Assessing cardiac mechanical dyssynchrony in left bundle branch area pacing and right ventricular septal pacing using myocardial perfusion scintigraphy in the acute phase of pacemaker implantation.

INTRODUCTION: Left bundle branch area pacing (LBBAP) has recently been reported to be a new, clinically feasible and safe physiological pacing strategy. The present study aims to investigate the usefulness of LBBAP in reducing mechanical dyssynchrony compared with right ventricular septal pacing (RVSP). METHODS AND RESULTS: A total of 39 LBBAP patients, 42 RVSP patients, and 93 healthy control participants were retrospectively evaluated. We compared phase analysis- (bandwidth, phase standard deviation [PSD], entropy) and regional wall motion analysis parameters. Wall motion analysis parameters included the time to the end-systolic frame (TES) assessed using single-photon emission computed tomography analysis. The maximum differences between segmental TES (MDTES), the standard deviation of TES (SDTES), and the TES difference between the lateral and septal segments (DTES-LS) were obtained. All phase analysis parameters were significantly smaller in the LBBAP group than in the RVSP group (bandwidth: LBBAP, 74 ± 31° vs. RVSP, 102 ± 59°, p = .009; PSD: LBBAP, 19 ± 6.7° vs. RVSP, 26 ± 15°, p = .007; entropy: LBBAP, 0.57 ± 0.07 vs. RVSP, 0.62 ± 0.11 p = .009). The regional wall motion analysis parameters were also smaller in the LBBAP group than in the RVSP group (MDTES:LBBAP, 17 ± 7.1% vs. RVSP, 25 ± 14%, p = .004; SDTES:LBBAP, 4.5 ± 1.7% vs. RVSP, 6.0 ± 3.5%, p = .015; DTES-LS: LBBAP, 4.1 ± 3.4% vs. RVSP, 7.1 ± 5.4%, p = .004). All phase analysis and wall motion analysis parameters were same in the LBBAP and control groups. CONCLUSION: LBBAP may reduce mechanical dyssynchrony and achieve greater physiological ventricular activation than RVSP.

A risk-stratified therapy for infants with acute lymphoblastic leukemia: a report from the JPLSG MLL-10 trial.

The prognosis for infants with acute lymphoblastic leukemia (ALL), particularly those with KMT2A gene rearrangement (KMT2A-r), is dismal. Continuous efforts have been made in Japan to investigate the role of hematopoietic stem cell transplantation (HSCT) for infants with KMT2A-r ALL, but improvement in outcome was modest. In the Japanese Pediatric Leukemia/Lymphoma Study Group MLL-10 trial, infants with ALL were stratified into 3 risk groups (low risk [LR], intermediate risk [IR], and high risk [HR]) according to KMT2A status, age, and presence of central nervous system leukemia. Children's Oncology Group AALL0631 modified chemotherapy with the addition of high-dose cytarabine in early intensification was introduced to KMT2A-r patients, and the option of HSCT was restricted to HR patients only. The role of minimal residual disease (MRD) was also evaluated. Ninety eligible infants were stratified into LR (n = 15), IR (n = 19), or HR (n = 56) risk groups. The 3-year event-free survival (EFS) rate for patients with KMT2A-r ALL (IR + HR) was 66.2% (standard error [SE], 5.6%), and for those with germline KMT2A (KMT2A-g) ALL (LR), the 3-year EFS rate was 93.3% (SE, 6.4%). The 3-year EFS rate was 94.4% (SE, 5.4%) for IR patients and 56.6% (SE, 6.8%) for HR patients. In multivariable analysis, female sex and MRD ≥0.01% at the end of early consolidation were significant factors for poor prognosis. Risk stratification and introduction of intensive chemotherapy in this study were effective and were able to eliminate HSCT for a subset of infants with KMT2A-r ALL. Early clearance of MRD seems to have translated into favorable outcomes and should be incorporated into risk stratifications in future trials. This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) as #UMIN000004801.

Four-dimensional flow magnetic resonance imaging visualizes reverse vortex pattern and energy loss increase in left bundle branch block.

