Endoscopic Retrograde Cholangiopancreatography-Related Procedures for the Differential Diagnosis of Isolated Immunoglobin G4-Related Sclerosing Cholangitis and Perihilar Cholangiocarcinoma.

BACKGROUND/PURPOSE: Differential diagnosis of isolated immunoglobin (Ig)G4-related sclerosing cholangitis (IgG4-SC) and cholangiocarcinoma is challenging. We aimed to clarify the role of endoscopic retrograde cholangiography (ERCP)-related procedures in the differential diagnosis of isolated IgG4-SC and perihilar cholangiocarcinoma (PHCC). METHODS: Seven patients with hilar-type isolated IgG4-SC diagnosed at Hiroshima University Hospital and sixty-five patients with surgically resected invasive PHCC were enrolled, and the diagnostic yields of intraductal ultrasonography (IDUS), peroral cholangioscopy (POCS), and pathological examinations were determined. RESULTS: In six of seven (86%) patients with isolated IgG4-SC, the stricture was in the perihilar bile duct. IDUS showed that symmetrical wall thickening (40% vs. 5%, p = 0.04), homogeneous internal echo (80% vs. 5%, p < 0.001), and smooth outer margins (80% vs. 6%, p < 0.001) were more frequent in isolated IgG4-SC than in PHCC. POCS showed a smooth mucosal surface more frequent in isolated IgG4-SC (75% vs. 7%, p = 0.006). Only one patient had two pathological findings characteristic of IgG4-SC. The sensitivity for diagnosing PHCC was 81% using two or more combined sampling methods. CONCLUSIONS: Pathological examinations have limitations in the differential diagnosis of isolated-IgG4-SC and PHCC, and a diagnostic strategy that combines multiple ERCP-related procedures, including IDUS and POCS, is recommended.

Impact of endoscopic ultrasound-guided fine needle aspiration on positive peritoneal lavage cytology in patients with resectable pancreatic body and tail cancer.

BACKGROUND/PURPOSE: A recent study has demonstrated that the timing of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) significantly influences the peritoneal lavage cytology (CY) outcomes in pancreatic body-tail cancer. The aim of this study was to clarify the impact of EUS-FNA on CY positivity in patients with resectable pancreatic body-tail cancer. METHODS: Patients with anatomically resectable pancreatic body-tail cancer surgically resected at Hiroshima University Hospital were enrolled, and elated clinicopathological factors, including EUS-FNA variables and CY positivity rate, were analyzed. RESULTS: Of the 129 eligible patients, 16 (12%) had positive CY. The EUS-FNA rates of the CY-positive and CY-negative groups were not significantly different (63% vs. 52%, p = .440). Multivariate analysis revealed that lymph node metastasis was the only independent risk factor for CY positivity (odds ratio: 5.734, p = .031). A total of 10 (14%) of the 69 patients who underwent EUS-FNA had positive CY; however, needle specifications and the interval between EUS-FNA and CY examination did not differ between the CY-positive and CY-negative groups. CY positivity rates were comparable for intervals ≤14 days and ≥15 days (17% vs. 14%, p = 1.000). CONCLUSIONS: EUS-FNA may not affect CY positivity in patients with resectable pancreatic body-tail cancer, regardless of the timing.

Association of computed tomography-derived muscle mass and quality with delayed acquisition independent walking after cardiovascular surgery.

