Sequential analysis of cfDNA reveals clonal evolution in neuroblastoma patients receiving ALK targeted therapy.

PURPOSE: The study of cell free DNA (cfDNA) enables sequential analysis of tumor cell-specific genetic alterations in neuroblastoma patients. EXPERIMENTAL DESIGN: Eighteen patients with relapsing neuroblastoma having received Lorlatinib, a 3rd generation ALK inhibitor, were identified (SACHA national registry and/or in the institution). cfDNA was analyzed at relapse for 9 patients, and sequentially for 5 patients (blood/bone marrow plasma) by performing WGS library construction followed by ALK-targeted ddPCR of the hotspot mutations (F1174L, R1275Q, I1170N) (variant allele fraction (VAF) detection limit 0.1%) and WES to evaluate disease burden and clonal evolution, following comparison with tumor/germline WES. RESULTS: Overall response rate to Lorlatinib was 33% (CI 13-59%), with response observed in 6/10 cases without versus 0/8 cases with MYCN amplification (MNA). ALK VAFs correlated with the overall clinical disease status, with a VAF<0.1% in clinical remission, versus higher VAFs (>30%) at progression. Importantly, sequential ALK ddPCR detected relapse earlier than clinical imaging. cfDNA WES revealed new SNVs, not seen in the primary tumor, in all instances of disease progression after Lorlatinib treatment, indicating clonal evolution, including alterations in genes linked to tumor aggressivity (TP53) or novel targets (EGFR). Gene pathway analysis revealed an enrichment for genes targeting cell differentiation in emerging clones, and cell adhesion in persistent clones. Evidence of clonal hematopoiesis could be observed in follow-up samples. CONCLUSION: We demonstrate the clinical utility of combining ALK cfDNA ddPCR for disease monitoring and cfDNA WES for the study of clonal evolution and resistance mechanisms in neuroblastoma patients receiving ALK targeted therapy.

Measuring Safety and Outcomes for the Use of Compassionate and Off-Label Therapies for Children, Adolescents, and Young Adults With Cancer in the SACHA-France Study.

Importance: Innovative anticancer therapies for children, adolescents, and young adults are regularly prescribed outside their marketing authorization or through compassionate use programs. However, no clinical data of these prescriptions is systematically collected. Objectives: To measure the feasibility of the collection of clinical safety and efficacy data of compassionate and off-label innovative anticancer therapies, with adequate pharmacovigilance declaration to inform further use and development of these medicines. Design, Setting, and Participants: This cohort study included patients treated at French pediatric oncology centers from March 2020 to June 2022. Eligible patients were aged 25 years or younger with pediatric malignant neoplasms (solid tumors, brain tumors, or hematological malignant neoplasms) or related conditions who received compassionate use or off-label innovative anticancer therapies. Follow up was conducted through August 10, 2022. Exposures: All patients treated in a French Society of Pediatric Oncology (SFCE) center. Main Outcomes and Measures: Collection of adverse drug reactions and anticancer activity attributable to the treatment. Results: A total of 366 patients were included, with a median age of 11.1 years (range, 0.2-24.6 years); 203 of 351 patients (58%) in the final analysis were male. Fifty-five different drugs were prescribed, half of patients (179 of 351 [51%]) were prescribed these drugs within a compassionate use program, mainly as single agents (74%) and based on a molecular alteration (65%). Main therapies were MEK/BRAF inhibitors followed by multi-targeted tyrosine kinase inhibitors. In 34% of patients at least a grade 2 clinical and/or grade 3 laboratory adverse drug reaction was reported, leading to delayed therapy and permanent discontinuation of the innovative therapy in 13% and 5% of patients, respectively. Objective responses were reported in 57 of 230 patients (25%) with solid tumors, brain tumors, and lymphomas. Early identification of exceptional responses supported the development of specific clinical trials for this population. Conclusions and Relevance: This cohort study of the SACHA-France (Secured Access to Innovative Medicines for Children with Cancer) suggested the feasibility of prospective multicenter clinical safety and activity data collection for compassionate and off-label new anticancer medicines. This study allowed adequate pharmacovigilance reporting and early identification of exceptional responses allowing further pediatric drug development within clinical trials; based on this experience, this study will be enlarged to the international level.

Correction to: Avoidable waste related to inadequate methods and incomplete reporting of interventions: a systematic review of randomized trials performed in Sub-Saharan Africa.

CORRECTION: In the original publication [1] the last sentence in the last paragraph under 'Perspectives and implications' in the Discussions section needs to be removed. The correct version can be found in this Erratum.

