Laser interstitial thermal therapy is effective and safe for the treatment of brain tumors in NF1 patients after cerebral revascularization for moyamoya angiopathy: a report on two cases

BackgroundThe co-occurrence of moyamoya vasculopathy and extra-optic pathway tumors is rare in neurofibromatosis type 1 (NF1), with only four cases described in the literature. Brain surgery in these patients may be challenging because of the risk of brain infarction after skin and dural incision. Given its percutaneous and minimally invasive nature, laser interstitial thermal therapy (LITT) is an ideal option for the treatment of brain tumors in these patients. Here, we report on two patients with NF1 and moyamoya syndrome (MMS) treated for a brain glioma with LITT, after cerebral revascularization.CasesThe first patient, with familial NF1, underwent bilateral indirect revascularization with multiple burr holes (MBH) for symptomatic MMS. Two years later, she was diagnosed with a left temporal tumor, with evidence of radiologic progression over 10 months. The second patient, also with familial NF1, developed unilateral MMS when he was 6 years old and was treated with MBH. At the age of 15 years, MRI showed a right cingular lesion, growing on serial MRIs. Both patients underwent LITT with no perioperative complications; they are progression free at 10 and 12 months, respectively, and the tumors have decreased in volume.DiscussionWhile the association of extra-optic neoplasm and moyamoya angiopathy is seldom reported in NF1, tumor treatment is challenging in terms of both avoiding stroke and achieving oncological control. Here, we show in 2 cases, that LITT could be a safe and effective option in these rare conditions

Medulloblastomas with ELP1 pathogenic variants: A weakly penetrant syndrome with a restricted spectrum in a limited age window

Background: ELP1 pathogenic variants (PV) have been recently identified as the most frequent variants predisposing to Sonic Hedgehog (SHH) medulloblastomas (MB); however, guidelines are still lacking for genetic counseling in this new syndrome. Methods: We retrospectively reviewed clinical and genetic data of a French series of 29 ELP1-mutated MB. Results: All patients developed SHH-MB, with a biallelic inactivation of PTCH1 found in 24 tumors. Other recurrent alterations encompassed the TP53 pathway and activation of MYCN/MYCL signaling. The median age at diagnosis was 7.3 years (range: 3-14). ELP1-mutated MB behave as sporadic cases, with similar distribution within clinical and molecular risk groups and similar outcomes (5 y - OS=86%); no unusual side effect of treatments was noticed. Remarkably, a germline ELP1 PV was identified in all patients with available constitutional DNA (n=26); moreover, all tested familial trio (n=11) revealed that the PVs were inherited. Two of the 26 index cases from the French series had a family history of MB; pedigrees from these patients and from 1 additional Dutch family suggested a weak penetrance. Apart from MB, no cancer was associated with ELP1 PVs; second tumors reported in 4 patients occurred within the irradiation fields, in the usual time-lapse for expected radiotherapy-induced neoplasms. Conclusions: The low penetrance, the "at risk' age window limited to childhood and the narrow tumor spectrum, question the actual benefit of genetic screening in these patients and their family. Our results suggest restricting ELP1 germline sequencing to patients with SHH-MB, depending on the parents"request