BACKGROUND: In the context of cardiovascular surgery, the foremost concern lies in delayed functional recovery, as typified by the acquisition of independent walking after surgery, among older patients with decline in skeletal muscle mass and quality. Computed tomography (CT), which is typically employed for the preoperative assessment of pathological conditions in patients undergoing cardiovascular surgery, is also suitable for screening for potential decline in skeletal muscle mass and quality. The aim of this study was to examine the predictive capabilities of CT-derived parameters such as muscle mass and muscle quality for the delayed acquisition of independent walking in the postoperative period. METHODS: This retrospective study enrolled consecutive Japanese patients who underwent elective cardiovascular surgery between May 2020 and January 2023. In total, 139 patients were included in the analyses. Based on the preoperative CT image, the psoas muscle volume index (PMVI) and psoas muscle attenuation (PMA) were calculated. Information on patient characteristics, including preoperative physical fitness such as handgrip strength/body mass index (GS/BMI), short physical performance battery (SPPB), and 6-min walking distance (6MWD), were obtained from the medical records. We defined delayed acquisition of independent walking after surgery as the inability to walk 100 m within 4 days after surgery. RESULTS: The median age of the patients was 72 (interquartile: 64-78) years, and 74.8% (104/139) were men; 47.5% corresponded to the delayed group. The areas under the curves of SPPB, GS/BMI, 6MWD, PMVI, and PMA against delayed acquisition of independent walking after surgery were 0.68 [95% confidence interval (CI): 0.59 to 0.77], 0.72 (95% CI: 0.63 to 0.80), 0.73 (95% CI: 0.65 to 0.82), 0.69 (95% CI: 0.60 to 0.78), and 0.78 (95% CI: 0.70 to 0.85), respectively. In the multivariate logistic regression analysis, low PMA was significantly associated with delayed acquisition of independent walking even after adjustment for patient characteristics including physical fitness [model 1: SPPB (OR, 1.14; 95% CI: 1.03-1.25), model 2: GS/BMI (OR, 1.13; 95% CI: 1.03-1.25), and model 3: 6MWD (OR, 1.14; 95% CI: 1.03-1.25)], but PMVI was not. CONCLUSIONS: Our study revealed a strong association between PMA, a marker of CT-derived muscle quality, and the postoperative delay in achieving independent walking in patients who underwent cardiovascular surgery. The technique to obtain information on muscle quality during the time period before surgery may be an option for timely therapeutic intervention in patients who may have delayed acquisition of independent walking after surgery.

Mixed neuroendocrine-non-neuroendocrine neoplasm of the bile duct with long-term prognosis after neoadjuvant chemotherapy.

A 74-year-old man with obstructive jaundice presented with a thickened distal bile duct wall. A transpapillary forceps biopsy revealed an adenocarcinoma; however, because the tumor image was different from that of a typical cholangiocarcinoma, endoscopic ultrasound-guided fine-needle aspiration was performed on the tumor and enlarged lymph nodes. The tumor cells were positive for synaptophysin and CD56 with a Ki67 labeling index of 95%, and he was diagnosed with small cell neuroendocrine carcinoma. We diagnosed a bile duct tumor with neuroendocrine carcinoma component with lymph node metastasis. Preoperative chemotherapy for neuroendocrine carcinoma was administered because R0 resection was difficult and the risk of postoperative recurrence was high. Three courses of chemotherapy with carboplatin and etoposide resulted in marked tumor shrinkage, and radical resection was performed 3 months after diagnosis. Postoperative pathology revealed adenocarcinoma in the mucosal epithelium and small cell neuroendocrine carcinoma in the submucosa, most of which resolved with chemotherapy. Carboplatin and etoposide were resumed as adjuvant chemotherapy, and 67 months of recurrence-free survival were achieved after surgery.

Enhanced inhibitory activity of compounds containing purine scaffolds compared to protein kinase CK2α considering crystalline water.

We recently reported novel purine-based CK2α inhibitors using the solvent ordering-based method as virtual screening. Among these, the X-ray crystal structure of a complex with CK2α was determined. The results showed that the crystalline water molecules observed in many previously reported complex structures of CK2α and its inhibitors had been eliminated. We then proposed a structure-based drug design. Since the removal of water molecules would be detrimental to inhibitor binding, new groups of compounds were designed by changing the position of the carboxy group located at the point where a water molecule would be present so as not to eliminate it. Compounds with (E)-2-carboxyethenyl and 3-carboxyphenyl substituted at the 2-position on the purine scaffold showed much higher inhibitory potency than 4-carboxyphenyl derivatives. Furthermore, in the presence of a 4-fluorophenyl group at the 9-position on the purine scaffold, the inhibitory activity of the 3-carboxyphenyl derivative against CK2α was 0.18 µM, a 167-fold improvement compared to the 4-carboxyphenyl derivative. The strategy of leaving crystalline water can significantly increase inhibitory activity.

