The Japanese Esophageal Society classification for prediction of superficial esophageal squamous cell neoplasia invasion depth: Validation in a Western population.

BACKGROUND: The Japan Esophageal Society proposed the JES microvessel classification to assess eligibility of early esophageal squamous cell neoplasia (ESCN) for endoscopic resection based on intrapapillary capillary loop assessment. We aimed to assess its diagnostic reproducibility and accuracy in Western ESCN patients. METHODS: Intrapapillary capillary loops on endoscopic images of Western ESCN lesions (n = 113) collected between 2010 and 2022 were assessed by nine endoscopists, including three Japanese expert endoscopists, three Western expert endoscopists, and three residents-in-training, and graded according to the JES microvessel classification where microvessel type A corresponds with normality or low-grade intraepithelial neoplasia, and microvessel types B1, B2, and B3 correspond with high-grade intraepithelial neoplasia or invasion into the lamina propria, muscularis mucosae or superficial submucosa, and deep submucosa, respectively. Outcomes included overall accuracy in predicting ESCN invasion depth and interobserver agreement. RESULTS: Good interobserver agreement was observed among expert endoscopists (Krippendorf's alpha 0.64, 95% CI 0.57-0.70), while agreement was moderate among residents-in-training (Krippendorf's alpha 0.58, 95% CI 0.52-0.72). Overall accuracy of the JES microvessel classification was 53% (95% CI 42-63), 52% (95% CI 41-62), and 44% (95% CI 34-55) for Japanese endoscopists, Western endoscopists, and residents-in-training, respectively. Sensitivity and specificity for vessel type A, B1, B2, and B3 across assessors were 0%-50% and 89%-100%, 55%-64% and 66%-77%, 42%-71% and 60%-76%, and 10%-24% and 92%-97%, respectively. Negative predictive value ranged between 80% and 85% for B3 vessels. CONCLUSION: Overall accuracy of the JES microvessel classification in Western ESCN patients is low, though absence of B3 vessels as assessed by experienced endoscopists may predict superficial ESCN amenable to endoscopic resection. TRIAL REGISTRY: www.trialregister.nl; NL8897 (6-9-2020).

Eradication of Helicobacter pylori in a Living Donor Liver Transplant Recipient With Immunosuppressive Therapy of Cyclosporine A: A Case Report.

A 54-year-old woman underwent living donor liver transplantation (LDLT) for primary biliary cholangitis (PBC) three years earlier. She took cyclosporine A (CyA) 150 mg/day as immunosuppression for prevention of rejection and PBC recurrence. Routine upper gastrointestinal endoscopy showed chronic atrophic gastritis and hyperplastic polyp, and rapid urease test was positive. Anti-Helicobacter pylori (H. pylori) serum IgG was elevated to 51 U/ml. We performed H. pylori eradication therapy with amoxicillin, clarithromycin and lansoprazole measuring the blood CyA concentration every day. Although the blood CyA concentration reached a peak (the concentration 2 hours after the administration: 818 ng/ml) on the second day, she did not develop renal dysfunction or other obvious adverse effects. Five weeks after the treatment, we confirmed eradication of H. pylori with the urea breath test. We herein reported a case of successful eradication of H. pylori in a LDLT recipient on immunosuppressive therapy with CyA without adverse effects.

Network meta-analysis of the relative efficacy of bariatric surgeries for diabetes remission.

BACKGROUND: Bariatric surgery leads to a higher remission rate for type 2 diabetes mellitus than non-surgical treatment. However, it remains unsolved which surgical procedure is the most efficacious. This network meta-analysis aimed to rank surgical procedures in terms of diabetes remission. METHODS AND FINDINGS: We electronically searched for randomized controlled trials in which at least one surgical treatment was included among multiple arms and the diabetes remission rate was included in study outcomes. A random-effects network meta-analysis was performed within a frequentist framework. The hierarchy of treatments was expressed as the surface under the cumulative ranking curve value. Results of the analysis of 25 eligible randomized controlled trials that covered non-surgical treatments and eight surgical procedures (biliopancreatic diversion [BPD], BPD with duodenal switch, Roux-en Y gastric bypass, mini gastric bypass [mini-GBP], laparoscopic adjustable gastric banding, laparoscopic sleeve gastrectomy, greater curvature plication and duodenal-jejunal bypass) showed that BPD and mini-GBP had the highest surface under the cumulative ranking curve values among the eight surgical treatments. CONCLUSION: Current network meta-analysis indicated that BPD or mini-GBP achieved higher diabetes remission rates than the other procedures. However, the result needs to be interpreted with caution considering that these procedures were in the minority of bariatric surgeries.

