First-line treatment for severe aplastic anemia in children: bone marrow transplantation from a matched family donor versus immunosuppressive therapy

The current treatment approach for severe aplastic anemia in children is based on studies performed in the 1980s, and updated evidence is required. We retrospectively compared the outcomes of children with acquired severe aplastic anemia who received immunosuppressive therapy within prospective trials conducted by the Japanese Childhood Aplastic Anemia Study Group or who underwent bone marrow transplantation from an HLA-matched family donor registered in the Japanese Society for Hematopoietic Cell Transplantation Registry. Between 1992 and 2009, 599 children (younger than 17 years) with severe aplastic anemia received a bone marrow transplant from an HLA-matched family donor (n=213) or immunosuppressive therapy (n=386) as first-line treatment. While the overall survival did not differ between patients treated with immunosuppressive therapy or bone marrow transplantation [88% (95% confidence interval: 86–90) versus 92% (90–94)], failure-free survival was significantly inferior in patients receiving immunosuppressive therapy than in those undergoing bone marrow transplantation [56% (54–59) versus 87% (85–90); P<0.0001]. There was no significant improvement in outcomes over the two time periods (1992–1999 versus 2000–2009). In multivariate analysis, age <10 years was identified as a favorable factor for overall survival (P=0.007), and choice of first-line immunosuppressive therapy was the only unfavorable factor for failure-free survival (P<0.0001). These support the current algorithm for treatment decisions, which recommends bone marrow transplantation when an HLA-matched family donor is available in pediatric severe aplastic anemia.     

Clinical characteristics and genetic analysis of childhood acute lymphoblastic leukemia with hemophagocytic lymphohistiocytosis: a Japanese retrospective study by the Kyushu–Yamaguchi Children’s Cancer Study Group

This present study sought to analyze acute lymphoblastic leukemia (ALL) patients with hemophagocytic lymphohistiocytosis (HLH) registered in Kyushu–Yamaguchi Children’s Cancer Study Group studies conducted between 1996 and 2007. Four of 357 patients, including two of 318 patients with B cell precursor acute lymphoblastic leukemia (BCP-ALL) and two of 39 of those with T cell acute lymphoblastic leukemia (T-ALL), were identified. HLH was observed more frequently in the T-ALL patients than in the BCP-ALL patients (P = 0.061). The mean age of 13.0 years at the diagnosis of leukemia in the HLH + ALL group was significantly higher than the 6.05 years observed in the remaining ALL groups (P = 0.001). A female predisposition was noted, as all four patients were female (P = 0.043). In two of four patients, the leukemic cells exhibited deletions on the long arm of chromosome 6 (P = 0.003). Three patients suffered from HLH during maintenance therapy. Parvovirus B19 infection and cytomegalovirus reactivation were identified as causes of HLH in one and two patients, respectively. All four patients are currently in complete remission, although one developed relapse of leukemia after receiving maintenance therapy. Based on the genetic analyses, non-synonymous single nucleotide polymorphisms (SNPs) in UNC13D, syntaxin 11, and STXBP2 were identified in all patients. Clinicians should therefore be aware of the risk of HLH during maintenance therapy, especially in older T-ALL patients with SNPs in familial HLH causative genes.     

Effects of mosapride on esophageal motor activity and esophagogastric junction compliance in healthy volunteers

Background

The effects of the prokinetic drug mosapride on esophageal motor activity vary at standard doses. In addition to esophageal motor activities, compliance of the esophagogastric junction (EGJ) is important for prevention of gastroesophageal reflux. However, the effects of mosapride on EGJ compliance have not been reported. Here, we investigated the effects of high-dose mosapride on esophageal motor activities and EGJ compliance.

Methods

Nine healthy volunteers were enrolled in the study. Peristaltic esophageal contraction and lower esophageal sphincter pressures before and after administration of 40 mg mosapride were examined by high resolution esophageal manometry. Esophageal compliance was also investigated by intra-esophageal impedance planimetry (EndoFLIP^®).

Results

High-dose mosapride augmented peristaltic contractions, especially in the distal esophageal segments (P < 0.05). The mean resting lower esophageal sphincter pressure was elevated from 25.0 mmHg before administration to 28.9 mmHg after (P < 0.05). In addition, mosapride significantly reduced EGJ compliance (P < 0.05).

Conclusions

Mosapride at 40 mg augmented esophageal motor activities and reduced EGJ compliance in healthy volunteers.     

