Low rate of nonrelapse mortality in under-4-year-olds with ALL given chemotherapeutic conditioning for HSCT: a phase 3 FORUM study.

ABSTRACT: Allogeneic hematopoietic stem cell transplantation (HSCT) is highly effective for treating pediatric high-risk or relapsed acute lymphoblastic leukemia (ALL). For young children, total body irradiation (TBI) is associated with severe late sequelae. In the FORUM study (NCT01949129), we assessed safety, event-free survival (EFS), and overall survival (OS) of 2 TBI-free conditioning regimens in children aged <4 years with ALL. Patients received fludarabine (Flu), thiotepa (Thio), and either busulfan (Bu) or treosulfan (Treo) before HSCT. From 2013 to 2021, 191 children received transplantation and were observed for ≥6 months (median follow-up: 3 years). The 3-year OS was 0.63 (95% confidence interval [95% CI], 0.52-0.72) and 0.76 (95% CI, 0.64-0.84) for Flu/Thio/Bu and Flu/Thio/Treo (P = .075), respectively. Three-year EFS was 0.52 (95% CI, 0.41-0.61) and 0.51 (95% CI, 0.39-0.62), respectively (P = .794). Cumulative incidence of nonrelapse mortality (NRM) and relapse at 3 years were 0.06 (95% CI, 0.02-0.12) vs 0.03 (95% CI: <0.01-0.09) (P = .406) and 0.42 (95% CI, 0.31-0.52) vs 0.45 (95% CI, 0.34-0.56) (P = .920), respectively. Grade >1 acute graft-versus-host disease (GVHD) occurred in 29% of patients receiving Flu/Thio/Bu and 17% of those receiving Flu/Thio/Treo (P = .049), whereas grade 3/4 occurred in 10% and 9%, respectively (P = .813). The 3-year incidence of chronic GVHD was 0.07 (95% CI, 0.03-0.13) vs 0.05 (95% CI, 0.02-0.11), respectively (P = .518). In conclusion, both chemotherapeutic conditioning regimens were well tolerated and NRM was low. However, relapse was the major cause of treatment failure. This trial was registered at www.clinicaltrials.gov as #NCT01949129.

Zoledronic Acid Add-on Therapy for Standard-Risk Ewing Sarcoma Patients in the Ewing 2008R1 Trial.

PURPOSE: The phase III, open-label, prospective, multicenter, randomized Ewing 2008R1 trial (EudraCT2008-003658-13) was conducted in 12 countries to evaluate the effect of zoledronic acid (ZOL) maintenance therapy compared with no add-on regarding event-free survival (EFS, primary endpoint) and overall survival (OS) in standard-risk Ewing sarcoma (EWS). PATIENTS AND METHODS: Eligible patients had localized EWS with either good histologic response to induction chemotherapy and/or small tumors (<200 mL). Patients received six cycles of VIDE induction and eight cycles of VAI (male) or eight cycles of VAC (female) consolidation. ZOL treatment started parallel to the sixth consolidation cycle. Randomization was stratified by tumor site (pelvis/other). The two-sided adaptive inverse-normal four-stage design (planned sample size 448 patients, significance level 5%, power 80%) was changed after the first interim analysis using the Müller-Schäfer method. RESULTS: Between April 2010 and November 2018, 284 patients were randomized (142 ZOL/142 no add-on). With a median follow-up of 3.9 years, EFS was not significantly different between ZOL and no add-on group in the adaptive design (HR, 0.74; 95% CI, 0.43-1.28, P = 0.27, intention-to-treat). Three-year EFS rates were 84.0% (95% CI, 77.7%-90.8%) for ZOL vs. 81.7% (95% CI, 75.2%-88.8%) for no add-on. Results were similar in the per-protocol collective. OS was not different between groups. The 3-year OS was 92.8% (95% CI, 88.4%-97.5%) for ZOL and 94.6% (95% CI, 90.9%-98.6%) for no add-on. Noticeable more renal, neurologic, and gastrointestinal toxicities were observed for ZOL (P < 0.05). Severe renal toxicities occurred more often in the ZOL arm (P = 0.003). CONCLUSIONS: In patients with standard-risk localized EWS, there is no additional benefit from maintenance treatment with ZOL.

Quantitative diffusion-weighted MRI response assessment in rhabdomyosarcoma: an international retrospective study on behalf of the European paediatric Soft tissue sarcoma Study Group Imaging Committee.