AIMS: This study aimed to investigate the intraventricular blood flow pattern of patients with left bundle branch block (LBBB) using four-dimensional flow magnetic resonance imaging (4D-flow MRI). METHODS AND RESULTS: We performed 4D-flow MRI for 16 LBBB patients (LBBB group) and 16 propensity score-matched patients with a normal QRS duration (non-LBBB group). The energy loss (EL) in the left ventricle was evaluated. In both groups, blood flow from the mitral valve to the apex of the heart and left ventricular (LV) outflow tract during LV diastole were observed. Vortices were also observed in both groups. There were two patterns of vortices: unidirectional clockwise rotation and counterclockwise rotation taking place from the mid-diastole to the systole (reverse pattern). The reverse pattern was observed significantly more frequently in the LBBB group (LBBB 94% vs. non-LBBB 19%, P < 0.001). The interobserver agreement for the streamline analysis was good (kappa = 0.68). The maximum EL was significantly higher in the LBBB group [LBBB 12 (11-15) mW vs. non-LBBB 8.0 (6.2-9.7) mW, P < 0.001]. CONCLUSION: Left bundle branch block patients may suffer from inefficient LV haemodynamics reflected by non-physiological counterclockwise vortices and increased EL. Thus, the shape of the vortices and EL in the left ventricle can serve as markers of LV mechanical dyssynchrony in LBBB patients and could be investigated as predictors of response to cardiac resynchronization therapy.

Usefulness of P-wave peak time as an electrocardiographic parameter in predicting left ventricular diastolic dysfunction in patients with mitral regurgitation.

INTRODUCTION: Conventional Doppler measurements have limitations in predicting left ventricular diastolic dysfunction (LVDD) in patients with mitral regurgitation (MR). Recently, electrocardiographic P-wave peak time (PWPT) has been proposed as a parameter of detecting LVDD. This study aimed to evaluate the association between PWPT and left ventricular end-diastolic pressure (LVEDP) in patients with MR. METHODS: We performed echocardiography and cardiac catheterization in 82 patients with moderate or severe MR. We classified patients into two groups: low LVEDP group (L-LVEDP) (LVEDP <16 mmHg, n = 40) and high LVEDP group (H-LVEDP) (LVEDP ≥16 mmHg, n = 42). We evaluated LVDD and PWPT based on echocardiographic and electrocardiographic findings in both groups. RESULTS: The PWPT in lead II (PWPTII ) was significantly longer in patients in the H-LVEDP group than in those in the L-LVEDP group (67 vs. 47 ms, p < .001). Using correlation analysis, LVEDP was positively correlated with PWPTII (r = .577, p < .001). Using multivariate analysis, PWPTII was found to be an independent predictor of increased LVEDP (95% CI: 0.1030-0.110; p < .001). Using receiver operating characteristic (ROC) curve analysis, the optimal cutoff value of PWPTII for predicting elevated LVEDP was 58.9 ms, with a sensitivity of 80.0% and a specificity of 73.8% (area under curve: 0.809, 95% CI: 0.713-0.905). CONCLUSION: To the best of our knowledge, this is the first study to assess the effect of a significant valvular disease on PWPT in lead II. These findings suggest that prolonged PWPTII may be an independent predictor of increased LVEDP in patients with moderate or severe MR.

Refractive error induced by intraocular lens tilt after intrascleral intraocular lens fixation.

PURPOSE: To investigate the spherical shift of intraocular lens (IOL) tilt after intrascleral fixation. METHODS: We retrospectively reviewed the medical records of patients who underwent flanged intrascleral IOL fixation with transconjunctival 25- or 27-gauge pars plana vitrectomy at the Department of Ophthalmology of the Jikei University Hospital. The minimum follow-up duration was 3 months. Second-generation anterior segment optical coherence tomography (CASIA2; TOMEY) was used to obtain the values of tilt and decentration of the intrasclerally fixated IOL and postoperative anterior chamber depth. We investigated the relationship between refractive error and various parameters, such as IOL tilt and decentration, axial length, and keratometry. In addition to our clinical investigation, we conducted optical simulations using Zemax to evaluate the spherical shift of the IOL tilt by means of the through-focus response and change in spherical equivalent power. RESULTS: The study involved 72 eyes of 67 patients. The degree of IOL tilt was correlated with the amount of refractive error (Spearman's rank correlation coefficient [CC] = - 0.32; P = 0.006). In particular, a tilt angle greater than 10° strongly affected the refractive error. The postoperative anterior chamber depth also correlated with the refractive error (CC = 0.50; P < 0.001), as opposed to decentration (CC = - 0.17; P = 0.15), axial length (CC = - 0.08; P = 0.49), and keratometry (CC = - 0.06; P = 0.64). Optical simulations also revealed a myopic shift that exponentially increased as the tilt became greater. CONCLUSION: IOL tilts that are greater than 10° induce refractive error.

