Transluminal antegrade drill dilation technique for hepaticojejunostomy stricture with cholangioscopic evaluation (with video).

Background and study aims Balloon dilation and plastic stent deployment have been performed as hepaticojejunostomy stricture (HJS) treatment techniques under endoscopic ultrasound guidance (EUS). Although these techniques have shown favorable clinical results, the treatment period can be long because stent deployment is required. In addition, HJS may recur even after treatment because the scar tissue itself remains. To overcome these challenges, we developed an EUS-guided antegrade drill dilation technique for treating HJS. The aim of this study was to evaluate the technical feasibility and safety of this technique in terms of the pre- and post-cholangioscopic findings. Patients and methods This retrospective study included consecutive patients whose conditions were complicated with symptomatic HJS between November 2022 and February 2023. Transluminal antegrade drill dilation (TAD) using a novel drill dilator was attempted within 14 days after EUS-guided hepaticogastrostomy (HGS). HJS was diagnosed with cholangioscopy before TAD, and resolution was evaluated after TAD using cholangioscopy. Results TAD was attempted at approximately 11 days after EUS-HGS. The cholangioscope was inserted successfully in all patients after this procedure. Cholangioscopy revealed stricture without evidence of malignancy in 19 patients. In the remaining three patients, stricture was not observed and these patients underwent stent exchange rather than TAD. Among the 19 patients, passage of the guidewire across the HJS into the intestine was unsuccessful in four patients, and the technical success rate for this procedure was 78.9%. TAD was successful in all 15 patients in whom passage of the guidewire was achieved. Conclusions In conclusion, TAD appears to be technically feasible and safe.

Evaluation of exclusive internal endoscopic drainage for complex biloma with transluminal and transpapillary stenting.

Background and study aims Biloma is treated endoscopically with endoscopic retrograde cholangiography (ERCP) or endoscopi ultrasound-guided transluminal biloma drainage (EUS-TBD). However, almost all previous studies have used both internal and external drainage. External drainage has the disadvantages of poor cosmetic appearance and self-tube removal. The aim of the present study was to evaluate the internal endoscopic drainage for complex biloma after hepatobiliary surgery with an ERCP- or EUS-guided approach, without external drainage. Patients and methods This retrospective study included consecutive patients who had bilomas. A 7F plastic stent was deployed from the biloma to the duodenum in the ERCP group and the metal stent was deployed from the biloma to the stomach in the EUS-TBD group. Results Forty-seven patients were enrolled. The technical success rate was similar between the groups (ERCP 94% vs EUS-TBD 100%, P =0.371); however, mean procedure time was significantly shorter in the EUS-TBD group (16.9 minutes) than in the ERCP group (26.6 minutes) ( P =0.009). The clinical success rate was 87% (25 of 32 patients) in the ERCP group and 84% (11 of 13 patients) in the EUS-TBD group ( P =0.482). The duration of median hospital stay was significantly shorter in the EUS-TBD group (22 days) than in the ERCP group (46 days) ( P =0.038). There was no significant difference in procedure-associated adverse events between the groups. Conclusions In conclusion, ERCP and EUS-TBD are complementary techniques, each with its own merits in specific clinical scenarios. If both techniques can be performed, EUS-TBD should be considered because of the short times for the procedure, hospital stay. and biloma resolution.

Moving scope technique improves technical success rate of device insertion during EUS-guided hepaticogastrostomy (with video).