Clinical Utility of the Combined Use of CA19-9 and DUPAN-2 in Pancreatic Adenocarcinoma.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) patients with normal carbohydrate antigen (CA) 19-9 levels can have early-stage cancer or advanced cancer without elevation of CA19-9 level; estimating their malignant potential is difficult. This study investigated the clinical utility of the combined use of preoperative CA 19-9 and Duke pancreatic monoclonal antigen type 2 (DUPAN-2) levels in patients with PDAC. METHODS: Patients who underwent curative-intent surgery for PDAC between November 2005 and December 2021 were investigated. Eligible patients were classified into four groups based on these two markers. Among patients with normal CA19-9 levels, those with normal and high DUPAN-2 levels were classified into normal/normal (N/N) and normal/high (N/H) groups, respectively. Among patients with high CA19-9 levels, those with normal and high DUPAN-2 levels were classified into high/normal (H/N) and high/high (H/H) groups, respectively. Survival rates were compared between the groups. RESULTS: Among 521 patients, the N/N, N/H, H/N, and H/H groups accounted for 25.0%, 10.6%, 35.1%, and 29.4% of patients, respectively. The proportions of resectable PDAC in the N/N and H/N groups (71.5% and 66.7%) were significantly higher than those in the N/H and H/H groups (49.1% and 54.9%) (P < 0.01). The 5-year survival rates in the N/N, N/H, H/N, and H/H groups were 66.0%, 31.1%, 34.9%, and 29.7%, respectively; the rate in the N/N group was significantly better than those in the other three groups (P < 0.0001, P < 0.0001, and P < 0.0001, respectively). CONCLUSIONS: Only patients with normal CA19-9 and DUPNA-2 values should be diagnosed with early-stage PDAC.

A case of young male with recurrent acute pancreatitis caused by an intrapancreatic gastric duplication cyst.

Gastric duplication cyst (GDC) is a rare gastrointestinal malformation that frequently occurs in the greater curvature of the gastric antrum or corpus. Herein, we reported a case of intrapancreatic GDC found as a result of recurring pancreatitis. A 15-year-old man experienced repeated episodes of acute pancreatitis and was found to have a cystic lesion in the pancreatic tail. Contrast-enhanced computed tomography revealed a 20-mm cystic lesion with an enhanced thick wall. Endoscopic ultrasonography revealed an anechoic cyst with a three-layered wall. Magnetic resonance cholangiopancreatography and endoscopic retrograde pancreatography (ERP) revealed a connection between the cyst and the main pancreatic duct (MPD), and the duplication of the MPD. ERP showed the pancreatic duct stenosis downstream of the cyst. Although preoperative diagnosis was difficult, distal pancreatectomy was performed to prevent recurrence of pancreatitis. Pathological examination revealed that the cystic lesion was circumferentially surrounded by the pancreatic parenchyma. The epithelial lining of the cyst was crypt epithelium containing the fundic or pyloric glands and surrounded by a smooth muscle layer. The final diagnosis was intrapancreatic GDC.

Role of the thiosugar ring in the inhibitory activity of salacinol, a potent natural α-glucosidase inhibitor.

Herein, ring-cleaved (24) and truncated (25) analogues of an azasugar, 1-deoxynojirimycin (23), exhibited inhibitory activity (Ki = 4-10 µM) equal to that of the parent compound (1, Ki = 14 µM). Based on this structure-activity relationship (SAR), four ring-cleaved (26a-26c and 27c) and three truncated (28a-28c) analogues of salacinol (1), a potent thiosugar-ring-containing α-glucosidase inhibitor, were synthesised. Bioassay results revealed that all the synthetics were inactive, indicating that the 5-membered thiosugar ring of 1 played an essential role in the potent activities of sulfonium-type inhibitors. The present findings are interesting and important in understanding the function of salacinol, considering that the observed inhibitory activity trend was contrary to the SAR observed in aza-compounds (23, 24, and 25) in a previous study, which suggested that the cyclic structure did not contribute to their strong inhibitory activity.

Prognostic impact of peritoneal washing cytology in patients with biliary tract cancer.

