Changes of cancer diagnosis disclosure to children in Japan in the last 20 years

International Journal of Clinical Oncology - The practice of cancer diagnosis disclosure to children has been changed with the times. The regulations of clinical trials in the 2000s might change...     

Population Pharmacokinetic and Exposure-Response Analyses of Baloxavir Marboxil in Adults and Adolescents Including Patients With Influenza

Baloxavir marboxil, a prodrug that is metabolized to baloxavir acid, suppresses viral replication by inhibiting cap-dependent endonuclease. Our aim is to characterize its pharmacokinetics and exposure-response relationships. Population pharmacokinetic analysis of the baloxavir acid was performed using 8310 plasma concentration data points from 1109 subjects. Exposure-response analyses were performed regarding the time to alleviation of symptoms and the reduction in the influenza virus titer. A 2-compartment model with first-order absorption and lag time well described the plasma concentration data for baloxavir acid, and body weight and race were found to be the most important factors influencing the clearance and distribution volume. A dose regimen based on the body weight (40 mg for patients weighing <80 kg and 80 mg for patients weighing ≥80 kg) could provide sufficient exposures for expecting efficacy irrespective of body weight or race; however, the exposures were dependent on the body weight and race. Exposure-response analyses suggested that the reduction in the influenza virus titer was greater in any exposure-based groups in baloxavir marboxil treatment than in the oseltamivir phosphate treatment and placebo groups. In conclusion, the population pharmacokinetic model and exposure-response relationships would be useful for understanding the pharmacokinetic and pharmacodynamic characteristics of baloxavir acid.     

Interaction of nicotinic acetylcholine receptors with dopamine receptors in synaptic plasticity of the mouse insular cortex

The insular cortex plays essential roles in nicotine addiction. However, much is still unknown about its cellular and synaptic mechanisms responsible for nicotine addiction. We have previously shown that in layer 5 pyramidal neurons of the mouse insular cortex, activation of the nicotinic acetylcholine receptors (nAChRs) suppresses synaptic potentiation through enhancing GABAergic synaptic transmission, although it enhances both glutamatergic and GABAergic synaptic transmission. In the present study, we examined whether dopamine receptors might contribute to the nicotine‐induced inhibition of synaptic potentiation. The nicotine‐induced inhibition of synaptic potentiation was decreased in the presence of a D1 dopamine receptor antagonist SCH23390 irrespective of the presence of a D2 dopamine receptor antagonist sulpiride, suggesting that D1 dopamine receptors are involved in nicotine‐induced inhibition. We also investigated how dopamine receptors might contribute to the nAChR‐induced enhancement of glutamatergic and GABAergic synaptic transmission. The nAChR‐induced enhancement of GABAergic synaptic transmission was decreased in the presence of SCH23390 irrespective of the presence of sulpiride, whereas that of glutamatergic synaptic transmission was not altered in the presence of SCH23390 and sulpiride. These results suggest that D1 dopamine receptors are involved in the nAChR‐induced enhancement of GABAergic synaptic transmission while dopamine receptors are not involved in that of glutamatergic synaptic transmission. These observations indicate that the interaction between nAChRs and D1 dopamine receptors plays critical roles in synaptic activities in layer 5 pyramidal neurons of the mouse insular cortex. These insular synaptic changes might be associated with nicotine addiction.     

Significance of intraoperative monitoring of arterial blood flow velocity and hepatic venous oxygen saturation for performing minimally invasive surgery in a patient with multiple calcified pancreaticoduodenal aneurysms with celiac artery occlusion

Even for patients with multiple pancreaticoduodenal aneurysms, successful treatment with noninvasive operative procedures can be employed, if intraoperative devices are considered. A 73‐year‐old man, without any symptoms, was admitted to our hospital and had computed tomography (CT) scanning to examine his liver for hepatitis C virus (HCV). Selective superior mesenteric artery (SMA) angiography confirmed multiple aneurysms in the anterior inferior pancreaticoduodenal artery (AIPDA), one aneurysm in the posterior inferior mesenteric artery (PIPDA), and another in the occluded celiac trunk, all with severe calcification. All of the aneurysms were thought to communicate with each other. With the celiac artery occlusion, the right hepatic artery (RHA) was revealed to be supplied by collateral arteries from the aneurysms in the AIPDA, and the left hepatic artery was shown to be supplied by collaterals from the left gastric artery. Intraoperative Doppler echography, at the time of the clamping of both IPDAs, demonstrated a marked decrease of blood velocity in all aneurysms (before clamping, >50 cm/s; after, <10 cm/s), although loss of pulsation and a marked decrease of flow in the RHA were inevitable. Therefore, each of these two IPDAs were ligated on the proximal side to the aneurysm, thus preserving the blood flow of the pancreas head fed by the PIPDA; bypass grafting from the AIPDA to the RHA, using the great saphenous vein, was done at the same time. After the creation of an anastomosis, the hepatic venous oxygen saturation (ShvO2) increased from 38% (at the time of ligation of the IPDAs) to 57% under ventilation. The patient's postoperative clinical course was uneventful. We describe and discuss our successful noninvasive operative management of multiple pancreaticoduodenal aneurysms, done while monitoring the blood flow and ShvO2, with some consideration of the literature.     

