Purpose
High-risk medulloblastomas (HR-MB) may not respond to induction chemotherapy, with either post-induction stable (SD) or progressive disease (PD). There is no consensus regarding their optimal ...management.
Methods
A retrospective, multicentre study investigated patients with non-responder HR-MB treated according to the PNET HR + 5 protocol (NCT00936156) between 01/01/2009 and 31/12/2018. After two courses of etoposide and carboplatin (induction), patients with SD or PD were analyzed. Upon clinician’s decision, the PNET HR + 5 protocol was either pursued with tandem high-dose chemotherapy (HDCT) and craniospinal irradiation (CSI) (continuation group) or it was modified (switched group).
Results
Forty-nine patients were identified. After induction, 37 patients had SD and 12 had PD. The outcomes were better for the SD group: the 5-y PFS and OS were 52% (95% CI 35–67) and 70% (95% CI 51–83), respectively, in the SD group while the 2-y PFS and OS were 17% (95% CI 3–41) and 25% (95% CI 6–50), respectively, in the PD group (p < 0.0001). The PNET HR + 5 strategy was pursued for 3 patients in the PD group, of whom only one survived. In the SD group, it was pursued for 24/37 patients whereas 13 patients received miscellaneous treatments including a 36 Gy CSI in 12 cases. Despite that continuation and switched group were well-balanced for factors impacting the outcomes, the latter were better in the continuation group than in the switched group: the 5-y PFS were 78% (95% CI 54–90) versus 0% (p < 0.001), and the 5-y OS were 78% (95% CI 54–90) versus 56% (95% CI 23–79) (p = 0.0618) respectively. In the SD group, multivariate analysis revealed that
MYC
amplification, molecular group 3, and a switched strategy were independent prognostic factors for progression.
Conclusion
Patients with post-induction SD may benefit from HDCT and CSI, whereas patients with early PD will require new therapeutic approaches.
The major role of interleukin (IL)-1 in the pathogenesis of hereditary recurrent fever syndromes favored the employment of targeted therapies modulating IL-1 signaling. However the best use of IL1 ...inhibitors in terms of dosage is difficult to define at present.
In order to better understand the use of IL1 inhibitors in a real-life setting, our study assessed the dosage regimens of French patients with one of the four main hereditary recurrent fever syndromes (Familial Mediterranean Fever (FMF), TNF receptor associated periodic syndrome (TRAPS), cryopyrin associated periodic fever (CAPS) and mevalonate kinase deficiency). The patients were retrieved retrospectively from the JIR cohort, an international platform gathering data of patients with pediatric inflammatory diseases.
Forty five patients of the JIR cohort with a hereditary recurrent fever syndrome had received at least once an IL1 inhibitor (anakinra or canakinumab). Of these, 43% received a lower dosage than the one suggested in the product recommendations, regardless of the type of the IL1 inhibitor. Especially patients with FMF and TRAPS seemed to need lower treatment regimens; in our cohort none of the FMF or TRAPS patients received an intensified dose of IL-inhibitor. On-demand treatment with a short half-life IL-1 inhibitor has also been used successfully for some patients with one of these two conditions The standard dose was given to 42% of the patients; whereas an intensified dose of IL-1 inhibitors was given to 15% of the patients (44% of CAPS patients and 17% of mevalonate kinase deficiency patients). In our cohort each individual patient's need for treatment seemed highly variable, ranging from on demand treatment regimens to intensified dosage maintenance therapies depending on the activity and the severity of the underlying disease.
IL-1 inhibitors are a good treatment option for patients with a hereditary recurrent fever syndrome, but the individual need of the dosage of IL-1 inhibitors to control the disease effectively seems highly variable. Severity, activity but also the type of the underlying disease, belong to the parameters underpinning the treat-to-target strategy implemented in an everyday life practice.
Relapses in pediatric high-risk brain tumors remain unmet medical needs. Over the last 15 years, metronomic chemotherapy has gradually emerged as an alternative therapeutic approach.
This is a ...national retrospective study of patients with relapsing pediatric brain tumors treated according to the MEMMAT or MEMMAT-like regimen from 2010 to 2022. Treatment consisted of daily oral thalidomide, fenofibrate, and celecoxib, and alternating 21-day cycles of metronomic etoposide and cyclophosphamide associated with bevacizumab and intraventricular chemotherapy.
Forty-one patients were included. The most frequent malignancies were medulloblastoma (22) and ATRT (8). Overall, the best responses were CR in eight patients (20%), PR in three patients (7%), and SD in three patients (7%), for a clinical benefit rate of 34%. The median overall survival was 26 months (IC95% = 12.4-42.7), and median EFS was 9.7 months (IC95% = 6.0-18.6). The most frequent grade ¾ toxicities were hematological. Dose had to be adjusted in 27% of the cases. There was no statistical difference in outcome between full or modified MEMMAT. The best setting seems to be when MEMMAT is used as a maintenance and at first relapse.