Background: Technical tips for device insertion during endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) have not been reported. To improve the technical success rate of device insertion without unnecessary tract dilation, the pushing force should be transmitted directly from the channel of the echoendoscope to the intrahepatic bile duct. Objectives: We developed a novel technique, termed the 'moving scope technique', the feasibility of which during EUS-HGS is described. Design: Retrospective study. Methods: The primary outcome of this study was the technical success rate of dilation device insertion without electrocautery dilation after the moving scope technique. The initial technical success rate of dilation device insertion was defined as successful insertion into the biliary tract. If dilation device insertion failed, the moving scope technique was attempted. Results: A total of 143 patients were enrolled in this study. The initial technical success rate for device insertion was 80.4% (115/143). The moving scope technique was therefore attempted in 28 patients. The mean angle between the intrahepatic bile duct and the guidewire was improved to 141.0° and resulted in a technical success rate of 100% (28/28). The area under the ROC curve (AUC) was 0.88, and 120° predicted successful dilation device insertion with sensitivity of 88.0% and specificity of 78.8%. Bile peritonitis (n = 8) and cholangitis (n = 2) were observed as adverse events, but were not severe. Conclusion: In conclusion, the moving scope technique may be helpful during EUS-HGS to achieve successful insertion of the dilation device into the biliary tract. These results should be evaluated in a prospective randomized controlled trial.

[A case of incipient pancreatic ductal adenocarcinoma concomitant with intraductal papillary mucinous neoplasm, confirmed by multiregion sequencing analysis].

Concomitant pancreatic ductal adenocarcinoma (PDA) is observed in a subset of patients with intraductal papillary mucinous neoplasm (IPMN) of the pancreas, and early detection of those progressing lesions is difficult. We present a case with a de novo carcinoma in situ (CIS) discovered incidentally around the resection margin of IPMNs. A man in his 70s with a history of acute pancreatitis at the age of 50 years and no family history of PDA had a pancreatoduodenectomy for three isolated branch duct IPMNs that caused recurrent pancreatitis. During the 2-year follow-up period, the index lesion in the pancreatic head grew significantly, whereas the other cysts remained small and without mural nodules. The majority of the cysts are histologically composed of low-grade dysplasia and are classified as gastric-type IPMN. CIS with nuclear overexpression of p53 was located in the main pancreatic duct and adjacent brunch duct, which involved the pancreatic resection margin. The precise pathological analysis combined with multiregion sequencing revealed the CIS harbored KRAS G12V and TP53 R248W. Conversely, IPMNs contained GNAS mutant cells as well as components containing additional KRAS mutations. These findings suggested that the CIS formed independently of the multiple IPMNs and appeared to be an early manifestation of concomitant PDA with coexisting IPMNs. Despite widespread agreement on the resection of the radiographically significant IPMN lesion (s), the latent invasive cancer was not eradicated. A detailed pathological and molecular assessment of the resected materials may aid in a better management strategy for concurrent lesions.

Clinical manifestations of diffuse large B-cell lymphoma that exhibits initial symptoms in the maxilla and mandible: a single-center retrospective study.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphatic tumor; however, extranodal DLBCLs that exhibit initial symptoms in the maxilla and mandible are rare. Moreover, DLBCL is clinically classified as a moderate to highly malignant lymphatic tumor that can progress rapidly; therefore, early diagnosis is crucial. However, diagnosis is difficult as the disease causes a diverse range of clinical symptoms with no characteristic imaging findings. We conducted a clinical investigation to clarify the clinical characteristics of DLBCL that exhibits initial manifestation in the maxilla and mandible. METHODS: Of the 2748 patients with malignant tumors of the oral and maxillofacial region examined at our hospital during a period of 11 years between January 2006 and December 2016, 27 primary cases diagnosed with DLBCL based on the chief complaint of symptoms in the gingiva and bone of the maxilla and mandible were enrolled in this study. Evaluations were based on sex, age, whether treatment was provided by a previous physician, symptoms, duration of disease until treatment was sought, clinical diagnosis, laboratory findings, and imaging results. RESULTS: There were 15 cases that involved the maxilla and 12 that involved the mandible. The median duration of disease until treatment was sought was 60 d (3-450 d). All cases exhibited a tumor or a mass, and hypoesthesia of the chin was confirmed in eight cases wherein the mandible was involved. The clinical stages were stage I in eight cases, stage II in ten cases, and stage IV in nine cases. Serum lactate dehydrogenase (LDH) levels were elevated in 13 of 22 patients. The overall survival rate was 63%. CONCLUSIONS: Symptoms associated with nontender swelling and numbness of the lip or chin in the absence of other findings such as dental infections should raise suspicions about DLBCL. Patients should be provided appropriate imaging and accurate biopsy assessments to improve prognosis.