OBJECTIVE: To investigate the feasibility of diffusion-weighted magnetic resonance imaging (DW-MRI) as a predictive imaging marker after neoadjuvant chemotherapy in patients with rhabdomyosarcoma. MATERIAL AND METHODS: We performed a multicenter retrospective study including pediatric, adolescent and young adult patients with rhabdomyosarcoma, Intergroup Rhabdomyosarcoma Study group III/IV, treated according to the European paediatric Soft tissue sarcoma Study Group (EpSSG) RMS2005 or MTS2008 studies. DW-MRI was performed according to institutional protocols. We performed two-dimensional single-slice tumor delineation. Areas of necrosis or hemorrhage were delineated to be excluded in the primary analysis. Mean, median and 5th and 95th apparent diffusion coefficient (ADC) were extracted. RESULTS: Of 134 included patients, 82 had measurable tumor at diagnosis and response and DW-MRI scans of adequate quality and were included in the analysis. Technical heterogeneity in scan acquisition protocols and scanners was observed. Mean ADC at diagnosis was 1.1 (95% confidence interval [CI]: 1.1-1.2) (all ADC expressed in * 10-3 mm2/s), versus 1.6 (1.5-1.6) at response assessment. The 5th percentile ADC was 0.8 (0.7-0.9) at diagnosis and 1.1 (1.0-1.2) at response. Absolute change in mean ADC after neoadjuvant chemotherapy was 0.4 (0.3-0.5). Exploratory analyses for association between ADC and clinical parameters showed a significant difference in mean ADC at diagnosis for alveolar versus embryonal histology. Landmark analysis at nine weeks after the date of diagnosis showed no significant association (hazard ratio 1.3 [0.6-3.2]) between the mean ADC change and event-free survival. CONCLUSION: A significant change in the 5th percentile and the mean ADC after chemotherapy was observed. Strong heterogeneity was identified in DW-MRI acquisition protocols between centers and in individual patients.

Germline founder variant c.1998delinsTTCT in the RET oncogene: a cohort study in 15 Belgian families.

OBJECTIVE: The c.1998delinsTTCT variant in the RET gene (codon 666) is linked to medullary thyroid carcinoma in Belgium. We aimed to study the clinical phenotype and the age-dependent penetrance in predictive variant carriers. DESIGN: Retrospective study of index patients and predictive variant carriers, identified through familial cascade testing between 2001 and 2020. RESULTS: The total cohort comprised 119 patients: 15 index patients, 102 heterozygous, and 2 homozygous predictive variant carriers. Among heterozygous carriers, high suspicion of clinical disease was present in 25 patients at initial evaluation and in 3 patients during follow-up. No high suspicion of clinical disease was observed during surveillance in 56 patients, and 18 patients did not proceed to screening for clinical disease. Compared to index patients, surgically treated heterozygous predictive variant carriers had a lower presurgical basal calcitonin, a lower disease stage, less need for adjuvant therapy, and higher chances of remission. In heterozygous carriers, median age at developing high suspicion of disease is 52 years (range 7-75), with a predicted penetrance of 62% (9% SE) at the age of 70 years. Two patients were identified with pheochromocytoma and 1 patient with primary hyperparathyroidism. The 2 homozygous predictive variant carriers presented with higher disease severity at first clinical evaluation. CONCLUSION: The c.1998delinsTTCT variant in the RET gene is pathogenic and associated with a moderate risk for medullary thyroid carcinoma and rarely with other multiple endocrine neoplasia type 2A (MEN2A) manifestations. Active surveillance is a possible option in heterozygous gene carriers with a negative first clinical evaluation.

The Quality of Life of Children Facing Life-Limiting Conditions and That of Their Parents in Belgium: A Cross-Sectional Study.

BACKGROUND: Paediatric palliative care (PPC) aims to improve children's quality of life, but this outcome is rarely measured in clinical care. PPC is provided in Belgium through six transmural paediatric liaison teams (PLTs) ensuring continuity of care for children with life-limiting or life-threatening conditions (LLC/LTC). This study aims to measure the quality of life (QoL) of children with LLC/LTC followed-up by PLTs and the QoL of their parents. METHODS: During interviews, an original socio demographic questionnaire, the Children palliative outcome scale-version 2 (CPOS-2), the Fragebogen für Kinder und Jugendliche zur Erfassung der gesundheitsbezogenen Lebensqualität (KINDL) and the Quality of life in life-threatening Illness-Family caregiver (QOLLTI-F) were filled in by PLT members. Statistics were used to investigate significant differences between scores. Results were discussed and interpreted with six PLTs. RESULTS: 73 children aged 1-18 were included in the study. Especially for items focusing on emotional items, children reported their QoL as higher than their parents did. The QoL scores were not significantly associated with the child's condition's severity. CONCLUSIONS: This study provides, for the first time, an overview of the QoL of children and parents followed-up by PLTs in Belgium.

