Serious infections after unrelated donor transplantation in 136 children: impact of stem cell source.

How the infection risks compare after umbilical cord blood (UCB) and bone marrow (BM) transplantation is not known. Therefore, we compared serious infections in the 2 years after pediatric myeloablative unrelated donor transplantation with unmanipulated BM (n = 52), T cell-depleted (TCD) BM (n = 24), or UCB (n = 60) for the treatment of hematologic malignancy. Overall, the cumulative incidence of 1 or more serious infections was comparable between groups (BM, 81%; TCD, 83%; UCB, 90%; P = .12). Furthermore, by taking all serious infections into account and using multivariate techniques with unmanipulated BM as the reference, there were also no significant differences between groups (TCD relative risk [RR], 1.6; P = .10; UCB RR, 1.0; P = .84). Within the time periods days 0 to 42, days 43 to 100, and days 101 to 180, the only difference was a greater risk of viral infections from days 0 to 42 in TCD recipients (RR, 3.5; P = .02). Notably, after day 180, TCD recipients had a significantly increased infection risk (RR, 3.1; P = .03), whereas the risk in UCB recipients (RR, 0.5; P = .23) was comparable to that in BM recipients. Other factors associated with an increased infection risk in the 2 years after transplantation were age > or = 8 years, graft failure, and severe acute graft-versus-host disease. These data suggest that the risk of serious infection after pediatric UCB transplantation is comparable to that with unmanipulated BM.     

Comprehensive genomic profiling of malignant phyllodes tumors of the breast

Purpose

Malignant phyllodes tumors (MPT) are exceptionally rare, and the genomic drivers of these tumors are still being elucidated. We performed comprehensive genomic profiling (CGP) of MPT to identify genomic alterations that will inform approaches to targeted therapy for patients with MPT, including relapsed, refractory, and metastatic disease.

Methods

DNA was extracted from formalin-fixed, paraffin-embedded samples from 24 consecutive patient cases of MPT. CGP was performed using a hybrid capture, adaptor ligation-based next generation sequencing assay to a high, uniform coverage (mean, 582×). Tumor mutational burden (TMB) was calculated from a minimum of 1.14 Mb of sequenced DNA as previously described and reported as mutations/Mb. The results were analyzed for all classes of genomic alterations, including short variants (SV; base substitutions, small insertions, and deletions), rearrangements, and copy number changes, including amplifications and homozygous deletions.

Results

The 24 cases of MPT included 15 patients with localized and 9 with metastatic disease. The median TMB was 2.7 mut/Mb, and no cases had a TMB > 10 mut/Mb. 20 out of 24 cases were evaluable for microsatellite status, and all were microsatellite stable. The most commonly mutated genes were TP53 (58.3%), TERT-promoter (57.9%), NF1 (45.8%), MED12 (45.8%), CDKN2A/B (33.3%), and MLL2 (33.3%). Targetable kinase fusions including KIAA1549-BRAF or FGFR3-TACC3 were identified in 2/24 (8.3%) tumors.

Conclusions

This study identifies clinically relevant genomic alterations that suggest novel targeted therapy approaches for patients with MPT.

     

Power and precision grip force control in three-to-five-year-old children: velocity control precedes amplitude control in development

The aim of this study was to examine the development of underlying motor control strategies in young children by characterizing the changes in performance of a visually guided force regulation task using two different grip formations; a whole-hand power grip (developmentally easier) and a thumb-index finger precision grip (developmentally more advanced). Typically developing preschool children (n=50, 3.0-5.5 years) used precision and power grips to perform a ramp and hold task with their dominant and non-dominant hands. Participants performed five trials with each hand and grip holding the force at 30% of their maximum volitional contraction for 3 s. The data were examined for both age-related and performance-related changes in motor performance. Across ages, children increased in strength, decreased in initial overshoot of the target force level, and decreased in rate of force release. Results of a cluster analysis suggest non-linear changes in the development of force control in preschool children, with a plateau in (or maturation of) velocity measures (rate of force increase and force decrease) earlier than in amplitude-related measures (initial force overshoot and force variability).     

Crystal methamphetamine use associated with non-fatal overdose among a cohort of injection drug users in Vancouver

OBJECTIVES: To evaluate the prevalence and correlates of non-fatal overdose among a polysubstance-using cohort of injection drug users (IDU) in Vancouver. STUDY DESIGN/METHODS: We evaluated factors associated with non-fatal overdose among participants enrolled in the Vancouver Injection Drug Users Study (VIDUS) using univariate statistics. Self-reports of the awareness of drugs taken and drug potency, polysubstance use, and assistance received at the time of non-fatal overdose were also recorded. RESULTS: From 1 December 2003 to 1 June 2005, 551 participants who were active injectors were followed. In total, 37 (6.7%) individuals reported experiencing a non-fatal overdose in the previous 6 months. Factors positively associated with non-fatal overdose included public injecting (odds ratio (OR)=4.74, 95% confidence interval (CI) 2.35-9.37, P<0.001), crystal methamphetamine use (OR=4.11) and injection (OR=3.63), morphine injection (OR=3.55), non-injection opiate use (OR=3.30), frequent heroin injection (OR=2.28) and sex trade work (OR=2.12). Factors negatively associated with non-fatal overdose included participation in methadone maintenance therapy (OR=0.31) and injecting alone (OR=0.36). Sixty-two percent of individuals were unaware of drug potency, 64.9% of IDU were taking other drugs at the time of overdosing, with crack being the main drug (37.0%). Fifty-four percent were assisted by ambulance personnel, 56.8% were taken to accident and emergency or hospital, 38.1% left accident and emergency or hospital before being released, and 35.1% were given Naloxone. CONCLUSION: Structural interventions are needed that seek to modify the social and contextual risks for overdose, increased access to treatment programmes, and trials of novel interventions for crystal methamphetamine users.     