Comparison of nifekalant and amiodarone for resuscitation of out-of-hospital cardiopulmonary arrest resulting from shock-resistant ventricular fibrillation

Purpose

Nifekalant is a pure potassium channel blocker that has been used to treat ventricular tachyarrhythmias since 1999 in Japan. Intravenous amiodarone was approved later than nifekalant in Japan, and it is still unclear which of the two agents is superior. The aim of this study was to compare the efficacy of nifekalant and amiodarone for resuscitation of out-of-hospital cardiopulmonary arrest caused by shock-resistant ventricular fibrillation.

Methods

From December 2005 to January 2011, ambulance services transported 283 out-of-hospital cardiopulmonary arrest patients to our hospital. Of these, 25 patients were treated with nifekalant or amiodarone in response to ventricular fibrillation that was resistant to two or more shocks. We undertook a retrospective analysis of these 25 patients.

Results

We enrolled 20 men and 5 women with a mean age (± standard deviation) of 61.1 ± 16.4 years. All 25 patients were treated with tracheal intubation and intravenous epinephrine. Fourteen patients received nifekalant and 11 patients received amiodarone. The rates of return of spontaneous circulation (ROSC) (nifekalant, 5/14, versus amiodarone, 4/11; P = 0.97) and survival to discharge (nifekalant, 4/14, versus amiodarone, 2/11; P = 0.89) were not significantly different between the two groups. The time from nifekalant or amiodarone administration to ROSC was 6.0 ± 6.6 and 20.3 ± 10.0 min, respectively, which was significantly different (P < 0.05).

Conclusion

In this small sample size study, nifekalant, compared with amiodarone, is equally effective for ROSC and survival to discharge after shock-resistant ventricular fibrillation and can achieve ROSC more quickly. Further prospective studies are needed to confirm our results.     

Mutations in the FHA-domain of ectopically expressed NBS1 lead to radiosensitization and to no increase in somatic mutation rates via a partial suppression of homologous recombination

Ionizing radiation induces DNA double-strand breaks (DSBs). Mammalian cells repair DSBs through multiple pathways, and the repair pathway that is utilized may affect cellular radiation sensitivity. In this study, we examined effects on cellular radiosensitivity resulting from functional alterations in homologous recombination (HR). HR was inhibited by overexpression of the forkhead-associated (FHA) domain-mutated NBS1 (G27D/R28D: FHA-2D) protein in HeLa cells or in hamster cells carrying a human X-chromosome. Cells expressing FHA-2D presented partially (but significantly) HR-deficient phenotypes, which were assayed by the reduction of gene conversion frequencies measured with a reporter assay, a decrease in radiation-induced Mre11 foci formation, and hypersensitivity to camptothecin treatments. Interestingly, ectopic expression of FHA-2D did not increase the frequency of radiation-induced somatic mutations at the HPRT locus, suggesting that a partial reduction of HR efficiency has only a slight effect on genomic stability. The expression of FHA-2D rendered the exponentially growing cell population slightly (but significantly) more sensitive to ionizing radiation. This radiosensitization effect due to the expression of FHA-2D was enhanced when the cells were irradiated with split doses delivered at 24-h intervals. Furthermore, enhancement of radiation sensitivity by split dose irradiation was not seen in contact-inhibited G0/G1 populations, even though the cells expressed FHA-2D. These results suggest that the FHA domain of NBS1 might be an effective molecular target that can be used to induce radiosensitization using low molecular weight chemicals, and that partial inhibition of HR might improve the effectiveness of cancer radiotherapy.     

Chronic Granulomatous Disease: Two Decades of Experience From a Tertiary Care Centre in North West India

Chronic granulomatous disease (CGD) results from an inherited defect in the phagocytic cells of the immune system. It is a genetically heterogenous disease caused by defects in one of the five major subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. There is a paucity of data from India on CGD. We herein describe the clinical features in 17 children with CGD from a single tertiary referral center in India. A detailed analysis of the clinical features, laboratory investigations and outcome of 17 children 7 with X-linked (XL) and 10 with autosomal recessive (AR) form was performed. Diagnosis of CGD was based on an abnormal granulocyte oxidative burst evaluated by either Nitroblue Tetrazolium (NBT) test or flow cytometry based Dihyrorhodamine 123 assay or both. The molecular diagnosis was confirmed by genetic mutation analysis in 13 cases. The mean age at diagnosis and the age at onset of symptoms was significantly lower in children diagnosed with XL- CGD compared those with AR disease. Mutations were detected in CYBB gene in 6 patients with XL-CGD and NCF-1 gene mutations were observed in 7 cases of AR- CGD. The course and outcome of the disease was much worse in children diagnosed with X-linked form of disease compared to AR forms of the disease; 4/7 (57 %) children with X-CGD were dead at the time of data analysis. This is one of the largest series on chronic granulomatous disease from any developing country.