Retrospective Analysis of Retroperitoneal-Abdominal-Pelvic Ganglioneuromas: An International Study by the Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG).

OBJECTIVE: The Transatlantic Australasian Retroperitoneal Sarcoma Working Group conducted a retrospective study on the disease course and clinical management of ganglioneuromas. BACKGROUND: Ganglioneuromas are rare tumors derived from neural crest cells. Data on these tumors remain limited to case reports and single-institution case series. METHODS: Patients of all ages with pathologically confirmed primary retroperitoneal, intra-abdominal, and pelvic ganglioneuromas between January 1, 2000, and January 1, 2020, were included. We examined demographic, clinicopathologic, and radiologic characteristics, as well as clinical management. RESULTS: Overall, 328 patients from 29 institutions were included. The median age at diagnosis was 37 years with 59.1% of patients being female. Symptomatic presentation comprised 40.9% of cases, and tumors were often located in the extra-adrenal retroperitoneum (67.1%). At baseline, the median maximum tumor diameter was 7.2 cm. One hundred sixteen (35.4%) patients underwent active surveillance, whereas 212 (64.6%) patients underwent resection with 74.5% of operative cases achieving an R0/R1 resection. Serial tumor evaluations showed that malignant transformation to neuroblastoma was rare (0.9%, N=3). Tumors undergoing surveillance had a median follow-up of 1.9 years, with 92.2% of ganglioneuromas stable in size. With a median follow-up of 3.0 years for resected tumors, 84.4% of patients were disease free after resections, whereas recurrences were observed in 4 (1.9%) patients. CONCLUSIONS: Most ganglioneuromas have indolent disease courses and rarely transform to neuroblastoma. Thus, active surveillance may be appropriate for benign and asymptomatic tumors particularly when the risks of surgery outweigh the benefits. For symptomatic or growing tumors, resection may be curative.

Extracranial germ cell tumours in children and adolescents: Results from the French TGM13 protocol.

BACKGROUND: Chemotherapy for non-seminomatous germ cell tumours (NSGCT) exposes to dose-dependent toxicities. The TGM13-NS protocol (EudraCT 2013-004039-60) aimed to decrease the chemotherapy burden compared to the previous TGM95 protocol while maintaining the 5-year event-free survival (EFS) at 80% or more. PROCEDURE: Patients less than 19 years of age with disseminated NSGCT were enrolled (May 2014 to May 2019) and stratified into four groups: two intermediate-risk (IR: localised tumour with low tumour markers [TM]) groups treated with VBP (vinblastine-bleomycin-cisplatin): three courses for IR1 (ovarian tumour any age/testis tumour less than or equal to 10 years) and four courses for IR2 (extragonadal tumour 10 years or less) groups, and two high-risk (HR: metastatic and/or high TM) groups treated with etoposide-cisplatin and either ifosfamide (VIP) or bleomycin (BEP): three courses for HR1 (ovarian tumour any age/testis tumour less than or equal to 10 years and low TM/testis tumour more than 10 years and very low TM) groups and four courses for HR2 (remainder) groups. RESULTS: One hundred fifteen patients were included: median age of 12.8 years (0.4-18.9); tumour sites: 44 ovaries, 37 testes and 34 extragonadal. The 5-year EFS and overall survival (OS) were 87% (95% CI: 80-92) and 95% (89-98), respectively (median follow-up: 3.5 years, range: 0.2-5.9), similar to those of the TGM95 protocol (5-year EFS 89% (84-93), 5-year OS 93% (89-95), p = .561). The 5-year EFS were 93% (95% CI: 80-98), 88% (71-95) and 79% (62-90) for ovarian, testicular and extragonadal tumours, respectively. The 5-year EFS varied (p = .02) according to the risk groups: 90% (66-97), 64% (30-85), 95% (72-99) and 87% (74-94) for IR1, IR2, HR1 and HR2, respectively. TM decline adjusted to tumour site, and alpha-fetoprotein (AFP) level revealed a prognostic impact of time to normalisation on EFS: HR = 1.03 (1.003-1.007). CONCLUSION: Risk-adapted and globally decreased chemotherapy burden maintains excellent outcomes, exclusive of the IR2 group, which warrants more intensive chemotherapy.

[18F] MFBG PET imaging: biodistribution, pharmacokinetics, and comparison with [123I] MIBG in neural crest tumour patients.

