Mutational patterns in therapy-related acute lymphoblastic leukemia subgroups: one step closer to unveiling the genetic odyssey.

There is increasing evidence that therapy-related acute lymphoblastic leukemia (trALL) resulting from chemo- and/or radiotherapy represents a distinct entity. However, apart from KMT2A rearrangements, which have been repeatedly reported in this subgroup, the relevance of other aberrations remains controversial due to divergent study results and sparse molecular analyses. Within our ALL patient cohort, 15% (n = 19/131) met the criteria for trALL with a high proportion of Ph + and KMT2A rearrangements. On the molecular level, the most frequently observed mutation was KMT2D, followed by CDKN2A, KRAS and DNMT3A. No TP53 mutation was detected. Outcome was particularly poor in Ph + trALL compared to Ph+ de novo ALL, which seemed to be mitigated by allogeneic stem cell transplantation. Our findings further define trALL as a distinct entity but highlight the need for further molecular genome sequencing of somatic and germline variants to advance our understanding of trALL.

Real-world outcomes in elderly ALL patients with and without allogeneic hematopoietic stem cell transplantation: a single-center evaluation over 10 years.

Elderly patients (EP) of 60 years and above with acute lymphoblastic leukemia (ALL) have a dismal prognosis, but pediatric-inspired chemotherapy and allogeneic stem cell transplantation (allo HCT) are used reluctantly due to limited data and historical reports of high treatment-related mortality in EP. We analyzed 130 adult ALL patients treated at our center between 2009 and 2019, of which 26 were EP (range 60-76 years). Induction with pediatric-inspired protocols was feasible in 65.2% of EP and resulted in complete remission in 86.7% compared to 88.0% in younger patients (YP) of less than 60 years. Early death occurred in 6.7% of EP. Three-year overall survival (OS) for Ph - B-ALL was significantly worse for EP (n = 16) than YP (n = 64) with 30.0% vs 78.1% (p ≤ 0.001). Forty-nine patients received allo HCT including 8 EP, for which improved 3-year OS of 87.5% was observed, whereas EP without allo HCT died after a median of 9.5 months. In Ph + B-ALL, 3-year OS did not differ between EP (60.0%, n = 7) and YP (70.8%, n = 19). Non-relapse mortality and infection rate were low in EP (14.3% and 12.5%, respectively). Our data indicate that selected EP can be treated effectively and safely with pediatric regimens and might benefit from intensified therapy including allo HCT.

Parameters affecting length of stay in a pediatric emergency department: a retrospective observational study.

Prolonged emergency department (ED) length of stay (LOS) is used as a proxy for ED overcrowding and is associated with adverse outcomes of patients requiring therapy and reduced patient satisfaction. Our aim was to identify and quantify variables which affect ED-LOS. Patients admitted to the pediatric ED of a large regional Swiss hospital during a 1-year period were analyzed for LOS (in minutes). Predictor variables included patient-associated parameters (time of admission and discharge, ED occupancy, triage score, diagnosis, and demographic data) and external factors (weekday, time, and season). A total of 4885 visits were included in a multivariable logistic regression analysis. Median LOS was 124 min. The most important factors associated with prolonged LOS were physician referral (adjusted odds ratio [OR], 1.97; 95% confidence interval [CI], 1.47-2.62); morning admissions, especially before noon (OR, 1.92; 95% CI, 1.23-3.07); and gastrointestinal infections (OR, 1.38; 95% CI, 1.08-1.76). Upper airway infections (OR, 0.37; 95% CI, 0.27-0.49) and triage level 5 (OR, 0.18; 95% CI, 0.06-0.61) were inversely associated with ED-LOS. Together with ED occupancy, these factors did significantly contribute to log LOS in a stepwise backward multiple regression model (p < 0.001). CONCLUSION: Several parameters are associated with prolonged ED-LOS. Notably, morning arrivals represent possible targets for strategies to reduce LOS. What is Known: • Prolonged length of stay (LOS) may affect care delivered to admitted patients in the emergency department (ED) and is well studied in the setting of adult patients with high acuity conditions. • Little is known about parameters which impact LOS in European pediatric EDs. What is New: • Several predictors of prolonged LOS could be identified in a European pediatric setting. • Our results indicate that prolonged LOS is associated with modifiable factors like morning and summer admission, which have the potential to be addressed by modification in staffing, infrastructure, and higher attention to faster processing.

Prevalence of Anti-infliximab Antibodies and Their Associated Co-factors in Children with Refractory Arthritis and/or Uveitis: A Retrospective Longitudinal Cohort Study.

OBJECTIVE: Infliximab (IFX) is a monoclonal tumor necrosis factor-α-inhibiting antibody used in children with refractory arthritis and uveitis. Immunogenicity is associated with a lack of clinical response and infusion reactions in adults; data on immunogenicity in children treated with IFX for rheumatic diseases are scarce. We aimed to describe the prevalence of anti-IFX antibodies and determine co-factors associated with anti-IFX antibodies in children with inflammatory rheumatic and ocular diseases. METHODS: Consecutive children treated between August 2009 and August 2012 with IFX at our department were included. Blood samples were collected every 6 months before IFX infusion and tested for anti-IFX antibodies by radioimmunoassay. Patients' charts were retrospectively reviewed for clinical features and analyzed for associations with anti-IFX antibodies. RESULTS: Anti-IFX antibodies occurred in 14/62 children (23%) and 32/253 blood samples (12.6%) after a mean treatment time of 1084 days (range 73-3498). Infusion reactions occurred in 10/62 (16%) children during the treatment period. With continuation of IFX, anti-IFX antibodies disappeared in 7/14 children. In the bivariate analysis, the occurrence of anti-IFX antibodies was associated with younger age at IFX treatment start (mean age 7.01 vs 9.88 yrs, p = 0.003) and infusion reactions (OR 15.0), while uveitis as treatment indication was protective against development of anti-IFX antibodies (OR 0.17), likely because of higher IFX doses. In the multivariate logistic regression, all 3 covariates remained highly significant. CONCLUSION: Anti-IFX antibodies occurred commonly at any time during IFX treatment. Anti-IFX antibodies were associated with younger age at IFX start, infusion reactions, and arthritis as treatment indication.