Functional characterization of a novel GFI1B mutation causing congenital macrothrombocytopenia.

UNLABELLED: Essentials Two groups recently reported GFI1B as a novel causative gene for congenital macrothrombocytopenia. We performed functional analysis of a novel GFI1B mutation and previous mutations. An immunofluorescence analysis of the platelet CD34 expression can be useful as a screening test. Mutant-transduced megakaryocytes produced enlarged proplatelet tips which were reduced in number. SUMMARY: Background GFI1B is an essential transcription factor for megakaryocyte and erythrocyte development. Two groups have recently identified GFI1B as a novel causative gene for congenital macrothrombocytopenia associated with α-granule deficiency. Methods We performed whole exome sequencing and identified a novel GFI1B p.G272fsX274 mutation in a family with macrothrombocytopenia, and a decreased number of platelet α-granules and abnormally shaped red blood cells. p.G272fsX274 and the previous two mutations all predicted disruption of an essential DNA-binding domain in GFI1B. We therefore performed functional studies to characterize the biochemical and biological effects of these three patient-derived mutations. Results An immunofluorescence analysis revealed decreased thrombospondin-1 and increased CD34 expression in platelets from our patient. Consistent with the previous studies, the three patient-derived mutants were unable to repress the expression of the reporter gene and had a dominant-negative effect over wild-type GFI1B. In addition, the three mutations abolished recognition of a consensus-binding site in gel shift assays. Furthermore, transduction of mouse fetal liver-derived megakaryocytes with the three GFI1B mutants resulted in the production of abnormally large proplatelet tips, which were reduced in number. Conclusions Our study provides further proof of concept that GFI1B is an essential protein for the normal development of the megakaryocyte lineage.

Dyskeratosis congenita associated with leukoplakia of the tongue.

Dyskeratosis congenita (DC) is an inherited disease characterized by the triad of skin pigmentation, nail dystrophy, and oral leukoplakia. Among other abnormalities, bone marrow failure and a predisposition to cancer are recognized as the major causes of premature mortality in patients with DC. This disease is associated with short telomeres and mutations in 10 genes associated with telomerase and telomere components. The case of a 35-year-old male patient diagnosed with DC, who presented with leukoplakia of the tongue and had a high degree of hypoplastic marrow, but no haematological abnormalities, is reported here. The diagnosis of DC was confirmed by detection of short telomeres in the blood cells and mutations in the DKC1 gene. This encounter with the case presented suggests that an awareness of the classical forms of DC is important for oral clinicians so that an early diagnosis can be made and the patient can be managed appropriately. Furthermore, genetic analysis is necessary to establish the diagnosis of DC.

A report from the 2013 international symposium: the evaluation of the effects of low-dose radiation exposure in the life span study of atomic bomb survivors and other similar studies.

The RERF International Low-Dose Symposium was held on 5-6 December 2013 at the RERF campus in Hiroshima, Japan, to discuss the issues facing the Life Span Study (LSS) and other low-dose studies. Topics included the current status of low-dose risk detection, strategies for low-dose epidemiological and statistical research, methods to improve communication between epidemiologists and biologists, and the current status of radiological studies and tools. Key points made by the participants included the necessity of pooling materials over multiple studies to gain greater insight where data from single studies are insufficient; generating models that reflect epidemiological, statistical, and biological principles simultaneously; understanding confounders and effect modifiers in the current data; and taking into consideration less studied factors such as the impact of dose rate. It is the hope of all participants that this symposium be used as a trigger for further studies, especially those using pooled data, in order to reach a greater understanding of the health effects of low-dose radiation.

Enhanced expression of the ß4-galactosyltransferase 2 gene impairs mammalian tumor growth.