Avoidable waste related to inadequate methods and incomplete reporting of interventions: a systematic review of randomized trials performed in Sub-Saharan Africa.

BACKGROUND: Randomized controlled trials (RCTs) are needed to improve health care in Sub-Saharan Africa (SSA). However, inadequate methods and incomplete reporting of interventions can prevent the transposition of research in practice which leads waste of research. The aim of this systematic review was to assess the avoidable waste in research related to inadequate methods and incomplete reporting of interventions in RCTs performed in SSA. METHODS: We performed a methodological systematic review of RCTs performed in SSA and published between 1 January 2014 and 31 March 2015. We searched PubMed, the Cochrane library and the African Index Medicus to identify reports. We assessed the risk of bias using the Cochrane Risk of Bias tool, and for each risk of bias item, determined whether easy adjustments with no or minor cost could change the domain to low risk of bias. The reporting of interventions was assessed by using standardized checklists based on the Consolidated Standards for Reporting Trials, and core items of the Template for Intervention Description and Replication. Corresponding authors of reports with incomplete reporting of interventions were contacted to obtain additional information. Data were descriptively analyzed. RESULTS: Among 121 RCTs selected, 74 (61%) evaluated pharmacological treatments (PTs), including drugs and nutritional supplements; and 47 (39%) nonpharmacological treatments (NPTs) (40 participative interventions, 1 surgical procedure, 3 medical devices and 3 therapeutic strategies). Overall, the randomization sequence was adequately generated in 76 reports (62%) and the intervention allocation concealed in 48 (39%). The primary outcome was described as blinded in 46 reports (38%), and incomplete outcome data were adequately addressed in 78 (64%). Applying easy methodological adjustments with no or minor additional cost to trials with at least one domain at high risk of bias could have reduced the number of domains at high risk for 24 RCTs (19%). Interventions were completely reported for 73/121 (60%) RCTs: 51/74 (68%) of PTs and 22/47 (46%) of NPTs. Additional information was obtained from corresponding authors for 11/48 reports (22%). CONCLUSION: Inadequate methods and incomplete reporting of published SSA RCTs could be improved by easy and inexpensive methodological adjustments and adherence to reporting guidelines.

Published randomized trials performed in Sub-Saharan Africa focus on high-burden diseases but are frequently funded and led by high-income countries.

BACKGROUND AND OBJECTIVE: In light of funding constraints in Sub-Saharan Africa (SSA), the value of research performed there must be increased. The objective of this study was to describe the epidemiology of published randomized controlled trials (RCTs) performed in SSA. METHODS: We searched PubMed, the Cochrane library, and African Index Medicus to identify reports of all RCTs performed in SSA and published between January 1, 2014 and March 31, 2015. We systematically recorded the country of the affiliation of the corresponding author and the funding source. The overall burden of disease was assessed by 2013 disability-adjusted life years (both sexes, all ages) in percentages for two locations: SSA and high-income countries (HICs). RESULTS: Only 12 of 121 RCTs were conducted in both Sub-Saharan Africa and another region, with 109 of 121 RCTs (90%) having trial centers exclusively located in SSA. The corresponding author's only affiliation was in SSA for 44/109 trials (40%) and was institutions in HICs for almost half of the trials. The funding source was nonprofit for 77/109 trials (70%) and was from HICs for 81% (n = 63/77). Overall, most RCTs targeted diseases with a high burden in SSA; 46% of the trials targeted the five diseases with the highest burden in SSA, mainly malaria (n = 25), HIV/AIDS (n = 24), lower respiratory tract infection (n = 2), diarrheal diseases (n = 3), and preterm birth complications (n = 2). Nevertheless, among the 25 diseases or health-related conditions with the highest burden in SSA, 9 (36%) were not assessed in any RCT. CONCLUSIONS: Published RCTs performed in SSA were mainly funded and led by HIC institutions, although investigations concerned diseases highly prevalent in SSA.

Comparison of central adjudication of outcomes and onsite outcome assessment on treatment effect estimates.

