mice versus APP/PS1/E2 or APP/PS1/E3 mice. These effects occured through shifting toward lessened amyloidogenic APP processing due to decreasing APP abundance at the plasma membrane, reducing APP transcription, and inhibiting p44/42 mitogen-activated protein kinase phosphorylation. Our findings provide the preclinical evidence that 6KApoEp therapy aimed at targeting apoE and N-terminal APP interaction is a promising strategy and may be suitable for patients with AD carrying the apoE4 isoform.

Atypical Pseudo-Meigs' Syndrome without Pleural Effusion Due to Ovarian Metastasis from Sigmoid Colon Cancer.

We herein report a case of atypical pseudo-Meigs' syndrome without pleural effusion. A 46-year-old woman was diagnosed with an ovarian tumor and sigmoid colon cancer with massive ascites. She underwent surgical resection of the sigmoid colon and bilateral salpingo-oophorectomy. The pathological diagnosis was sigmoid colon cancer with ovarian metastasis. A few days after the operation, the massive ascites disappeared. Immunostaining for vascular endothelial growth factor (VEGF) suggested its overproduction was involved in the development of the ascites. Although cases of pseudo-Meigs' syndrome without pleural effusion are rare, reporting such cases will facilitate the choice of more appropriate treatment strategies in future.

Clinical benefit of early precut sphincintroterotomy for difficult biliary cannulation during endoscopic retrograde cholangiopancreatography.

OBJECTIVES: A precut procedure is sometimes required for difficult biliary cannulation during endoscopic retrograde cholangiopancreatography (ERCP). However, it is unclear whether the biliary access rate has improved for early precut procedures compared to conventional techniques. This study aimed to identify the benefit of early precut sphincterotomy in cases showing difficult biliary access. METHODS: Between April 2017 and August 2021, consecutive patients who underwent precutting for difficult biliary cannulation were retrospectively enrolled. The outcomes of early (≤ 10 min from start of cannulation) and delayed (> 10 min) precut groups were evaluated. All adverse events were defined according to Cotton criteria. RESULTS: A total of 70 patients were enrolled in this study. The biliary cannulation rate for a first ERCP was significantly higher in the early compared to delayed precut group (95% vs. 73.3%; P = 0.015). A difference in overall cannulation rate between the two groups was not observed (97.5% vs. 83.3%; P > 0.05). Significantly higher rates of prophylactic pancreatic stents were described in the delayed compared to early precut group (36.7% vs. 12.5%; P = 0.009). Significant differences in the frequency of pancreatitis, bleeding, penetration, and perforation were not noted between the two groups. Overall, the success rate was statistically significant between the experienced and less experienced endoscopists (87.2% vs. 63.9%; P = 0.017). CONCLUSIONS: Early precutting within 10 min from the start of cannulation in ERCP is safe and effective in cases with a difficult biliary cannulation, and can improve the biliary cannulation rate.

Effects of 6-Aminonicotinic Acid Esters on the Reprogrammed Epigenetic State of Distant Metastatic Pancreatic Carcinoma.

In the search for alternatives to 6-aminonicotinamide (6AN), a series of 6-aminonicotinic acid esters were designed and synthesized as precursors of 6-amino-NADP+, a potent inhibitor of 6-phosphogluconate dehydrogenase (6PGD). Like 6AN, some of these esters were found to reverse the loss of histone 3 lysine 9 trimethylation (H3K9me3) in patient-derived pancreatic ductal adenocarcinoma (PDAC) distant metastasis (A38-5). Among them, 1-(((cyclohexyloxy)carbonyl)oxy)ethyl 6-aminonicotinate (5i) showed more potent antiproliferative activity than 6AN. Metabolite analysis revealed that compound 5i produced a marked increase in metabolites upstream of 6PGD, indicating intracellular inhibition of 6PGD by 6-amino-NADP+ derived from compound 5i through 6-aminonicotinic acid (6ANA) via the Preiss-Handler pathway. Despite the more potent pharmacological effects shown by compound 5i in A38-5, compound 5i was found to be substantially less toxic to primary hippocampal rat neurons compared to 6AN, indicating its therapeutic potential in targeting distant metastatic cells.