PURPOSE: To elucidate the clinical significance of peritoneal washing cytology (PWC) in patients with resectable biliary tract cancer (BTC). METHODS: Clinical data of patients with BTC, who received PWC at curative intent surgery from March 2009 to December 2021, were retrospectively analyzed. Eligible patients were stratified into two groups according to positive or negative PWC. Recurrence-free survival and overall survival were compared between the two groups. Independent factors associated with positive PWC were investigated using multivariate analysis. RESULTS: Among the 284 patients analyzed, all 53 patients with ampullary carcinoma showed negative PWC and these patients were excluded. Among the remaining eligible 231 patients, 41 patients had intrahepatic cholangiocarcinoma, 55 had gall bladder carcinoma, 72 had hilar cholangiocarcinoma, and 63 had distal cholangiocarcinoma. Eleven (4.8%) patients had positive PWC, and 220 (95.2%) had negative PWC. The median recurrence-free survival in the positive and negative PWC groups were 12.0 vs. 60.7 months (p = 0.005); the median overall survival times were 17.0 vs. 60.6 months (p = 0.008), respectively. Multivariate analysis revealed that serum carbohydrate antigen 19-9 level over 80 U/mL and multiple lymph node metastasis were independently associated with positive PWC (odds ratio [OR]: 5.84, p = 0.031; OR: 5.28, p = 0.021, respectively). CONCLUSION: Patients with positive PWC exhibited earlier recurrence and shorter survival times compared with those with negative PWC.

Clinical and safety outcomes of simultaneous bilateral total knee arthroplasty for Japanese octogenarian patients: a retrospective analysis.

PURPOSE: The demand for simultaneous bilateral total knee arthroplasty (SiBTKA) in older adults is expected to increase with an aging population, thus necessitating evaluating its efficacy and safety. However, there is limited information regarding the clinical outcomes of SiBTKA in older adults, particularly in octogenarians. We aimed to assess the clinical outcomes and safety of SiBTKA in Japanese patients aged ≥ 80 years. METHODS: Of the 176 consecutive knees that underwent SiBTKA between July 2016 and January 2022 at our hospital, 172 were selected. They were divided into two groups according to the patient age as follows: the octogenarian group (≥ 80 years, 74 knees) and the younger control group (< 80 years, 98 knees). In addition, we assessed their preoperative clinical information, clinical outcomes using the Knee Society Score for knee (KSS-K) and function (KSS-F), and the incidence of early (≤ 90 days) and late (> 90 days) postoperative complications. RESULTS: The mean follow-up period was 3.5 years. The KSS-K scores of both groups improved postoperatively than that preoperatively. Both preoperative and postoperative KSS-F scores were lower in the octogenarians; however, their improvement rates were similar to those of the younger controls. We observed no significant intergroup differences in early or late postoperative complications, including infection, systemic complications, periprosthetic fractures, aseptic loosening, and mortality. CONCLUSION: SiBTKA for octogenarians had clinical outcomes and postoperative complication incidence similar to that for younger controls. Therefore, SiBTKA may be a safe and effective treatment option for octogenarians with painful bilateral knee deformities.

Recent progress in the reprogramming of nonribosomal peptide synthetases.

Nonribosomal peptide synthetases (NRPSs) biosynthesize nonribosomal peptide (NRP) natural products, which belong to the most promising resources for drug discovery and development because of their wide range of therapeutic applications. The results of genetic, biochemical, and bioinformatics analyses have enhanced our understanding of the mechanisms of the NRPS machinery. A major goal in NRP biosynthesis is to reprogram the NRPS machinery to enable the biosynthetic production of designed peptides. Reprogramming strategies for the NRPS machinery have progressed considerably in recent years, thereby increasing the yields and generating modified peptides. Here, the recent progress in NRPS reprogramming and its application in peptide synthesis are described.

A case of congenital biliary dilatation without pancreaticobiliary maljunction, so-called Type Ib according to Todani's classification.

Congenital biliary dilatation (CBD) is a congenital malformation of focal dilatation of the extrahepatic bile ducts, including the common bile duct, and is often associated with pancreaticobiliary maljunction (PBM). In this article, we report a CBD case that presented with focal dilation of the common bile duct without PBM (Todani's classification type Ib). The patient was a 32-year-old man who visited a doctor with a chief complaint of abdominal distension. Computed tomography revealed cystic dilatation of the common bile duct, and the patient was referred to our institution. Magnetic resonance cholangiopancreatography showed cystic dilatation of the common bile duct with a maximum diameter of 7 cm; however, evaluating the presence of PBM was challenging. Endoscopic ultrasonography showed small gallstones and debris in the dilated common bile duct and no thickening of the gallbladder wall. Endoscopic retrograde cholangiopancreatography revealed no PBM or markedly elevated bile amylase levels. Based on these findings, the patient was diagnosed with Todani Type Ib CBD. Since this patient did not have pancreatobiliary reflux, it was unclear whether the risk of developing biliary tract cancer was high, and since the treatment was highly invasive, the decision was to follow up without surgical treatment.