Relationship Between the Loaded Pressure and Flow Rate of Packed Red Blood Cells and Various Infusion Solutions in Normal Infusion Lines and Catheters.

BACKGROUND: We investigated the relationship between the loaded pressure and flow rate in various catheters and the entire infusion line including the catheters, in several infusion solutions and packed red blood cells. METHODS: We connected the infusion line and catheter to the infusion solution and used an outer pressure bag or a compressor to pressurize the infusion solution bag to a pressure within the clinical (up to 450 mm Hg) or higher range (up to 1050 mm Hg). We approximated the relationship between the loaded pressure and flow rate in the entire infusion line including the catheter, versus the catheter alone, as a power function and compared the power numbers. RESULTS: In the clinical pressure range of normal saline, the power numbers of the entire infusion line for the 24-, 22-, 20-, and 18-gauge catheters were 0.76, 0.82, 0.81, and 0.86, respectively, while those for the catheter alone were 0.67, 0.63, 0.56, and 0.44, respectively. In the higher pressure range of normal saline, the power numbers of the entire infusion line for the 24-, 22-, 20-, and 18-gauge catheters were 0.68, 0.70, 0.71, and 0.73, respectively, while those for the catheter alone were 0.62, 0.61, 0.59, and 0.58, respectively. As the power number of the entire infusion line was closer to 1.00 than the values of the catheter, the relation between the loaded pressure and the flow rate was more linear in the entire infusion line than that in the catheter. Similar results were obtained using packed red blood cells and 40% glycerin mixture in normal saline. CONCLUSIONS: Regardless of the type of infusion solution or transfusion, the pressure-flow relationship in the catheter was nonlinear and not directly proportional. However, within the clinical pressure range (up to 450 mm Hg), the relationship between the flow rate and pressure in the entire infusion line was almost linear and proportional.

The usefulness of a delivery catheter system for right ventricular "true" septal pacing.

Right ventricular (RV) septum is an alternate site for the placement of RV lead tip instead of RV apex. Recent studies have demonstrated that less than half of the RV leads targeted for septal implantation are placed on the RV septum using a conventional stylet system; new guiding catheter systems have become available for RV lead placement. This study aimed to investigate the usefulness of the delivery catheter system in lead placement on the RV septum when compared with the stylet system. We retrospectively evaluated 198 patients who underwent fluoroscopically guided pacemaker implantation with RV leads targeted to be placed in the RV septum and in whom computed tomography was incidentally and subsequently performed. A delivery catheter was used in 16 patients, and a stylet in 182 patients. The primary endpoint of this study was the success rate of RV lead placement on the RV septum. The proportion of RV lead placement on the RV septum was higher in the delivery catheter group than in the stylet group (100% vs. 44%; p < 0.001). In the stylet group, the lead tips were placed at the hinge in 92 cases (51%) and on the free wall in 9 cases (5%). Paced QRS duration was narrower in the delivery catheter group than in the stylet group (128 ± 16 vs. 150 ± 21 ms, p < 0.01). The delivery catheter system designated for pacing leads may aid in selecting RV septal sites and achieve good physiologic ventricular activation.

Receptor selectivity from minimal backbone modification of a polypeptide agonist.

Human parathyroid hormone (PTH) and N-terminal fragments thereof activate two receptors, hPTHR1 and hPTHR2, which share ∼51% sequence similarity. A peptide comprising the first 34 residues of PTH is fully active at both receptors and is used to treat osteoporosis. We have used this system to explore the hypothesis that backbone modification of a promiscuous peptidic agonist can provide novel receptor-selective agonists. We tested this hypothesis by preparing a set of variants of PTH(1-34)-NH2 that contained a single ß-amino-acid residue replacement at each of the first eight positions. These homologs, each containing one additional backbone methylene unit relative to PTH(1-34)-NH2 itself, displayed a wide range of potencies in cell-based assays for PTHR1 or PTHR2 activation. The ß-scan series allowed us to identify two homologs, each containing two αâ†’ß replacements, that were highly selective, one for PTHR1 and the other for PTHR2. These findings suggest that backbone modification of peptides may provide a general strategy for achieving activation selectivity among polypeptide-modulated receptors, and that success requires consideration of both ß2- and ß3-residues, which differ in terms of side-chain location.