The metronomic MEMMAT combination can lead to sustained control of relapsed high-risk pediatric brain tumors.
Prednisone (PDN) in juvenile dermatomyositis (JDM), alone or in association with other immunosuppressive drugs, namely methotrexate (MTX) and cyclosporine (CSA), represents the first-line treatment ...option for new onset JDM patients. No clear evidence based guidelines are actually available to standardize the tapering and discontinuation of glucocorticoids (GC) in JDM. Aim of our study was to provide an evidence-based proposal for GC tapering/discontinuation in new onset juvenile dermatomyositis (JDM), and to identify predictors of clinical remission and GC discontinuation.
New onset JDM children were randomized to receive either PDN alone or in combination with methotrexate (MTX) or cyclosporine (CSA). In order to derive steroid tapering indications, PRINTO/ACR/EULAR JDM core set measures (CSM) and their median absolute and relative percent changes over time were compared in 3 groups. Group 1 included those in clinical remission who discontinued PDN, with no major therapeutic changes (MTC) (reference group) and was compared with those who did not achieve clinical remission, without or with MTC (Group 2 and 3, respectively). A logistic regression model identified predictors of clinical remission with PDN discontinuation.
Based on the median change in the CSM of 30/139 children in Group 1, after 3 pulses of methyl-prednisolone, GC could be tapered from 2 to 1 mg/kg/day in the first two months from onset if any of the CSM decreased by 50-94%, and from 1 to 0.2 mg/kg/day in the following 4 months if any CSM further decreased by 8-68%, followed by discontinuation in the ensuing 18 months. The achievement of PRINTO JDM 50-70-90 response after 2 months of treatment (ORs range 4.5-6.9), an age at onset > 9 years (OR 4.6) and the combination therapy PDN + MTX (OR 3.6) increase the probability of achieving clinical remission (p < 0.05).
This is the first evidence-based proposal for glucocorticoid tapering/discontinuation based on the change in JDM CSM of disease activity.
Trial full title: Five-Year Single-Blind, Phase III Effectiveness Randomized Actively Controlled Clinical Trial in New Onset Juvenile Dermatomyositis: Prednisone versus Prednisone plus Cyclosporine A versus Prednisone plus Methotrexate. EUDRACT registration number: 2005-003956-37 .
gov is NCT00323960 . Registered on 17 August 2005.
Medulloblastomas are the most common malignant childhood brain tumors arising in the posterior fossa. Treatment improvements for these tumors have meant that there are a greater number of survivors, ...but this long-term patient survival has increased the awareness of resulting neurocognitive deficits. Impairments in attention, memory, executive functions, and intelligence quotient demonstrate that the cerebellum likely plays a significant role in numerous higher cognitive functions such as language, cognitive, and emotional functions. In addition, children with medulloblastoma not only have cerebellar lesions but also brain white matter damages due to radiation and chemotherapy. Functional neuroimaging, a noninvasive method with many advantages, has become the standard tool in clinical and cognitive neuroscience research. By reviewing functional neuroimaging studies, this review aims to clarify the role of the cerebellum in cognitive function and explain more clearly cognitive sequelae due to polytherapy in children with medulloblastoma. This review suggests that the posterior cerebellar lobes are crucial to maintaining cognitive performance. Clinical investigations could help to better assess the involvement of these lobes in cognitive functions.
Spinal cord compression in Wilms’ tumor (WT) is an extremely rare event that can have a very poor prognosis if not taken care of rapidly. Most cases reported in the literature involve widely ...metastatic patient with bone or paraspinal metastases or occasionally intradural metastasis. Here, we present the case of a 3-year-old girl of WT confirmed by biopsy, with spinal cord compression due to the direct contiguous spread of a tumor through 2 vertebral foramina. Abdominal ultrasonography and magnetic resonance imaging performed for an abdominal mass revealed a large heterogeneous tumor near the upper pole of the left kidney. A nodular infiltration extended through the T11-L1 and L1-L2 neural foramina, forming an intraspinal mass that compressed the spinal cord. Major paresthesia subsequently occurred, requiring urgent treatment with corticosteroids and chemotherapy. The evolution was rapidly satisfying. After six courses of chemotherapy, a left nephrectomy was performed. Macroscopic examination identified a large tumor attached to the kidney without renal infiltration. Microscopical examination concluded to a nephroblastoma with regressive changes, of intermediate risk. Evolution at 6 months is satisfactory, with no neurological deficit. The histological aspect of the tumor and the clinical outcome suggest that she had an extrarenal WT that spread through the vertebral foramina and was secondarily attached to the kidney.
To prospectively investigate the role of local hyperfractionated radiotherapy (RT) after surgical resection in the treatment of intracranial ependymomas in children.