PURPOSE: Despite its limitations, [123I]MIBG scintigraphy has been the standard for human norepinephrine transporter (hNET) imaging for several decades. Recently, [18F]MFBG has emerged as a promising PET alternative. This prospective trial aimed to evaluate safety, biodistribution, tumour lesion pharmacokinetics, and lesion targeting of [18F]MFBG and perform a head-to-head comparison with [123I]MIBG in neural crest tumour patients. METHODS: Six neural crest tumour patients (4 phaeochromocytoma, 1 paraganglioma, 1 neuroblastoma) with a recent routine clinical [123I]MIBG scintigraphy (interval: - 37-75 days) were included. Adult patients (n = 5) underwent a 30-min dynamic PET, followed by 3 whole-body PET/CT scans at 60, 120, and 180 min after injection of 4 MBq/kg [18F]MFBG. One minor participant underwent a single whole-body PET/CT at 60 min after administration of 2 MBq/kg [18F]MFBG. Normal organ uptake (SUVmean) and lesion uptake (SUVmax; tumour-to-background ratio (TBR)) were measured. Regional distribution volumes (VT) were estimated using a Logan graphical analysis in up to 6 lesions per patient. A lesion-by-lesion analysis was performed to compare detection ratios (DR), i.e. fraction of detected lesions, between [18F]MFBG and [123I]MIBG. RESULTS: [18F]MFBG was safe and well tolerated. Its biodistribution was overall similar to that of [123I]MIBG, with prominent uptake in the salivary glands, liver, left ventricle wall and adrenals, and mainly urinary excretion. In the phaeochromocytoma subgroup, the median VT was 37.4 mL/cm3 (range: 18.0-144.8) with an excellent correlation between VT and SUVmean at all 3 time points (R2: 0.92-0.94). Mean lesion SUVmax and TBR at 1 h after injection were 19.3 ± 10.7 and 23.6 ± 8.4, respectively. All lesions detected with [123I]MIBG were also observed with [18F]MFBG. The mean DR with [123I]MIBG was significantly lower than with [18F]MFBG (61.0% ± 26.7% vs. 99.8% ± 0.5% at 1 h; p = 0.043). CONCLUSION: [18F]MFBG is a promising hNET imaging agent with favourable imaging characteristics and improved lesion targeting compared with [123I]MIBG scintigraphy. TRIAL REGISTRATION: Clinicaltrials.gov : NCT04258592 (Registered: 06 February 2020), EudraCT: 2019-003872-37A.

Evaluating the feasibility, effectiveness and costs of implementing person-centred follow-up care for childhood cancer survivors in four European countries: the PanCareFollowUp Care prospective cohort study protocol.

INTRODUCTION: Long-term survival after childhood cancer often comes at the expense of late, adverse health conditions. However, survivorship care is frequently not available for adult survivors in Europe. The PanCareFollowUp Consortium therefore developed the PanCareFollowUp Care Intervention, an innovative person-centred survivorship care model based on experiences in the Netherlands. This paper describes the protocol of the prospective cohort study (Care Study) to evaluate the feasibility and the health economic, clinical and patient-reported outcomes of implementing PanCareFollowUp Care as usual care in four European countries. METHODS AND ANALYSIS: In this prospective, longitudinal cohort study with at least 6 months of follow-up, 800 childhood cancer survivors will receive the PanCareFollowUp Care Intervention across four study sites in Belgium, Czech Republic, Italy and Sweden, representing different healthcare systems. The PanCareFollowUp Care Intervention will be evaluated according to the Reach, Effectiveness, Adoption, Implementation and Maintenance framework. Clinical and research data are collected through questionnaires, a clinic visit for multiple medical assessments and a follow-up call. The primary outcome is empowerment, assessed with the Health Education Impact Questionnaire. A central data centre will perform quality checks, data cleaning and data validation, and provide support in data analysis. Multilevel models will be used for repeated outcome measures, with subgroup analysis, for example, by study site, attained age, sex or diagnosis. ETHICS AND DISSEMINATION: This study will be conducted in accordance with the guidelines of Good Clinical Practice and the Declaration of Helsinki. The study protocol has been reviewed and approved by all relevant ethics committees. The evidence and insights gained by this study will be summarised in a Replication Manual, also including the tools required to implement the PanCareFollowUp Care Intervention in other countries. This Replication Manual will become freely available through PanCare and will be disseminated through policy and press releases. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NL8918; https://www.trialregister.nl/trial/8918).

European regulatory strategy for supporting childhood cancer therapy developments.