Asset pricing during pandemic lockdown.

This paper examines the implications of lockdown policies during early stages of pandemics for asset prices. We build a simple susceptible-infected-recovered model with microeconomic foundations, which allows us to obtain qualitative results with economic implications. In our model, lockdown policies reduce (i) labour income by decreasing working hours and (ii) precautionary savings by decreasing susceptible agents' probability of getting infected in the future. We qualitatively show that strengthening lockdown measures negatively impacts asset prices at the time of implementation. Our empirical analysis using data from advanced countries supports this finding. Depending on parameter values, our numerical analysis displays a V-shaped recovery of asset prices and an L-shaped recession of consumption. The rapid recovery of asset prices occurs only if the lockdown policies are insufficiently stringent to reduce the number of new periodic cases. This finding implies the possibility that lenient lockdowns have contributed to rapid stock market recovery at the beginning of the COVID-19 pandemic.

Minimal residual disease detection in multiple myeloma: comparison between BML single-tube 10-color multiparameter flow cytometry and EuroFlow multiparameter flow cytometry.

Minimal residual disease (MRD)-negative status in multiple myeloma (MM) is associated with favorable outcomes. Although EuroFlow next-generation flow (NGF) is a global standard for MRD detection, its operating cost is high. Therefore, it is desirable to develop a less expensive method with equivalent sensitivity to that of EuroFlow-NGF. In this study, we compared the analytical ability of our BML 10-color multiparameter flow cytometry (MFC) to that of EuroFlow-NGF. Bone marrow samples collected from 51 patients with MM were subjected to MRD detection using BML 10-color-MFC and EuroFlow-NGF. Our antibody panel consisted of CD38 multiepitope, CD138, CD45, CD56, CD19, CD27, CD81, CD117, cytoplasmic immunoglobulin (cIg) κ, and cIgλ in a single tube. The median percentages of total plasma cells, as per 10-color-MFC and EuroFlow-NGF, were 0.2148% and 0.2200%, respectively, with a good correlation between the methods (r = 0.950). The median percentages of myeloma cells determined via 10-color-MFC and EuroFlow-NGF were 0.0012% and 0.0007%, respectively, with a strong correlation (r = 0.954). Our 10-color-MFC demonstrated high sensitivity to detect MRD; the results showed a good correlation with those obtained using EuroFlow-NGF. Therefore, our cost-effective single-tube MFC (approximately 100 USD/sample) is a promising alternative method for the detection of MRD in patients with MM.

Low Quality of Warfarin Therapy is Associated With Female Gender but Not With Polypharmacy in Patients With Atrial Fibrillation.

Background: We examined the impact of polypharmacy on the quality of the anticoagulation therapy in patients with atrial fibrillation. We also examined the factors that affect the stability of warfarin therapy. Methods and Results: This retrospective study was conducted using data from 157 consecutive outpatients with atrial fibrillation in a single tertiary referral hospital. Patients who were prescribed warfarin continuously and for whom PT-INR was examined at least three times in a year were included in this study. We examined the quality of warfarin therapy using time in the therapeutic INR range (TTR), percentage of PT-INR determinations in range (PINRR), and the coefficient variation (CV) of PT-INR. We found that the number of prescribed medicines was significantly associated with high BMI and low eGFR, but not with TTR, PINRR, and the coefficient variation of PT-INR in patients with atrial fibrillation. We also found that female gender was independently associated with low PINRR in this study population. Conclusion: Polypharmacy did not deteriorate the quality of warfarin therapy in patients with atrial fibrillation treated in the tertiary referral hospital. Female gender was an independent predictor of the low quality of warfarin therapy.

Genetic Tracing of Clonal Expansion and Progression of Pancreatic Ductal Adenocarcinoma: A Case Report and Multi-Region Sequencing Analysis.