Postoperative local ...hyperfractionated RT was proposed for every child (>5 years old at diagnosis) with localized intracranial ependymoma. The planned dose was 60 Gy after complete resection (CR) and 66 Gy after partial resection, delivered in two daily fractions of 1 Gy, according to the early postoperative imaging findings.
Between November 1996 and December 2002, 24 children with infratentorial (n = 20) or supratentorial (n = 4) intracranial ependymoma were included. The median age was 8.6 years (range, 5-17). The World Health Organization grade was anaplastic in 10 of the 24 patients (not assessable in 1). After a retrospective central review, a CR was reported in 16 patients, partial resection in 4, and doubtful resection in 4. The radiation dose was 60 Gy in 18 cases (one partial resection), 66 Gy in 5 cases (one CR), and 54 Gy in 1 case (CR). The 5-year overall survival rate was 74.8%, and the progression-free survival rate was 54.2%. Of the 24 patients, 11 developed a relapse: 7 local only and 4 metastatic and local. The histological grade and extent of resection were not prognostic factors. More than 3 in 4 children had no sequelae of RT at a median follow-up of 7 years (95% confidence interval, 66.4-90.0 months).
The results of our study have shown that hyperfractionated RT is safe but provides no outcome benefit compared with other strategies of RT such as standard fractionated regimens.
L’angiœdème héréditaire est une pathologie rare dont le diagnostic positif au décours d’un œdème laryngé ou devant des douleurs abdominales récurrentes est difficile en milieu pédiatrique, les ...diagnostics différentiels à cet âge étant beaucoup plus fréquents.
Il n’existe pas chez l’enfant de facteurs biologiques validés pour le diagnostic des formes d’angiœdème à C1 inhibiteur normal, sans mutation du facteur XII, le diagnostic reste clinique.
La reconnaissance et la prise en charge précoces des crises d’angiœdème, et l’éducation thérapeutique pourraient néanmoins diminuer la morbidité et le retentissement à moyen et long terme sur la qualité de vie, notamment dans les formes abdominales, source d’absentéisme scolaire.
Il n’y a actuellement pas de médicament injectable par voie sous-cutanée pour les crises ayant l’AMM chez l’enfant, les études pharmacocinétiques sont en cours. Il convient donc à cet âge de définir un circuit d’urgence optimal pour injection intraveineuse des concentrés de C1 inhibiteur.
Hereditary angioedema is a rare disease. In case of laryngeal edema or chronic abdominal pains, diagnosis is difficult in childhood because numerous differential diagnoses possibilities are to be considered.
The diagnosis of hereditary angioedema with normal C1Inh (type III) is also a challenge because it is based only on clinical features.
Important school absenteeism can be due to recurrent abdominal attacks. Early diagnosis, specific management, and therapeutic education are necessary for improvement of quality of life.
Actually, subcutaneous treatment is not yet available for children. Studies are going on. In the meantime, C1Inh concentrate intravenous administration must be available for children quickly and safely.
Off-label use of vemurafenib (VMF) to treat
mutation-positive, refractory, childhood Langerhans cell histiocytosis (LCH) was evaluated.
Fifty-four patients from 12 countries took VMF 20 mg/kg/d. They ...were classified according to risk organ involvement: liver, spleen, and/or blood cytopenia. The main evaluation criteria were adverse events (Common Terminology Criteria for Adverse Events version 4.3) and therapeutic responses according to Disease Activity Score.
LCH extent was distributed as follows: 44 with positive and 10 with negative risk organ involvement. Median age at diagnosis was 0.9 years (range, 0.1 to 6.5 years). Median age at VMF initiation was 1.8 years (range, 0.18 to 14 years), with a median follow-up of 22 months (range, 4.3 to 57 months), whereas median treatment duration was 13.9 months (for 855 patient-months). At 8 weeks, 38 complete responses and 16 partial responses had been achieved, with the median Disease Activity Score decreasing from 7 at diagnosis to 0 (
< .001). Skin rash, the most frequent adverse event, affected 74% of patients. No secondary skin cancer was observed. Therapeutic plasma VMF concentrations (range, 10 to 20 mg/L) seemed to be safe and effective. VMF discontinuation for 30 patients led to 24 LCH reactivations. The blood
allele load, assessed as circulating cell-free DNA, decreased after starting VMF but remained positive (median, 3.6% at diagnosis, and 1.6% during VMF treatment;
< .001) and was associated with a higher risk of reactivation at VMF discontinuation. None of the various empirical therapies (hematopoietic stem-cell transplantation, cladribine and cytarabine, anti-MEK agent, vinblastine, etc) used for maintenance could eradicate the
clone.
VMF seemed safe and effective in children with refractory
-positive LCH. Additional studies are needed to find effective maintenance therapy approaches.