Poor and delayed microbiological documentation of episodes of febrile neutropenia (EFN) deserves improvement. We assessed the impact of a new blood culture (BC) sampling protocol to optimize the ...diagnosis of bloodstream infection during EFN, compared with standard of care protocol.
This pre/post intervention included patients who presented an EFN in a pediatric hematology-oncology center. Data were compared between 1-year periods P1 (110 EFN, 53 patients) and P2 (124 EFN, 53 patients). Pre-intervention settings were 1-2 mL of blood cultured per BC set and several samplings over days (multisampling strategy) during period P1 vs. one unique early sampling of a large volume of blood (0.5-60 mL) depending on patient weight during period P2 (single-sampling weight-adapted strategy). Microbial detection and time-to-diagnosis were evaluated.
Seventeen EFNs were microbiologically documented in P1 (15.5%) and 26 in P2 (21%). The rate of positive BC sets increased during P2 (10.4% vs. 5.8%). All cases of bacteremia were documented by BC drawn during the first 4 days of fever, and during P2 by samples obtained on the first day of fever.
Bacteremia detection was improved. This proof-of-concept study shows benefits of combining the single-sampling strategy with large weight-adapted blood sampling strategy during EFN.
Combination of single-sampling and weight-adapted blood culture strategies showed benefits in the documentation of bloodstream infections during febrile neutropenia. Bacteremia detection was improved in this preliminary study and this warrants further evaluation in the overall pediatric population. We observed no adverse effects associated with the new strategy while overall blood sparing was improved and handling of intravascular devices was reduced. The good tolerance of the blood sampling suggests that the recommended 1% volume limitation in children could be reconsidered. A similar evaluation is justified in the overall pediatric population suspected for bloodstream infection.
This study aimed to detect late sub-clinical patterns of cardiac dysfunction using speckle tracking echocardiography (STE) in children with cancer remission more than 12 months after the end of ...anthracycline treatment.
This prospective controlled study enrolled 196 children, 98 of which had been treated with anthracyclines (mean age 10.8 ± 3.6 years; 51% female) and 98 were age- and gender-matched healthy subjects in a 1:1 case-control design. Conventional echocardiographic variables were collected for left ventricle (LV) and right ventricle (RV). STE analyses were performed in the LV longitudinal, radial, and circumferential displacements and in the RV free wall longitudinal displacement. The association between LV global longitudinal strain (GLS) and the main clinical and biological parameters was evaluated.
After a mean time interval of 5.1 ± 3.2 years since the end of chemotherapy (mean cumulative anthracycline dose of 192 ± 96 mg/m2), conventional echocardiographic measures were normal. GLS was significantly decreased in the anthracycline group (−19.1% vs. −21.5%, P < 0.0001), with a higher proportion of children with abnormal values (Z-score < −2 in 18.6% vs. 1.0%, P < 0.0001). No association was found between GLS and clinical or biological parameters. Circumferential strain was significantly worse in the anthracycline group (−16.8% vs. −19.4%, P < 0.0001), and radial strain significantly better (+51.4% vs. +35.9%, P < 0.0001). RV conventional echocardiography and STE parameters were normal and not different between anthracycline and control groups.
The existence of a modified LV strain despite normal LV function in children treated with anthracyclines represents an important perspective for cardiomyopathy surveillance in childhood cancer survivors.
Clinical Trial Registration -ClinicalTrials.gov Identifier: NCT02893787.
•Children have normal conventional echocardiograms 5-years after chemotherapy.•Global longitudinal strain and circumferential strain are lower in this population.•Radial strain is significantly higher.
The purpose was to describe first and subsequent relapses in patients from the OS2006/Sarcome-09 trial, to help future trial design. We prospectively collected and analysed relapse data of all French ...patients included in the OS2006/Sarcome-09 trial, who had achieved a first complete remission. 157 patients experienced a first relapse. The median interval from diagnosis to relapse was 1.7 year (range 0.5-7.6). The first relapse was metastatic in 83% of patients, and disease was not measurable according to RECIST 1.1 criteria in 23%. Treatment consisted in systemic therapy (74%) and surgical resection (68%). A quarter of the patients were accrued in a phase-II clinical trial. A second complete remission was obtained for 79 patients. Most of them had undergone surgery (76/79). The 3-year progression-free and overall survival rates were 21% and 37%, respectively. In patients who achieved CR2, the 3y-PFS and OS rates were 39% and 62% respectively. Individual correlation between subsequent PFS durations was poor. For osteosarcoma relapses, we recommend randomised phase-II trials, open to patients from all age categories (children, adolescents, adults), not limited to patients with measurable disease (but stratified according to disease status), with PFS as primary endpoint, response rate and surgical CR as secondary endpoints.