Altered N-glycosylation of membrane proteins is associated with malignant transformation of cells. We found that the expression of the ß4-galactosyltransferase 2 (ß4GalT2) gene is decreased markedly during the transformation. Here, we examined whether the tumor growth activity of B16-F10 mouse melanoma cells can be reduced by the enhanced expression of the ß4GalT2 gene. We isolated a clone, B16-ß4GalT2, showing its ß4GalT2 transcript 2.5 times higher than a control clone, B16-mock, by transducing its cDNA, and transplanted them subcutaneously into C57BL/6 mice to examine their tumor growth activity. The results showed that the average size of tumors formed with B16-mock cells is 13.1±0.76 mm, whereas that of tumors formed with B16-ß4GalT2 cells is 5.1±1.13 mm (P<0.01) 2 weeks after transplantation. Immunohistochemical analyses showed that the apoptosis and the suppression of angiogenesis are induced in the tumors upon transduction of the ß4GalT2 gene. To pursue a clinical usefulness of the ß4GalT2 gene for suppressing human tumor growth, we injected adenoviruses carrying the human ß4GalT2 cDNA into HuH-7 human hepatocellular carcinomas developed in severe combined immunodeficient mice, and observed marked growth retardation of the tumors. The enhancement of the ß4GalT2 gene expression in tumors is one of the promising approaches to suppress human tumor growth.

Chylous ascites after hepatopancreatobiliary surgery.

BACKGROUND: Postoperative chylous ascites following abdominal surgery is uncommon. It potentially induces malnutrition and immunodeficiency, contributing to increased mortality. In the field of hepatopancreatobiliary (HPB) surgery, no large studies have been conducted that focused on postoperative chylous ascites. The aim of this study was to determine the incidence, risk factors and management of chylous ascites following HPB surgery, with particular emphasis on pancreatic resection. METHODS: Consecutive patients who had HPB surgery between 2000 and 2011 at a single institution were reviewed retrospectively. Chyle leak was defined as 100 ml/day or more of milky, amylase-free peritoneal fluid with a triglyceride concentration of 110 mg/dl or above. Risk factors for chylous ascites associated with pancreatic resection and the clinical efficacy of octreotide in treating chylous ascites were evaluated. RESULTS: Of 2002 consecutive patients who underwent HPB surgery during the study period, 21 (1·0 per cent) developed chylous ascites. Chylous ascites occurred relatively frequently in patients who had a pancreatic resection, such as pancreaticoduodenectomy (3·3 per cent) or distal pancreatectomy (3·8 per cent). Multivariable analysis revealed that manipulation of the para-aortic area (P < 0·001), retroperitoneal invasion (P = 0·031) and early enteral feeding after operation (P < 0·001) were independent risk factors for chylous ascites following pancreatic resection. Octreotide treatment decreased drainage output of chylous ascites on day 1 after initiation of treatment (P = 0·002). CONCLUSION: Chylous ascites is a rare complication following HPB surgery. It is more common after pancreatic resection. Treatment with octreotide combined with total parenteral nutrition is recommended.

Glycosphingolipids regulate ameloblastin expression in dental epithelial cells.

Neurotrophin 4 (NT-4) and its receptors regulate the differentiation of ameloblasts in tooth development. Gangliosides, sialic acids that contain glycosphingolipids (GSLs), are involved in a variety of membrane-associated cell physiological functions such as ligand-receptor signal transmission. However, the expression patterns and functions of GSLs during tooth development remain unclear. In this study, we identified strong expressions of GM3 and LacCer in dental epithelium, which give rise to differentiation into enamel-secreting ameloblasts. Exogenous GM3 and LacCer in dental epithelial cells induced the expression of ameloblastin (Ambn), while it was also interesting that GM3 synergistically exerted enhancement of NT-4-mediated Ambn expression. In addition, consistently exogenous GM3 and LacCer in dental epithelial cells induced distinct activation of extracellular signal-regulated kinase 1/2 (ERK1/2), an event upstream of the expression of Ambn. Furthermore, depletion of GSLs from dental epithelial cells by D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP) inhibited Ambn expression as well as phosphorylation of ERK1/2. In contrast, exogenous addition of GM3 or LacCer rescued the phosphorylation of ERK1/2 repressed by pre-treatment with D-PDMP. Taken together, these results suggest that GM3 and LacCer are essential for NT-4-mediated Ambn expression, and contribute to dental epithelial cell differentiation into ameloblasts.

