The Development of New Agents for Post-Hematopoietic Stem Cell Transplantation Non-Infectious Complications in Children.

Hematopoietic stem cell transplantation (HSCT) is often the only curative treatment option for patients suffering from various types of malignant diseases and some non-cancerous conditions. Nevertheless, it is associated with a high risk of complications leading to transplant-related mortality and long-term morbidity. An increasing number of therapeutic and prevention strategies have been developed over the last few years to tackle the complications arising in patients receiving an HSCT. These strategies have been mainly carried out in adults and some are now being translated into children. In this manuscript, we review the recent advancements in the development and implementation of treatment options for post-HSCT non-infectious complications in pediatric patients with leukemia and other non-malignant conditions, with a special attention on the new agents available within clinical trials. We focused on the following conditions: graft failure, prevention of relapse and early interventions after detection of minimal residual disease positivity following HSCT in acute lymphoblastic and myeloid leukemia, chronic graft versus host disease, non-infectious pulmonary complications, and complications of endothelial origin.

Implementation of paediatric precision oncology into clinical practice: The Individualized Therapies for Children with cancer program 'iTHER'.

iTHER is a Dutch prospective national precision oncology program aiming to define tumour molecular profiles in children and adolescents with primary very high-risk, relapsed, or refractory paediatric tumours. Between April 2017 and April 2021, 302 samples from 253 patients were included. Comprehensive molecular profiling including low-coverage whole genome sequencing (lcWGS), whole exome sequencing (WES), RNA sequencing (RNA-seq), Affymetrix, and/or 850k methylation profiling was successfully performed for 226 samples with at least 20% tumour content. Germline pathogenic variants were identified in 16% of patients (35/219), of which 22 variants were judged causative for a cancer predisposition syndrome. At least one somatic alteration was detected in 204 (90.3%), and 185 (81.9%) were considered druggable, with clinical priority very high (6.1%), high (21.3%), moderate (26.0%), intermediate (36.1%), and borderline (10.5%) priority. iTHER led to revision or refinement of diagnosis in 8 patients (3.5%). Temporal heterogeneity was observed in paired samples of 15 patients, indicating the value of sequential analyses. Of 137 patients with follow-up beyond twelve months, 21 molecularly matched treatments were applied in 19 patients (13.9%), with clinical benefit in few. Most relevant barriers to not applying targeted therapies included poor performance status, as well as limited access to drugs within clinical trial. iTHER demonstrates the feasibility of comprehensive molecular profiling across all ages, tumour types and stages in paediatric cancers, informing of diagnostic, prognostic, and targetable alterations as well as reportable germline variants. Therefore, WES and RNA-seq is nowadays standard clinical care at the Princess Máxima Center for all children with cancer, including patients at primary diagnosis. Improved access to innovative treatments within biology-driven combination trials is required to ultimately improve survival.

Disaster zones-should we be clowning around?

Medical clowns have an important role in helping patients cope with their pain and distress. This is especially true in the pediatric population. However, their activity in a disaster area is unheard of. Following the Nepal earthquake in 2015, the Israeli field hospital set up in Kathmandu, Nepal was joined by five volunteer medical clowns. They were active in all parts of the field hospital. Following the hospital's activity, an online questionnaire was sent to the field hospital members to assess the impact of medical clowning on the hospital in general and its members' individual performance. Physicians and nurses found that medical clowning had a positive impact both generally and personally. (65.4 and 78.3% respectively on general impact.) Personnel that were not previously exposed to medical clowning also found them to have a positive impact; however, they were less likely to view it as impacting their personal performance. CONCLUSION: Medical teams in disaster areas may benefit from the presence of medical clowns. What is known about this topic: • Medical clowns are used for alleviation and distraction in painful and distressful medical procedures and treatments. Its positive effect on patients, and their families are well established. WHAT THIS STUDY ADDS: • This is the first description of medical clowning in a disaster area. In addition, the impact of medical clowning on the medical staff working in a disaster area is evaluated. No previous studies have explored the impact of medical clowns on the medical staff.

Therapy with eculizumab for patients with CD59 p.Cys89Tyr mutation.

