Characterizations of a neutralizing antibody broadly reactive to multiple gluten peptide:HLA-DQ2.5 complexes in the context of celiac disease.

In human celiac disease (CeD) HLA-DQ2.5 presents gluten peptides to antigen-specific CD4+ T cells, thereby instigating immune activation and enteropathy. Targeting HLA-DQ2.5 with neutralizing antibody for treating CeD may be plausible, yet using pan-HLA-DQ antibody risks affecting systemic immunity, while targeting selected gluten peptide:HLA-DQ2.5 complex (pHLA-DQ2.5) may be insufficient. Here we generate a TCR-like, neutralizing antibody (DONQ52) that broadly recognizes more than twenty-five distinct gluten pHLA-DQ2.5 through rabbit immunization with multi-epitope gluten pHLA-DQ2.5 and multidimensional optimization. Structural analyses show that the proline-rich and glutamine-rich motif of gluten epitopes critical for pathogenesis is flexibly recognized by multiple tyrosine residues present in the antibody paratope, implicating the mechanisms for the broad reactivity. In HLA-DQ2.5 transgenic mice, DONQ52 demonstrates favorable pharmacokinetics with high subcutaneous bioavailability, and blocks immunity to gluten while not affecting systemic immunity. Our results thus provide a rationale for clinical testing of DONQ52 in CeD.

Steroid therapy has an acceptable role as the initial treatment in autoimmune pancreatitis patients with pancreatic cyst formation: Based on a Japanese nationwide study.

BACKGROUND: We attempted to determine the indications and limitations of steroid therapy as the first-line therapy in patients with autoimmune pancreatitis (AIP) with cyst formation (ACF). METHODS: This Japanese multicenter survey was conducted to examine the merits/demerits of steroid treatment as the initial therapy for ACF. RESULTS: Data of a total of 115 patients with ACF were analyzed. Complete remission was achieved in 86% (86/100) of patients who had received steroid treatment, but only 33.3% (5/15) of patients who had not received steroids. Relapse after the remission (n = 86) occurred in 7.6% (6/86) of patients who had received steroid therapy, but 40% (2/5) of patients who had not received steroid therapy. Multivariate analysis identified adoption of the wait and watch approach without steroid treatment (odds ratio = 0.126, P < .001) as a significant and independent negative predictor of remission of ACF. As for predictors of relapse, the presence of varix (odds ratio = 5.83, P = .036) was identified as an independent risk factor. CONCLUSION: Steroid therapy plays an important role as first-line therapy in AIP patients with pancreatic cyst formation, however, varix formation, besides the diameter of the cyst(s), is a risk factor for refractoriness to steroid therapy.

[Leptomeningeal carcinomatosis from duodenal papillary carcinoma].

A woman in her 50s presented with ataxia and repeated falls during 2nd line S-1 therapy for duodenal papillary carcinoma with metastasis. She was diagnosed with leptomeningeal carcinomatosis based on gadolinium contrast-enhanced magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) examination, although plain computed tomography (CT) and MRI of the head showed no intracranial occupying lesions. This is a rare leptomeningeal carcinomatosis case with duodenal papillary carcinoma as the primary lesion, although aggressive treatment was not possible due to the decreased consciousness level.

Usefulness of Global Longitudinal Strain-Guided Management in Preventing Human Epidermal Growth Factor Receptor 2 (HER2) Inhibitor-Induced Myocardial Damage.

Background: Trastuzumab, an anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody, is a specific first-line treatment for patients with HER2-positive cancers. Cardiac dysfunction is among the most problematic adverse events associated with trastuzumab. Although regular echocardiographic screening is recommended for early detection of cardiac damage, few reports have investigated the validity of echocardiographic screening in chemotherapy. Therefore, the aim of this study was to determine whether a GLS-guided management approach could reduce cardiotoxicity and discontinuation of trastuzumab chemotherapy. Methods and Results: To evaluate the usefulness of global longitudinal strain (GLS)-guided cardioprotective interventions, we retrospectively analyzed 67 patients treated with trastuzumab who underwent structured echocardiographic assessments before and after 1, 3, and 6 courses of trastuzumab administration. If a >15% relative decrease in GLS was identified, cardioprotective agents were administered. Thirty (44.8%) patients had breast cancer; the remaining patients had salivary gland cancer. The median observation period for the intervention group was 304 days from the initial evaluation. Nineteen (28.4%) patients exhibited a >15% relative decrease in GLS, and consequently received cardioprotective agents. The incidence of trastuzumab discontinuation for cardiogenic reasons was significantly lower among patients receiving GLS-guided interventions than among those not receiving the intervention (2.4% vs. 24.0%; P=0.009). The incidence of a subsequent decline in left ventricular ejection fraction was lower among patients receiving the intervention than among those not receiving the intervention (4.8% vs. 24.0%; P=0.04). Conclusions: GLS-guided cardioprotective intervention significantly decreased the incidence of trastuzumab discontinuation.

