Pediatric high‑grade glioma (HGG) is a type of malignancy that carries a poor prognosis. The genetic analysis of HGGs has previously identified useful mutations, the targeting of which has improved prognosis. Thus, further research into the more common mutations, such as H3 histone variants (HIST1H3B and H3F3A) and BRAF V600E, may be useful in identifying tumors with different prognoses, as the mutations are considered to drive two distinct oncogenic programs. The present study performed a retrospective analysis of pediatric HGGs. In total, 42 cases of HGG, including 32 cases (76.1%) of anaplastic astrocytoma and 10 cases (23.8%) of glioblastoma multiforme (GBM), were assessed. The median age of the patients was 7 years (range, 0‑32 years). Mutations on histone H3, in particular the K27M and G34R mutations in the distinct variants HIST1H3B and H3F3A, in addition to the presence of the BRAF V600E mutation, were analyzed in 24 patients. The H3F3A K27M mutation was identified in 7 patients (29.1%), while the HIST1H3B K27M mutation was only observed in 1 patient with GBM. In addition, 5 patients harbored a BRAF V600E mutation (21%), while the H3F3A G34R mutation was not recorded in any of the patients. The overall survival of the wild‑type patients at 20 months was 68% [confidence interval (CI): 38‑85%] compared with 28% (CI: 0.4‑60%) in patients with the H3F3A K27M mutation. These results suggested that patients with the H3F3A K27M mutation had a worse prognosis compared with wild‑type patients (P=0.0045). Moreover, 3/5 patients with the BRAF V600E mutation had HGGs that were derived from a previous low‑grade glioma (LGG; P=0.001). In conclusion, these results suggested that histone H3 mutations may help predict the outcome in patients with HGG. In addition, the BRAF V600E mutation was found to be associated with an increased risk of anaplastic progression. The novel data of the present study may help better define the clinical and radiological characteristics of glioma.
Somatic TP53 mutations have been reported to occur in almost every type of cancer. They are common alterations in brain tumors. Nevertheless, germline mutations of TP53 gene are linked to Li-Fraumeni syndrome (LFS), a tumor susceptibility condition, characterized by an increased risk of developing early synchronous or metachronous malignancies. TP53 germline mutations have also been reported in individuals with no family history or with a family history not fulfilling LFS characteristics. We retrospectively considered 7 patients with brain tumors followed at the Neuro-Oncology Unit between September 2008 and January 2018. The median age at diagnosis was 13,7 years (range 1–31); Six patients were male and one female. Five patients developed metachronous tumors. Two LFS patients had only a primary anaplastic astrocytoma. Five (71,4%) patients had primary brain tumor (3 anaplastic astrocytoma, 1 ependymoma, 1 medulloepithelioma). Molecular analysis of TP53 gene was performed in all patients. Family’s cancer history was investigated. Six patients (85,7%) had a germline TP53 mutation all contained between exons 4 and 7. Only one patient with metachronous tumors (leukemia and ependymoma) and without a family’s cancer history did not show a TP53 mutation. Two patients (28,6%) were negative for family’s cancer history but positive for germline TP53 mutation, ones with history of primary medulloepithelioma and osteosarcoma. The second patient had two brain tumors (anaplastic astrocytoma and PNET). The second tumors developed after two years from the first diagnosis. One LFS patient positive for germline TP53 mutation died for an anaplastic astrocytoma. The other four patients (57,1%) resulted positive both for germline TP53 mutation and for family’s cancer history. The median time between the first and second diagnosis was 7,2 years. Germline TP53 mutation predisposes to develop synchronous or methachronous tumors even after many years. Our study evidenced that germline TP53 mutation is also frequent in brain tumor patients without cancer family’s history. Therefore they must necessarily be constantly monitored with a correct follow-up and the decisions to be made to avoid unnecessary therapy when they have a poor outcome.