Attempts to optimize postinduction treatment in childhood acute myeloid leukemia without core-binding factors: A report from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG).

We previously reported that risk-stratified therapy and intensive postremission chemotherapy (PRC) contributed to the improved survival of childhood acute myeloid leukemia (AML) in the AML99 study, which led us to consider a reduction in the number of PRC courses with more restrictive indications for stem cell transplantation (SCT) in the successor AML-05 study. We here report the outcome of AML patients without core-binding factor mutation (non-CBF AML) in the AML-05 study. Two-hundred eighty-nine children (age < 18 years old) with non-CBF AML were eligible. Patients with unfavorable cytogenetics and/or poor bone marrow response to the first induction course were candidates for SCT in the AML-05 study. After two courses of induction, a further three courses of PRC were given in AML-05, while four courses were given in the AML99 study. The 3-year event-free survival (EFS) rate in the AML-05 study (46.7%, 95% CI: 40.6-52.6%) was comparable to that of non-CBF AML in the AML99 study (51.5%, 95% CI: 42.7-59.6%) (P = .16). However, the 3-year overall survival (OS) rate in the AML-05 study (62.9%, 95% CI: 56.3-68.8%) was slightly lower than that in the AML99 study (71.6%, 95% CI: 63.2-78.5%) (P = .060), mainly due to decreased remission induction rate and increased nonrelapsed mortality. In conclusion, reductions in the number of PRC courses from four to three, together with repetitive cycles of high-dose cytarabine, were acceptable for non-CBF childhood AML.

An outcome study of adult in-hospital cardiac arrests in non-monitored areas with resuscitation attempted using AED.

OBJECTIVES: To investigate the outcomes of patients with in-hospital cardiac arrest (IHCA) who underwent cardiopulmonary resuscitation (CPR) using an automated external defibrillator (AED) in non-monitored areas. Additionally, to detect correlated factors associated with rate of return of spontaneous circulation (ROSC) and survival rate, among collected data. METHODS: This study included 109 patients. After investigating patient characteristics and resuscitation-related factors, the correlated factors associated with ROSC rates and survival rate were analyzed using univariate and multivariate analyses. RESULTS: The rate of survival to hospital discharge was 21.1%. CPR with AED performed since 2013 was associated with a higher ROSC rate (adjusted odds ratio [AOR] 3.24, 95% confidence interval [CI]: 1.21 to 9.52, p < 0.05), but not with the survival rate after ROSC. Tracheal intubation was significantly associated with a higher ROSC rate (AOR 3.62, 95% CI: 1.27 to 11.7, p < 0.05) and a lower survival rate after ROSC (hazard ratio 6.6, 95% CI: 1.2 to 43.3, p < 0.05). Dysrhythmia as the cause of cardiac arrest and intensive care unit (ICU) admission after ROSC were associated with higher survival rates (hazard ratio 0.056, 95% CI: 0.004 to 0.759, p < 0.05, and hazard ratio 0.072, 95% CI: 0.017 to 0.264, p < 0.0001, respectively). CONCLUSIONS: The factors associated with ROSC rate and those associated with the survival rate after ROSC were different. Although initial shockable rhythms on AED were not associated with the survival rate, dysrhythmia as the etiology of cardiac arrest, and ICU admission were significantly associated with higher survival rates after ROSC.

Complications of femtosecond laser-assisted cataract surgery combined with vitrectomy.

PURPOSE: To evaluate the safety of femtosecond laser-assisted cataract surgery (FLACS) combined with 25- or 27-gauge vitrectomy. METHODS: This retrospective study included patients who underwent FLACS combined with 25- or 27-gauge vitrectomy at the Jikei University School of Medicine in Tokyo, Japan, between August 2016 and April 2018 and were followed up for ≥ 3 months postoperatively. In all cases, anterior capsulotomies and fragmentations of crystalline lenses were performed using a femtosecond laser. After FLACS, 25- or 27-gauge vitrectomy was performed. All intraoperative and postoperative complications due to FLACS and vitrectomy were examined. RESULTS: A total of 34 eyes from 34 patients were included. In 33 cases, complete coverage of the intraocular lens (IOL) by the anterior capsular edge was achieved. One case had posterior capsule rupture due to mis-suction during emulsification and aspiration of a fragment of the nuclear lens after capsulotomy. The IOL was fixed at the sulcus. Postoperative complications included endophthalmitis and macular edema in one eye, epiretinal membranes in two eyes, and postoperative capsular opacification in two eyes. The femtosecond laser caused no postoperative complications. There were no cases of intraoperative or postoperative iris capture or IOL subluxation. CONCLUSIONS: In most cases, FLACS provided good IOL fixation in the capsule without affecting the intra- or extraocular pressure and good vision during or after the operation. FLACS combined with 25- or 27-gauge vitrectomy should be performed considering the advantages and disadvantages of femtosecond laser usage. CLINICAL TRIAL REGISTRATION: Japan Clinical Trials Register; number: UMIN000021814.