The role of EUS elastography-guided fine needle biopsy in the histological diagnosis of solid pancreatic lesions: a prospective exploratory study.

This study aimed to evaluate the feasibility and efficacy of Endoscopic ultrasound elastography-guided fine needle biopsy (EUS-EG-FNB) for the diagnosis of pancreatic mass lesions. EUS-EG images were classified into heterogeneous and homogeneous groups. For the heterogeneous group, EUS-FNB was separately performed in both hard areas and soft areas. Only samples obtained during the first two passes (hard/soft areas) were used to compare the diagnostic accuracy as well as the quality and quantity of the specimens. We investigated the association of EUS-EG findings using strain histogram analysis with the histological findings. Fifty-five patients were enrolled including 25 patients with heterogeneous group. The homogeneous group had significantly lower mean strain value (hard) lesions. The adequate sampling rates from hard and soft areas were 88 and 92%, respectively (P = 0.6374). Comparison of the diagnostic accuracy and the quality and quantity of the histological core between hard and soft areas showed no significant differences. In pancreatic adenocarcinoma cases, the proportion of fibrous stroma in the core tissue was significantly correlated with the elasticity of the region. (R2 = 0.1226: P = 0.0022) EUS-EG may reflect tissue composition in pancreatic tumors, however, EUS-EG did not affect either the quality and quantity of the tissues obtained.Clinical Trial Registry No: UMIN-000033073.

Endoscopic ultrasound-guided fine-needle biopsy for the diagnosis of gastric metastasis from breast cancer mimicking primary linitis plastica: A case report.

For gastric lesions in a patient with a history of breast cancer, it is essential to distinguish between primary gastric cancer and gastric metastasis from breast cancer. However, gastric metastasis from breast cancer often mimics primary linitis plastica, and histological diagnosis may be difficult with conventional endoscopic biopsies. Herein, we describe the case of a 75-year-old woman who presented at our hospital with epigastralgia and vomiting. She had a history of mastectomy for carcinoma of the right breast and had received hormone therapy as adjuvant therapy. Computed tomography at arrival showed thickening of the gastric wall at the antrum and peritoneal dissemination. Esophagogastroduodenoscopy showed mucosal swelling of the antrum and stenosis of the pylorus, and histological diagnosis failed with conventional endoscopic biopsies. Endoscopic ultrasound-guided fine-needle biopsy using a Franseen needle was performed, and a diagnosis of gastric metastasis from breast cancer was made. She received hormone therapy and chemotherapy after deployment of a metallic stent for gastric outlet obstruction. To the best of our knowledge, this is the first case of gastric metastasis from breast cancer diagnosed using endoscopic ultrasound-guided fine-needle biopsy.

Routine assessment of cardiotoxicity in patients undergoing long-term immune checkpoint inhibitor therapy.

The indications for immune checkpoint inhibitors (ICIs) are expanding in cancer drug therapy, and while cardiac events associated with ICIs are often fatal, there are few reports regarding cardiac complications associated with long-term ICI therapy. We aimed to study cardiac complications in patients undergoing long-term ICI therapy. From the database of our local cardio-oncology unit, we enrolled patients with cancer undergoing ICI therapy for more than 6 months and for whom cardiologists continuously performed routine follow-ups. We defined the primary endpoint as discontinuation of ICI due to cardiac events. We also analyzed changes in cardiac biomarkers and echocardiographic parameters. We retrospectively analyzed 55 consecutive patients (43 males, mean age: 65 ± 11 years) treated with ICI therapy in our hospital between January 2017 and June 2021. None of the patients discontinued ICI therapy due to cardiac events more than 6 months after treatment was initiated. Among the participants, we observed four patients with elevated serum troponin I levels, seven patients with decreased global longitudinal strain values, and two patients with elevated plasma brain natriuretic peptide levels. No patient required drug intervention for these cardiac events; furthermore, there were no cases of clinically diagnosed myocarditis. In the present study, there were no cardiac events causing ICI discontinuation in patients undergo ICI therapy for more than 6 months.

