Multicenter prospective trial of total gastrectomy versus proximal gastrectomy for upper third cT1 gastric cancer.

BACKGROUND: The appropriate surgical procedure for patients with upper third early gastric cancer is controversial. We compared total gastrectomy (TG) with proximal gastrectomy (PG) in this patient population. METHODS: A multicenter, non-randomized trial was conducted, with patients treated with PG or TG. We compared short- and long-term outcomes between these procedures. RESULTS: Between 2009 and 2014, we enrolled 254 patients from 22 institutions; data from 252 were included in the analysis. These 252 patients were assigned to either the PG (n = 159) or TG (n = 93) group. Percentage of body weight loss (%BWL) at 1 year after surgery, i.e., the primary endpoint, in the PG group was significantly less than that of the TG group (- 12.8% versus - 16.9%; p = 0.0001). For short-term outcomes, operation time was significantly shorter for PG than TG (252 min versus 303 min; p < 0.0001), but there were no group-dependent differences in blood loss and postoperative complications. For long-term outcomes, incidence of reflux esophagitis in the PG group was significantly higher than that of the TG group (14.5% versus 5.4%; p = 0.02), while there were no differences in the incidence of anastomotic stenosis between the two (5.7% versus 5.4%; p = 0.92). Overall patient survival rates were similar between the two groups (3-year survival rates: 96% versus 92% in the PG and TG groups, respectively; p = 0.49). CONCLUSIONS: Patients who underwent PG were better able to control weight loss without worsening the prognosis, relative to those in the TG group. Optimization of a reconstruction method to reduce reflux in PG patients will be important.

Differences in Cerebral Aneurysm Rupture Rate According to Arterial Anatomies Depend on the Hemodynamic Environment.

BACKGROUND AND PURPOSE: Cerebral aneurysms have significantly different rupture rates depending on their size and location. The mechanisms underlying these differences are unclear. We examined whether anatomic rupture risks are dependent on the hemodynamic environment on the aneurysmal surface. MATERIALS AND METHODS: Patient-specific geometries and flow rates of 84 cerebral aneurysms (42 anterior communicating artery and 42 MCA aneurysms) were acquired from our clinical study, the Computational Fluid Dynamics Analysis of Blood Flow in Cerebral Aneurysms: Prospective Observational Study. Pulsatile blood flow was simulated to calculate hemodynamic metrics with special attention to wall shear stress magnitude and temporal disturbance. Multivariate analyses were performed to identify associations between hemodynamic metrics and known rupture predictors (age, sex, hypertension, smoking history, location, and size). RESULTS: All the wall shear stress magnitude-based metrics showed a significant negative association with size and location (P < .03), but not other risk factors. All the wall shear stress disturbance-based metrics were significantly related to size (P < .001). Only normalized transverse wall shear stress, a metric for multidirectional wall shear stress disturbance, was related to location (P = .03). The normalized transverse wall shear stress had the highest odds ratio for location and size among hemodynamic metrics (odds ratios, 1.275 and 1.579; 95% confidence intervals, 1.020-1.693 and 1.238-2.219, respectively). Among the arterial geometric parameters, the aspect ratio had the second strongest association with all hemodynamic metrics, after our newly proposed aspect ratio-asphericity index. CONCLUSIONS: The differences in aneurysm rupture rates according to size and location may reflect differences in hemodynamic environments in qualitatively different ways. An enhanced multidirectional wall shear stress disturbance may be especially associated with aneurysm rupture.

Gut commensal Bacteroides acidifaciens prevents obesity and improves insulin sensitivity in mice.

In humans, the composition of gut commensal bacteria is closely correlated with obesity. The bacteria modulate metabolites and influence host immunity. In this study, we attempted to determine whether there is a direct correlation between specific commensal bacteria and host metabolism. As mice aged, we found significantly reduced body weight and fat mass in Atg7ΔCD11c mice when compared with Atg7f/f mice. When mice shared commensal bacteria by co-housing or feces transfer experiments, body weight and fat mass were similar in both mouse groups. By pyrosequencing analysis, Bacteroides acidifaciens (BA) was significantly increased in feces of Atg7ΔCD11c mice compared with those of control Atg7f/f mice. Wild-type C57BL/6 (B6) mice fed with BA were significantly more likely to gain less weight and fat mass than mice fed with PBS. Of note, the expression level of peroxisome proliferator-activated receptor alpha (PPARα) was consistently increased in the adipose tissues of Atg7ΔCD11c mice, B6 mice transferred with fecal microbiota of Atg7ΔCD11c mice, and BA-fed B6 mice. Furthermore, B6 mice fed with BA showed elevated insulin levels in serum, accompanied by increased serum glucagon-like peptide-1 and decreased intestinal dipeptidyl peptidase-4. These finding suggest that BA may have potential for treatment of metabolic diseases such as diabetes and obesity.

