Clinical outcomes and patient-matched molecular composition of relapsed medulloblastoma

© 2021 by American Society of Clinical Oncology. Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: https://creativecommons.org/licenses/by-nc-nd/4.0/Purpose: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors. Methods: Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing. Results: A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms. Conclusion: Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.info:eu-repo/semantics/publishedVersio

Randomized Trial of Late Surfactant Treatment in Ventilated Preterm Infants Receiving Inhaled Nitric Oxide.

ObjectiveTo assess whether late surfactant treatment in extremely low gestational age (GA) newborn infants requiring ventilation at 7-14 days, who often have surfactant deficiency and dysfunction, safely improves survival without bronchopulmonary dysplasia (BPD).Study designExtremely low GA newborn infants (GA ≤28 0/7 weeks) who required mechanical ventilation at 7-14 days were enrolled in a randomized, masked controlled trial at 25 US centers. All infants received inhaled nitric oxide and either surfactant (calfactant/Infasurf) or sham instillation every 1-3 days to a maximum of 5 doses while intubated. The primary outcome was survival at 36 weeks postmenstrual age (PMA) without BPD, as evaluated by physiological oxygen/flow reduction.ResultsA total of 511 infants were enrolled between January 2010 and September 2013. There were no differences between the treated and control groups in mean birth weight (701 ± 164 g), GA (25.2 ± 1.2 weeks), percentage born at GA <26 weeks (70.6%), race, sex, severity of lung disease at enrollment, or comorbidities of prematurity. Survival without BPD did not differ between the treated and control groups at 36 weeks PMA (31.3% vs 31.7%; relative benefit, 0.98; 95% CI, 0.75-1.28; P = .89) or 40 weeks PMA (58.7% vs 54.1%; relative benefit, 1.08; 95% CI, 0.92-1.27; P = .33). There were no between-group differences in serious adverse events, comorbidities of prematurity, or severity of lung disease to 36 weeks.ConclusionLate treatment with up to 5 doses of surfactant in ventilated premature infants receiving inhaled nitric oxide was well tolerated, but did not improve survival without BPD at 36 or 40 weeks. Pulmonary and neurodevelopmental assessments are ongoing.Trial registrationClinicalTrials.gov: NCT01022580

The Randomized, Controlled Trial of Late Surfactant: Effects on Respiratory Outcomes at 1-Year Corrected Age.

ObjectiveTo determine the effects of late surfactant on respiratory outcomes determined at 1-year corrected age in the Trial of Late Surfactant (TOLSURF), which randomized newborns of extremely low gestational age (≤28 weeks' gestational age) ventilated at 7-14 days to late surfactant and inhaled nitric oxide vs inhaled nitric oxide-alone (control).Study designCaregivers were surveyed in a double-blinded manner at 3, 6, 9, and 12 months' corrected age to collect information on respiratory resource use (infant medication use, home support, and hospitalization). Infants were classified for composite outcomes of pulmonary morbidity (no PM, determined in infants with no reported respiratory resource use) and persistent PM (determined in infants with any resource use in ≥3 surveys).ResultsInfants (n = 450, late surfactant n = 217, control n = 233) were 25.3 ± 1.2 weeks' gestation and 713 ± 164 g at birth. In the late surfactant group, fewer infants received home respiratory support than in the control group (35.8% vs 52.9%, relative benefit [RB] 1.28 [95% CI 1.07-1.55]). There was no benefit of late surfactant for No PM vs PM (RB 1.27; 95% CI 0.89-1.81) or no persistent PM vs persistent PM (RB 1.01; 95% CI 0.87-1.17). After adjustment for imbalances in baseline characteristics, relative benefit of late surfactant treatment increased: RB 1.40 (95% CI 0.89-1.80) for no PM and RB 1.24 (95% CI 1.08-1.42) for no persistent PM.ConclusionTreatment of newborns of extremely low gestational age with late surfactant in combination with inhaled nitric oxide decreased use of home respiratory support and may decrease persistent pulmonary morbidity.Trial registrationClinicalTrials.gov: NCT01022580

The Randomized, Controlled Trial of Late Surfactant: Effects on Respiratory Outcomes at 1-Year Corrected Age.

ObjectiveTo determine the effects of late surfactant on respiratory outcomes determined at 1-year corrected age in the Trial of Late Surfactant (TOLSURF), which randomized newborns of extremely low gestational age (≤28 weeks' gestational age) ventilated at 7-14 days to late surfactant and inhaled nitric oxide vs inhaled nitric oxide-alone (control).Study designCaregivers were surveyed in a double-blinded manner at 3, 6, 9, and 12 months' corrected age to collect information on respiratory resource use (infant medication use, home support, and hospitalization). Infants were classified for composite outcomes of pulmonary morbidity (no PM, determined in infants with no reported respiratory resource use) and persistent PM (determined in infants with any resource use in ≥3 surveys).ResultsInfants (n = 450, late surfactant n = 217, control n = 233) were 25.3 ± 1.2 weeks' gestation and 713 ± 164 g at birth. In the late surfactant group, fewer infants received home respiratory support than in the control group (35.8% vs 52.9%, relative benefit [RB] 1.28 [95% CI 1.07-1.55]). There was no benefit of late surfactant for No PM vs PM (RB 1.27; 95% CI 0.89-1.81) or no persistent PM vs persistent PM (RB 1.01; 95% CI 0.87-1.17). After adjustment for imbalances in baseline characteristics, relative benefit of late surfactant treatment increased: RB 1.40 (95% CI 0.89-1.80) for no PM and RB 1.24 (95% CI 1.08-1.42) for no persistent PM.ConclusionTreatment of newborns of extremely low gestational age with late surfactant in combination with inhaled nitric oxide decreased use of home respiratory support and may decrease persistent pulmonary morbidity.Trial registrationClinicalTrials.gov: NCT01022580