Abstract BACKGROUND Pediatric high-grade gliomas (pHGGs) comprise a very poor prognosis. Current treatment consists of maximal surgical resection followed by radiotherapy plus concomitant and adjuvant temozolomide (Stupp’s regimen). Despite innovative approaches, outcome remains dismal. Based on the results of previous in vitro and in vivo assays, also considering the wide experience in other pediatric tumors, we aimed to introduce doxorubicin (DOX) as add-on therapy to the standard of care. METHODS For testing safety and efficacy of add-on doxorubicin treatment in newly-diagnosed pHGGs, two open-label monocentric not-randomized phase II studies were consequently opened at our institution: GBM TMZ/DOX 2015 (EudraCT 2015-002307-28) and pGBM-WBRT/DOX2020 (EudraCT 2020-005131-74). GBM TMZ/DOX 2015 consisted of DOX 100 mg/mq in 96 hours infusion for 1-3 cycles at 8 week after radiotherapy. pGBM-WBRT/DOX2020 study introduced pan-encephalic radiotherapy followed by DOX 75 mg/mq in 48 hours for 4 cycles starting at week 12 after irradiation, to reduce metastatic relapse rate and to facilitate radiotherapy-induced blood brain barrier opening. Concomitant and adjuvant temozolomide were preserved. RESULTS Twenty-one heterogeneous malignant glioma patients (12 hystological diagnosis, 12 males and 8 females, mean age 9.1 ± 4.2 years, age range 2-22 years) were enrolled in the first study. However, for study exiting or for no clinical permissiveness at the time of DOX treatment, only 12 patients were treated with DOX: 2 received three DOX courses and 10 a single course, reducing hematological toxicities. DOX-group showed a longer progression free survival (PFS) compared to standard of care group (median PFS 9 versus 6 months respectively), although this trend was not statistically significative. The second study is on course. CONCLUSIONS The adjuvant DOX use in addition to the standard treatment in pHHGs is a practicable option, although to be consolidated, in terms of effectiveness on outcome.
Congenital malignant brain tumors are extremely rare characterized by a poor prognosis. This could be due to a massive size of these tumors when they are diagnosed, the surgical difficulties and the lack of consolidated therapeutic approaches. Being radiotherapy not recommend for very young patients, the most favorable outcome is correlated to the gross total resection. We evaluated genetic characteristics, response rate, progression-free survival (PFS), and overall survival (OS) of high-dose chemotherapy and autologous stem cell transplant (ASCT) after surgery of infants with congenital brain malignancy. Ten infant aged less than 12 months were included in this study. The median age at diagnosis was 56 days (range: 1–279 days; mean: 80,9 days). All patients were subjected to a regimen of induction chemotherapy, two high-dose chemotherapy courses and autologous stem cell transplant after surgery. Furthermore, we analyzed the Copy Number Variants (CNVs) profile using SNP/CGH array approach in all patients. We also performed a sequence analysis of the coding regions for investigating the clinical relevance of germline INI1 gene mutation in atypical teratoid/rhabdoid tumors (AT/RT) patients. Pathological diagnosis was available in all cases: 4 anaplastic astrocytomas, 2 glioblastoma multiforme, 2 supratentorial primitive neuroectodermal tumors and 2 AT/RT. In our study only two patients were subjected to maximal surgery. A tumor debulking with macroscopic residual was performed in the other patients. At 1–5 years from diagnosis, the PFS was 80% and 58% and the OS was 90%, 69%, respectively. Two germline INI1 mutations were found in both patients with AT/RT. One patients with AT/RT had a c.618G>A (p.Trp206*) mutation in exon 5 of INI1 gene. The genetic analysis of other patient showed c.175C>T mutation in exon 2 of INI1 in heterozygosis in tumor’s DNA. The two patients with AT/RT died early, whereas the other congenital patients showed an 5-years OS of 85%. We found a statistical correlation with OS and PFS with the presence of mutation (p: 0,0009; p: 0,01) and the histology (p:0.007 and p:0.0590). Intensive postoperative chemotherapy and ASCT represents the most effective therapeutic approach for congenital brain tumors with a high response rate. The determination of germline INI1 mutation in AT/RT could be a decisive prognostic marker for the palliative choice.