Impact of Hydrostatic Pressure Variations Caused by Height Differences in Supine and Prone Positions on Fractional Flow Reserve Values in the Coronary Circulation.

OBJECTIVES: To examine the influence of hydrostatic pressure on fractional flow reserve (FFR) in vivo. BACKGROUND: Systematic differences in FFR values have been observed previously in the left anterior descending artery (LAD), left circumflex artery (LCX), and right coronary artery (RCA). It has been suggested that as the hydrostatic pressure variations caused by the height differences between the catheter tip (mean aortic pressure (Pa)) and pressure-wire sensor (mean distal intracoronary pressure (Pd)) are small, intracoronary pressure need not be corrected. METHODS: Resting Pd/Pa and FFR values in 23 patients (27 lesions) were measured and compared in supine and prone positions. These values were corrected by hydrostatic pressure influenced by height levels and compared. Height differences between Pa and Pd were calculated using coronary computed tomography angiographies. RESULTS: In LAD, resting Pd/Pa and FFR values were significantly higher in the prone position than in the supine position (0.97 ± 0.05 vs 0.89 ± 0.04, P < 0.001 (resting Pd/Pa); 0.81 ± 0.09 vs 0.72 ± 0.07, P < 0.001 (FFR)). Conversely, in LCX and RCA, these values were significantly lower in the prone position (LCX: 0.93 ± 0.03 vs 0.98 ± 0.03, P < 0.001 (resting Pd/Pa); 0.84 ± 0.05 vs 0.89 ± 0.04, P < 0.001 (FFR); RCA: 0.91 ± 0.04 vs 0.98 ± 0.03, P=0.005 (resting Pd/Pa); 0.78 ± 0.07 vs 0.84 ± 0.07, P=0.019 (FFR)). FFR values corrected by hydrostatic pressure showed good correlations in the supine and prone positions (R 2 = 0.948 in LAD; R 2 = 0.942 in LCX; R 2 = 0.928 in RCA). CONCLUSIONS: Hydrostatic pressure variations due to height levels influence intracoronary pressure measurements and largely affect resting Pd/Pa and FFR, which might have caused systematic differences in FFR values between the anterior and posterior coronary territories.

Common carotid artery kinking is a predictor of cardiovascular events: A long-term follow-up study using carotid ultrasonography.

BACKGROUND: Kinking of the internal carotid artery is a cardiovascular (CV) risk factor. However, it remains unclear as to whether kinking of the common carotid artery (CCA) can also predict CV events. We conducted a long-term follow-up study to examine whether CCA kinking as assessed by carotid ultrasonography is a predictor of CV events in asymptomatic patients with CV risk factors. METHODS: We enrolled 598 patients (mean age, 66.8 ± 11.8 years) who were divided into two groups according to CCA kinking severity: kinking of 0-29° (Group I); and kinking at ≥30° (Group II). We assessed whether CCA kinking predicts CV events during follow-up. RESULTS: A total of 91 CV events were observed during the follow-up period (median, 124 months). Hypertension (P < .0001), prior CV events (P < .0001), CCA kinking (P < .0001), intima-media thickness (P < .0001), and max plaque score (P < .0001) were significantly higher in patients with CV events than those without. The age-adjusted hazard ratio of CCA kinking for CV events was 3.42 (95% CI: 2.2-5.3) in Group II compared to Group I. Cox proportional hazard regression analysis revealed that CCA kinking (HR: 3.02, 95% CI: 1.97-4.67), prior CV events (HR: 2.53 95% CI: 1.604.00), hypertension (HR: 2.19 95% CI: 1.17-4.57), and age (HR: 1.04, 95% CI: 1.02-1.07) were independent predictors of CV events. CONCLUSION: CCA kinking is a powerful independent predictor of CV events in asymptomatic patients with CV risk factors.