Genome-wide association studies (GWAS) have identified that frequent polymorphisms in ARID5B and IKZF1, two genes involved in lymphoid differentiation, increase the risk of childhood acute ...lymphoblastic leukemia (ALL). These findings markedly modified the current field of research on the etiology of ALL. In this new context, the present exploratory study investigated the possible interactions between these at-risk alleles and the non-genetic suspected ALL risk factors that were of sufficient prevalence in the French ESCALE study: maternal use of home insecticides during pregnancy, preconception paternal smoking, and some proxies for early immune modulation, i.e. breastfeeding, history of common infections before age one year, and birth order. The analyses were based on 434 ALL cases and 442 controls of European origin, drawn from the nationwide population-based case-control study ESCALE. Information on non-genetic factors was obtained by standardized telephone interview. Interactions between rs10740055 in ARID5B or rs4132601 in IKZF1 and each of the suspected non-genetic factors were tested, with the SNPs coded as counts of minor alleles (trend variable). Statistical interactions were observed between rs4132601 and maternal insecticide use (p = 0.012), breastfeeding p = 0.017) and repeated early common infections (p = 0.0070), with allelic odds ratios (OR) which were only increased among the children not exposed to insecticides (OR = 1.8, 95%CI: 1.3, 2.4), those who had been breastfed (OR = 1.8, 95%CI: 1.3, 2.5) and those who had had repeated early common infections (OR = 2.4, 95%CI: 1.5, 3.8). The allelic ORs were close to one among children exposed to insecticides, who had not been breastfed and who had had no or few common infections. Repeated early common infections interacted with rs10740055 (p = 0.018) in the case-only design. Further studies are needed to evaluate whether these observations of a modification of the effect of the at-risk alleles by non-genetic factors are chance findings or reflect true underlying mechanisms.
Late cardiomyopathy in childhood acute myeloid leukemia survivors: a study from the L.E.A. program Prognosis of pediatric acute myeloid leukemia (AML) has improved significantly over the past two ...decades with survival rates now approaching 70%. 1 Therapy consists of a limited number of intensive chemotherapy courses mainly based on cytarabine and anthracycline. 2,3 Many pediatric late anthracycline cardiotoxicity studies have concerned heterogeneous diagnostic groups. Moreover, single childhood cancer studies were mainly conducted in acute lym-phoblastic leukemia, whereas the highest doses of anthra-cycline are given in children with AML. 4-6 We report here a prospective multi-centric study of late cardiotoxicity in 185 patients surviving childhood AML. All were treated after 1989 in French clinical trials using intensive chemotherapy alone or chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). L.E.A. (Leucémie Enfant & Adolescent) is a French prospective long-term follow-up program involving all childhood acute leukemia survivors treated in the participating centers since 1980. Details of the programm are provided elsewhere. 7 As of 31 December 2011, 282 childhood AML survivors fulfilled the L.E.A. inclusion criteria and 218 (77.3%) of them agreed to participate. Among these 218, 185 were treated according to one of the 6 multicenter trial protocols ongoing in France after January 1989. All 185 had serial echocardiographic examination as part of their L.E.A. program, and all were included in the present study. All provided written informed consent. Cardiotoxicity was defined by either clinical symptoms of congestive heart failure or by an abnormal echocardiographic left ventricular function. Left ventricular function was considered abnormal when the shortening fraction (SF) was less than 28% or when the left ventricular ejection fraction (LVEF) was less than 55% on 2D echocardiography. 8-10 Cardiotoxicity was classified as late when it started or persisted beyond one year after the completion of first-line treatment. 9 Cumulative anthracycline doses used in each trial are described in the Online Supplementary Table S1, as well as the doxorubicin-equivalent doses using conversion factors of 0.83, 4.0 and 5.0 for daunorubicin, mitoxantrone and idarubicin, respectively. 