Reduction of blood eosinophil counts in eosinophilic chronic rhinosinusitis after surgery.

OBJECTIVE: This study aimed to predict eosinophilic chronic rhinosinusitis prognosis by investigating changes in the blood eosinophil count and other disease biomarkers after surgery. METHODS: Blood eosinophil numbers and serum interleukin-5 levels were measured in 22 eosinophilic chronic rhinosinusitis patients before and after functional endoscopic sinus surgery, and compared with equivalent measures in non-eosinophilic chronic rhinosinusitis patients and chronic rhinosinusitis without polyps patients. Differences between well-controlled eosinophilic chronic rhinosinusitis patients and those who experienced recurrence were also assessed. RESULTS: Blood eosinophil numbers and serum interleukin-5 level decreased after surgery in eosinophilic chronic rhinosinusitis patients. In this patient group, blood eosinophil counts before surgery were significantly higher in patients who experienced recurrence (825.7 ± 26.1 vs 443.9 ± 76.6 cells/µl, p < 0.05), and decreased significantly after surgery (825.7 ± 26.1 vs 76.7 ± 25.8 cells/µl, p < 0.05). CONCLUSION: Blood eosinophil numbers may reflect disease severity in eosinophilic chronic rhinosinusitis patients and their prognosis after surgery.

Anti-desmocollin autoantibodies in nonclassical pemphigus.

BACKGROUND: Despite the established pathogenic role of anti-desmoglein (Dsg) antibodies in classical pemphigus, the significance of autoantibodies to another desmosomal cadherin, desmocollin (Dsc) is at present unknown. No consistent immunoassay for immunoglobulin (Ig) G autoantibodies to Dscs has been developed. OBJECTIVES: The aim of this study was to develop reliable assays to detect anti-Dsc autoantibodies. METHODS: We expressed soluble recombinant proteins (RPs) of human Dsc1-3 in mammalian cells and examined sera of various types of pemphigus, including 79 paraneoplastic pemphigus (PNP) sera, by novel enzyme-linked immunosorbent assays (ELISAs) using the RPs. We also performed ELISAs of Dsc baculoproteins and used the complementary DNA (cDNA) transfection method, and compared the results with those of mammalian ELISAs. RESULTS: Through mammalian ELISAs, IgG autoantibodies to Dsc1, Dsc2 and Dsc3 were detected in 16.5%, 36.7% and 59.5% of PNP sera, respectively, and considerable numbers of pemphigus herpetiformis (PH) and pemphigus vegetans (PVeg) sera reacted strongly with Dsc1 and Dsc3. Mammalian ELISAs were highly specific and more sensitive than baculoprotein ELISAs or the cDNA transfection method. Several Dsc-positive sera, particularly PH sera, showed no reactivity with Dsgs. The reactivity of PNP serum and PVeg serum with Dscs was not abolished by pre-absorption with Dsg RPs. CONCLUSIONS: The results of these novel ELISAs indicated that IgG anti-Dsc autoantibodies were frequently detected and potentially pathogenic in nonclassical pemphigus.

Survivin modulates genes with divergent molecular functions and regulates proliferation of hematopoietic stem cells through Evi-1.

The inhibitor of apoptosis protein Survivin regulates hematopoiesis, although its mechanisms of regulation of hematopoietic stem cells (HSCs) remain largely unknown. While investigating conditional Survivin deletion in mice, we found that Survivin was highly expressed in phenotypically defined HSCs, and Survivin deletion in mice resulted in significantly reduced total marrow HSCs and hematopoietic progenitor cells. Transcriptional analysis of Survivin(-/-) HSCs revealed altered expression of multiple genes not previously linked to Survivin activity. In particular, Survivin deletion significantly reduced expression of the Evi-1 transcription factor indispensable for HSC function, and the downstream Evi-1 target genes Gata2, Pbx1 and Sall2. The loss of HSCs following Survivin deletion and impaired long-term HSC repopulating function could be partially rescued by ectopic Evi-1 expression in Survivin -/- HSCs. These data demonstrate that Survivin partially regulates HSC function by modulating the Evi-1 transcription factor and its downstream targets and identify new genetic pathways in HSCs regulated by Survivin.