INTRODUCTION: Regulatory decisions on paediatric investigation plans (PIPs) aim at making effective and safe medicines timely available for children with high unmet medical need. At the same time, scientific knowledge progresses continuously leading frequently to the identification of new molecular targets in the therapeutic area of oncology. This, together with further efforts to optimise next generation medicines, results in novel innovative products in development pipelines. In the context of global regulatory development requirements for these growing pipelines of innovative products (e.g. US RACE for children Act), it is an increasing challenge to complete development efforts in paediatric oncology, a therapeutic area of rare and life-threatening diseases with high unmet needs. OBJECTIVE: Regulators recognise feasibility challenges of the regulatory obligations in this context. Here, we explain the EU regulatory decision making strategy applied to paediatric oncology, which aims fostering evidence generation to support developments based on needs and robust science. Because there is a plethora of products under development within given classes of or within cancer types, priorities need to be identified and updated as evidence evolves. This also includes identifying the need for third or fourth generation products to secure focused and accelerated drug development. CONCLUSION: An agreed PIP, as a plan, is a living document which can be modified in light of new evidence. For this to be successful, input from the various relevant stakeholders, i.e. patients/parents, clinicians and investigators is required. To efficiently obtain this input, the EMA is co-organising with ACCELERATE oncology stakeholder engagement platform meetings.

High-Dose Treosulfan and Melphalan as Consolidation Therapy Versus Standard Therapy for High-Risk (Metastatic) Ewing Sarcoma.

PURPOSE: Ewing 2008R3 was conducted in 12 countries and evaluated the effect of treosulfan and melphalan high-dose chemotherapy (TreoMel-HDT) followed by reinfusion of autologous hematopoietic stem cells on event-free survival (EFS) and overall survival in high-risk Ewing sarcoma (EWS). METHODS: Phase III, open-label, prospective, multicenter, randomized controlled clinical trial. Eligible patients had disseminated EWS with metastases to bone and/or other sites, excluding patients with only pulmonary metastases. Patients received six cycles of vincristine, ifosfamide, doxorubicin, and etoposide induction and eight cycles of vincristine, actinomycin D, and cyclophosphamide consolidation therapy. Patients were randomly assigned to receive additional TreoMel-HDT or no further treatment (control). The random assignment was stratified by number of bone metastases (1, 2-5, and > 5). The one-sided adaptive-inverse-normal-4-stage-design was changed after the first interim analysis via Müller-Schäfer method. RESULTS: Between 2009 and 2018, 109 patients were randomly assigned, and 55 received TreoMel-HDT. With a median follow-up of 3.3 years, there was no significant difference in EFS between TreoMel-HDT and control in the adaptive design (hazard ratio [HR] 0.85; 95% CI, 0.55 to 1.32, intention-to-treat). Three-year EFS was 20.9% (95% CI, 11.5 to 37.9) in TreoMel-HDT and 19.2% (95% CI, 10.8 to 34.4) in control patients. The results were similar in the per-protocol collective. Males treated with TreoMel-HDT had better EFS compared with controls: median 1.0 years (95% CI, 0.8 to 2.2) versus 0.6 years (95% CI, 0.5 to 0.9); P = .035; HR 0.52 (0.28 to 0.97). Patients age < 14 years benefited from TreoMel-HDT with a 3-years EFS of 39.3% (95% CI, 20.4 to 75.8%) versus 9% (95% CI, 2.4 to 34); P = .016; HR 0.40 (0.19 to 0.87). These effects were similar in the per-protocol collective. This observation is supported by comparable results from the nonrandomized trial EE99R3. CONCLUSION: In patients with very high-risk EWS, additional TreoMel-HDT was of no benefit for the entire cohort of patients. TreoMel-HDT may be of benefit for children age < 14 years.

Brachytherapy for Pediatric Patients at Gustave Roussy Cancer Campus: A Model of International Cooperation for Highly Specialized Treatments.

PURPOSE: Childhood cancer is rare, and treatment is frequently associated with long-term morbidity. Disparities in survival and long-term side effects encourage the establishment of networks to increase access to complex organ-conservative strategies, such as brachytherapy. We report our experience of an international cooperation model in childhood cancers. METHODS AND MATERIALS: We examined the outcome of all children referred to our center from national or international networks to be treated according to a multimodal organ-conservative approach, including brachytherapy. RESULTS: We identified 305 patients whose median age at diagnosis was 2.2 years (range, 1.4 months to 17.2 years). Among these patients, 99 (32.4%) were treated between 2015 and 2020; 172 (56.4%) were referred from national centers; and 133 (43.6%) were international patients from 31 countries (mainly Europe). Also, 263 patients were referred for primary treatment and 42 patients were referred for salvage treatment. Genitourinary tumors were the most frequent sites, with 56.4% bladder/prostate rhabdomyosarcoma and 28.5% gynecologic tumors. In addition to brachytherapy, local treatment consisted of partial tumor resection in 207 patients (67.9%), and 39 patients (13%) had additional external radiation therapy. Median follow-up was 58 months (range, 1 month to 48 years), 93 months for national patients, and 37 months for international patients (P < .0001). Five-year local control, disease-free survival, and overall survival rates were 90.8% (95% confidence interval [CI], 87.3%-94.4%), 84.4% (95% CI, 80.1%-89.0%), and 93.3% (95% CI, 90.1%-96.5%), respectively. Patients referred for salvage treatment had poorer disease-free survival (P < .01). Implementation of image guided pulse-dose-rate brachytherapy was associated with better local control among patients with rhabdomyosarcoma referred for primary treatment (hazard ratio, 9.72; 95% CI, 1.24-71.0). At last follow-up, 16.7% patients had long-term severe treatment-related complications, and 2 patients (0.7%) had developed second malignancy. CONCLUSIONS: This retrospective series shows the feasibility of a multinational referral network for brachytherapy allowing high patient numbers in rare pediatric cancers. High local control probability and acceptable late severe complication probability could be achieved despite very challenging situations. This cooperation model could serve as a basis for generating international reference networks for high-tech radiation such as brachytherapy to increase treatment care opportunities and cure probability.