Factors associated with misdiagnosis of preoperative endoscopic ultrasound in patients with pancreatic cystic neoplasms undergoing surgical resection.

PURPOSE: Pancreatic cystic lesions (PCLs) include various types of cysts. Accurate preoperative diagnosis is essential to avoid unnecessary surgery on benign cysts. In this study, we aimed to identify the factors associated with misdiagnosis in preoperative endoscopic ultrasound (EUS) imaging and clinicopathological findings for PCLs. METHODS: This study included 302 surgically resected patients with PCLs who underwent preoperative EUS. The preoperative EUS findings were re-evaluated and compared with the pathological diagnosis. Additionally, the factors associated with misdiagnosis of PCLs were investigated by multivariate analysis. RESULTS: The preoperative diagnoses of PCLs were intraductal papillary mucinous neoplasm (IPMN) in 213 patients (70.5%), mucinous cystic neoplasm (MCN) in 33 patients (10.9%), serous neoplasm (SN) in 7 patients (2.3%), cystic degeneration cyst of solid tumor in 46 patients (15.2%), and pancreatic cancer with cystic degeneration in three patients (1.0%). A discrepancy between preoperative and postoperative diagnosis was found in 47 patients (15.6%). Based on the pathological diagnosis, the sensitivity of preoperative EUS imaging was IPMN 97.6% (206/211), MCN 90.0% (18/19), cystic degeneration 87.1% (27/31), and SN 15.4% (2/13). Multivariate analysis revealed that main pancreatic duct (MPD) communication ( - ) (odds ratio (OR), 4.54; 95% confidence interval (CI) 1.29-15.9), honeycomb-like structure ( +) (OR, 14.7; 95% CI 2.61-83.3), and MPD size â‰¦ 2 mm (OR, 16.3; 95% CI 3.93-67.6) were independently associated with misdiagnosis. CONCLUSION: For cases in which MCN and cystic degeneration of solid tumor are presumed based on preoperative EUS imaging and cases with PCLs with a honeycomb-like structure, diagnosis with multimodalities or fluid analysis with EUS-guided fine-needle aspiration should be considered.

Evaluation of ulcerative colitis activity using transabdominal ultrasound shear wave elastography.

BACKGROUND: Transabdominal ultrasound (US) has been reported to be effective in the evaluation of ulcerative colitis (UC). US can measure shear wave elastography (SWE) and shear wave dispersion (SWD), which may be correlated with inflammation and necrosis. We aimed to investigate the relationship between UC activity and SWE and SWD. METHODS: Patients with UC who underwent US within 2 days before or after a colonoscopy between April 2019 and March 2020 were included. SWE and SWD were measured in the sigmoid colon; the correlations of SWE and SWD with the Lichtiger index and the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) were investigated. We also compared SWE and SWD between patients with mucosal healing and those in the active phase according to the UCEIS. RESULTS: Twenty-six UC patients were enrolled. The median Lichtiger index, UCEIS, SWE values, and SWD values were 8 [interquartile range (IQR), 5.3-10.8], 4 (IQR, 3.3-5), 1.69 (IQR, 1.49-2.16) m/s, and 11.9 (IQR, 10.9-13.3) (m/s)/kHz, respectively. The Lichtiger index and UCEIS were negatively correlated with the SWE values (rs=-0.404 and rs=-0.506) but not with the SWD values (rs=0.004 and rs=0.002). The SWE values differed significantly between the mucosal healing and active phase groups [2.40 (IQR, 2.18-3.38) vs. 1.62 (IQR, 1.44-1.95) m/s, P=0.007], whereas the SWD values did not [13.1 (IQR, 7.05-21.6) vs. 11.9 (IQR, 11.1-13.2) (m/s)/kHz, P=0.918]. CONCLUSIONS: SWE may be useful for the evaluation of UC activity and could be a noninvasive method of assessing disease severity.