Pancreatobiliary tumors frequently contain multiple malignant and precancerous lesions; however, the origin of the driver mutations and the mechanisms that underlie the generation of distinct clones within an organ field remain unclear. Herein, we describe a 76-year-old male suffering from moderately differentiated adenocarcinomas of the pancreas that primarily involved the distal bile duct and multiple "dispersing" invasive lesions in the pancreatic head. The patient underwent pylorus-preserving pancreaticoduodenectomy with superior mesenteric vein resection, and targeted sequencing of 18 genes associated with pancreatic tumorigenesis and immunohistochemical analysis of RNF43 and ARID1A were performed on each tumor compartment, including the invasive and non-invasive areas. Multi-region sequencing revealed shared KRAS and TGFBR1 mutations in all invasive foci, including those involving the distal bile duct. Distinct KRAS variants were found to be present in other non-continuous and non-invasive lesions in the pancreas. Intraductal lesions with KRAS G12D and RNF43 V50R mutations were evident in the main pancreatic duct. This appeared to be a founder clone, given that the mutation profile was common to the invasive foci as well as the additional high-grade dysplasia harboring ARID1A mutations, thereby suggesting a clonal branch-off during tumor evolution. In addition, we also observed independent intraductal papillary mucinous neoplasms with KRAS G12V and GNAS R201H mutations. Our theory, learned from this patient, was that lesions skipped dissemination and wide-spread movement potentially through the pancreatic ductal system as a process of pancreatic cancer development.

Polypharmacy Is Associated With Accelerated Deterioration of Renal Function in Cardiovascular Outpatients.

BACKGROUND: Polypharmacy is associated with poor prognosis of patients with various diseases. However, it has not been precisely addressed how polypharmacy affects the clinical characteristics of the cardiovascular outpatients. The aim of this study is to search for the clinical characteristics related to the number of prescribed drugs in the cardiovascular outpatients. Also, we examine whether the number of the prescribed drugs affects the worsening of renal function. METHODS: This retrospective study was conducted using the data of 259 continuous cardiovascular outpatients who were examined complete blood count (CBC) and serum creatinine. RESULTS: In the univariate analysis, the number of prescribed drugs were associated with the number of cardiovascular diseases or their risk factors, age, white blood cells, platelet, body mass index, anemia, and chronic kidney disease stage 3b or higher. In the multivariable analysis, independent variables that significantly correlated with the number of prescribed drugs were the number of cardiovascular diseases or their risk factors, anemia, and chronic kidney disease stage 3b or higher. Among 259 patients, 208 patients received follow-up examination of serum creatinine. The number of prescribed drugs was the only factor that was associated with accelerated deterioration of renal function. CONCLUSIONS: Polypharmacy is associated not only with poor renal function but with accelerated deterioration of renal function. Polypharmacy may be causally related with renal dysfunction.

Effects of Adipocyte-derived Factors on the Adrenal Cortex.

BACKGROUND AND OBJECTIVE: Obesity is highly complicated by hypertension and hyperglycemia. In particular, it has been proposed that obesity-related hypertension is caused by adipocyte-derived factors that are recognized as undetermined proteins secreted from adipocytes. Adipocyte-derived factors have been known to be related to aldosterone secretion in the adrenal gland. So far, Wnt proteins, CTRP-1, VLDL, LDL, HDL and leptin have been demonstrated to stimulate aldosterone secretion. In contrast, it has not yet been clarified whether adipocyte-derived factors also affect adrenal cortisol secretion. METHODS AND RESULTS: In the present study, we investigated the effect of adipocyte-derived factors on cortisol synthase gene CYP11B1 mRNA expression in vitro study using adrenocortical carcinoma H295R cells and mouse fibroblast 3T3-L1cells. Interestingly, adipocyte-derived factors were demonstrated to have the ability to stimulate CYP11B1 mRNA expression. CONCLUSION: Since CYP11B1 is well known as a limiting enzyme of cortisol synthesis, our study suggests that adipocyte-derived factors may stimulate cortisol secretion, as well as aldosterone secretion. Taken together, adipocyte-derived factors may be the cause of metabolic syndrome due to their stimulating effects on aldosterone/cortisol secretion. Therefore, the innovation of novel drugs against them may possibly be a new approach against metabolic syndrome.