Biopsie liquide dans les sarcomes pédiatriques

Résumé : Les biopsies liquides ouvrent de nouveaux champs d'applications dans la prise en charge des patients au diagnostic, au cours de leur suivi et également en recherche translationnelle. Ces dernières années, de nombreux efforts ont été consacrés au développement de l'ADN tumoral circulant (ADNct) et des cellules tumorales circulantes (CTC). Il y a malgré tout de nombreux terrains encore en friches dans les cancers de l'enfant, et parmi eux dans les sarcomes pédiatriques.Nous avons souhaité explorer dans ce travail différents aspects des applications cliniques éventuelles et d'utilisation de ces technologies pour la compréhension de la biologie des tumeurs. La première partie de ce projet est une revue de la littérature qui se rapporte à l'application de l'ADNct dans les cancers solides pédiatriques. Nous présentons ensuite un travail de recherche qui vise à utiliser les CTC à visée diagnostique dans les sarcomes à translocation. Cette étude présente une approche permettant d'identifier des fusions pathognomoniques de sarcome à partir de très faibles quantités de tissu fixé, de CTC sur des modèles murins ou chez des patients. La deuxième étude présentée s'intéresse à la détection de l'ADNct au diagnostic de rhabdomyosarcome en utilisant les altérations de nombre de copie de chromosome, les réarrangements chromosomiques et les variants de nucléotide. Nous avons démontré que la détection au diagnostic est faisable et a un impact pronostique fort sur le devenir des patients. La dernière partie de ce manuscrit présente le développement d'un processus de traitement d'échantillons de patient pour détecter et isoler des cellules tumorales circulantes dans le but d'analyser les particularités génomiques de cette population à une résolution cellulaire.Ce travail explore certains aspects de l'utilisation de la biopsie liquide dans les sarcomes pédiatriques, parmi de nombreux autres. Il est crucial dans le développement de ce champ de recherche, de maîtriser les particularités intrinsèques de chaque type tumoral et des technologies disponibles. Nous avons démontré l'utilité d'une telle approche au diagnostic dans deux applications. Cette aire de recherche ouvre de nombreuses possibilités qui appellent à poursuivre les efforts afin d'élargir les applications en recherche et en clinique.Abstract: Liquid biopsy is an opportunity for improved diagnosis, treatment monitoring and genomic studies in oncology. Substantial effort in recent years has focused on circulating tumor DNA (ctDNA) and circulating tumor cells (CTC). However, pediatric cancer, including sarcomas, are still largely unexplored disease areas in this field.In this work, we sought to explore several aspects of liquid biopsy applied to pediatric sarcomas including their clinical use at diagnosis and as a tool to understand tumor biology. We first present a review of the literature demonstrating the feasibility of applying liquid biopsy to pediatric solid malignancies. Then, we report a methodological study using CTC for diagnostic purposes in translocation driven sarcomas. This approach identified fusions from as little as two unstained slides of FFPE tumor biopsy tissue, from CTC collected from tumor-bearing mice, and from liquid biopsy samples from patients with known fusion-positive cancers. The second study focuses on ctDNA for prognostication at the time of diagnosis in rhabdomyosarcoma by detecting copy number alterations, rearrangements, and single-nucleotide variants. Our study demonstrates that baseline ctDNA detection is feasible and has prognostic value. The last part of this work presents the development of a workflow to isolate single sarcoma cancer cells for sequencing, with an ultimate goal to analyze CTC genomic features at a single-cell resolution.This work explores several clinically and scientifically relevant aspects of liquid biopsy in pediatric sarcoma. We showed that liquid biopsy has utility at diagnosis in two different applications. Further development in this field will require a strong knowledge of tumor-specific biology, the clinical care of patients with these diseases, and the adaption of new technologies. My findings demonstrate the transformative possibilities this research may bring to the care of patients with pediatric sarcomas

Polo-like Kinase Inhibitor Volasertib Exhibits Antitumor Activity and Synergy with Vincristine in Pediatric Malignancies

Polo-like kinase 1 (PLK1) controls the main cell-cycle checkpoints, suggesting utility of its inhibition for cancer treatment, including of highly proliferative pediatric cancer. This preclinical study explored the selective PLK1 inhibitor volasertib (BI 6727) alone and combined with chemotherapy in pediatric malignancies. Inhibition of proliferation was explored in vitro using dimethylthiazol carboxymethoxyphenyl sulfophenyl tetrazolium (MTS) assay. Mice bearing human xenografts were treated with weekly intravenous injections of volasertib. Volasertib inhibited proliferation in all 40 cell lines tested, with a mean half-maximal growth inhibitory concentration of 313 nmol/l (range: 4-5000 nmol/l). Volasertib was highly active against RMS-1 alveolar rhabdomyosarcoma xenografts, resulting in 100% tumor regression. Activity was associated with complete and prolonged G2/M arrest and subsequent apoptotic cell death. Volasertib showed synergistic activity with vincristine but antagonistic effects with etoposide. These findings support the further exploration of volasertib for pediatric malignancies, particularly alveolar rhabdomyosarcoma, and its combination with mitotic spindle poiso