The role of microscopic bone marrow examination and [123I]MIBG scintigraphy in detection of bone marrow involvement in patients with neuroblastoma.

OBJECTIVES: For the detection of bone marrow (BM) metastases in patients with neuroblastoma, microscopic BM examination and [123I]MIBG scintigraphy are advised. The aims of this study were to assess the concordance of [123I]MIBG and microscopic BM examination (aspirate and biopsy) in detecting BM involvement and to compare invasive disease in BM biopsies and aspirates, both at diagnosis and before autologous stem cell collection (ASCC). METHODS: Fifty-five patients with stage 4 or stage 4S disease were included, and 37 of them received an autologous hematopoietic stem cell transplantation (AHSCT). The concordance rate was measured and paired binary data were analysed by the McNemar test to look for a systematic difference between diagnostic tests. RESULTS: At diagnosis and before ASCC, we found acceptable concordance rates for [123I]MIBG versus microscopic BM examination (77.1% and 85.3% respectively). Discordant results were found in both directions and at both time points. The concordance rate for biopsy versus aspirate at diagnosis was 80.6%, however, before ASCC a much higher concordance rate between both microscopic examinations was found (94.1%). While none of the aspirates showed neuroblastoma cells before ASCC, two biopsies still showed tumor invasion. CONCLUSION: For patients with neuroblastoma, a [123I]MIBG scintigraphy and a microscopic examination of BM aspirate and its biopsy should be used as complementary tools in the evaluation of BM involvement, and this both at diagnosis and during treatment (before ASCC).

European PanCareFollowUp Recommendations for surveillance of late effects of childhood, adolescent, and young adult cancer.

BACKGROUND: Long-term follow-up (LTFU) care for childhood, adolescent, and young adult (CAYA) cancer survivors is essential to preserve health and quality of life (QoL). Evidence-based guidelines are needed to inform optimal surveillance strategies, but many topics are yet to be addressed by the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG). Therefore, the PanCareFollowUp Recommendations Working Group collaborated with stakeholders to develop European harmonised recommendations in anticipation of evidence-based IGHG guidelines. METHODS: The PanCareFollowUp Recommendations Working Group, consisting of 23 late effects specialists, researchers, and survivor representatives from nine countries, collaborated in the first Europe-wide effort to provide unified recommendations in anticipation of evidence-based guidelines. A pragmatic methodology was used to define recommendations for topics where no evidence-based IGHG recommendations exist. The objective was to describe the surveillance requirements for high-quality care while balancing the different infrastructures and resources across European health care systems. The process included two face-to-face meetings and an external consultation round involving 18 experts from 14 countries. RESULTS: Twenty-five harmonised recommendations for LTFU care were developed collaboratively and address topics requiring awareness only (n = 6), awareness, history and/or physical examination (n = 9), or additional surveillance tests (n = 10). CONCLUSIONS: The PanCareFollowUp Recommendations, representing a unique agreement across European stakeholders, emphasise awareness among survivors and health care providers in addition to tailored clinical evaluation and/or surveillance tests. They include existing IGHG guidelines and additional recommendations developed by a pragmatic methodology and will be used in the Horizon 2020-funded PanCareFollowUp project to improve health and QoL of CAYA cancer survivors.

Infantile Rhabdomyosarcomas With VGLL2 Rearrangement Are Not Always an Indolent Disease: A Study of 4 Aggressive Cases With Clinical, Pathologic, Molecular, and Radiologic Findings.