Dabrafenib plus trametinib is a promising new therapy for patients affected by BRAFV600E -mutant glioma, with high overall response and manageable toxicity. We described a complete and long-lasting response in a case of recurrent anaplastic pleomorphic xanthoastrocytoma CNS WHO-grade 3 BRAFV600E mutated. Due to very poor prognosis, there are a few described cases of high-grade glioma (HGG) patients treated with the combined target therapy as third-line treatment. The emergence of optimized sequencing strategies and targeted agents, including multimodal and systemic therapy with dabrafenib plus trametinib, will continue to broaden personalized therapy in HGG improving patient outcomes.
Abstract Intracranial germ cell tumors (IGCTs) represent about 4% of all childhood brain tumors. They are common in both the pineal and pituitary regions and sometimes they can be bifocal. Suprasellar and bifocal IGCTs usually present stereotypical symptoms, including primary polyuria-polydipsia syndrome (PPS). Consolidated IGCTs’ therapy is based on the International Society of Pediatric Oncologic (SIOP) CNS GCT II protocol consisting of primary pre-radiation chemotherapy combining etoposide, carboplatin and/or cisplatin and ifosfamide. PPS management in these patients requires monitoring of electrolytes and fluids during chemotherapy, especially for cisplatin and/or ifosfamide-based cycles, for which hyperhydratation is required. We report the results of our single-center cohort of patients with IGCTs treated between 2008 and 2021, focusing on the clinical presentation, treatment and long-term follow-up. Thirty-one patients were analyzed (median age=13 years, 87% male). Twelve children (39%) presented a PPS and needed desmopressin treatment, maintained at long-term follow-up data update in all. Over these PPS patients, 6 had bifocal germinomas, 4 suprasellar germinomas, 1 metastatic germinoma and 1 non-germinomatous IGCT. Eleven PPS children (92%) received cisplatin and/or ifosfamide-based chemotherapy: all of them had optimal biochemical urine and blood investigations before, during and after chemotherapy. None of them presented serious complications during treatment. After a median follow-up of 5 years, two patients (6.5%) died (1 IGCT-related, 1 non-cancer related) and one had a second malignancy (parotid gland mucoepidermoid carcinoma, 6 years after IGCT diagnosis). Childhood IGCTs have an excellent prognosis, but present a significant risk of long-lasting severe endocrine sequelae which may be worsened by the primary oncological strategy, requiring careful management of complications related to fluid and electrolytes disturbances. In order to avoid post-treatment pituitary insufficiency, guidelines for diabetes insipidus management when cisplatin and/or ifosfamide-based protocols are used should be established and all patients should receive meticulous endocrine follow-up.
In immunocompetent individuals, cytomegalovirus (CMV) infection is usually mild but may cause severe complications such as retinitis, pneumonitis, and encephalitis in immunocompromised individuals. So far, cases of CMV retinitis in patients with medulloblastoma undergoing chemotherapy and radiotherapy, have not been reported. We herein report the case of a pediatric patient with high-risk medulloblastoma who experienced an unexpected CMV retinopathy and leukoencephalopathy following high dose thiotepa and proton irradiation. The patient underwent a four-course induction therapy (1st cycle: methotrexate and vinorelbine; 2nd cycle: etoposide and hematopoietic stem cells apheresis; 3rd cycle: cyclophosphamide and vinorelbine; 4th cycle: carboplatin and vinorelbine) and then a consolidation phase consisting in high dose thiotepa followed by autologous HSC transplant and proton cranio-spinal irradiation plus boost to the primary tumor site and pituitary site with concomitant vinorelbine. After two months of maintenance treatment with lomustine and vinorelbine, the patient showed complete blindness and leukoencephalopathy. A diagnosis of CMV retinopathy was made and oral valganciclovir was administered. CMV retinopathy was judged to be possibly related to the use of high dose thiotepa worsened by radiotherapy. This case report suggests that in pediatric patients undergoing immunosuppressive chemo-radiotherapy, CMV reactivation should be carefully monitored to prevent serious complications such as retinopathy and visual loss.