The Significance of Histopathological Findings on Clinical Outcomes in Endoscopic Papillectomy with Endocut.

This study aimed to evaluate primary clinical outcomes in patients who underwent endoscopic papillectomy (EP) using the Endocut mode while examining the pathological characteristics of the margin of the resected specimen. To this end, 70 patients who underwent Endocut EP were included. Resection margins were classified according to pathological findings as "negative", "positive", or "uncertain (difficult pathological evaluation)". The effect of pathological resection margins on residual tumor recurrence rates was evaluated. The median follow-up was 47 months (range, 22-84). Eleven patients (15.7%) were diagnosed with residual tumors, ten of whom were diagnosed within 6 months after EP. The resection margins were pathologically negative in 27 patients, positive in 15, and uncertain in 28; residual tumors occurred in 5 patients (33.3%) in the positive group, 5 (17.9%) in the uncertain group, and 1 (3.7%) in the negative group. The patient in the negative group had familial adenomatous polyposis (FAP). Female sex, FAP, and uncertain or positive resection margins were significantly more common in residual patients (p = 0.009, 0.044, and 0.041, respectively). Pathological resection margins can be used to infer the residual tumor incidence, leading to early post-treatment of residual tumors.

Difficulty of adjuvant chemotherapy administration in patients with biliary tract cancer.

PURPOSE: This study aimed to elucidate the difficulty of adjuvant chemotherapy administration in patients with biliary tract carcinoma (BTC). METHODS: Clinical data of patients with BTC who underwent curative-intent surgery were retrospectively analyzed. The eligible patients were stratified into two groups according to the presence or absence of adjuvant chemotherapy administration (adjuvant and non-adjuvant groups), and the clinicopathological features were compared between the two groups. The ratios of adjuvant chemotherapy administration were investigated in each surgical procedure. Independent factors associated with no administration of adjuvant chemotherapy were analyzed using multivariate analyses. RESULTS: Among 168 eligible patients, 141 (83.9%) received adjuvant chemotherapy (adjuvant group), while 27 (16.1%) did not (non-adjuvant group). The most common surgical procedure was pancreaticoduodenectomy in the adjuvant group, and it was hepatectomy with extrahepatic bile duct resection (BDR) in the non-adjuvant group, respectively. The rate of no adjuvant chemotherapy was significantly higher in patients who underwent hepatectomy with BDR than in those who underwent other surgeries (p < 0.001). The most common cause of no adjuvant chemotherapy was bile leak in 12 patients, which occurred after hepatectomy with BDR in ten patients. Multivariate analyses revealed that hepatectomy with BDR and preoperative anemia were independently associated with no adjuvant chemotherapy (p < 0.001 and p < 0.001, respectively). CONCLUSIONS: Hepatectomy with BDR and subsequent refractory bile leak can be the obstacle to adjuvant chemotherapy administration in patients with BTC.

Utility of Covered Self-Expanding Metal Stents for Biliary Drainage during Neoadjuvant Chemotherapy in Patients with Borderline Resectable Pancreatic Cancer.

OBJECTIVES: We aimed to compare the utility of covered self-expanding metal stents (CSEMSs) with that of plastic stents (PSs) for biliary drainage during neoadjuvant chemotherapy in patients with borderline resectable pancreatic cancer. METHODS: Forty patients with borderline resectable pancreatic cancer underwent biliary stenting during neoadjuvant chemotherapy at Hiroshima University Hospital. PSs and CSEMSs were placed in 19 and 21 patients, respectively. Two gemcitabine-based regimens for chemotherapy were used. Treatment outcomes and postoperative complications were compared between both groups. RESULTS: The incidence of recurrent biliary obstruction was significantly lower in the CSEMS group (0% vs. 47.4%, p < 0.001), and the median time to recurrent biliary obstruction in the PS group was 47 days. There was no difference in the incidence of other complications such as non-occlusive cholangitis, pancreatitis, and cholecystitis between the two groups. Delays in the chemotherapy schedule due to stent-related complications were significantly frequent in the PS group (52.6% vs. 4.8%, p = 0.001). There was no significant difference in the incidence of postoperative complications between the two groups. CONCLUSIONS: CSEMSs may be the best choice for safely performing neoadjuvant chemotherapy for several months in patients with borderline resectable pancreatic cancer with bile duct stricture.