High percentages of resistance to tetracycline and penicillin and reduced susceptibility to azithromycin characterize the majority of strain types of Neisseria gonorrhoeae isolates in Cuba, 1995-1998

BACKGROUND: In many regions the susceptibility of Neisseria gonorrhoeae isolates to antimicrobial agents is rarely tested. The Gonococcal Antimicrobial Surveillance Program (GASP) in Cuba was established as part of a larger regional GASP program to facilitate the collection and reporting of antimicrobial susceptibility data for N gonorrhoeae isolates. GOAL: The goal was to retrospectively determine the antimicrobial susceptibility and molecular epidemiology of 91 isolates of N gonorrhoeae isolated from 11 centers in Cuba. STUDY DESIGN: Isolates of N gonorrhoeae were collected and presumptively identified from 11 Cuban provincial health centers. They were then forwarded to the National Laboratory of Pathogenic Neisseria Havana for confirmatory identification and were subsequently analyzed at the Center for GASP in Ottawa. Isolates were tested for susceptibility to penicillin, tetracycline, spectinomycin, ceftriaxone, ciprofloxacin, and azithromycin by the agar dilution method. To establish baseline data for molecular epidemiologic profiles, the auxotype (A), serovar (S), plasmid content (P), and TetM type of the isolates were determined. Certain A/S/P classes were further analyzed by pulsed field gel electrophoresis (PFGE). RESULTS: High percentages of the 91 N gonorrhoeae isolates were resistant to penicillin (68%) and tetracycline (83.5%), with 56% being penicillinase-producing (PPNG) and 64% carrying plasmid-mediated tetracycline resistance (TRNG; 50% were PP/TRNG). An additional 14% of the isolates carried chromosomal resistance (CMRNG) to either tetracycline or penicillin or both antibiotics. All isolates were susceptible to spectinomycin, ceftriaxone, and ciprofloxacin. However, nine isolates were resistant to azithromycin (MIC, > or = 1.0 microgram/ml), and 43 other isolates displayed reduced susceptibility to this antibiotic (MIC, 0.25-0.5 microgram/ml). Although a total of 21 different A/S classes were identified, most of the isolates (61) belonged to three A/S classes: NR/IA-6 (35 isolates), NR/IB-1 (15 isolates), and P/IA-6 (11 isolates). Thirty-two of 45 PP/TRNG were A/S class NR/IA-6, and nine of the P/IA-6 isolates were TRNG. By contrast, most of A/S class NR/IB-1 (8) were CMRNG. PFGE analysis following digestion with NheI or SpeI further clustered the isolates into separate groups. CONCLUSIONS: This study demonstrates high percentages of N gonorrhoeae isolates with penicillin and tetracycline resistance in Cuba. As has been noted in other studies in the Caribbean region and Latin America, resistance and reduced susceptibility to azithromycin are developing as emerging problems. Since penicillin and tetracycline continue to be widely used for the treatment of gonococcal infections in Cuba, this study indicates the importance of antimicrobial susceptibility surveillance so that effective antibiotics may be recommended for treatment of gonococcal infections.     

Detection of a novel Tet M determinant in tetracycline-resistant Neisseria gonorrhoeae from Uruguay, 1996-1999

BACKGROUND: Determination of the diversity within the tet(M) sequence from N gonorrhoeae is a useful epidemiologic tool for monitoring the movement or importation of strains within a geographic region. Only two distinct tet(M) genes in clinical gonococcal isolates have been described up to now: the Dutch and the American types. GOAL: The study involved surveillance of the tet(M) gene types in high-level-tetracycline-resistant gonococcal isolates from Uruguay during the period 1996 to 1999. STUDY DESIGN: Among 181 gonococcal isolates, those showing MICs >/=16 microg/ml to tetracycline were analyzed for detection and characterization of the tet(M) gene by a polymerase chain reaction (PCR) and further HpaII restriction fragment polymorphism methods, respectively. The plasmid content and antibiogram were determined. RESULTS: Twenty-two of 181 isolates (12%) exhibited high levels of resistance to tetracycline (MICs >/=16 microg/ml) and harbored a putative 25.2-Mda plasmid that contained the tet(M) gene. A high percentage of isolates (95%; 21/22) presented the Dutch type tet(M) gene. One isolate from 1999 revealed a new restriction pattern. Such a pattern had been previously noted in 1991. This new restriction pattern has not been described previously as occurring in isolates of N gonorrhoeae. The tet(M) amplimer sequence showed 100% identity with a previously described tet(M)-carrying plasmid from N meningitidis. CONCLUSION: A new HpaII restriction pattern of the tet(M) gene is present in low frequency. The tet(M) sequence was different from the gonococcal tet(M) sequences already known and not typable with the use of a differential PCR assay. Accordingly, with the genetic diversity already present within the tet(M) sequence of N gonorrhoeae isolates, we should be aware of the sensitivity of the PCR assays in use for tetracycline-resistant N gonorrhoeae detection.