Invasive fungal infections in pediatric patients with central nervous system tumors: novel insights for prophylactic treatments?

Background and aims: Invasive fungal disease (IFD) poses significant morbidity and mortality risks, especially in pediatric patients with neoplastic diseases. However, there is a notable lack of data concerning patients with central nervous system (CNS) tumors. Considering vulnerability factors to infections such as neutropenia, corticosteroids, chemotherapy, surgical interventions, and others, this study aims to evaluate the incidence of IFD in pediatric patients with CNS tumors and determine appropriate indications for prophylactic measures. This is a single-center, retrospective study conducted between 2011 and 2022 at the Pediatric Institute of Oncology (IOP-GRAACC-UNIFESP). Results: A total of 38 cases of IFD were diagnosed in 818 children with CNS malignancies (4,6%). The mean age was 3.5 years (0.4-28y), with 22 (57.9%) male patients. Embryonal tumors (18/38, 47.3%) were the most prevalent CNS tumors, followed by low-grade gliomas (13/38, 34.2%). All episodes met the EORTC IFD criteria, and 36/38 (94.7%) were proven. Invasive yeast infections (33/36, 91.6%), predominantly Candida (30/33, 90.9%), were the most common diagnosis. In total, 25 patients (25/38, 65.8%) were receiving chemotherapy, with 13 of them having embryonal tumors. A total of 11 infants were in the Head Start scheme, resulting in a high prevalence of IFD in these group of patients (11/58, 18.9%). In total, 13 (13/38, 34.2%) patients underwent neurosurgery, mostly ventricular-peritoneal shunts revisions (10/13, 76.9%). Nine (9/38, 23.7%) were with prolonged use of corticosteroids, eight of them associated with neurosurgery. Conclusion: Routine systemic antifungal prophylaxis based solely on diagnosis is not recommended for low-risk cases. Evaluating patient- and treatment-specific risk factors is crucial in infants undergoing high-dose chemotherapy with expected neutropenia and in patients requiring prolonged corticosteroid therapy alongside neurosurgical procedures.

Diencephalic syndrome-like presentation of brainstem tumor: a series case-based review.

PURPOSE: Russel described a rare clinical entity known as diencephalic syndrome (DS) in 1951, which was traditionally caused by a neoplasm in the hypothalamic-optic chiasmatic region. DS is characterized by severe emaciation despite adequate or slightly reduced caloric intake, locomotor hyperactivity, euphoria and other minor features. Current evidence suggests that a rare population of children with a similar phenotype may have their tumor located in the posterior fossa instead, defining the DS-like presentation, a rare entity with few cases reported in the literature. METHODS: A thorough search of three databases (PubMed, Ovid Medline, and Ovid Embase) was conducted to identify relevant papers reporting children with DS associated with brainstem tumors. To our knowledge, only seven cases have been documented in the literature. Moreover, we present four of our own cases, focusing on the unusual clinical presentation, the diagnosis process, and the lag time between the initial symptoms and the definitive diagnosis. RESULTS: In this review, the mean lag time between the onset of symptoms and diagnosis was 20.9 months (median: 16 months; range: 1.5-72 months), whereas in our series of cases, the time was 32.5 months (median: 33 months; range: 7-57 months). CONCLUSION: Despite recent significant advances in neuro-oncology diagnostic tools, this mean lag time did not improve when compared with the previous literature review from 1976. Throughout these data, we aim to raise awareness in the hopes of detecting intracranial neoplasms earlier in cases of children with profound emaciation of unknown cause.

Childhood Craniopharyngioma: A 22-Year Challenging Follow-Up in a Single Center.

Craniopharyngioma is a sellar/suprasellar benign tumor whose aggressiveness may imply in endocrine disturbances (hypothalamic obesity and hormone deficiencies). Fifty-seven patients were evaluated according to clinical characteristics, hypothalamic involvement, type of treatment, anthropometric variables, adiposity indexes (body mass index Z score category at diagnosis and post-treatment, total body fat, visceral adipose tissue, and metabolic syndrome components) and analyzed through multiple regression and logistic models. Patients were stratified according to growth hormone deficiency and recombinant human growth hormone use. Mean ages at diagnosis and at study evaluation were 9.6 and 16.6 years old, respectively. A set of 43/57 (75.4%) patients presented with important hypothalamic involvement, 24/57 (42.1%) received surgical treatment and cranial radiotherapy, and 8/57 (14%) interferon-α exclusively. Fifty-five patients (96.5%) were considered growth hormone deficient, and 26/57 (45.6%) grew despite no recombinant human growth hormone replacement therapy. At diagnosis, 12/57 (21%) patients were obese, and 33/57 (57.9%) at study evaluation, and after 3.2 years (median) post first therapy. There was no influence of height Z score on body mass index Z score. Body mass index Z score at diagnosis positively influenced body mass index Z score, total body fat, waist circumference and the presence of the metabolic syndrome post-treatment. Replacement of recombinant human growth hormone decreased total body fat and visceral adipose tissue. Craniopharyngioma patients worsened body mass index Z score category 3.2 years (median) after first treatment. Body mass index Z score increased due to real weight gain, without height decrease. Replacement of recombinant human growth hormone had beneficial effect on adiposity.