Impact of lower muscle stiffness on ankle dorsiflexion restriction in children with cerebral palsy evaluated using ultrasound elastography.

BACKGROUND: Plantar flexor muscles always contribute to limiting the range of motion of ankle dorsiflexion in children with spastic cerebral palsy, but the individual contributions of these muscles are not well defined. This study aimed to identify which muscles' stiffness impacts the dorsiflexion range of motion in children with cerebral palsy. METHODS: Twenty-five children with cerebral palsy were included. The maximum passive dorsiflexion range of motion was measured in two positions: hip and knee joints in flexion, and both joints in full extension. Strain ratios indicating muscle stiffness were measured using strain elastography of the lateral and medial gastrocnemius, soleus, flexor hallucis longus, peroneus longus, peroneus brevis, and tibialis posterior muscles. To analyze which muscles impact the limitation of the dorsiflexion range, multiple regression analyses were conducted. The values of muscle stiffness were included as independent valuables, and the values of the dorsiflexion range were included as dependent valuables. A p-value <0.05 was considered statistically significant. FINDINGS: In the analyses, the soleus and flexor hallucis longus muscle stiffness were significant independent factors for the dorsiflexion range of motion of hip and knee flexion (adjusted R2: 0.50). The lateral gastrocnemius muscle stiffness was a significant independent factor for the dorsiflexion range of motion with both joints in full extension (adjusted R2: 0.61). INTERPRETATION: Flexor hallucis longus muscle stiffness, in addition to triceps surae muscle stiffness, was shown to impact dorsiflexion range; attention should be paid to muscle stiffness in children with cerebral palsy.

Relapse rate and predictors of relapse after cessation of glucocorticoid maintenance therapy in type 1 autoimmune pancreatitis: a multicenter retrospective study.

BACKGROUND: Type 1 autoimmune pancreatitis responds well to glucocorticoid therapy with a high remission rate. Moreover, glucocorticoid maintenance therapy can help prevent relapse. However, the relapse rate following cessation of long-term glucocorticoid therapy is unknown. The aim of this study was to clarify the relapse rate and predictors of relapse following long-term glucocorticoid therapy cessation. METHODS: We analyzed 94 patients who achieved remission after undergoing glucocorticoid therapy, discontinued treatment after at least 6 months of maintenance therapy, and were subsequently followed up for at least 6 months. The patients were divided into three groups based on treatment duration (< 18, 18-36, and ≥ 36 months), and their relapse rates were compared. Univariate and multivariate analyses of clinical factors were conducted to identify relapse predictors. RESULTS: After discontinuing glucocorticoid therapy, relapse was observed in 43 (45.7%) patients, with cumulative relapse rates of 28.2% at 1 year, 42.1% at 3 years, 47.0% at 5 years, and a plateau of 77.6% at 9 years. Of the 43 patients who relapsed, 25 (58.1%) relapsed within 1 year after after cessation of glucocorticoid therapy. Relapse and cumulative relapse rates did not differ significantly according to treatment duration. In the multivariate analysis, an elevated serum IgG4 level at the time of glucocorticoid cessation was found to be an independent predictor of relapse (hazard ratio, 4.511; p < 0.001). CONCLUSIONS: A high relapse rate occurred after cessation of glucocorticoid maintenance therapy, regardless of the duration of maintenance therapy, especially within the first year after cessation. However, the normalization of long-term serum IgG4 levels may be a factor in considering cessation.

Diagnostic Ability and Safety of Repeated Pancreatic Juice Cytology Using an Endoscopic Nasopancreatic Drainage Catheter for Pancreatic Ductal Adenocarcinoma: A Multicenter Prospective Study.