BACKGROUND: Assessment of events by adjudication committees (ACs) is recommended in multicentre randomised controlled trials (RCTs). However, its usefulness has been questioned. OBJECTIVES: The aim of this systematic review was to compare 1) treatment effect estimates of subjective clinical events assessed by onsite assessors versus by AC, and 2) treatment effect estimates according to the blinding status of the onsite assessor as well as the process used to select events to adjudicate. SEARCH METHODS: We searched Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, PsycINFO, CINAHL and Google Scholar (25 August 2015 as the last updated search date), using a combination of terms to retrieve RCTs with commonly used terms to describe ACs. SELECTION CRITERIA: We included all reports of RCTs and the published RCTs included in reviews and meta-analyses that reported the same subjective outcome event assessed by both an onsite assessor and an AC. DATA COLLECTION AND ANALYSIS: We extracted the odds ratio (OR) from onsite assessment and the corresponding OR from AC assessment and calculated the ratio of the odds ratios (ROR). A ratio of odds ratios < 1 indicated that onsite assessors generated larger effect estimates in favour of the experimental treatment than ACs. MAIN RESULTS: Data from 47 RCTs (275,078 patients) were used in the meta-analysis. We excluded 11 RCTs because of incomplete outcome data to calculate the OR for onsite and AC assessments. On average, there was no difference in treatment effect estimates from onsite assessors and AC (combined ROR: 1.00, 95% confidence interval (CI) 0.97 to 1.04; I(2) = 0%, 47 RCTs). The combined ROR was 1.00 (95% CI 0.96 to 1.04; I(2) = 0%, 35 RCTs) when onsite assessors were blinded; 0.76 (95% CI 0.48 to 1.12, I(2) = 0%, two RCTs) when AC assessed events identified independently from unblinded onsite assessors; and 1.11 (95% CI 0.96 to 1.27, I(2) = 0%, 10 RCTs) when AC assessed events identified by unblinded onsite assessors. However, there was a statistically significant interaction between these subgroups (P = 0.03) AUTHORS' CONCLUSIONS: On average, treatment effect estimates for subjective outcome events assessed by onsite assessors did not differ from those assessed by ACs. Results of subgroup analysis showed an interaction according to the blinded status of onsite assessors and the process used to submit data to AC. These results suggest that the use of ACs might be most important when onsite assessors are not blinded and the risk of misclassification is high. Furthermore, research is needed to explore the impact of the different procedures used to select events to adjudicate.

Artesunate-amodiaquine versus artemether-lumefantrine for the treatment of acute uncomplicated malaria in Congolese children under 10 years old living in a suburban area: a randomized study.

BACKGROUND: The Republic of Congo adopted a new anti-malarial treatment policy in 2006, with artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) as the first- and second-line anti-malarial drugs, respectively. Only three clinical studies had been conducted before the policy change. A randomized study on these two artemisinin-based combinations was conducted, and the effect that sickle cell trait may have on treatment outcomes was evaluated in children under 10 years old followed during 12 months in Brazzaville in 2010-2011. METHODS: A cohort of 330 children under 10 years of age living in a suburban area in the south of Brazzaville were passively followed for registration of malaria episodes. Uncomplicated Plasmodium falciparum episodes were randomly treated with co-formulated ASAQ (Coarsucam(®)) or AL (Coartem(®)). Patients were followed according to the 2009 World Health Organization protocol for the evaluation of anti-malarial drug efficacy. Plasmodium falciparum recrudescent isolates were compared to pre-treatment isolates by polymerase chain reaction (PCR) to distinguish between re-infection and recrudescence. PCR-uncorrected and PCR-corrected responses to treatment were determined using per protocol analysis. Haemoglobin type (AA, AS, SS) was determined by PCR. RESULTS: Of 282 clinical malaria episodes registered during 1-year follow-up period, 262 children with uncomplicated malaria were treated with ASAQ (129 patients) or AL (133 patients). The PCR-corrected efficacy, expressed as the percentage of adequate clinical and parasitological response, was 97.0 % for ASAQ and 96.4 % for AL. Among ASAQ-treated patients, 112 (86.8 %) carried AA genotype and 17 (13.2 %) were AS carriers. The PCR-corrected efficacy was 96.4 % for AA-carriers and 100 % for AS-carriers treated with ASAQ [relative risk (RR) = 0.96; 95 % confidence interval, 0.93-1.00, p = 0.5]. Among 133 AL-treated children, 109 (82 %) carried AA, and 24 (18 %) AS genotypes. The PCR-corrected efficacy was 96.7 % among AA-carriers and 95.2 % among AS-carriers [RR = 1.01 (0.92-1.12), p = 0.6]. Nausea, jaundice, headache, dizziness, vomiting, pruritus, abdominal pain, and diarrhoea were registered as adverse events in both groups. ASAQ was associated with significantly more frequent adverse events (P < 0.05). CONCLUSION: This first randomized study in Brazzaville confirmed the excellent efficacy of these co-formulated anti-malarial drugs in children. Sickle cell genotype did not influence the treatment efficacy of artemisinin-based combination therapy.