OBJECTIVE: The objective of this work was to report on the outcome of eculizumab treatment in pediatric patients with recurrent acute predominantly motor, demyelinating neuropathy with conduction block, and chronic hemolysis attributed to p.Cys89Tyr mutation in the CD59 gene. METHODS: Four patients were recruited from our new registry of patients with homozygosity for the p.Cys89Tyr mutation on CD59. Participants received repeated intravenous eculizumab. In this 24-month open-label phase IIa study, we aimed to determine whether eculizumab reduces chronic hemolysis, and cumulative doses of steroids and intravenous immunoglobulin (IVIG), and ameliorates neurological deficits, compared to pretreatment status. Treatment response was evaluated every 2 to 4 weeks over 104 weeks and included examination with gross motor scoring by American Spinal Injury Association Impairment Scale and Inflammatory Neuropathy Cause and Treatment disability score, laboratory examination, well-being [12-item Short Form Health Survey; SF-12]). Neurological relapses and cumulative dose of IVIGs and/or corticosteroids before and after treatment were documented. Red blood cells (RBCs) and neutrophils were stained to evaluate C5b-9 deposition. ClinicalTrials.gov: NCT01579838. RESULTS: Dramatic and significant neurological amelioration in the upper limbs and trunk with more-modest amelioration in the lower limbs was observed in all patients. Corticosteroid and IVIG treatment was completely stopped. No patient relapsed during treatment despite infections, and there were no hospital admissions. Decreased C3bi and C5b-9 deposition on RBCs and neutrophils was documented (p < 0.0001). The SF-12 health questionnaires indicated significant improvement (p < 0.003). INTERPRETATION: Eculizumab was safely administered to these patients. Marked clinical improvement suggests that eculizumab may be a life-saving treatment for patients with acute predominantly motor, demyelinating neuropathy with conduction block, and secondary axonal damage attributed to primary p.Cys89Tyr mutation in the CD59 gene. Ann Neurol 2016;80:708-717.

Procedural sedation and analgesia in the emergency room of a field hospital after the Nepal earthquake.

Procedural sedation and analgesia (PSA) should be a priority in the emergency care of injured children. This humanistic approach is particularly important in paediatric victims of disaster, because these patients are prone to psychological distress secondary to the traumatic event. Following the Nepal earthquake, an Israeli field hospital (IFH) was deployed in Kathmandu. We report our experience with PSA in the emergency room (ER) of the IFH. 22 children underwent surgery in the operating room and 10 underwent PSA in the ER by paediatric emergency physicians: 6 had wound debridement, 2 had fracture reduction and 2 had laceration repair. All the procedures were successfully completed in the ER and no patient required intubation or admission to the intensive care unit due to an adverse event. The present study is the first report of the practice of paediatric PSA by non-anaesthesiologists in a field hospital.

Unexplained complaints in primary care: evidence of action bias.

PURPOSE: Primary care physicians sometimes encounter patients with clinical complaints that do not fit into a recognized diagnostic pattern. This study was undertaken to assess the way physicians respond to patients whose symptoms are unusual or unexplained that is, what approach they take in the absence of a working hypothesis. METHODS: We surveyed 130 primary care physicians affiliated with 3 academic centers in Israel, presenting 5 clinical vignettes describing patients who had unusual complaints, no clear diagnosis, and no apparent need for urgent care. We asked physicians to provide the most likely diagnosis for each case and to rate their level of confidence in that diagnosis;respondents were also asked to provide a management strategy for each case and their level of confidence in the chosen approach. Finally, we asked the physicians to estimate how many of their own patients have presentations similar to the individuals in the clinical vignettes. RESULTS: Physicians proposed, on average, 22 diagnoses for each case. Most indicated that they would choose action (testing, consulting, sending the patient to the emergency department, or prescribing) rather than follow-up only (87% vs 13%; P<.01). Respondents' confidence in the management approach they had chosen for all the cases was higher than their confidence in the diagnoses (5.6 vs 4.3, respectively, on a scale of1-10; P<.001). Physicians estimated that 10% to 20% of the patients they see in their practice have unusual or unexplained symptoms that are difficult to diagnose. CONCLUSION: Uncertain diagnosis is a regular challenge for primary care physicians. In such cases, we found that physicians prefer a workup to follow-up, an inclination consistent with"action bias."

Underdiagnosed menorrhagia in adolescents is associated with underdiagnosed anemia.

OBJECTIVE: To test the hypothesis that adolescent girls with menorrhagia rarely seek medical attention. STUDY DESIGN: A total of 705 adolescent girls attended a lecture on menorrhagia, completed an initial anonymous questionnaire, and were asked to participate in a more comprehensive study comprising a detailed bleeding questionnaire, a pictorial blood loss assessment chart, and blood tests. RESULTS: A total of 105 adolescents (15%) reported they had heavy periods on the initial questionnaire. Among the 94 girls who completed the full questionnaire, 34 reported menorrhagia (36%; 95% CI, 26.5%-46.7%). Almost one-third (11 of 34) of these girls did not perceive having menorrhagia according to their response to the initial questionnaire. Menorrhagia was not related to age, years since menarche, or family history of menorrhagia. Among the 62 girls who consented to blood testing, 6 had anemia (9.6%; 95% CI, 3.6%-19.6%), all of whom had bleeding symptoms. CONCLUSION: Using standardized questionnaires, we were able to identify adolescents with menorrhagia associated with anemia. Importantly, some of these adolescents were not aware of having menorrhagia and/or anemia. Screening programs for menorrhagia in schools could result in better detection of menorrhagia among adolescents and consequent appropriate referral for medical consultation.