Clinical and immunological profiles in 17 Japanese patients with drug-induced pemphigus studied at Kurume University.

BACKGROUND: Drug-induced pemphigus (DIP) shows clinical, histopathological and immunological features of pemphigus. However, little is known about immunological profiles in DIP. OBJECTIVES: To characterize clinical and immunological profiles in patients with DIP. METHODS: We studied 17 Japanese patients with DIP who were treated at Kurume University Hospital or who consulted from other hospitals between 1997 and 2012. Complicated diseases, clinical and histopathological manifestations, responsible drugs and findings in immunofluorescence, enzyme-linked immunosorbent assays (ELISAs), immunoblotting (IB) and prognosis were analysed. RESULTS: Eight of the 17 patients with DIP showed pemphigus foliaceus-like appearance, three showed pemphigus herpetiformis-like appearance, and six showed atypical bullous lesions. Responsible drugs were thiol-containing drugs in 16 patients (bucillamine in nine cases, d-penicillamine in four cases, and cetapril, thiopronine and captopril in one patient each), and a nonthiol drug, sulfasalazine, in one patient. By ELISAs and/or IB analyses, nine patients reacted only with desmoglein 1 (Dsg1), four reacted with Dsg1 and Dsg3, and four showed no specific reactivity. By IB of normal human epidermal extracts, in addition to positive reactivity with Dsg1, four patients with no detectable malignancy showed paraneoplastic pemphigus-like reactivity with the 210-kDa envoplakin and the 190-kDa periplakin. Four cases showed anti-Dsg3 antibodies without mucosal lesions. While 11 cases recovered after discontinuation of the causative drugs, six patients had a very protracted or intractable disease course, and might develop true pemphigus. CONCLUSIONS: The present study indicated that the majority of the patients with DIP studied showed a pemphigus foliaceus-type phenotype with anti-Dsg1 autoantibodies, caused by thiol-containing drugs.

Superselective intra-arterial cisplatin infusion and concomitant radiotherapy for maxillary sinus cancer.

BACKGROUND: The purpose of this study was to evaluate the efficacy of superselective cisplatin infusion with concomitant radiotherapy (RADPLAT) for previously untreated patients with the squamous cell carcinoma of maxillary sinus (SCC-MS). METHODS: Between 1999 and 2010, 54 patients were given superselective intra-arterial infusions of cisplatin (100-120 mg m(-2) per week) with simultaneous intra-venous infusions of thiosulfate to neutralise cisplatin toxicity and conventional radiotherapy (65-70 Gy). RESULTS: One patient (1.9%) was diagnosed with T2, 14 (25.9%) with T3, 27 (50%) with T4a, and 12 (22.2%) with T4b disease. Lymph-node involvement was present in 12 patients (22.2%). During the median follow-up period of 6.4 years, the 5-year local progression-free and overall survival rates were 65.8 and 67.9% for all patients, respectively. No patient died as a result of treatment toxicity or experienced a cerebrovascular accident. Osteonecrosis (n=5), brain necrosis (n=1), and ocular/visual problems (n=14) were observed as late adverse reactions. CONCLUSION: We have shown excellent overall survival and local progression-free rate in SCC-MS patients treated by RADPLAT with acceptable rates of acute and late toxicity. A multi-institutional trial is needed to prove that this strategy is a feasible and effective approach for the treatment of SCC-MS.

IgA pemphigus with paraneoplastic pemphigus-like clinical features showing IgA antibodies to desmoglein 1/3 and desmocollin 3, and IgG and IgA antibodies to the basement membrane zone.

A 79-year-old Japanese woman presented with severe recalcitrant erosions on her oral mucosa, resembling paraneoplastic pemphigus. Using indirect immunofluorescence, we detected IgA antibodies against the cell surface, and both IgG and IgA antibodies against the basement membrane zone. Immunoblotting showed that the IgG antibodies reacted weakly with bullous pemphigoid 230 and periplakin, whereas the IgA antibodies did not react with any antigen. IgA antibodies to both desmoglein (Dsg)1 and Dsg3 were detected by ELISA. IgA antibodies to desmocollin (Dsc)3 were also detected by using cDNAs for human Dsc1-3 transfected into COS-7 cells. Despite treatment with oral prednisolone, high-dose intravenous immunoglobulin and double-filtration plasmapheresis, the skin lesions remained active, and the patient died from bronchiolitis obliterans-like respiratory failure. Despite extensive investigations and postmortem examination, no underlying neoplasms were found. The complex immunopathological findings probably played an important role in the development of the patient's unusual clinical features.