Usefulness of Macroscopic On-Site Evaluation Using a Stereomicroscope during EUS-FNB for Diagnosing Solid Pancreatic Lesions.

METHODS: We reviewed a total of 60 consecutive patients who underwent both S-MOSE and rapid on-site cytopathological evaluation (ROSE) during EUS-FNB between July 2019 and October 2020, and the usefulness of S-MOSE in comparison with histology was evaluated. A 22-gauge Franseen needle was used to perform EUS-FNB in all patients, and only the specimens obtained by the first pass were evaluated. The final diagnosis was based on the surgical specimen or the clinical course consistent with the EUS-FNB results. RESULTS: The final diagnoses of the 60 patients included 45 patients with pancreatic ductal adenocarcinoma, 6 with autoimmune pancreatitis, 4 with mass-forming pancreatitis, 1 with pancreatic metastasis, 2 with pancreatic neuroendocrine tumor, and 2 with intraductal papillary mucinous carcinoma. The histological diagnostic accuracy of the first pass of EUS-FNB was 83.3% (50/60). The agreement between the S-MOSE and the histological diagnosis was 90% (54/60). The positive predictive value of S-MOSE for histological diagnosis was 90.7%, which can be an indicator of when to stop the EUS-FNB procedure. There were no immediate or delayed adverse events reported after the FNB based on the chart and medical visit history review. CONCLUSION: In the EUS-FNB of SPLs, S-MOSE can be an alternative to ROSE for specimen evaluation and has the potential to shorten the procedure time.

Longitudinal Strain and Troponin I Elevation in Patients Undergoing Immune Checkpoint Inhibitor Therapy.

Background: Immune checkpoint inhibitors (ICIs) are a central part of cancer therapy; however, cardiac complications, such as myocarditis, have the potential for significant morbidity and mortality. Within this population, the clinical significance of longitudinal strain (LS) remains unknown. Objectives: This study sought to define the changes in LS in ICI-treated patients, and their associations with high-sensitivity troponin I (hsTnI) and myocarditis. Methods: We conducted a retrospective cohort study of patients who received ICIs at our hospital from April 2017 to September 2021. All patients underwent echocardiography and blood sampling at standardized time intervals. We measured the changes in global and regional LS before and after ICI administration. Age- and sex-adjusted Cox regression analysis was used to evaluate the association between LS and elevations in hsTnI and myocarditis. Results: In a cohort of 129 patients with a median follow-up period of 170 (IQR: 62-365) days; 6 and 18 patients had myocarditis and hsTnI elevation, respectively. In an age- and sex-adjusted Cox proportional hazards model, an early relative worsening of ≥10% in the basal and mid LS and ≥15% in global LS was associated with hsTnI elevation. Relative reductions in LS were not significantly associated with myocarditis; however, 4 of the 6 patients with myocarditis had relative reduction of ≥10% in the basal LS. Conclusions: An early worsening in the global and regional LS was associated with increased hsTnI in patients receiving ICIs. Assessment of LS early after ICI administration should be further studied as a strategy for risk stratification of ICI-treated patients.

Double common bile duct associated with pancreaticobiliary maljunction.

A 45-year-old female was admitted to the hospital with a diagnosis of acute pancreatitis. A computed tomography scan showed two extrahepatic bile ducts. Magnetic resonance cholangiopancreatography suggested a stone in one of the bile ducts. Endoscopic retrograde cholangiopancreatography revealed two extrahepatic bile ducts joining at the hilum of the liver accompanied with pancreaticobiliary maljunction. Sphincterotomy was performed and a protein plug was drained from the bile duct. Several treatment options were discussed, and the patient was treated with laparoscopic cholecystectomy without extrahepatic bile duct resection and planned to be followed up considering the risk of carcinogenesis in the bile ducts.

Utility of multiphase contrast enhancement patterns on CEH-EUS for the differential diagnosis of IPMN-derived and conventional pancreatic cancer.