VGLL2-rearranged rhabdomyosarcomas (RMS) are rare low-grade tumors with only favorable outcomes reported to date. We describe 4 patients with VGLL2-rearranged RMS confirmed by molecular studies, who experienced local progression and distant metastases, including 2 with fatal outcomes. Tumors were diagnosed at birth (n=3) or at 12 months of age (n=1), and were all localized at initial diagnosis, but unresectable and therefore managed with chemotherapy and surveillance. Metastatic progression occurred from 1 to 8 years from diagnosis (median, 3.5 y). Three patients experienced multimetastatic spread and one showed an isolated adrenal metastasis. At initial diagnosis, 3 tumors displaying bland morphology were misdiagnosed as fibromatosis or infantile fibrosarcoma and initially managed as such, while 1 was a high-grade sarcoma. At relapse, 3 tumors showed high-grade morphology, while 1 retained a low-grade phenotype. Low-grade primary tumors showed only very focal positivity for desmin, myogenin, and/or MyoD1, while high-grade tumors were heterogenously or diffusely positive. Whole-exome sequencing, performed on primary and relapse samples for 3 patients, showed increased genomic instability and additional genomic alterations (eg, TP53, CDKN2A/B, FGFR4) at relapse, but no recurrent events. RNA sequencing confirmed that high-grade tumors retained VGLL2 fusion transcripts and transcriptomic profiles consistent with VGLL2-rearranged RMS. High-grade samples showed a high expression of genes encoding cell cycle proteins, desmin, and some developmental factors. These 4 cases with distinct medical history imply the importance of complete surgical resection, and suggest that RMS-type chemotherapy should be considered in unresectable cases, given the risk of high-grade transformation. They also emphasize the importance of correct initial diagnosis.

Covariates of amikacin disposition in a large pediatric oncology cohort.

OBJECTIVE: Amikacin pharmacokinetics (PK) in children display large variability due to maturational and disease-related covariates. The objective was to explore amikacin PK in a large pediatric oncology cohort, taking into account within-patient changes. MATERIALS AND METHODS: Clinical data and amikacin therapeutic drug monitoring (TDM) observations were collected retrospectively from children with an oncology diagnosis receiving amikacin during febrile neutropenia. Individual amikacin PK parameters were calculated using a 1-compartment model with instantaneous input and first-order output. This approach was selected based on a pragmatic study design using TDM from routine clinical care, with availability of 2 TDM samples per treatment episode. To explore covariates of clearance (Cl) and volume of distribution (Vd), linear mixed models were used, modelling a random effect for patient to account for clustering due to repeated measurements. RESULTS: Based on 188 amikacin treatment episodes in 114 patients, median (interquartile range) amikacin Cl was 1.37 (1.05; 2.46) L/h and Vd 7.98 (5.66; 12.73) L. Height and creatinemia were significant covariates for Cl (marginal R2 71.1%), while weight, height, and creatinemia determined Vd (marginal R2 59.5%). CONCLUSION: We described extensive variability of amikacin PK in a large cohort of pediatric oncology patients, including within-patient changes across treatment episodes. Maturational covariates and creatinemia determined amikacin Cl and Vd, while primary non-maturational covariates were not significant. Our observations, based on combined clinical and PK data in children with oncology diagnoses, can be useful to feed dosing software programs to improve drug exposure in special populations.

Long-term leukoencephalopathy and neurocognitive functioning in childhood sarcoma patients treated with high-dose intravenous chemotherapy.

PURPOSE: Knowledge is limited regarding the prevalence and persistence of chemotherapy-induced leukoencephalopathy in childhood sarcoma patients. This study explored the presence, clinical relevance, and potential risk factors of leukoencephalopathy in childhood bone and soft tissue sarcoma survivors, treated with intravenous chemotherapy. METHODS: We acquired cross-sectional neurocognitive data in adult survivors (n = 34) (median age at diagnosis [AaD] = 13.32 years, age range = 16-35 years) and healthy age-matched controls (n = 34). Additionally, magnetic resonance imaging included T2-weighted FLAIR (leukoencephalopathy Fazekas rating), multiexponential T2 relaxation (MET2), and multishell diffusion MRI to estimate myelin integrity-related metrics and fluid movement restrictions. Finally, chemotherapy subgroups (methotrexate, alkylating agents, or combination), AaD, and Apoε and MTHFRC677T polymorphisms were explored as potential risk factors for leukoencephalopathy. RESULTS: At the group level, quality of life, working memory, processing speed, and visual memory were significantly lower in patients compared to controls. Furthermore, long-term leukoencephalopathy was observed in 27.2% of the childhood sarcoma survivors, which was related to attentional processing speed. Lesions were related to diffusion-derived, but not to myelin-sensitive metrics. A significant interaction effect between AaD and chemotherapy group demonstrated more lesions in case of high-dose methotrexate (HD-MTX) (F = 3.434, P = .047). However, patients treated with alkylating agents (without HD-MTX) also showed lesions in younger patients. Genetic predictors were nonsignificant. CONCLUSION AND IMPLICATION: This study suggests long-term leukoencephalopathy with possibly underlying changes in vasculature, inflammation, or axonal injury, but not necessarily long-term demyelination. Such lesions could affect processing speed, and as such long-term daily life functioning of these patients.