Structural basis of the 24B3 antibody against the toxic conformer of amyloid ß with a turn at positions 22 and 23.

Amyloid ß-protein (Aß) oligomers are involved in the early stages of Alzheimer's disease (AD) and antibodies against these toxic oligomers could be useful for accurate diagnosis of AD. We identified the toxic conformer of Aß42 with a turn at positions 22/23, which has a propensity to form toxic oligomers. The antibody 24B3, developed by immunization of a toxic conformer surrogate E22P-Aß9-35 in mice, was found to be useful for AD diagnosis using human cerebrospinal fluid (CSF). However, it is not known how 24B3 recognizes the toxic conformation of wild-type Aß in CSF. Here, we report the crystal structure of 24B3 Fab complexed with E22P-Aß11-34, whose residues 16-26 were observed in electron densities, suggesting that the residues comprising the toxic turn at positions 22/23 were recognized by 24B3. Since 24B3 bound only to Aß42 aggregates, several conformationally restricted analogs of Aß42 with an intramolecular disulfide bond to mimic the conformation of toxic Aß42 aggregates were screened by enzyme immunoassay. As a result, only F19C,A30homoC-SS-Aß42 (1) bound significantly to 24B3. These data provide a structural basis for its low affinity to the Aß42 monomer and selectivity for its aggregate form.

Nephronectin influences EAE development by regulating the Th17/Treg balance via reactive oxygen species.

Blood levels of the extracellular matrix protein nephronectin (Npnt), a protein critical for kidney development, are elevated in autoimmune experimental autoimmune encephalitis (EAE) mice, which are a model for multiple sclerosis. We found here that treatment with anti-Npnt antibody directed against the α8ß1 integrin-binding site (Npnt-blocking antibody) inhibits EAE development. The selenium transporter selenoprotein P (SeP) was identified as a novel Npnt-binding partner. In EAE, Npnt induced SeP and glutathione peroxidase 1 (GPx1) expression, followed by reactive oxygen species (ROS) inhibition in CD4+ T cells; these changes were disturbed by Npnt-blocking antibody treatment, which also caused suppressed differentiation of interleukin (IL)-17-producing CD4+ T-helper cells (Th17s) and elevated differentiation of regulatory T cells (Tregs). Treatment of EAE mice with the ROS scavenger N-acetyl cysteine (NAC) blocked the Npnt-blocking antibody-induced decrease in Th17 differentiation and increase in Treg differentiation. In conclusion, the interaction between Npnt and SeP contributes to EAE development by regulating the Th17/Treg balance via the ROS level.

Efficacy of Mechanical Thrombectomy Using an Aspiration Catheter Compared with a Stent Retriever Alone for Middle Cerebral Artery M2 Occlusion.

Objective: Mechanical thrombectomy (MT) for middle cerebral artery M2 occlusion (M2O) is challenging because the procedure is performed in a narrow and tortuous artery. In this study, we compared MT using an aspiration catheter (AC) versus a stent retriever (SR) used alone, and retrospectively evaluated the efficacy and safety of MT using an AC for M2O. Methods: Seventy-four consecutive patients who underwent MT for M2O at our institution between April 2016 and April 2020 were evaluated. The subjects were classified into those treated by AC (AC group) or SR alone (SR group). The AC group included patients treated by both contact aspiration and a combination technique of AC and SR. Background factors and outcomes, including modified treatment in cerebral infarction (mTICI) 2c-3 recanalization, were compared between the groups. Results: AC and SR groups consisted of 47 and 27 patients respectively. Among them, the rate of mTICI 2b-3 was 93.6% vs 92.6%, and that of mTICI 2c-3 was 72.3% vs 48.2% (P = 0.004). The perioperative symptomatic subarachnoid hemorrhage (SAH) rate was 0% vs 7.4%, and modified Rankin scale scores of 0-2 were 78.6% vs 50% (P = 0.03). In the AC group, the mTICI 2c-3 rate was higher in patients in whom the AC was adequately advanced to the thrombus compared to those with inadequate AC advancement (83.3% vs 36.3%, P = 0.002). Conclusion: The rate of mTICI 2c-3 was higher in the AC than SR group, with no cases of symptomatic SAH. MT using AC for M2O might achieve safe and effective thrombectomy.