Br-DIF-1 accelerates dimethyl sulphoxide-induced differentiation of P19CL6 embryonic carcinoma cells into cardiomyocytes.

BACKGROUND AND PURPOSE: Stem cell transplantation therapy is a promising option for treatment of severe ischaemic heart disease. Dimethyl sulphoxide (DMSO) differentiates P19CL6 embryonic carcinoma cells into cardiomyocyte-like cells, but with low differentiation capacity. To improve the degree of this differentiation, we have assessed several derivatives of the differentiation-inducing factor-1 (DIF-1), originally found in the cellular slime mould Dictyostelium discoideum, on P19CL6 cells. EXPERIMENTAL APPROACH: P19CL6 cells were cultured with each derivative and 1% DMSO for up to 16 days. Differentiation was assessed by measuring the number of beating and non-beating aggregates, and the expression of genes relevant to cardiac tissue. The mechanism of action was investigated using a T-type Ca(2+) channel blocker. KEY RESULTS: Of all the DIF-1 derivatives tested only Br-DIF-1 showed any effects on cardiomyocyte differentiation. In the presence of 1% DMSO, Br-DIF-1 (0.3-3 µM) significantly and dose-dependently increased the number of spontaneously beating aggregates compared with 1% DMSO alone, by day 16. Expression of mRNA for T-type calcium channels was significantly increased by Br-DIF-1 + 1% DMSO compared with 1% DMSO alone. Mibefradil (a T-type Ca(2+) channel blocker; 100 nM) and a small interfering RNA for the T-type Ca(2+) channel both significantly decreased the beating rate of aggregates induced by Br-DIF-1 + 1% DMSO. CONCLUSIONS AND IMPLICATIONS: Br-DIF-1 accelerated the differentiation, induced by 1% DMSO, of P19CL6 cells into spontaneously beating cardiomyocyte-like cells, partly by enhancing the expression of the T-type Ca(2+) channel gene.

SU-E-T-557: A Planning Strategy of Volumetric Modulated Arc Therapy with Simultaneous Integrated Boost for Intracranial Stereotactic Radiotherapy.

PURPOSE: The purpose of this planning study was to evaluate the dosimetric effect of dose escalation for intracranial stereotactic radiotherapy by volumetric modulated arc therapy (RapidArc) with simultaneous integrated boost (SIB-VMAT). METHODS: Dynamic conformal arc therapy (DCA), VMAT, and SIB-VMAT plans using Novalis Tx (Varian/BrainLAB) were performed for twenty target volumes in patients with intracranial metastases with median PTV of 16.0 cm3 (range 2.4-35.2 cm3 ). PTV was created with 2 mm expansion from GTV. All plans were generated with a prescribed dose of 35 Gy in 5 fractions to the PTV (D95 = 95%), and dose escalation up to 40 Gy (SIB-VMAT40) and 45 Gy (SIB-VMAT45) was performed only to the PTV-boost (PTV shrunk by 5 mm) for SIB-VMAT. Each plan was compared using conformity parameters. RESULTS: The average Paddick conformity index (CI) was 0.78, 0.90, 0.91, and 0.89 for DCA, VMAT, SIB-VMAT40, and SIB-VMAT45, respectively. The average healthy tissue overdosage factor (HTOF), suggested by SALT was 0.118, 0.006, 0.007, and 0.011 for DCA, VMAT, SIB-VMAT40, and SIB-VMAT45, respectively. The average V30, V20, and V10 of normal brain for VMAT and SIB-VMAT decreased by 3.0 cm3 (range 0.1-8.2 cm3 ), 3.0 cm3 (range 0.1-8.7 cm@@@3@@), and 7.5 cm@@@3@@ (range 0.3-26.2 cm@@@3@@), respectively, compared to DCA depending on the target volume. CONCLUSIONS: SIB-VMAT improved dose conformity to the PTV for intracranial stereotactic radiotherapy, and decreased high and low dose volume of normal brain compared to DCA. SIB-VMAT offers the ability of dose escalation due to high conformity of high dose regions inside the target volume.