Survival and prognosis with osteosarcoma: outcomes in more than 2000 patients in the EURAMOS-1 (European and American Osteosarcoma Study) cohort.

BACKGROUND: High-grade osteosarcoma is a primary malignant bone tumour mainly affecting children and young adults. The European and American Osteosarcoma Study (EURAMOS)-1 is a collaboration of four study groups aiming to improve outcomes of this rare disease by facilitating randomised controlled trials. METHODS: Patients eligible for EURAMOS-1 were aged ≤40 years with M0 or M1 skeletal high-grade osteosarcoma in which case complete surgical resection at all sites was deemed to be possible. A three-drug combination with methotrexate, doxorubicin and cisplatin was defined as standard chemotherapy, and between April 2005 and June 2011, 2260 patients were registered. We report survival outcomes and prognostic factors in the full cohort of registered patients. RESULTS: For all registered patients at a median follow-up of 54 months (interquartile range: 38-73) from biopsy, 3-year and 5-year event-free survival were 59% (95% confidence interval [CI]: 57-61%) and 54% (95% CI: 52-56%), respectively. Multivariate analyses showed that the most adverse factors at diagnosis were pulmonary metastases (hazard ratio [HR] = 2.34, 95% CI: 1.95-2.81), non-pulmonary metastases (HR = 1.94, 95% CI: 1.38-2.73) or an axial skeleton tumour site (HR = 1.53, 95% CI: 1.10-2.13). The histological subtypes telangiectatic (HR = 0.52, 95% CI: 0.33-0.80) and unspecified conventional (HR = 0.67, 95% CI: 0.52-0.88) were associated with a favourable prognosis compared with chondroblastic subtype. The 3-year and 5-year overall survival from biopsy were 79% (95% CI: 77-81%) and 71% (95% CI: 68-73%), respectively. For patients with localised disease at presentation and in complete remission after surgery, having a poor histological response was associated with worse outcome after surgery (HR = 2.13, 95% CI: 1.76-2.58). In radically operated patients, there was no good evidence that axial tumour site was associated with worse outcome. CONCLUSIONS: In conclusion, data from >2000 patients registered to EURAMOS-1 demonstrated survival rates in concordance with institution- or group-level osteosarcoma trials. Further efforts are required to drive improvements for patients who can be identified to be at higher risk of adverse outcome. This trial reaffirms known prognostic factors, and owing to the large numbers of patients registered, it sheds light on some additional factors to consider.

Impact of Disease on Amikacin Pharmacokinetics and Dosing in Children.

BACKGROUND: Amikacin is widely used to treat severe Gram-negative bacterial infections. Its peak concentration in plasma is associated with treatment efficacy. Amikacin pharmacokinetics (PK) is influenced by disease conditions, in addition to other patient characteristics. In this retrospective study, we evaluated the impact of clinical characteristics and disease condition on amikacin PK in children with burn injuries and those with cancer. METHODS: Amikacin PK data from 66 children with burn injuries and 112 children with cancer were analyzed. A population PK model was developed using the nonlinear mixed-effects modeling approach. Models were developed using NONMEM 7.3 (ICON Development Solutions, LLC, Ellicott City, MD). Data processing and visualization was performed using R packages. RESULTS: The amikacin PK data were best described by a 2-compartment model. The parameters were estimated with mean values (95% confidence intervals) as follows: central volume of distribution (V1), 5.70 L (4.64-6.76 L); central clearance, 2.12 L/h (1.79-2.46 L/h); peripheral volume of distribution (V2), 4.79 L (2.36-7.22 L); and distribution clearance (Q), 0.71 L/h (0.25-1.16 L/h). The final model identified the disease condition as a significant covariate and indicated 55% (28%-82%) higher central clearance and 17% (1%-34%) higher V1 in burn patients compared with cancer patients. Volume of distribution was significantly influenced by age and body weight. Clearance was significantly influenced by age, body weight, and creatinine clearance. Using the final PK model, we developed a workflow for selecting optimal dosing strategies for 3 representative pediatric patient profiles. CONCLUSIONS: Disease condition was significant in influencing amikacin PK in children. To reach the same target concentrations (64 mg/L peak concentration) with a daily-dose plan, burn patients need higher doses than cancer patients. Future investigations are needed to explore the impact of other diseases on amikacin disposition in children, and to prospectively validate the proposed dosing strategy.