Successful pembrolizumab treatment of microsatellite instability-high intrahepatic cholangiocarcinoma: A case report.

The tumor reduction effect of pembrolizumab is extremely high compared to standard chemotherapy and might show prolonged survival. Therefore, the MSI status should be examined in patients with cholangiocarcinoma.

Oil Thickening with Organoclay Enhances the Ultraviolet Absorption Ability of Sunscreen on a Skin-mimicking Substrate.

The performance of sunscreen products depends on their ultraviolet (UV) absorption ability through the film formed on the skin surface upon their application. Therefore, it is important that a uniform film is formed on the uneven skin surface for effective sunscreen performance. Because most UV filters are oil soluble, we hypothesized in this study that increasing the viscosity of the oil phase of a sunscreen product can improve the performance of the sunscreen. We first examined the association between the concentration of the oil thickener and the UV absorption ability of the sunscreen product using a skin-mimicking substrate (SMS). Among all thickeners examined (petrolatum, dextrin palmitate, silica silylate, and organoclay), organoclay and silica silylate significantly increased the UV absorbance of sunscreen on the SMS in a concentration-dependent manner. Thereafter, we examined film uniformity to elucidate the mechanism underlying the observed increase in UV absorption. The uniformity of film thickness on the SMS increased with increasing organoclay content, based on decreased standard deviations of film thickness. Our results showed that increasing the viscosity of the oil phase with organoclay resulted in the formation of a uniform film by preventing the sunscreen from flowing into the grooves when applied on the SMS, thereby increasing UV absorbance by more than two-fold that of sunscreen without organoclay. Thus, the use of thickeners, such as organoclay, increases the viscosity of the oil phase at a low shear rate after the high shear of application. This is an effective strategy for improving the overall quality and performance of sunscreen products.

Laparoscopic Distal Gastrectomy for Synchronous Gastric Cancer and Gastrointestinal Stromal Tumor With Situs Inversus Totalis.

BACKGROUND: Situs inversus totalis (SIT) is a rare congenital condition in which the thoracic and abdominal organs are inverted like a mirror image. CASE REPORT: We present a case of synchronous gastric cancer and gastrointestinal stromal tumor (GIST) associated with SIT in a 74-year-old man who was admitted to our department to treat gastric cancer. Esophagogastroduodenoscopy revealed a depressed lesion and a submucosal tumor (SMT) in the middle-third of the stomach. Abdominal contrast-enhanced computed tomography revealed complete inversion of the internal organs, and the common hepatic artery branched from the superior mesenteric artery. The patient underwent laparoscopic distal gastrectomy with regional lymph node dissection and Billroth I reconstruction. The macroscopic observation of the resected specimen revealed a depressed lesion measuring 2.0×1.5 cm in diameter and an SMT measuring 2.2×1.8 cm. CONCLUSION: Careful preoperative anatomic evaluation is important in SIT because the situs anomalies may be accompanied by major vascular anomalies.

Enteral Vitamin B12 Supplementation Is Effective for Improving Anemia in Patients Who Underwent Total Gastrectomy.