[Cardiac surgery in an octogenarian with idiopathic thrombocytopenic purpura: report of a case].

An 81-year-old woman was referred to our hospital for surgical treatment for mitral valve regurgitation, tricuspid valve regurgitation and atrial fibrillatory bradycardia. The platelet count on admission was 4.9 x 10(4)/microl. and the results of other studies were compatible with idiopathic thrombocytopenic purpura. Although we performed high-dose transvenous immunoglobulin infusion (400 mg/kg/day) for 5 consecutive days, the platelet count showed no remarkable change. Because of progression of heart failure, we underwent cardiac operation under thrombocytopenic condition. Intra and post-operative platelet transfusion might contribute to postoperative course uneventful without bleeding tendency. In this case, high-dose immunoglobulin therapy was not effective. However the operative course was satisfactory with adequate surgical hemostasis and platelet transfusion.

[Anomalous origin of the right coronary artery from the ascending aorta].

The patient was a 77-year-old man. In June 2008, he underwent off-pump coronary artery bypass (OPCAB) for unstable angina Intraoperative epiaortic echo showed an anomalous origin of theright coronary artery from the ascending aorta 4 cm above the sinotubular junction (STJ). The right coronary artery traveled through the planned proximal anastomotic site of the saphenous vein graft (SVG). If diagnosis of the anomalous origin of the right coronary artery had not been made, there would have been a high likelihood that the right coronary artery could have been injured. Thus, the usefulness of epiaortic echo was reaffirmed. An anomalous origin of the coronary artery is a rare congenital anomaly and its incidence is approximately 1%. An anomalous origin of the right coronary artery is very rare from the ascending aorta 4 cm above the STJ and only a few cases have been reported. An anomalous origin of the coronary artery can cause serious complications affecting the prognosis after open heart surgery. Thus, such an anomalous origin needs to be considered in preoperative evaluation.

[Aortitis syndrome with repeated restenoses of a drug eluting stent].

The patient was a 49-year-old female who developed acute myocardial infarction of the right coronary artery in August 2005. In a short period of time, the patient had restenosis repeatedly after percutaneous coronary intervention (PCI). Restenosis could not be prevented even with a drug eluting stent (DES), and thus, off-pump coronary artery bypass grafting (OPCAB) was performed. The diagnosis of aortitis syndrome was made due to protracted postoperative inflammation. Aortitis syndrome was determined to be the main cause of repeated restenosis. This case was a middle-aged female who had restenosis in a short period of time, and aortitis syndrome should have been included in the differential diagnosis. Although some positive results have been reported on DES placement for coronary lesions of aortitis syndrome, DES was completely ineffective in our patient. Further studies with more patients are necessary to examine the effectiveness of DES.

Significance of repeated resection for recurrent intrahepatic cholangiocarcinoma.

BACKGROUND/AIMS: Management of patients with recurrent intrahepatic cholangiocarcinoma (ICC) following surgical resection is difficult, and surgical resection is rarely indicated. We retrospectively reviewed patients with recurrent intrahepatic cholangiocarcinoma. METHODOLOGY: Between April 1998 and March 2007, 57 consecutive patients with ICC underwent surgical resection. Mode of recurrence and treatment of recurrent tumors, especially surgical resection for these tumors, in patients with cancer recurrence were evaluated. RESULTS: 37 (65%) patients experienced tumor recurrence. Out of these patients, 24 underwent some type of cancer-directed therapy, including 9 patients (24%) for whom surgical resection was attempted: the latter included 4 hepatic resections, 2 pulmonary resections, 2 tumor resections, and 1 gastric resection. For 6 patients with recurrent tumor in the liver or the lung, microscopic complete resection was achieved, while incomplete resection was resulted in the remaining 3 patients. No postoperative mortality was encountered. Among patients with complete resection, 3 are alive without disease 32, 39 and 77 months after the second operation, one has lived with disease for 13 months, and 2 died of disease after 22 and 26 months. No significant difference in overall survival was observed between patients undergoing primary and second surgical resections, calculated from the primary and the second operations, respectively. CONCLUSIONS: Repeated surgical resection for recurrent ICC can be performed with acceptable morbidity, and affords selected patients a chance for long-term survival.