Visual function assessed by visually evoked potentials in optic pathway low-grade gliomas with and without neurofibromatosis type 1.

PURPOSE: To investigate the contribution of full-field transient pattern-reversal visually evoked potentials (PRVEP) on cross-sectional evaluations of visual function in patients with and without neurofibromatosis type 1 (NF1) affected by optic pathway low-grade gliomas (OPLGG). METHODS: Participants were children and adolescents referred for visual function evaluation and receiving treatment for OPLGG, linked (NF1-OPLGG) or not to NF1 (Non-NF1-OPLGG). An age-adjusted control group was included for comparison. Monocular full-field PRVEPs were recorded from each eye in accordance with ISCEV standards. Parameters of peak-to-peak P100 amplitude (µV) and P100 peak time (ms) were measured. Cutoff normative values obtained from controls for 15' and 60' check sizes were ≥ 9.0 µV for N75-P100 amplitude and ≤ 103.0 ms for P100 peak time. The association of age, gender, tumor resection and NF1 with P100 amplitude reduction and P100 peak time delay was explored by Firth logistic regression modeling. RESULTS: Participants were 30 patients (15 males, 60% Non-NF1) with ages from 3.6 to 19.9 years (mean ± SD = 9.2 ± 3.8 years; median = 8.4 years) and 19 controls (12 males) with ages from 3.7 to 19.9 years (mean ± SD = 10.4 ± 4.9 years; median = 9.5 years). Overall, 68% of tested eyes presented reduced P100 amplitudes for both check sizes (46% in the NF-1 and 83% in the Non-NF1) and delayed P100 for both check sizes (38% in NF1 and 89% in Non-NF1). Absence of NF1 adjusted for age, gender and tumor resection was significantly associated with marginally reduced P100 amplitude for 15' checks [odds ratio (OR): 6.26; 95% confidence interval (CI) = 0.96-40.94; p = 0.055]. CONCLUSIONS: Full-field PRVEP on cross-sectional evaluations contributed to detect visual dysfunction in two-thirds of patients with OPLGG by highlighting subclinical evidence of visual loss. Abnormalities were more frequent and more severe in OPLGG not linked to NF1 than in NF1-OPLGG; however, there was a difference in surgical management between these groups. PRVEP parameters may provide reliable evidence of visual pathway involvement in OPLGG, helping to hasten treatment before optic atrophy is detected.

Single agent vinorelbine in pediatric patients with progressive optic pathway glioma.

The management of progressive unresectable low-grade glioma remains controversial. Treatment options have included radiotherapy, and more recently chemotherapy, usually following an initial period of observation. Within this context, we evaluated vinorelbine, a semi-synthetic vinca alkaloid that has shown evidence of activity against glioma. From July 2007 an institutional protocol with vinorelbine (30 mg/m(2) days 0, 8, 22) for a total of 18 cycles, has been conducted at IOP/GRAACC/UNIFESP for children with optic pathway glioma (OPG). The main objectives were clinical and radiological response, as well as toxicity profile. Twenty-three patients with progressive OPG with a mean age of 69 months (4-179) were enrolled. Three patients had a diagnosis of neurofibromatosis type 1. Twenty-two patients were assessable for response with an overall objective response rate of 63 %, with eight patients showing stable disease. The most important toxicity was hematologic (grade III/IV neutropenia) observed in four patients. Gastrointestinal toxicity (grade I/II vomiting) was observed in seven patients and only 1 patient showed grade I peripheral neuropathy. The median progression-free survival (PFS) was 33 months (6.9-69) with a 3 and 5 year PFS of 64 ± 19 and 37 ± 20 %, respectively, for an overall 3 and 5 year-survival of 95 ± 10 %. This study suggests that vinorelbine may be an interesting option for pediatric low-grade gliomas, showing low toxicity profile and providing a good quality of life for patients with such chronic disease.

Ototoxicity evaluation in medulloblastoma patients treated with involved field boost using intensity-modulated radiation therapy (IMRT): a retrospective review.