Influence of SNPs in cytokine-related genes on the severity of food allergy and atopic eczema in children

Although many single nucleotide polymorphism (SNP) studies have reported an association of atopy, allergic diseases and total serum immunoglobulin E (IgE) levels, almost all of these studies sought risk factors for the onset of these allergic diseases. Furthermore, many studies have analyzed a single gene and hardly any have analyzed environmental factors. In these analyses, the results could be masked and the effects of other genes and environmental factors may be decreased. Here, we described the correlation between four genes [interleukin (IL)-4 (C-590T), IL-4 receptor (A1652G), FCER1B (G6842A) and STAT6 (G2964A)] in connection with IgE production; the role of IL-10 (C-627A) as a regulatory cytokine of allergy; and the severity of food allergy (FA) and atopic eczema (AE) in 220 Japanese allergic children. In addition to these SNPs, environmental factors, i.e., patient's attitude, indoor environment, and so on, were also investigated in this study. Our study was retrospective, and the correlation was analyzed by our defined clinical scores divided into three terms: worst symptoms, recent symptoms and general amelioration at the most recent examination during the disease course. Our results indicated that IL-10 AA, the genotype with lower IL-10 production, is associated with higher IgE levels in the serum (p < 0.0001, estimate; 0.912). Marginal liver abnormalities were observed in the subject group with both FA and AE (p < 0.1191, estimate; 0.1490). Our defined clinical scores enabled evaluation of various aspects of disease severity. Based on the scores, while no single SNP selected in this study determined severity, the combination of the SNP with laboratory data and environmental factors appeared to determine severity.     

Long-term vardenafil therapy improves hemodynamics in patients with pulmonary hypertension.

The phosphodiesterase-5 (PDE-5) inhibitor, sildenafil, has been reported to produce sustained pulmonary vasodilatation in patients with pulmonary hypertension (PH). Recently, vardenafil, a more potent and selective PDE-5 inhibitor than sildenafil, has been approved for the treatment of erectile dysfunction. However, the long-term effects of oral vardenafil in patients with PH are unknown. We studied five consecutive patients with PH; one with primary pulmonary hypertension, two with chronic pulmonary thromboembolism, one with Eisenmenger syndrome (ventricular septal defect) and one with secondary pulmonary hypertension after a ventricular septal defect closure operation. In an acute hemodynamic trial, vardenafil (5 mg) significantly decreased both the pulmonary vascular resistance (PVR) and systemic vascular resistance (SVR) with an increase in cardiac output. In a chronic hemodynamic trial, the maintenance dose of vardenafil (10 to 15 mg) for 3 months significantly decreased the PVR, but not the SVR, with a 20.7% reduction of the PVR/ SVR ratio. Plasma brain natriuretic peptide (BNP) levels were also significantly decreased after 3 months. This pilot study demonstrates that long-term oral vardenafil therapy may be a safe and effective treatment for patients with PH.     

LONG‐TERM FOLLOW UP OF PATIENTS WITH SMALL GASTROINTESTINAL STROMAL TUMORS IN THE STOMACH USING ENDOSCOPIC ULTRASONOGRAPHY‐GUIDED FINE‐NEEDLE ASPIRATION BIOPSY

Background: Gastrointestinal stromal tumors (GIST) are one of the most common mesenchymal tumors of the gastrointestinal tract. GIST are defined by positive immunohistochemical staining for KIT or CD34 and thus are generally diagnosed after surgery. Because small GIST are rarely diagnosed before surgery, the clinical course of these small tumors is not clear. The aim of the present study was to follow changes in size and configuration of small GIST that were pathologically confirmed using endoscopic ultrasonography‐guided fine‐needle aspiration biopsy (EUS‐FNAB). Methods: Between July 1997 and December 2003, 16 tumors in 16 patients (10 men and 6 women) with an immunohistochemical diagnosis of GIST were regularly followed in our hospital. The median patient age when EUS‐FNAB was performed was 62 years (range 26–82 years) and the median follow‐up period was 4.9 years (range 0.5–9.6 years). Results: Fourteen tumors showed no remarkable changes in size and shape during follow up compared with the initial diagnosis. Two tumors enlarged: one tumor approximately doubled its diameter in 8 years and the other tumor increased from 1.8 cm at diagnosis to up to 10 cm after only 2 years. Doubling time of the latter tumor was calculated as 3.1 months. Conclusions: We conclude that EUS‐FNAB might be a good modality for final diagnosis of GIST without surgery, and that GIST without rapid growth on follow up can be endoscopically followed.     