Profound and sustained response with next-generation ALK inhibitors in patients with relapsed or progressive ALK-positive anaplastic large cell lymphoma with central nervous system involvement

International audienc

Development of a Hospital Compounded, Taste-Masked, Temozolomide Oral Suspension and 5-Year Real-Life Experience in Treating Paediatric Patients

The development of oral pediatric forms by pharmaceutical companies is still insufficient. In fact, many drugs used in paediatric oncology, such as temozolomide, are not labeled and adapted for paediatric use. Temozolomide (TMZ) is an alkylating agent used as the standard of care for many adult and pediatric brain tumours, such as neuroblastoma, glioblastoma and medulloblastoma. The present study was carried out to propose a suitable and palatable formulation of the oral liquid preparation of TMZ. The suspension is composed of TMZ suspended in SyrSpend SF pH 4, as well as TMZ crystallization stabilizing agents and sweetening agents. To reach this formulation, several taste-masking agents were evaluated. Here, we describe the method of preparation of the formation as well as the monocentric population treated with the formulation over a 5–year period. A 20 mg/mL TMZ suspension was developed. TMZ suspension is stable for 6 weeks, stored between 2 and 8 degrees, protected from light, and compatible with nasogastric tubes. Thirty-eight patients participated in the palatability study and choose cola flavour, and 104 patients were treated in Gustave Roussy with the developed suspension; no unexpected event was reported. To conclude, we propose here a new TMZ liquid formulation which is stable for at least 6 weeks and well-tolerated with extensive feedback

Circulating Tumor DNA Is Prognostic in Intermediate-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group

International audiencePURPOSE Novel biomarkers are needed to differentiate outcomes in intermediate-risk rhabdomyosarcoma (IR RMS). We sought to evaluate strategies for identifying circulating tumor DNA (ctDNA) in IR RMS and to determine whether ctDNA detection before therapy is associated with outcome. PATIENTS AND METHODS Pretreatment serum and tumor samples were available from 124 patients with newly diagnosed IR RMS from the Children's Oncology Group biorepository, including 75 patients with fusion-negative rhabdomyosarcoma (FN-RMS) and 49 with fusion-positive rhabdomyosarcoma (FP-RMS) disease. We used ultralow passage whole-genome sequencing to detect copy number alterations and a new custom sequencing assay, Rhabdo-Seq, to detect rearrangements and single-nucleotide variants. RESULTS We found that ultralow passage whole-genome sequencing was a method applicable to ctDNA detection in all patients with FN-RMS and that ctDNA was detectable in 13 of 75 serum samples (17%). However, the use of Rhabdo-Seq in FN-RMS samples also identified single-nucleotide variants, such as MYOD1 L122R , previously associated with prognosis. Identification of pathognomonic translocations between PAX3 or PAX7 and FOXO1 by Rhabdo-Seq was the best method for measuring ctDNA in FP-RMS and detected ctDNA in 27 of 49 cases (55%). Patients with FN-RMS with detectable ctDNA at diagnosis had significantly worse outcomes than patients without detectable ctDNA (event-free survival, 33.3% v 68.9%; P = .0028; overall survival, 33.3% v 83.2%; P < .0001) as did patients with FP-RMS (event-free survival, 37% v 70%; P = .045; overall survival, 39.2% v 75%; P = .023). In multivariable analysis, ctDNA was independently associated with worse prognosis in FN-RMS but not in the smaller FP-RMS cohort. CONCLUSION Our study demonstrates that baseline ctDNA detection is feasible and is prognostic in IR RMS