We report the case of a 16-year-old girl presenting with spinal clear-cell multiple meningiomas (CCMs). In view of this presentation, we sequenced a bioinformatic panel of genes associated with susceptibility to meningioma, identifying a germline heterozygous variant in SMARCE1. Somatic DNA investigations in the CCM demonstrated the deletion of the wild-type allele (loss of heterozygosity, LOH), supporting the causative role of this variant. Family segregation study detected the SMARCE1 variant in the asymptomatic father and in the asymptomatic sister who, nevertheless, presents 2 spinal lesions. Germline heterozygous loss-of-function (LoF) variants in SMARCE1, encoding a protein of the chromatin-remodeling complex SWI/SNF, have been described in few familial cases of susceptibility to meningioma, in particular the CCM subtype. Our case confirms the role of NGS in investigating predisposing genes for meningiomas (multiple or recurrent), with specific regard to SMARCE1 in case of pediatric CCM. In addition to the age of onset, the presence of familial clustering or the coexistence of multiple synchronous meningiomas also supports the role of a genetic predisposition that deserves a molecular assessment. Additionally, given the incomplete penetrance, it is of great importance to follow a specific screening or follow-up program for symptomatic and asymptomatic carriers of pathogenic variants in SMARCE1.
Abstract BACKGROUND The diagnosis of a child’s brain tumor is a terrible situation for every member of the family. Numerous are the case of separations and divorces in Italy after a diagnosis of a child’s cancer. In particular, it happens with parents of children affected with brain tumor, being the most frequent solid tumor and the first cause of a tumor child’s death. The crisis related to the discovery of a tumor consists of four phases: shock, reaction, processing and re-orientation. It can happen that the diagnosis, experienced as a traumatic experience, can unite the family members as well as separate them. If there is already a process of family disintegration, a trauma can be a cause for breakup. The aim of our study was to investigate the possible correlation between brain tumor diagnosis in children and parental separations/divorces. MATERIAL AND METHODS We considered 427 patients afferent from 2012 to 2018 to the Neuro-Oncology Unit of the Meyer Children’s Hospital. Brain tumors are the 55–60% of all the tumors of our hospital, with an extra-regionality greater than 65%. The data analysis was conducted through information obtained directly from the families during follow-up visits or by telephone interviews. RESULTS Consistent with literature data in our series, the most frequent brain tumors were low-grade gliomas medulloblastomas, high-grade gliomas, ependymomas, midline diffuse gliomas, craniopharyngiomas, germ cell tumors and other rare pediatric tumors. The population was divided in 16 females and 18 males from different Italian regions: 65% from Central Italy, 23% from the South and Islands, 12% from the North. Data analysis showed 34 cases of separation and/or divorce, equal to 7% of our whole population, during treatment and more frequently at the end of treatment or after death. The median age of the 34 patients at the diagnosis of brain tumor was 9.5 years (range 1–19 years), with a higher percentage of cases of separations (41%) for parents of patients aged 10 years-14 years; 7 were the cases of separation and/or divorce when the diagnosis of brain tumor was made around 12–48 months after the child birth. CONCLUSION The diagnosis of a child’s brain tumor can generate stress in the family leading to different reactions, such as conflicts between parents or a real family crisis. The results of our study suggest a possible correlation between the diagnosis of a child’s brain tumor and the cases of separation and/or divorce. High risk medulloblastomas and high-grade gliomas that are likely to have a shorter path due to the unfavorable prognosis of the disease, appear to be the pathologies more often related to situations of family disputes. However, further investigations are necessary to verify the trend emerged from our study respect to the normal population.