Relationship between serum albumin level before initiating haemodialysis and angiographic severity of coronary atherosclerosis in end-stage renal disease patients.

BACKGROUND: In patients with chronic kidney disease (CKD), although strong associations have been observed between malnutrition and atherosclerosis, the relationship between serum albumin concentration and angiographic changes of coronary artery disease (CAD) remains poorly explored. The goal of the present study was, in patients with CKD, to clarify the relationship between the angiographic severity of CAD and serum albumin concentration reflecting either inflammation or nutrition or both. METHODS: In this study, 100 end-stage renal disease (ESRD) patients were enrolled, who commenced long-term dialysis therapy at our hospital and underwent coronary angiography within 3 months of the first haemodialysis (HD) session. Mean age was 63+/-11 years, 20% of the subjects were female and 62% had diabetes. Severity of CAD was evaluated in terms of (i) number of vessels exhibiting CAD (>or=75% stenosis) and (ii) Gensini score (GS). Clinical characteristics and laboratory findings were recorded at initiation of long-term HD therapy. We then evaluated a possible association with the presence and degree of CAD. RESULTS: Sixty-four patients exhibited signs of CAD. Forty-one among them (64%) had multivessel disease. On univariate logistic regression analysis, age, diabetes and hypoalbuminaemia were significantly associated with multivessel CAD. Univariate linear regression analysis demonstrated a positive correlation of age and diabetes with GS, and an inverse correlation of BMI and serum albumin level with GS. Stepwise regression analysis showed age and serum albumin level to be independently associated with multivessel CAD and GS. The ROC curves demonstrated best cut-off levels of age and albumin for predicting multivessel CAD to be 70 years and 3.15 g/dl, respectively. CONCLUSION: Hypoalbuminaemia at the initiation of dialysis is an important predictor of advanced CAD, particularly in male and in diabetic patients. It may reflect mainly a state of inflammation. However, malnutrition as a confounding factor cannot be entirely excluded.     

Studies of the induction and maintenance of long-term graft acceptance by treatment with FK506 in heterotopic cardiac allotransplantation in rats

Immunosuppressive activities of the newly discovered FK506, isolated from Streptomyces tsukubaensis, were examined by using cardiac allotransplantation in the rat, and the mechanisms underlying induction and maintenance of FK506-induced long-term allograft survival were studied. Male rats of WKA (RT1k) and F344 (RT1lvl) strains were used as recipients and donors, respectively, and those of BN (RT1n) strain were used as third-party donors. Treatment with FK506, beginning from the day of allografting for 14, 10, or as few as 4 days, prolonged allograft survival significantly across the major histocompatibility barrier. The minimum doses for prolonging graft survival were 0.1 mg/kg/day by intramuscular treatment and 1.0 mg/kg/day by oral treatment. Treatment with FK506 at a dose of 0.32 mg/kg/day from day 4 until day 10 resulted in all the grafts surviving indefinitely and from days 5 to 10, half the grafts survived indefinitely, suggesting that the agent inhibited ongoing rejection. On the other hand, cyclosporine treatment at a dose of 20 mg/kg/day from day 2 did not prolong graft survival time statistically significantly. Induction of prolonged graft survival was not obtained by pretreatment of the prospective donor or recipient; prolonging effects were observed only when the agent was administered after allografting. Thus, the primary effect of the agent is exerted on responder lymphocytes reacting to the donor antigens in the induction phase of long-term graft acceptance. The mechanisms underlying the maintenance of long-term grafts were analyzed by testing the capacity of lymphocytes or serum of long-term graft-bearing rats to inhibit graft rejection in irradiated grafted hosts. Transfer of 2 x 10(8) lymphocytes from FK506-induced long-term F344 graft-bearing WKA rats resulted in indefinite survival of F344 heart allografts, but it did not prolong survival of third-party BN hearts. Transfer of 2.5 ml serum from long-term graft-bearing rats also prolonged graft survival of F344 hearts, but not BN hearts. These results suggest that donor strain-specific suppressor cells and humoral factor(s) are induced by treatment with FK506 in the presence of allografts, and that they play at least partial roles in the maintenance of long-term allograft acceptance.