The protein tyrosine phosphatase, Shp2, positively contributes to FLT3-ITD-induced hematopoietic progenitor hyperproliferation and malignant disease in vivo.

Internal tandem duplications (ITDs) in the fms-like tyrosine kinase receptor (FLT3-ITDs) confer a poor prognosis in acute myeloid leukemia (AML). We hypothesized that increased recruitment of the protein tyrosine phosphatase, Shp2, to FLT3-ITDs contributes to FLT3 ligand (FL)-independent hyperproliferation and STAT5 activation. Co-immunoprecipitation demonstrated constitutive association of Shp2 with the FLT3-ITD, N51-FLT3, as well as with STAT5. Knockdown of Shp2 in Baf3/N51-FLT3 cells significantly reduced proliferation while having little effect on WT-FLT3-expressing cells. Consistently, mutation of N51-FLT3 tyrosine 599 to phenylalanine or genetic disruption of Shp2 in N51-FLT3-expressing bone marrow low-density mononuclear cells reduced proliferation and STAT5 activation. In transplants, genetic disruption of Shp2 in vivo yielded increased latency to and reduced severity of FLT3-ITD-induced malignancy. Mechanistically, Shp2 co-localizes with nuclear phospho-STAT5, is present at functional interferon-γ activation sites (GAS) within the BCL2L1 promoter, and positively activates the human BCL2L1 promoter, suggesting that Shp2 works with STAT5 to promote pro-leukemogenic gene expression. Further, using a small molecule Shp2 inhibitor, the proliferation of N51-FLT3-expressing bone marrow progenitors and primary AML samples was reduced in a dose-dependent manner. These findings demonstrate that Shp2 positively contributes to FLT3-ITD-induced leukemia and suggest that Shp2 inhibition may provide a novel therapeutic approach to AML.

Antitumor efficacy of oncolytic herpes simplex virus adsorbed onto antigen-specific lymphocytes.

Although several studies have reported that locally administering oncolytic viruses effectively targets malignancies, the efficacy of systemically administered oncolytic viruses is restricted. Recently, however, it was reported that systemic administration of oncolytic vesicular stomatitis virus adsorbed onto antigen-specific lymphocytes was effective against malignancies. We hypothesized that intravenously administering such virus might have significant potential in treatment of the malignant tumors. We adsorbed oncolytic herpes simplex virus-1 mutant R3616 onto lymphocytes harvested from mice with acquired antitumor immunity. We administered adsorbed R3616 to peritoneally disseminated tumors and analyzed the efficacy of this treatment. Mice administered adsorbed R3616 survived significantly longer than mice administered R3616 adsorbed onto non-specific lymphocytes, or mice administered either virus or tumor antigen-specific lymphocytes alone. In this context, herpes oncolytic virus is a promising treatment not only for primary lesions, but also for multiple metastasizing lesions. This treatment strategy may become one of the most effective methods for systemic virus delivery.

AFOMP POLICY STATEMENT No. 2: recommended clinical radiation oncology medical physicist staffing levels in AFOMP countries.

This document is the second of a series of policy statements being issued by the Asia-Oceania Federation of Organizations for Medical Physics (AFOMP). The document was developed by the AFOMP Professional Development Committee (PDC) and was released by the AFOMP Council in 2009. The main purpose of the document is to give guidance as to how many medical physicists are required to staff a radiation oncology department. Strict guidelines are difficult to define as work practices vary from country-to-country and from hospital-to-hospital. A calculation scheme is presented to aid in estimating medical physics staffing requirements that is primarily based on equipment levels and patient numbers but also with allowances for staff training, professional development and leave requirements.

[Constrictive pericarditis after minimally invasive coronary artery bypass grafting: report of a case].

Constrictive pericarditis (CP) after off-pump coronary bypass surgery, especially after minimally invasive direct coronary artery bypass (MIDCAB), had rarely been reported. We presened a surgically treated case of CP after MIDCAB via left anterior small thoracotomy. A 57-year-old man underwent MIDCAB with placement of an internal mammary artery to the left anterior descending coronary artery uneventfully. Four years after the operation, he began to experience exertional dyspnea. Computed tomography of the chest showed pericardial thickening. Cardiac catheterization revealed elevation and equalization of the pressures in the 4 chambers, as well as low cardiac output. Pericardiectomy using cardiopulmonary bypass through a median sternotomy was performed successfully without injury to the bypass graft. Postoperative hemodynamic measurements were improved. The patient has resumed normal activity and remained free from heart failure for over 5 years.