BACKGROUND: Ototoxicity is a known side effect of combined radiation therapy and cisplatin chemotherapy for the treatment of medulloblastoma. The delivery of an involved field boost by intensity modulated radiation therapy (IMRT) may reduce the dose to the inner ear when compared with conventional radiotherapy. The dose of cisplatin may also affect the risk of ototoxicity. A retrospective study was performed to evaluate the impact of involved field boost using IMRT and cisplatin dose on the rate of ototoxicity. METHODS: Data from 41 medulloblastoma patients treated with IMRT were collected. Overall and disease-free survival rates were calculated by Kaplan-Meier method Hearing function was graded according to toxicity criteria of Pediatric Oncology Group (POG). Doses to inner ear and total cisplatin dose were correlated with hearing function by univariate and multivariate data analysis. RESULTS: After a mean follow-up of 44 months (range: 14 to 72 months), 37 patients remained alive, with two recurrences, both in spine with CSF involvement, resulting in a disease free-survival and overall survival of 85.2% and 90.2%, respectively.Seven patients (17%) experienced POG Grade 3 or 4 toxicity. Cisplatin dose was a significant factor for hearing loss in univariate analysis (p < 0.03). In multivariate analysis, median dose to inner ear was significantly associated with hearing loss (p < 0.01). POG grade 3 and 4 toxicity were uncommon with median doses to the inner ear bellow 42 Gy (p < 0.05) and total cisplatin dose of less than 375 mg/m2 (p < 0.01). CONCLUSIONS: IMRT leads to a low rate of severe ototoxicity. Median radiation dose to auditory apparatus should be kept below 42 Gy. Cisplatin doses should not exceed 375 mg/m2.

Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma.

PURPOSE: Long-term survival for children with diffuse intrinsic pontine glioma (DIPG) is less than 10%, and new therapeutic targets are urgently required. We evaluated a large cohort of DIPGs to identify recurrent genomic abnormalities and gene expression signatures underlying DIPG. PATIENTS AND METHODS: Single-nucleotide polymorphism arrays were used to compare the frequencies of genomic copy number abnormalities in 43 DIPGs and eight low-grade brainstem gliomas with data from adult and pediatric (non-DIPG) glioblastomas, and expression profiles were evaluated using gene expression arrays for 27 DIPGs, six low-grade brainstem gliomas, and 66 nonbrainstem low-grade gliomas. RESULTS: Frequencies of specific large-scale and focal imbalances varied significantly between DIPGs and nonbrainstem pediatric glioblastomas. Focal amplifications of genes within the receptor tyrosine kinase-Ras-phosphoinositide 3-kinase signaling pathway were found in 47% of DIPGs, the most common of which involved PDGFRA and MET. Thirty percent of DIPGs contained focal amplifications of cell-cycle regulatory genes controlling retinoblastoma protein (RB) phosphorylation, and 21% had concurrent amplification of genes from both pathways. Some tumors showed heterogeneity in amplification patterns. DIPGs showed distinct gene expression signatures related to developmental processes compared with nonbrainstem pediatric high-grade gliomas, whereas expression signatures of low-grade brainstem and nonbrainstem gliomas were similar. CONCLUSION: DIPGs comprise a molecularly related but distinct subgroup of pediatric gliomas. Genomic studies suggest that targeted inhibition of receptor tyrosine kinases and RB regulatory proteins may be useful therapies for DIPG.

Diffuse intrinsic brainstem tumor in an infant: a case of therapeutic efficacy with vinorelbine.

Brainstem gliomas constitute 10% to 20% of all pediatric tumors of the central nervous system, and diffusely infiltrative brainstem gliomas are the most common brainstem tumors associated with a poor prognosis. A small subset of these tumors is benign, showing low-grade features on histology. The role of chemotherapy in the management of these tumors is ill defined, especially in the neonates. There are anecdotal reports of spontaneous remission, but the natural history of these tumors does not support a wait-and-see approach. Thus, we report a successful experience of chemotherapy in a 4-month-old girl with a diffuse brainstem fibrillary astrocytoma, treated with vinorelbine (30 mg/m/d on days 0, 8, and 22), a vinca alkaloid that has shown activity against glioma. Our experience suggests that vinorelbine may be effective in pediatric low-grade gliomas as this patient showed significant clinical improvement over a short period of time.

Primary chemotherapy for intracranial germ cell tumors: results of the third international CNS germ cell tumor study.