Effect of Fluconazole Prophylaxis on Candidiasis and Mortality in Premature Infants

IMPORTANCE: Invasive candidiasis in premature infants causes mortality and neurodevelopmental impairment. Fluconazole prophylaxis reduces candidiasis, but its effect on mortality and the safety of fluconazole is unknown. OBJECTIVE: To evaluate the efficacy and safety of fluconazole in preventing death or invasive candidiasis in extremely low-birth-weight infants. DESIGN, SETTING, AND PATIENTS: This study was a randomized, blinded, placebo-controlled trial of fluconazole in premature infants. Infants weighing less than 750 g at birth (N = 361) from 32 neonatal intensive care units (NICUs) in the United States were randomly assigned to receive either fluconazole or placebo twice weekly for 42 days. Surviving infants were evaluated at 18 to 22 months corrected age for neurodevelopmental outcomes. The study was conducted between November 2008 and February 2013. INTERVENTIONS: Fluconazole (6 mg/kg of body weight) or placebo. MAIN OUTCOMES AND MEASURES: The primary end point was a composite of death or definite or probable invasive candidiasis prior to study day 49 (1 week after completion of study drug). Secondary and safety outcomes included invasive candidiasis, liver function, bacterial infection, length of stay, intracranial hemorrhage, periventricular leukomalacia, chronic lung disease, patent ductus arteriosus requiring surgery, retinopathy of prematurity requiring surgery, necrotizing enterocolitis, spontaneous intestinal perforation, and neurodevelopmental outcomes—defined as a Bayley-III cognition composite score of less than 70, blindness, deafness, or cerebral palsy at 18–22-months corrected age. RESULTS: Among infants receiving fluconazole, the composite primary end point of death or invasive candidiasis was 16% (95% CI, 11%–22%) vs 21% in the placebo group (95% CI, 15%–28%; odds ratio 0.73 [95% CI 0.43–1.23]; P=.24; treatment difference −5% [95% CI, −13%–3%]). Invasive candidiasis occurred less frequently in the fluconazole group (3% [95% CI, 1%–6%] vs the placebo group (9% [95% CI, 5%–14%]; P=.02; treatment difference −6% [95% CI, −11%–−1%]). The cumulative incidences of other secondary outcomes were not statistically different between groups. Neurodevelopmental impairment did not differ between the groups (fluconazole 31% [95% CI, 21–41%] vs placebo, 27% [95% CI, 18–37%]; P=.60; treatment difference 4% [95% CI, −10–17%]). CONCLUSIONS AND RELEVANCE: Among infants with a birth weight of less 750 g, 42 days of fluconazole prophylaxis compared with placebo did not result in a lower incidence of the composite of death or invasive candidiasis. These findings do not support the universal use of prophylactic fluconazole in extremely-low-birth-weight infants. TRIAL REGISTRATION: ClinicalTrials.gov number NCT0073453

Composition of hydrothermal fluids and mineralogy of associated chimney material on the East Scotia Ridge back-arc spreading centre

The East Scotia Ridge is an active back-arc spreading centre located to the west of the South Sandwich island arc in the Southern Ocean. Initial exploration of the ridge by deep-tow surveys provided the first evidence for hydrothermal activity in a back-arc setting outside of the western Pacific, and we returned in 2010 with a remotely operated vehicle to precisely locate and sample hydrothermal sites along ridge segments E2 and E9. Here we report the chemical and isotopic composition of high- and low-temperature vent fluids, and the mineralogy of associated high-temperature chimney material, for two sites at E2 (Dog’s Head and Sepia), and four sites at E9 (Black & White, Ivory Tower, Pagoda and Launch Pad). The chemistry of the fluids is highly variable between the ridge segments. Fluid temperatures were ∼350 °C at all vent sites except Black & White, which was significantly hotter (383 °C). End-member chloride concentrations in E2 fluids (532 - 536 mM) were close to background seawater (540 mM), whereas Cl in E9 fluids was much lower (98 - 220 mM) indicating that these fluids are affected by phase separation. Concentrations of the alkali elements (Na, Li, K and Cs) and the alkaline earth elements (Ca, Sr and Ba) co-vary with Cl, due to charge balance constraints. Similarly, concentrations of Mn and Zn are highest in the high Cl fluids but, by contrast, Fe/Cl ratios are higher in E9 fluids (3.8 – 8.1 × 10−3) than they are in E2 fluids (1.5 - 2.4 × 10−3) and fluids with lowest Cl have highest Cu. Although both ridge segments are magmatically inflated, there is no compelling evidence for input of magmatic gases to the vent fluids. Fluid δD values range from 0.2 to 1.5 ‰, pH values (3.02 - 3.42) are not especially low, and F concentrations (34.6 - 54.4 μM) are lower than bottom seawater (62.8 μM). The uppermost sections of conjugate chimney material from E2, and from Ivory Tower and Pagoda at E9, typically exhibit inner zones of massive chalcopyrite enclosed within an outer zone of disseminated sulphide, principally sphalerite and pyrite, in an anhydrite matrix. By contrast, the innermost part of the chimneys that currently vent fluids with lowest Cl (Black & White and Launch Pad), is dominated by anhydrite. By defining and assessing the controls on the chemical composition of these vent fluids, and associated mineralisation, this study provides new information for evaluating the significance of hydrothermal processes at back-arc basins for ocean chemistry and the formation of seafloor mineral deposits