BACKGROUND: Intraductal papillary mucinous neoplasm (IPMN) is reported as a high-risk factor for pancreatic cancer (PC) that includes IPMN-derived cancers (IPMC) and the development of invasive pancreatic ductal adenocarcinoma (PDAC) concomitant with IPMN. Since invasive IPMC and PDAC exhibit different oncological behaviors, their differentiation is clinically important. We aimed to investigate the use of contrast-enhanced harmonic endoscopic ultrasound (CEH-EUS) for the differential diagnosis between invasive IPMC and PDAC. METHODS: This study involved 183 consecutive patients with PC (invasive IPMC: 42, PDAC concomitant with IPMN: 9, without IPMN: 132) who underwent CEH-EUS preoperatively. While investigating the patterns, enhanced effects in the solid part of the tumor were compared with those in the surrounding pancreatic parenchyma after administration of Sonazoid® and evaluated as hyperenhanced, isoenhanced, or hypoenhanced. We retrospectively compared the enhanced pattern of CEH-EUS by using multiphasic analysis and clinicopathological factors between invasive IPMC and PDAC. RESULTS: In multiphase evaluations at 20, 40 and 60 s in CEH-EUS, 75.2% (106/141) of PDACs were hypoenhanced (-) at ≥2 of the 3 time points, with significant differences from those of invasive IPMC (P < 0.001). The solid tumor diameter was significantly larger in PDAC than in invasive IPMC, and the tumor stage and preoperative serum carbohydrate antigen 19-9 level were higher. After propensity score matching of stage and solid tumor diameter, contrast enhancement patterns were significantly more persistent in invasive IPMC than in PDAC (P = 0.0013). CONCLUSIONS: Multiphase evaluation using CEH-EUS is a useful method for differentiating between invasive IPMC and PDAC.

Diagnostic performance of endoscopic ultrasonography-guided elastography for solid pancreatic lesions: Shear-wave measurements versus strain elastography with histogram analysis.

BACKGROUND AND AIMS: Endoscopic ultrasound (EUS) elastography (EUS-EG) is a minimally invasive diagnostic method for evaluating tissue elasticity. The aim of this study was to evaluate the feasibility of newly developed EUS shear-wave measurement (EUS-SWM) and to compare diagnostic performance between EUS-SWM and the conventional strain elastography (SE) for the measurement of elasticity of solid pancreatic lesions (SPLs). METHODS: From December 2017 until August 2019, we retrospectively reviewed 64 consecutive cases with SPLs who underwent both EUS-SWM and SE. EUS-SWM was used to measure the shear-wave velocity, Vs (m/s), and the unique measurement reliability index, VsN (%), in the target lesion. SE images were assessed by strain histogram (SH) analysis, and the mean strain value of the elasticity index was measured. We evaluated the diagnostic performance of EUS-SWM and SE with SH to characterize the SPLs. RESULTS: The Vs (m/s) values of SPLs were 2.19 for pancreatic cancer (PC), 1.31 for pancreatic neuroendocrine neoplasm (PanNEN), 2.56 for mass-forming pancreatitis (MFP) and 1.58 for metastatic tumors. Vs showed no significant difference based on the disease. The mean strain values were 45.5 for PC, 47.3 for PanNEN, and 74.5 for MFP. In the comparison of tissue elasticity between PC and MFP, Vs showed no significant difference (P = 0.5687); however, the mean strain value was significantly lower in PC cases (45.4 vs 74.5: P = 0.0007). CONCLUSION: Endoscopic ultrasound SWM tended to be unstable for the measurement of elasticity of SPLs, and conventional SE with SH was superior for their characterization.

Lophachinins A-E, abietane diterpenes from a Mongolian traditional herbal medicine Lophanthus chinensis.

Five new abietane diterpenes, lophachinins A-E (1-5), and eleven known related diterpenes were isolated from a Mongolian traditional herbal medicine, the aerial parts of Lophanthus chinensis (Lamiaceae). The structures of new diterpenes were assigned by spectroscopic analyses. Lophachinins A (1) and B (2) were abietane diterpene possessing an endoperoxy bridge at C-ring. In contrast, lophachinins C-E (3-5) had an abietane skeleton with an aromatized C-ring. The absolute configuration of 1 was elucidated by application of the modified Mosher's method, while those of 2, 3, and 5 were assigned by chemical conversions. The absolute configuration of lophachinin D (4) was deduced by ECD calculation. Anti-inflammatory activity of isolated diterpenes on microglial cells were evaluated.