[Surgical treatment for ischemic heart disease].

BACKGROUND: Surgical treatment for ischemic heart disease (IHD) has changed after the administration of off-pump coronary artery bypass grafting (CABG) [OPCAB] and left ventricular restoration (LVR). We studied the development of the treatment and the surgical results. PATIENTS AND METHODS: Since May 2000 when the indication for OPCAB and LVR was defined, surgical treatment for IHD has been performed in 1,251 patients. The age ranged from 32 to 91 (mean 66 +/- 10) years and there were 977 men and 274 women. The elective operation was 1,130 and emergency 121. Definite indication for OPCAB was calcified ascending aorta, significant cerebrovascular disease, hemorrhagic tendency, and single vessel lesion. Conventional CABG (C-CAB) was the first choice and morbidity and surgical results were examined. RESULTS: OPCAB was performed in 297 (29.9%) and combined operation with CABG was required in 258 patients (20.6%). In elective operation, hospital mortality was one in OPCAB and one in C-CAB. In OPCAB and C-CAB, stroke was none and one, and mediastinitis was 0 and 0, respectively. CONCLUSION: The technique for OPCAB is necessary for CABG; however, it is not appropriate to persist with only OPCAB for CABG. Combined operation is often required with CABG and it is essential to perform precise C-CAB.

New beam-charge interlock system for radiation safety at the KEKB injector linac.

A new beam-charge interlock system is under development for radiation safety and machine protection at the KEKB injector linac. A hardware-based interlock system is required instead of the present software-based interlock system in order to boost its reliability. This system restricts the integrated amount of beam charges delivered to four different storage rings. The beam charges are measured using wall-current monitors and detection electronics at six locations along the linac. The detection electronics independently transmits a beam-abort request through a twisted hardwire cable directly to the safety control system of the linac, when the integrated amount of beam charges exceeds a certain threshold level prescribed for each location. We describe the characteristics and performance of the new beam-charge interlock system along with the details of the experimental tests.

High expression of GADD-45alpha and VEGF induced tumor recurrence via upregulation of IL-2 after photodynamic therapy using NPe6.

NPe6 is a novel second-generation photosensitizer used for photodynamic therapy (PDT). PDT using NPe6 and diode laser (664 nm) induces cell death, inflammatory reactions, immunological responses and damage to the microvasculature. In this study, we evaluated the influence of the immunological responses and of enhanced angiogenesis on the anti-tumor effect of NPe6-PDT using cytokine-overexpressing Lewis lung carcinoma (LLC), LLC-IL-2 cells both in vitro and in vivo. We showed by DNA microarray analysis in vitro that IL-2 and GADD-45alpha (growth arrest and DNA damage 45 alpha) mRNA expressions were induced by 3 h after NPe6-PDT applied at a dose killing 90% of the cells (LD90). IL-2-overexpressing cells (LLC/IL-2 cells) were resistant to the loss of clonogenicity as compared to the parental LLC cells in vitro. Furthermore, in female C57BL/6 mice, NPe6-PDT produced a cure rate of 66.7% in LLC tumors, whereas the cure rate was only 16.6% in LLC/IL-2 tumors, and overexpression of IL-2 caused failure of NPe6-PDT, with tumor recurrence, in vivo. These results suggest that IL-2 expression may play an unfavorable role in attenuation of the antitumor effect of NPe6-PDT. It has been reported that the expression of vascular endothelial growth factor (VEGF), in particular, may cause tumor recurrence after PDT and exert unfavorable effect in relation to attenuate the anti-tumor activity of PDT. Results of immunohistochemical analysis of LLC/IL-2 tumors have revealed that the expressions of GADD-45alpha and VEGF are induced in these tumors after PDT, and in particular, 12 h after PDT, the expression levels were much higher as compared with those in the LLC tumors. The results of our studies using in vitro and in vivo models suggest that the cell death caused by PDT was inhibited by induction of GADD-45alpha expression and that tumor recurrence was promoted by the enhancement of VEGF expression mediated by IL-2 upregulation. Therefore, it is speculated that the use of an IL-2 inhibitor may improve the efficacy of NPe6-PDT.