Discovery and characterization of a small-molecule enteropeptidase inhibitor, SCO-792.

Enteropeptidase, localized into the duodenum brush border, is a key enzyme catalyzing the conversion of pancreatic trypsinogen proenzyme to active trypsin, thereby regulating protein digestion and energy homeostasis. We report the discovery and pharmacological profiles of SCO-792, a novel inhibitor of enteropeptidase. A screen employing fluorescence resonance energy transfer was performed to identify enteropeptidase inhibitors. Inhibitory profiles were determined by in vitro assays. To evaluate the in vivo inhibitory effect on protein digestion, an oral protein challenge test was performed in rats. Our screen identified a series of enteropeptidase inhibitors, and compound optimization resulted in identification of SCO-792, which inhibited enteropeptidase activity in vitro, with IC 50 values of 4.6 and 5.4 nmol/L in rats and humans, respectively. In vitro inhibition of enteropeptidase by SCO-792 was potentiated by increased incubation time, and the calculated Kinact/KI was 82 000/mol/L s. An in vitro dissociation assay showed that SCO-792 had a dissociation half-life of almost 14 hour, with a calculated koff rate of 0.047/hour, which suggested that SCO-792 is a reversible enteropeptidase inhibitor. In normal rats, a ≤4 hour prior oral dose of SCO-792 effectively inhibited plasma elevation of branched-chain amino acids in an oral protein challenge test, which indicated that SCO-792 effectively inhibited protein digestion in vivo. In conclusion, our new screen system identified SCO-792 as a potent and reversible inhibitor against enteropeptidase. SCO-792 slowly dissociated from enteropeptidase in vitro and inhibited protein digestion in vivo. Further study using SCO-792 could reveal the effects of inhibiting enteropeptidase on biological actions.

Clinical course of conservative management for isolated superior mesenteric arterial dissection.

OBJECTIVES: Isolated superior mesenteric arterial dissection (ISMAD) is an uncommon type of arterial dissection and treated with surgery, stenting, or conservative management. This study aimed to evaluate the criteria for conservative therapy for ISMAD patients based on imaging findings. METHODS: Eighteen consecutive ISMAD patients without peritoneal irritation at onset were retrospectively studied. The decision to perform stenting was based on the emergence of peritoneal irritation, aneurysm, or mesenteric ischemia. Clinical manifestations, follow-up contrast-enhanced computed tomography (CECT) findings, and patient outcome were evaluated. RESULTS: Most patients (16, 89%) were successfully treated conservatively; two patients (11%) required endovascular stenting because of an aneurysm or ulcer-like projection (ULP) sign. The median duration of fasting and hospital stays was 3 (range, 1-8) and 9 (range, 4-34) days, respectively. On CECT, the median distance from the superior mesenteric artery (SMA) origin to the entry site was 12 mm (range, 5-35 mm), and the median length of dissection was 87.5 mm (range, 20-150 mm). Among 16 patients treated conservatively, serial imaging was obtained in 11 patients (69%), and disappearance of the dissection within 4 months occurred in five patients. Two patients treated with endovascular stent underwent follow-up CECT 1 year after onset, and there were no complications. CONCLUSIONS: ISMAD patients without peritoneal irritation can be treated conservatively if there are no signs of an aneurysm, ULP, or mesenteric ischemia. When an aneurysm or ULP sign exists, endovascular stenting was able to preserve SMA blood flow with the improvement of the dissection.

Weyl Invariance of String Theories in Generalized Supergravity Backgrounds.

We revisit Weyl invariance string theories in generalized supergravity backgrounds. A possible counterterm was constructed in a work by Sakamoto, Sakatani, and Yoshida, but it seems to be a point of controversy in some literatures whether or not it is nonlocal. To settle down this issue, we show that the counterterm may be local and exactly cancels out the one-loop trace anomaly in generalized supergravity backgrounds.