Can contrast-enhanced harmonic endoscopic ultrasonography accurately diagnose main pancreatic duct involvement in intraductal papillary mucinous neoplasms?

BACKGROUND: Main pancreatic duct (MPD) involvement in branch duct-type intraductal papillary mucinous neoplasms (BD-IPMNs) is a high risk finding for malignant IPMNs. However, discrepancies exist in the identification of MPD involvement between imaging findings and pathological diagnosis. The purpose of this study was to evaluate the diagnostic accuracy of preoperative assessment of MPD involvement in IPMNs using contrast-enhanced harmonic endoscopic ultrasound (CH-EUS). METHODS: This study involved 166 consecutive patients with BD-IPMNs who underwent surgical resection. CH-EUS was used to evaluate the MPD involvement according to the presence of mural nodules (MN) that advanced into the MPD or involved the MPD. The CH-EUS findings were compared with the pathological findings. Additionally, we analyzed the risk factors for malignant BD-IPMNs using multivariate analysis. RESULTS: A total of 77, 51, and 38 patients were pathologically diagnosed with low-grade or intermediate-grade dysplasia, high-grade dysplasia and invasive IPMNs, respectively. MPD involvement was diagnosed using CH-EUS (MPD-inv.-EUS) in 90 (54.2%) patients with a sensitivity, specificity and accuracy of 83.5%, 87.0% and 84.9%, respectively. The malignancy rate in patients with MPD-inv.-EUS was 71.6% (63/90). Multivariate logistic regression analysis showed that MPD-inv.-EUS (OR, 3.61; 95% CI:1.45-8.98), age (OR, 5.70; 95% CI: 1.47-22.2), cyst size (OR, 2.45; 95% CI:1.04-5.78) and MN size (OR, 7.05; 95% CI:2.48-20.0) were significant for malignant BD-IPMNs. CONCLUSIONS: MPD-inv.-EUS accurately represents the pathological involvement of IPMN and may be a useful predictor of malignant BD-IPMNs.

Risks and characteristics of pancreatic cancer and pancreatic relapse in autoimmune pancreatitis patients.

BACKGROUND AND AIM: We examined the differences in the risks and characteristics of pancreatic relapse (PR) and pancreatic cancer (PC) in patients with autoimmune pancreatitis (AIP). METHODS: We retrospectively reviewed 123 type 1 AIP patients with a median follow-up of 55 months (interquartile range, 27-98). The following items were evaluated: (i) cumulative relapse rates and risk factors, (ii) the incidence of PC, (iii) PR versus PC, and (iv) outcomes after the appearance of morphological changes in the pancreas (focal enlargement, apparent mass lesions, or main pancreatic duct dilation). RESULTS: (i) The cumulative PR rates were 1.7% within 1 year, 11.5% within 3 years, and 22.6% within 5 years. Lack of maintenance therapy, IgG4-related sclerosing cholangitis, and IgG4-related kidney disease were identified as independent predictors of relapse. (ii) Two patients (1.6%) were diagnosed with PC at 17 and 22 months after initial AIP diagnosis. (iii) Thirteen (59.1%) and four (18.2%) patients with PR had focal enlargement and main pancreatic duct dilation, respectively. The median CA19-9 level at initial diagnosis was significantly higher in PC patients (21 vs 220.5 U/mL, P = 0.014). (iv) Eight PR patients underwent endoscopic ultrasound-guided fine-needle aspiration, none of whom had malignant findings. PC was diagnosed by ultrasound-guided fine-needle aspiration in both cancer patients. CONCLUSIONS: Although the incidence of PC is low, it may mimic PR in AIP patients. Surveillance is important, and when morphological changes occur, biopsy and evaluation of serum IgG4 and CA19-9 levels (particularly if the levels were high before) should be considered.

Diagnosis of vascular invasion in pancreatic ductal adenocarcinoma using endoscopic ultrasound elastography.