10,11 Assessment of health status, long-term late effects on health-related quality of life (QoL), and statistical analysis are described in the Online Supplementary Appendix. Characteristics of the study cohort are summarized in Table 1. Median age at the time of AML diagnosis and median follow-up duration to last cardiac evaluation were 6.53 and 9.5 years, respectively. Thirty-seven patients had a history of relapse. Median cumulative anthracycline dose was 372 mg/m² (Online Supplementary Figure S1). Ninety-nine patients were treated by chemotherapy alone, whereas the other 86 patients also received HSCT (57 in first remission, 25 in second remission, and 4 in more advanced disease). Thirty children received total body irradiation (TBI), but only 10 among the 57 transplanted in first remission did so. Median number of echographic evaluations was 3 per patient. Subclinical cardiotoxicity (SCC) was observed in 23 of 185 patients (12.4%) at least once during their follow-up program. Median time from AML diagnosis to SCC detection was 4.40 years. In these 23 patients, the median value of the worst SF was 27% and the median value of the worst LVEF was 52. Only 3 of 23 patients had a worse SF value of less than 25% (2 had 20%; 1 had 24%). Six of 23 received anti-congestive therapy and none had cardiac transplantation. Five of those receiving anti-congestive therapy were still being treated at time of last evaluation, and 4 had more than 28% SF and more than 55% LVEF. Seventeen patients never received treatment: 11 had spontaneous improvement with more than 28% SF and more than 55% LVEF at last evaluation. Finally, at last cardiac evaluation, only 8 patients had an abnormal left ventricular function. Cumulative incidence (CI) of cardiotoxicity, estimated by the Kaplan-Meier method was 16% and 27% at 10 and 15 years, respectively (Figure 1A). CI of anti-conges-tive treatment at the same follow-up times was 5% and 7%. The risk of developing cardiotoxicity depended on a previous history of relapse and on the cumulative anthracy-cline dose. At ten years from diagnosis, CI was 35% versus 11% in patients with or without history of relapse (P=0.02) (Figure 1B). Among 148 patients without any history of relapse, 10-year CI of cardiotoxicity was 14% in 97 patients treated with chemotherapy alone versus 8% in 51 patients who underwent HSCT in first remission (NS, Figure 1C). In transplanted children, the risk was not modified by either a grade 2-4 acute or an extensive chronic graft-versus-host disease. The CI of anti-congestive treatment in these 148 patients who never experienced relapse was 3% at ten and
In most countries, reference chemotherapy for osteosarcoma is MAP regimen (M = high-dose methotrexate, AP = doxorubicin-cisplatinum). In France, the standard preoperative chemotherapy for ...children/adolescents combines M and etoposide-ifosfamide (EI), based on the OS94-trial. We report the safety and efficacy results of patients ≤25 years treated with preoperative M-EI regimen enroled in the French OS2006-study, between 2007 and 2014.
Treatment comprised preoperative chemotherapy with the 7 M-courses and 2 EI-courses, then surgery and postoperative chemotherapy assigned by risk's groups: standard-risk (good histological response without metastases) received 12 M-courses, 3 EI-courses; high-risk (poor histologic response, initial metastases or unresectable primary) received 5 M-courses alternated with 5 AP-courses. 253 patients were randomised to receive (n = 128) or not (n = 125) zoledronate.
409/522 patients enroled in the OS2006 study who received preoperative M-EI were analysed. Median age was 14.3 years (4.7–24.5), with 55 patients aged 18–25 years. Primary tumour location was limb in 383 patients (94%) and 85 (21%) presented metastases. Median chemotherapy duration was 37.4 weeks. 381 (96%) patients underwent surgery, 258 patients (65%) had a good histologic response. 187/324 patients (58%) with localised disease did not receive doxorubicin nor cisplatinum. Toxicity was evaluated in the randomised study: most patients experienced ≥1 severe toxicity (grade IV haematological or grade III/IV extra-haematological). Median follow-up was 4.8 years, and 168 patients had events. Five-year event-free survival was 56% (95% CI, 51–62%) and overall survival 71% (66–76%).
M-EI regimen/strategy was feasible for patient aged ≤25 years with survival rates are comparable to those obtained with MAP regimen.