Clinical Features and Prognosis According to Immunophenotypic Subtypes Including the Early T-Cell Precursor Subtype of T-Lymphoblastic Lymphoma in the Japanese Pediatric Leukemia/Lymphoma Study Group ALB-NHL03 Study.

We reviewed the immunophenotypic subtypes of pediatric T-cell lymphoblastic lymphoma in the Japanese Pediatric Leukemia/Lymphoma Study Group ALB-NHL03 study. Of the 104 patients, 40 patients each had sufficient data to evaluate the immunophenotypes and early T-cell precursor (ETP) subtype. Pro-T, pre-T, intermediate T, and mature T cells were observed in 1, 9, 21, and 9 cases, respectively. The 3-year event-free survival (EFS) rates of those with pro-T/pre-T, intermediate T, and mature T cells were 80.0±12.6%, 71.4±9.9%, and 88.9±10.5%, respectively (P=0.546). There were 8 and 32 cases of ETP and non-ETP subtypes, with 3-year EFS rates of 75.0±15.3% and 71.9±8.0%, respectively (P=0.828), indicating that the immunophenotypic subtype was not predictive of EFS in this study.

Structural Characterization of Cholestane Rhamnosides from Ornithogalum saundersiae Bulbs and Their Cytotoxic Activity against Cultured Tumor Cells.

Previous phytochemical studies of the bulbs of Ornithogalum saundersiae, an ornamental perennial plant native to South Africa, resulted in the isolation of 29 new cholestane glycosides, some of which were structurally unique and showed potent cytotoxic activity against cultured tumor cell lines. Therefore, we aimed to perform further phytochemical examinations of methanolic extracts obtained from Ornithogalum saundersiae bulbs, isolating 12 new cholestane rhamnosides (1-12) and seven known compounds (13-19). The structures of the new compounds (1-12) were identified via NMR-based structural characterization methods, and through a sequence of chemical transformations followed by spectroscopic and chromatographic analysis. The cytotoxic activity of the isolated compounds (1-19) and the derivatives (1a and 6a) against HL-60 human promyelocytic leukemia cells and A549 human lung adenocarcinoma cells was evaluated. Compounds 10-12, 16, and 17 showed cytotoxicity against both HL-60 and A549 cells. Compound 11 showed potent cytotoxicity with an IC50 value of 0.16 µM against HL-60 cells and induced apoptotic cell death via a mitochondrion-independent pathway.

High event-free survival rate with minimum-dose-anthracycline treatment in childhood acute promyelocytic leukaemia: a nationwide prospective study by the Japanese Paediatric Leukaemia/Lymphoma Study Group.

We evaluated the efficacy of treatment using reduced cumulative doses of anthracyclines in children with acute promyelocytic leukaemia (APL) in the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-P05 study. All patients received two and three subsequent courses of induction and consolidation chemotherapy respectively, consisting of all-trans retinoic acid (ATRA), cytarabine and anthracyclines, followed by maintenance therapy with ATRA. Notably, a single administration of anthracyclines was introduced in the second induction and all consolidation therapies to minimize total doses of anthracycline. The 3-year event-free (EFS) and overall survival rates for 43 eligible children were 83·6% [95% confidence interval (CI): 68·6-91·8%] and 90·7% (95% CI: 77·1-96·4%), respectively. Although two patients died of intracranial haemorrhage or infection during induction phases, no cardiac adverse events or treatment-related deaths were observed during subsequent phases. Patients not displaying M1 marrow after the first induction therapy, or those under 5 years of age at diagnosis, showed inferior outcomes (3-year EFS rate; 33·3% (95% CI: 19·3-67·6%) and 54·6% (95% CI: 22·9-78·0%), respectively). In conclusion, a single administration of anthracycline during each consolidation phase was sufficient for treating childhood APL. In younger children, however, conventional ATRA and chemotherapy may be insufficient so that alternative therapies should be considered.

Endosomal GPCR signaling turned off by negative feedback actions of PKA and v-ATPase.

The PTH receptor is to our knowledge one of the first G protein-coupled receptor (GPCR) found to sustain cAMP signaling after internalization of the ligand-receptor complex in endosomes. This unexpected model is adding a new dimension on how we think about GPCR signaling, but its mechanism is incompletely understood. We report here that endosomal acidification mediated by the PKA action on the v-ATPase provides a negative feedback mechanism by which endosomal receptor signaling is turned off.