BACKGROUND: Vascular invasion is an important criterion for resectability and deciding the therapeutic strategy for pancreatic ductal adenocarcinoma (PDAC), but imaging diagnosis is currently difficult. Endoscopic ultrasound (EUS) elastography (EG) images have band-like artifacts on the border between tumor and vessel due to different movement if the tumor is not connected to the vessel, i.e., no invasion. Based on this phenomenon, we assessed the usefulness of EUS-EG in the diagnosis of vascular invasion in PDAC. METHODS: The subjects were 44 out of 313 patients with PDAC who underwent EUS between January 2015 and November 2018, followed by surgery, no chemotherapy or radiotherapy, and pathological evaluation. Diagnostic accuracies of vascular invasion using dynamic computed tomography (CT), EUS B-mode and EUS-EG were compared with histopathological diagnosis. RESULTS: In 44 subjects (48 sites) who underwent both dynamic CT and EUS-B mode, the sensitivity, specificity and accuracy were 0.733, 0.697 and 0.708 on dynamic CT (48 sites); 0.733, 0.606 and 0.646 in EUS B-mode (48 sites); and 0.917, 0.900 and 0.906 in EUS-EG (32 sites). In 27 subjects (29 sites) with a tumor contacting a vessel with no vascular obstruction or stenosis on dynamic CT, the sensitivity, specificity and accuracy were 0.556, 0.750 and 0.690 on dynamic CT; 0.667, 0.700 and 0.690 in EUS B-mode; and 0.889, 0.850 and 0.862 in EUS-EG. CONCLUSIONS: These results suggest that EUS combined with EG improves diagnostic performance of vascular invasion in PDAC, especially in cases of which vascular invasion cannot be clearly assessed by dynamic CT.

Dynamics of nitric oxide controlled by protein complex in bacterial system.

Nitric oxide (NO) plays diverse and significant roles in biological processes despite its cytotoxicity, raising the question of how biological systems control the action of NO to minimize its cytotoxicity in cells. As a great example of such a system, we found a possibility that NO-generating nitrite reductase (NiR) forms a complex with NO-decomposing membrane-integrated NO reductase (NOR) to efficiently capture NO immediately after its production by NiR in anaerobic nitrate respiration called denitrification. The 3.2-Å resolution structure of the complex of one NiR functional homodimer and two NOR molecules provides an idea of how these enzymes interact in cells, while the structure may not reflect the one in cells due to the membrane topology. Subsequent all-atom molecular dynamics (MD) simulations of the enzyme complex model in a membrane and structure-guided mutagenesis suggested that a few interenzyme salt bridges and coulombic interactions of NiR with the membrane could stabilize the complex of one NiR homodimer and one NOR molecule and contribute to rapid NO decomposition in cells. The MD trajectories of the NO diffusion in the NiR:NOR complex with the membrane showed that, as a plausible NO transfer mechanism, NO released from NiR rapidly migrates into the membrane, then binds to NOR. These results help us understand the mechanism of the cellular control of the action of cytotoxic NO.

High-Risk Neuroblastoma with Metastases to Bilateral Kidneys at Diagnosis.

Renal metastasis at diagnosis with neuroblastoma is rare. We present a 14-month-old boy who was diagnosed with high-risk neuroblastoma with multiple metastases, including bilateral kidneys. He received five cycles of induction chemotherapy and high-dose chemotherapy with autologous peripheral blood stem cell transplantation. All of the lesions shrank, and magnetic resonance imaging indicated that some of the metastases had disappeared. However, there were residual masses in the bilateral kidneys, and histological examination revealed the presence of tumor cells. Therefore, the patient underwent unrelated cord blood stem cell transplantation, which involved killer-ligand incompatibility in the graft-versus-host direction, in addition to human leukocyte antigen C and DRB1 mismatches. Three months later, tumor progression occurred from the residual mass in the sacral canal and a new lesion in the pancreas. Although tumor progression could not be controlled by additional chemotherapy and local radiotherapy, the metastatic nodules in bilateral kidneys did not increase in size before his death. To the best of our knowledge, this is the first report of neuroblastoma with bilateral renal metastases in the English medical literature. In addition, this case suggests that the combination of chemotherapy and immunotherapy may inhibit the progression of the renal lesions under certain conditions.