BACKGROUND: This study aimed to investigate the efficacy of enteral supplementation of vitamin B12 for vitamin B12 deficiency in patients who underwent total gastrectomy for gastric cancer. METHODS: The study enrolled 133 patients who underwent total gastrectomy for gastric cancer at Kochi Medical School. Clinical data were obtained to investigate associations between vitamin B12 supplementation and vitamin B12 levels. Vitamin B12 deficiency was defined as serum vitamin B12 less than 200 pg/mL. Baseline characteristics and changes in hematological variables, including vitamin B12 levels, were examined. RESULTS: Vitamin B12 deficiency was present in 71.4% of the 133 patients. Vitamin B12 levels at 3, 6, and 12 months after enteral supplementation were 306 pg/mL, 294 pg/mL, and 367 pg/mL, respectively, which were all significantly higher than those before supplementation (p < 0.001 for all comparisons). The median red blood cell count at 3, 6, and 12 months after enteral supplementation were 380 × 104/mm3, 394 × 104/mm3, and 395 × 104/mm3, respectively, which were all significantly higher than those before supplementation (p = 0.020, p = 0.001, and p = 0.003, respectively). Vitamin B12 levels at 3, 6, and 12 months after supplementation were significantly higher in patients supplemented enterally than those supplemented parenterally (p < 0.001 for all comparisons). CONCLUSIONS: Vitamin B12 deficiency was found in 71.4% of postoperative patients who underwent total gastrectomy for gastric cancer, and enteral vitamin B12 supplements might be effective to improve anemia in these patients.

[Curative Resection for Advanced Gastric Cancer with Lymph Node Metastasis along the Middle Colic Artery].

Mesenteric lymph node metastasis of gastric cancer is extremely rare. We report the case of a patient with advanced gastric cancer having lymph node metastasis in the transverse mesocolon who underwent gastrectomy with lymph node dissection followed by chemotherapy. A 74-year-old male complaining of tarry stool was referred to our hospital for further examination following a diagnosis of gastric cancer by a local medical doctor. Esophagogastroduodenoscopy revealed an irregular and ulcerated lesion in the lower third of the stomach, and analyses of biopsy specimens revealed adenocarcinoma. Abdominal computed tomography revealed abdominal wall thickening in the lower third of the stomach, with enlarged lymph nodes in the perigastric area and the left side area of the middle colic artery. With a clinical diagnosis of gastric cancer, the patient underwent distal gastrectomy with lymph node dissection followed by Billroth Ⅰ reconstruction. During surgery, the enlarged lymph node along with the middle colic artery in the transverse mesocolon was dissected. The gross appearance of the resected specimen shows a large and ulcerated tumor measuring 6.0×5.5 cm in the lesser curvature side of the lower third of the stomach. The pathological examination of the resected specimen showed solid-type poorly-differentiated adenocarcinoma with lymph nodes metastases, which was detected in the perigastric area and transverse mesocolon. The final diagnosis according to the Japanese classification of gastric carcinoma by the Japanese Gastric Cancer Association was L, Less-Post-Ant, Type 2, 6.0×5.5 cm, T3(SS), N2(5/19), M1(LYM), P0, H0, CY0, por1, Ly0, V1a, Stage Ⅳ, R0. Subsequently, the patient received S-1 plus oxaliplatin chemotherapy; however, he developed para-aortic lymph node metastases 18 months after surgery. Therefore, the patient was treated with ramucirumab plus nab-paclitaxel and was alive 20 months after the operation. Although mesocolonic lymph node metastasis of gastric cancer is rare, future identification of risk factors and the development of novel treatments should be achieved through further investigations and the accumulation of 3 cases.

A Patient with a Delayed Diagnosis of Artery of Percheron Occlusion in Whom Thrombectomy Was Effective.

Objective: A case of posterior cerebral artery (P1 segment) occlusion with consciousness disturbance and Weber's syndrome treated by mechanical thrombectomy is reported. Case Presentation: The patient was a 69-year-old man with consciousness disturbance, left hemiparesis, and anisocoria. MRI revealed acute cerebral infarction in the midbrain and right thalamus. Angiography demonstrated that the right P1 segment was occluded and mechanical thrombectomy was performed. The right P1 segment and its perforator artery, the artery of Percheron (AOP), were both recanalized after the treatment, and the symptoms of perforator occlusion significantly improved. Conclusion: Mechanical thrombectomy for P1 segment occlusion may be effective for improving the symptoms caused by occlusion of its perforator, the AOP.