Infliximab in pediatric rheumatology patients: a retrospective analysis of infusion reactions and severe adverse events during 2246 infusions over 12 years.

OBJECTIVE: To describe infusion reactions (IR) and severe adverse events (SAE) associated with infliximab (IFX) in pediatric patients with rheumatologic and ocular inflammatory diseases in a real-world setting. METHODS: This is a retrospective chart review of all patients treated with IFX at the pediatric rheumatology division of a university hospital between October 2000 and December 2012. RESULTS: A total of 2446 IFX infusions were given to 82 patients (72% female). IR occurred in 46 infusions (2%) of 14 patients (17%) after a mean IFX treatment time of 340 days (range 41-780); 9/14 patients (64%) experienced repeated IR. IR were classified as mild (26%), moderate (74%), or severe (0%). Indications for IFX were arthritis (60%), uveitis (20%), arthritis and uveitis (13%), and other inflammatory diseases (5%). The most common clinical symptoms were respiratory signs (72%), cutaneous manifestations (69%), and malaise (61%). In 6/14 patients (43%) with IR, IFX was discontinued: 4 patients because of repeated IR and 2 patients wished to stop treatment immediately following a mild IR. The other 8/14 patients (57%) received premedication with high-dose antihistamine (100%), corticosteroids (75%), and IFX dose increase (75%) and continued IFX treatment for a mean followup period of 146 weeks (range 26-537) after the first IR. We observed severe infections in 5/82 patients (6%); other SAE were rare. CONCLUSION: Mild and moderate IR occurred in 17% of our patients. Treatment with antihistamines and methylprednisolone, and increasing the IFX dose, allowed continued treatment despite IR in > 50% of patients. Other SAE were infrequent.

Various anti-motion sickness drugs and core body temperature changes.

INTRODUCTION: Blood flow changes and inactivity associated with motion sickness appear to exacerbate the rate of core temperature decrease during subsequent body cooling. We investigated the effects of various classes of anti-motion sickness drugs on core temperature changes. METHODS: There were 12 healthy male and female subjects (20-35 yr old) who were given selected classes of anti-motion sickness drugs prior to vestibular Coriolis cross coupling induced by graded yaw rotation and periodic pitch-forward head movements in the sagittal plane. All subjects were then immersed in water at 18 degrees C for a maximum of 90 min or until their core temperature reached 35 degrees C. Double-blind randomized trials were administered, including a placebo, a non-immersion control with no drug, and six anti-motion sickness drugs: meclizine, dimenhydrinate, chlorpheniramine, promethazine + dexamphetamine, promethazine + caffeine, and scopolamine + dexamphetamine. A 7-d washout period was observed between trials. Core temperature and the severity of sickness were monitored throughout each trial. RESULTS: A repeated measures design was performed on the severity of sickness and core temperature changes prior to motion provocation, immediately after the motion sickness end point, and throughout the period of cold-water immersion. The most effective anti-motion sickness drugs, promethazine + dexamphetamine (with a sickness score/duration of 0.65 +/- 0.17) and scopolamine + dexamphetamine (with a sickness score/duration of 0.79 +/- 0.17), significantly attenuated the decrease in core temperature. The effect of this attenuation was lower in less effective drugs. CONCLUSION: Our results suggest that the two most effective anti-motion sickness drugs are also the most effective in attenuating the rate of core temperature decrease.

Failure of cetirizine and fexofenadine to prevent motion sickness.

OBJECTIVE: To determine the effectiveness of 2 second-generation antihistamines in modulating motion sickness induced by Coriolis vestibular cross-coupling stimulation. METHODS: This prospective, randomized, double-blind, crossover, placebo-controlled study was conducted in 18 healthy adults. Subjects were exposed to Coriolis vestibular cross-coupling in the laboratory using the Staircase Profile Test for baseline susceptibility and when under the influence of cetizirine, fexofenadine, and placebo. Subjective evaluation of sickness symptoms was based on the Graybiel diagnostic criteria of acute motion sickness, Golding's scale, and the Coriolis Sickness Susceptibility Index. RESULTS: Repeated measures ANOVA and Friedman nonparametric ANOVA of rank tests revealed that there were significant differences in symptom assessments based on Graybiel's diagnostic criteria (p < or = 0.001), subjective symptoms of motion sickness (p < or = 0.001), and state-anxiety (p < or = 0.001) before and after motion exposure. However, there are no significant differences between the baseline susceptibility to motion sickness and treatment with placebo, cetirizine, or fexofenadine. CONCLUSIONS: The failure of the second-generation antihistamines cetirizine and fexofenadine to prevent motion sickness suggests that the therapeutic actions of this class of antihistamines against motion sickness may be mediated through central versus peripheral receptors. The sedative effect of other antihistamines, such as hydroxyzine, may play a more significant role in alleviating motion sickness than previously thought.