•Paediatric and young adult methotrexate-based chemotherapy regimen of OS2006 protocol.•Event-free survival and overall survival rates were similar to those with standard Methotrexate-Doxorubicin-Cisplatinum (MAP) regimen used worldwide.•First-line treatment with doxorubicin and cisplatinum was avoided in 58% patients with localised tumours.
Anthracyclines are key chemotherapeutic agents used in various adult and pediatric cancers, however, their clinical use is limited due to possible congestive heart failure (HF) caused by acute and ...irreversible cardiotoxicity. Currently, there is no method to predict the future development of the HF in these patients. In order to identify early biomarkers to predict anthracycline cardiotoxicity in long-term survivors of childhood cancer, this longitudinal study aimed to analyze early and late
regional myocardial anthracycline-induced cardiotoxicity, related to
cardiac myocytes dysfunction, in a juvenile rat model.
Young male Wistar rats (4 weeks-old) were treated with different cumulative doses of doxorubicin (7.5, 10 or 12.5 mg/kg) or NaCl (0.9%) once a week for 6 weeks by intravenous injection. Cardiac function was evaluated
by conventional (left ventricular ejection fraction, LVEF) and regional two-dimensional (2D) speckle tracking echocardiography over the 4 months after the last injection. The animals were assigned to preserved (pEF) or reduced EF (rEF) groups at the end of the protocol and were compared to controls.
We observed a preferential contractile dysfunction of the base of the heart, further altered in the posterior segment, even in pEF group. The first regional alterations appeared 1 month after chemotherapy. Functional investigation of cardiomyocytes isolated from the LV base 1 month after doxorubicin treatment showed that early
contractile alterations were associated with both decreased myofilament Ca
sensitivity and length-dependent activation. Changes in post-translational modifications (phosphorylation; S-glutathionylation) and protein degradation of the cardiac myosin binding protein-C may contribute to these alterations.
Our data suggest that screening of the contractile defaults of the base of the heart by regional 2D strain echocardiography is useful to detect subclinical myocardial dysfunction prior to the development of delayed anthracycline-induced cardiomyopathy in pediatric onco-cardiology.
Background:
Desmoid-type fibromatosis are rare intermediate tumors in children and adolescents. Owing to local aggressiveness and relapse, systemic treatment for symptomatic advanced or progressive ...forms is recommended. Following promising results in adult patients, oral vinorelbine is investigated in young patients.
Methods:
A retrospective review of young patients (<25 years old) with advanced or progressive desmoid type fibromatosis treated with oral vinorelbine in eight large centers of the Société Française des Cancers de l’Enfant was performed. In addition to tumor assessment according to RECIST 1.1, pre-treatment and during-treatment imagery were reviewed centrally to assess tumor volume and estimate fibrosis score through the change in percentage in hypoT2 signal intensity.
Results:
From 2005 to 2020, 24 patients (median age 13.9 years range, 1.0-23.0) received oral vinorelbine. Median number of prior systemic lines of treatment was 1 (range, 0-2), mainly based on intravenous low dose methotrexate and vinblastine. Before vinorelbine initiation, all patients had a progressive disease: radiological for 19, radiological and clinical (pain) for three and only clinical for two. Oral vinorelbine was delivered for a median duration of 12 months (range, 1-42). The toxicity profile was favorable, with no grade 3-4 event. Overall response estimated on 23 evaluable patients according to RECIST 1.1 criteria was three partial responses (13%), 18 stabilization (78%) and two progressive disease (9%). Overall progression-free survival was 89.3% (95% confidential intervals 75.2-100) at 24 months. Four stable tumors according to standard RECIST criteria displayed a partial response with > 65% tumor volume reduction. Among 21 informative patients, the estimated fibrosis score decreased for 15 patients, was stable for four patients and increased for two patients.
Conclusion:
Oral vinorelbine seems to be effective to control advanced or progressive desmoid type fibromatosis in young patients, with a well-tolerated profile. These results support testing this drug as first-line alone or in combination to improve response rate while preserving quality of life.
Vaginal malignant germ cell tumors (MGCT) are rare, occurring in children less than 2 years old and raise the question of the optimal local treatment.