BACKGROUND: The treatment of central nervous system (CNS) germ cell tumors (GCT) remains controversial. The purpose of this study was to demonstrate efficacy of a chemotherapy only strategy, with less morbidity, when compared to regimens with irradiation. METHODS: Between January 2001 and December 2004 newly diagnosed patients with CNS GCT were treated with one of two risk-tailored chemotherapy regimens. Twenty-five patients aged 4 months to 24.5 years were stratified: Regimen A consisted of 4-6 cycles of carboplatin/etoposide alternating with cyclophosphamide/etoposide for low risk (LR) localized germinoma with normal cerebrospinal fluid (CSF) and serum tumor markers. Regimen B consisted of 4-6 cycles of carboplatin/cyclophosphamide/etoposide for intermediate-risk (IR) germinoma with positive human chorionic gonadotrophin-beta (HCGbeta) and/or CSF HCGbeta <50 mIU/ml and high-risk (HR) biopsy-proven non-germinomatous malignant elements (MMGCT) or elevated serum/CSF alpha-fetoprotein and/or HCGbeta serum/CSF >50 mIU/ml. RESULTS: Eleven patients were classified as LR, 2 IR, and 12 HR. Seventeen (68%) patients achieved complete radiographic and marker responses after two courses and 19 (76%) after four courses of chemotherapy. Eleven patients relapsed at a mean of 30.8 months; eight of them subsequently received irradiation. The 6-year event free and overall survival for the 25 patients was 45.6% and 75.3%, respectively. CONCLUSION: These intensive chemotherapy regimens proved less effective than irradiation containing regimens. Our results indicate that, at the present time, standard treatment for CNS GCT continues to include irradiation either alone or combined with chemotherapy for pure germinomas and with chemotherapy for those with MMGCT.

Speech-language and hearing complaints of children and adolescents with brain tumors.

Central nervous system (CNS) tumors generally leave sequelae that may compromise speech, language, swallowing, hearing, and voice functions. This report describes the incidence of speech-language and hearing complaints and disorders in children and adolescents with CNS tumor under treatment at one of the most important Brazilian reference center for pediatric cancer. One-hundred ninety patients were examined for speech-pathology screening and analysis: forty-two percent presented with complaints and symptoms. From the remaining patients, 68% presented clinical symptoms and 32% were actually free from any speech-language and hearing-related symptoms. The high incidence of complaints and symptoms indicate that these patients might benefit from specific rehabilitation interventions.

Cavectomy for the treatment of Wilms tumor with vascular extension.

PURPOSE: Vascular extension to the vena cava occurs in 4% of Wilms tumor cases and can reach the right atrium in up to 1%. When this happens the thrombus is usually not adherent to the vessel wall, and there is blood flow around it. Preoperative chemotherapy can cause thrombus regression and even resolution. If the thrombus persists after chemotherapy, surgery will be a challenge. On the other hand, if the thrombus invades the vessel wall, its removal may not be feasible. In this situation cavectomy is a good surgical strategy because it provides complete resection. The prerequisite for cavectomy is the absence of blood flow in the vena cava on preoperative Doppler ultrasonography. We report 3 cases of Wilms tumor with vena caval invasion in which cavectomy was performed, and discuss the principles, indications and operative technique. MATERIALS AND METHODS: A total of 171 patients with Wilms tumor were treated at our institution between 1984 and 2004. Of these patients 6 with intravascular extension of thrombus within the right atrium were treated with extracorporeal circulation, cardiac arrest and profound hypothermia, and 3 were treated with cavectomy. RESULTS: There were no instances of surgical complications or postoperative renal failure in our patients who underwent cavectomy. All remain well and free of disease. CONCLUSIONS: Cavectomy is a safe procedure for treating pediatric patients with Wilms tumor when there is extension and invasion of the vena cava wall without blood flow.

Comparative genomic hybridization analysis of pediatric adamantinomatous craniopharyngiomas and a review of the literature.

OBJECT: The purpose of this study was to examine chromosomal gains and losses in 11 pediatric adamantinomatous craniopharyngiomas by using comparative genomic hybridization (CGH), as well as to review the cytogenetic literature that has contributed to the characterization of these tumors. One source of confusion in the cytogenetic and CGH literature concerning craniopharyngioma is that the authors of most studies fail to distinguish between pediatric and later-onset forms of the disease. Thus, this study was focused on pediatric craniopharyngioma. METHODS: To determine an overview of the genetic events leading to the development of these tumors, 10 adamantinomatous craniopharyngiomas were analyzed using CGH; none of the tumor specimens demonstrated gains or losses of DNA sequence. CONCLUSIONS: In view of these findings as well as those published in the majority of previous cytogenetic studies of craniopharyngiomas, the authors conclude that the recurrent acquisition of chromosomal imbalances does not play a major role in tumorigenesis and that chromosomal gains and losses are a relatively rare event in primary tumors of pediatric origin.