Prognostic Impact of Intensified Maintenance Therapy on Children With Advanced Lymphoblastic Lymphoma: A Report From the Japanese Pediatric Leukemia/Lymphoma Study Group ALB-NHL03 Study.

BACKGROUND: Childhood advanced lymphoblastic lymphoma (LBL) has a favorable outcome with an event-free survival (EFS) rate of over 80% in response to treatment strategies for acute lymphoblastic leukemia (ALL). However, no progress has been made in this outcome over the past 10 years. PROCEDURE: We conducted the first nationwide prospective study of childhood advanced LBL to assess the efficacy and safety of ALL-directed therapy with an intensified maintenance phase. We omitted local radiotherapy including prophylactic cranial radiotherapy except for patients with initial central nervous system disease. The total duration of the treatment was 24 months. RESULTS: For the 136 patients analyzed in this study, 5-year overall survival (OS) was 82.9% and 5-year EFS was 77.9%. Thirty events were observed and 14 occurred before the initiation of intensified maintenance phase. Of 14 events, nine were observed as mediastinal enlargement. There was no significant difference in outcome when stratified according to gender or by immunophenotype. The 5-year EFS according to clinical stage in patients with T-cell LBL (T-LBL) was 70.6% for stage III and 88.9% for stage IV (P = 0.037). CONCLUSIONS: Our first nationwide study provided about 80% cure rate with only one case of toxic death in childhood advanced LBL. However, our intensified maintenance therapy could not improve the survival outcome. There was a trend of better EFS in Japanese patients with T-LBL stage IV than T-LBL stage III.

Preserved High Probability of Overall Survival with Significant Reduction of Chemotherapy for Myeloid Leukemia in Down Syndrome: A Nationwide Prospective Study in Japan.

BACKGROUND: On the basis of results of previous Japanese trials for myeloid leukemia in Down syndrome (ML-DS), the efficacy of risk-oriented therapy was evaluated in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-D05 study. PROCEDURE: All patients received induction chemotherapy that consisted of pirarubicin, intermediate-dose cytarabine, and etoposide. Patients who achieved complete remission (CR) after initial induction therapy were stratified to the standard risk (SR) group and received four courses of reduced-dose intensification therapy. Patients who did not achieve CR were stratified to the high risk (HR) group and received intensified therapy that consisted of continuous or high-dose cytarabine. RESULTS: A total of 72 patients were eligible and evaluated. One patient died of sepsis during initial induction therapy. Sixty-nine patients were stratified to SR and two patients to HR. No therapy-related deaths were observed during intensification therapy. The 3-year event-free and overall survival rates were 83.3% ± 4.4% and 87.5% ± 3.9%, respectively. Age at diagnosis less than 2 years was a significant favorable prognostic factor for risk of relapse (P = 0.009). CONCLUSIONS: The attempt of risk-oriented prospective study for ML-DS was unsuccessful, but despite the dose reduction of chemotherapeutic agents, the overall outcome was good, and further dose reduction might be possible for specific subgroups.

Awareness of folic acid use increases its consumption, and reduces the risk of spina bifida.

The majority of neural tube defects were believed to be folic acid (FA)-preventable in the 1990s. The Japanese government recommended women planning pregnancy to take FA supplements of 400 µg/d in 2000, but the incidence of spina bifida has not decreased. We aimed to evaluate the OR of having an infant with spina bifida for women who periconceptionally took FA supplements and the association between an increase in supplement use and possible promoters for the increase. This is a case-control study which used 360 case women who gave birth to newborns afflicted with spina bifida, and 2333 control women who gave birth to healthy newborns during the first 12 years of this century. They were divided into two 6-year periods; from 2001 to 2006 and from 2007 to 2012. Logistic regression analyses were conducted to compute OR between cases and controls. The adjusted OR of having an infant with spina bifida for supplement users was 0.48 in the first period, and 0.53 in the second period. The proportion of women who periconceptionally consumed supplements significantly increased from 10 % in the first period to 30 % in the second period. Awareness of the preventive role of FA was a promoter for an increase in supplement use, and thus an FA campaign in high school seems rational and effective. The failure of the current public health policy is responsible for an epidemic of spina bifida. Mandatory food fortification with FA is urgent and long overdue in Japan.