Carbon-ion radiotherapy: clinical aspects and related dosimetry.

The features of relativistic carbon-ion beams are attractive from the viewpoint of radiotherapy. They exhibit not only a superior physical dose distribution but also an increase in biological efficiency with depth, because energy loss of the beams increases as they penetrate the body. This paper reviews clinical aspects of carbon-beam radiotherapy using the experience at the National Institute of Radiological Sciences. The paper also outlines the dosimetry related to carbon-beam radiotherapy, including absolute dosimetry of the carbon beam, neutron measurements and radiation protection measurements.

Vision-related quality of life and visual function in patients undergoing vitrectomy, gas tamponade and cataract surgery for macular hole.

AIM: To evaluate the relationship between vision-related quality of life (VR-QOL) and visual function in patients undergoing vitrectomy, gas tamponade and cataract surgery for macular hole (MH). METHODS: The 25-item National Eye Institute Visual Function Questionnaire (VFQ-25) was self-administered by 32 patients with MH (age 66.2 (SD 5.4) years) preoperatively and at 3 months postoperatively. Clinical data were collected, including logarithm of minimum angle of resolution (logMAR) best corrected visual acuity (BCVA), severity of metamorphopsia and letter contrast sensitivity. The severity of metamorphopsia was evaluated by the M-Charts. MH index was measured using optical coherence tomography. The presence and severity of cataract were graded using the Lens Opacities Classification System III reference standards. Multiple regression analysis was performed to investigate the relationship between various explanatory variables and VFQ-25 questionnaire scores. Explanatory variables tested were the severity of metamorphopsia, visual acuity, letter contrast sensitivity, MH index and grade of cataract. RESULTS: Vitrectomy for MH significantly improved VFQ-25 composite score as well as subscale scores, including general vision, near activities, distance activities, social functioning, mental health and dependency (p<0.05, Wilcoxon signed-rank test). Multiple regression analysis revealed that, both preoperatively and postoperatively, the severity of metamorphopsia had a significant correlation with VFQ-25 composite score (p<0.05), whereas other explanatory variables did not. In addition, changes in the severity of metamorphopsia was the single variable that was significantly related to changes in VFQ-25 composite score (p<0.01). CONCLUSION: Vitrectomy for MH significantly improved VR-QOL. The severity of metamorphopsia was significantly associated with both preoperative and postoperative VR-QOL.

Corticosteroid enhances TNF-alpha-mediated leukocyte adhesion to pulmonary microvascular endothelial cells.

BACKGROUND: Some severe asthma patients are characterized by elevated levels of tumor necrosis factor alpha (TNF-alpha) and neutrophilic inflammation in the airways. Although such phenotypic changes in asthma might contribute to corticosteroid refractoriness, the role of TNF-alpha in the process remains unclear. TNF-alpha exerts its biological effects mainly by acting on the vascular endothelium, and thereby upregulates leukocyte recruitment into inflamed tissues. The aim of this study was to investigate the effects of dexamethasone (DEX) on the TNF-alpha-mediated responses of human microvascular endothelial cells from lung blood vessels (HMVEC-LBl) in vitro. METHODS: HMVEC-LBl were cultured with TNF-alpha in the presence and absence of DEX. The effects of DEX on various TNF-alpha-mediated responses, such as the expressions of chemokines and cellular adhesion molecules, leukocyte adhesion were determined. RESULTS: TNF-alpha significantly induced growth-related oncogene alpha (GRO-alpha), interleukin 8 (IL-8), regulated on activation, normal T-cell expressed and secreted (RANTES) and interferon-inducible protein 10 (IP-10) productions and cell surface expressions of intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) on HMVEC-LBl. TNF-alpha-induced GRO-alpha and IL-8 were slightly attenuated by DEX treatment (reaches to 89% and 79%, respectively), whereas expressions of IP-10, ICAM-1 and VCAM-1 were significantly enhanced by the same treatment (up to 172%, 152% and 139%, respectively). Correspondingly, in vitro adhesion of eosinophils and neutrophils to TNF-alpha-treated HMVEC-LBl were significantly enhanced by DEX. CONCLUSIONS: Some proinflammatory effects of DEX, a corticosteroid, were found in TNF-alpha-mediated in vitro reactions of pulmonary microvascular endothelial cells, i.e. chemokine productions and leukocyte adhesion. These in vitro results may explain, at least in part, the corticosteroid refractoriness accompanied by a marked increase in TNF-alpha production that is seen in severe asthmatic patients.