Pathological examination is essential for the diagnosis and treatment of pancreatic ductal adenocarcinoma (PDAC). Moreover, a reliable pathological diagnosis is extremely important for improving prognosis, especially in early-stage PDAC. This study prospectively evaluated the usefulness of repeated pancreatic juice cytology (PJC) using an endoscopic nasopancreatic drainage (ENPD) catheter for the diagnosis of PDAC. We enrolled 82 patients suspected of having resectable PDAC, based on imaging studies, and judged the necessity for cytology. The diagnostic yield of up to six repeated PJCs and the incidence of complications, such as pancreatitis, was evaluated. A total of 60 patients were diagnosed with PDAC. The overall sensitivity and specificity were 46.7% and 95.5%, respectively. The cumulative positivity rate increased with the number of sampling sessions, reaching 58.3% in the sixth session. The sensitivity was significantly higher in the pancreatic head than in the pancreatic tail (p = 0.043). Additionally, it was 100% in four patients with a tumor size ≤10 mm. Pancreatitis occurred in six patients (7.3%), all of whom were treated conservatively. In the diagnosis of PDAC, repeated PJC using an ENPD catheter revealed a cumulative effect of sensitivity up to six times and an excellent diagnostic yield for small PDAC.

Design, Synthesis and Structure-Activity Relationship Studies of Protein Kinase CK2 Inhibitors Containing a Purine Scaffold.

Protein kinase CK2 (CK2) is involved in the suppression of gene expression, protein synthesis, cell proliferation, and apoptosis, thus making it a target protein for the development of therapeutics toward cancer, nephritis, and coronavirus disease 2019. Using the solvent dipole ordering-based method for virtual screening, we identified and designed new candidate CK2α inhibitors containing purine scaffolds. Virtual docking experiments supported by experimental structure-activity relationship studies identified the importance of the 4-carboxyphenyl group at the 2-position, a carboxamide group at the 6-position, and an electron-rich phenyl group at the 9-position of the purine scaffold. Docking studies based on the crystal structures of CK2α and inhibitor (PDBID: 5B0X) successfully predicted the binding mode of 4-(6-carbamoyl-8-oxo-9-phenyl-8,9-dihydro-7H-purin-2-yl) benzoic acid (11), and the results were used to design stronger small molecule targets for CK2α inhibition. Interaction energy analysis suggested that 11 bound around the hinge region without the water molecule (W1) near Trp176 and Glu81 that is frequently reported in crystal structures of CK2α inhibitor complexes. X-ray crystallographic data for 11 bound to CK2α was in very good agreement with the docking experiments, and consistent with activity. From the structure-activity relationship (SAR) studies presented here, 4-(6-Carbamoyl-9-(4-(dimethylamino)phenyl)-8-oxo-8,9-dihydro-7H-purin-2-yl) benzoic acid (12) was identified as an improved active purine-based CK2α inhibitor with an IC50 of 4.3 µM. These active compounds with an unusual binding mode are expected to inspire new CK2α inhibitors and the development of therapeutics targeting CK2 inhibition.

Preoperative incidence and risk factors of deep vein thrombosis in Japanese patients undergoing total hip arthroplasty.

PURPOSE: Preoperative deep vein thrombosis (DVT) is a risk factor for postoperative venous thromboembolism (VTE), causing severe mortality. Early detection of preoperative DVT is essential to prevent postoperative VTE. However, little is known regarding preoperative DVT in patients undergoing major surgery. The present study aimed to determine the incidence and risk factors of preoperative DVT in patients admitted for total hip arthroplasty (THA). METHODS: From August 2017 to September 2022, 243 patients admitted for THA at our institution were enrolled in this study. Patients medical records and preoperative laboratory data were retrospectively collected. According to the results of lower-limb ultrasonography, patients were divided into either the non-DVT (n = 136) or DVT (n = 43) group. The incidence of DVT and independent risk factors for preoperative DVT were investigated using univariate and multivariate logistic regression analyses. RESULTS: The mean age was 74.0 ± 8.4 years. Preoperative DVT was diagnosed in 43 of the 243 (17.7%) patients. The risk of DVT was significantly high (p < 0.05) in patients with advanced age, increased D-dimer levels, and malnutrition status, as assessed by the Geriatric Nutritional Risk Index (GNRI). Multivariate analysis showed that advanced age, increased D-dimer level, and malnutrition status assessed by the GNRI were independent risk factors for preoperative DVT. CONCLUSION: A high incidence of preoperative DVT was observed in patients undergoing THA. Advanced age, increased D-dimer levels, and malnutrition assessed by the GNRI increased the risk of preoperative DVT. Screening high-risk subgroups for preoperative DVT is necessary to prevent postoperative VTE.