Breaking the chains of lipoprotein lipase deficiency: A pediatric perspective on the efficacy and safety of Volanesorsen.

RATIONALE: Lipoprotein lipase (LPL) deficiency, a rare inherited metabolic disorder, is characterized by high triglyceride (TG) levels and life-threatening acute pancreatitis. Current treatment for pediatric patients involves a lifelong severely fat-restricted diet, posing adherence challenges. Volanesorsen, an EMA-approved RNA therapy for adults, effectively reduces TG levels by decreasing the production of apolipoprotein C-III. This 96-week observational open-label study explores Volanesorsen's safety and efficacy in a 13-year-old female with LPL deficiency. METHODS: The patient, with a history of severe TG elevations, 53 hospital admissions, and life-threatening recurrent pancreatitis despite dietary restrictions, received weekly subcutaneous Volanesorsen injections. We designed a protocol for this investigator-initiated study, primarily focusing on changes in fasting TG levels and hospital admissions. RESULTS: While the injections caused occasional pain and swelling, no other adverse events were observed. TG levels decreased during treatment, with more measurements below the pancreatitis risk threshold compared to pre-treatment. No hospital admissions occurred in the initial 14 months of treatment, contrasting with 21 admissions in the 96 weeks before. In the past 10 months, two pancreatitis episodes may have been linked to dietary noncompliance. Dietary restrictions were relaxed, increasing fat intake by 65% compared to baseline. While not fully reflected in the PedsQL, both parents and the patient narratively reported an improved quality of life. CONCLUSION: This study demonstrates, for the first time, that Volanesorsen is tolerated in a pediatric patient with severe LPL deficiency and effectively lowers TG levels, preventing life-threatening complications. This warrants consideration for expanded access in this population.

Dexamethasone in the maintenance phase of acute lymphoblastic leukaemia treatment: is the risk of lethal infections too high?

We report an increased incidence of infectious deaths during maintenance treatment of the ninth protocol for acute lymphoblastic leukaemia of the Dutch Childhood Oncology Group (DCOG-ALL-9). The main difference in maintenance treatment between DCOG-ALL-9 and the DCOG-ALL-7 and DCOG-ALL-8 protocols is the interruption of methotrexate and 6-mercaptopurine by vincristine (2mg/m(2) weekly) and dexamethasone (6mg/m(2) daily) for 14 days every 7 weeks in the DCOG-ALL-9 protocol. The 1107 children treated with the DCOG-ALL-7, DCOG-ALL-8 or DCOG-ALL-9 protocol were included and screened for infectious death during maintenance treatment (July 1988-July 2002). Seven of the 510 children died of severe infections during the maintenance phase of DCOG-ALL-9, compared to none of the 597 patients during the DCOG-ALL-7 and DCOG-ALL-8 protocols (1.37% versus 0.0%; p=0.013). Results from the current study suggest that repeated, prolonged exposure to dexamethasone results in an increase of lethal infections from 0% to 1.37%. In the dosing-schedule used, the advantage of dexamethasone may not outweigh the higher risk of infectious death.

Longitudinal study of fetal body movements: nomograms, intrafetal consistency, and relationship with episodes of heart rate patterns a and B.

Our objective was to investigate the longitudinal development of incidence parameters of fetal body movements to define normal reference ranges, to relate them to episodes of fetal heart rate patterns A and B, and to determine the intrafetal consistency for these parameters. Twenty-nine fetuses were studied longitudinally from 24 wk of gestation. Fetal body movements and heart rate were recorded at fortnightly intervals between 24 and 36 wk of gestation and weekly from 36 wk of gestation. Data were analyzed using multilevel analysis. Reference ranges were constructed for the percentage of observation time that movements were present, the number of movement bursts per hour, the mean burst duration, and the median onset-onset interval. The median percentage incidence of fetal body movements decreased from 17% at 24 wk to about 7% near term. The developmental course was the same during active episodes. Body movements also decreased during episodes of relative quiescence, in the course of pregnancy. Intrafetal variance was on average 40-80% of the total range of the four movement parameters. Normal reference ranges were developed for incidence parameters of fetal body movements from 24 wk of gestation onward. The overall decline in the incidence of movements during pregnancy appeared to be a developmental phenomenon and not due to progressively increasing episodes of fetal quiescence. Individual fetuses showed a degree of consistency in the percentage incidence of body movements, but intra- and interfetal variances were generally high, resulting in wide ranges.