We included children treated for vaginal MGCT ...according to the French TGM-95/2013 regimen. Patients were classified as standard risk (SR: localized disease and alpha-fetoprotein (AFP) < 10,000 ng/mL) or high risk (HiR: metastatic and/or AFP > 10,000 ng/mL) and were treated, respectively, with three to five VBP (vinblastine-bleomycin-cisplatin) or four to six VIP (etoposide-ifosfamide-cisplatin), followed by conservative surgery and/or brachytherapy in case of post-chemotherapy residuum.
Fourteen patients were included (median age = 12 months), of which six (43%) were classified as HiR. AFP levels were normalized after first-line chemotherapy in all cases but one. A vaginal post-chemotherapy residuum (median size = 8 mm, range: 1-24 mm) was observed in 13/14 patients, treated by complete resection in seven of 13 (viable cells in three of seven), incomplete resection in four of 13 (viable cells in two of four), with adjuvant brachytherapy in two of 13, and exclusive brachytherapy in two of 13 (viable cells in one of six). Among the six patients with viable disease, four patients received adjuvant chemotherapy. One patient (SR) experienced immediate postoperative relapse despite presenting no viable residual cells and was treated with four VIP cycles and brachytherapy. At last follow-up (median = 4.6 years, range: 0.5-16), all patients were alive in complete remission. Five patients suffered from vaginal sequelae with synechiae and/or stenosis (of whom four had undergone brachytherapy).
Childhood vaginal MGCTs show a highly favorable prognosis with risk-adapted chemotherapy and local treatment of post-chemotherapy residuum (preferably by conservative surgery with partial vaginectomy). Brachytherapy could be an alternative when conservative surgery is not deemed possible or in cases of incomplete resection with residual viable cells.
In Euro‐EWING99‐R1 randomized trial, cyclophosphamide was shown to be noninferior to ifosfamide in the consolidation of standard‐risk Ewing sarcoma (SR‐EWS) after a common induction with VIDE ...(vincristine‐ifosfamide‐doxorubicin‐etoposide). We present the results of the late effects analysis of VAC (vincristine‐dactinomycin‐cyclophoshamide) vs VAI (vincristine‐dactinomycin‐ifosfamide) conducted in Euro‐EWING99‐R1 French cohort. Of 267 French randomized patients, 204 were alive and free‐of‐relapse at 5‐years including 172 with available long‐term follow‐up data concerning cardiac, renal and/or gonadal functions (sex‐ratio M/F = 1.3, median age at diagnosis = 14 years): 84 randomized in VAC (median cumulative doses: cyclophosphamide = 9.7 g/m2, ifosfamide = 59.4 g/m2) and 88 in VAI (ifosfamide = 97.1 g/m2). With a median follow‐up of 10 years (range = 5‐17), five late relapses and five second malignancies were recorded. The 10‐year event‐free survival among 5‐year free‐of‐relapse survivors was similar between VAC and VAI (93% vs 95%, P = .63). We estimated the 10‐year cumulative probabilities of cardiac and kidney toxicities at 4.4% (95% confidence interval 95% CI = 1.1%‐7.6%) and 34.8% (95% CI = 26.8%‐42.0%), respectively. Cardiac toxicity cumulative probability was similar in both arms, whereas kidney toxicity was higher in VAI (at 10 years, 43.0% vs 25.7%, P = .02), resulting from significant difference in glomerular toxicity (31.1% vs 13.1%, P < .01). At 10 years, gonadal toxicity was observed in 27% and 28% of pubertal men and women, respectively, without significant difference between VAC and VAI. Kidney and gonadal toxicities represent major issues in Euro‐EWING99‐R1, with significantly higher risk of kidney toxicities with VAI, without significant gonadal toxicity reduction. These results support the need to limit cumulative doses of both alkylating agents and to use mixed regimen as in VIDE‐VAC or VDC/IE (vincristine‐doxorubicin‐cyclophoshamide/ifosfamide‐etoposide).
What's new?
The Euro‐EWING99‐R1 trial compared the alkylating agents cyclophosphamide with ifosfamide in combination treatment for Ewing sarcoma. Here, the authors compare the late events between the two combination treatments using data from 172 patients enrolled in Euro‐EWING99‐R1. The combination containing ifosfamide carried a higher risk of kidney toxicity, but both regimens carried high rates of gonadal toxicity. Some of this toxicity could be avoided, they suggest, by using a mixed regimen to limit the dose of both alkylating agents.
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