Treatment of NF1-Associated Optic Pathway/Hypothalamic Gliomas in Patients With Diencephalic Syndrome.

Diencephalic syndrome is usually associated with tumors in the hypothalamic region, rarely occurring in patients with neurofibromatosis type 1 (NF1)-associated gliomas. We describe the clinical presentation and response to treatment in 3 patients with NF1 presenting with diencephalic syndrome as first symptom of optic pathway/hypothalamic glioma (OPHG). Because of the rarity of this constellation, knowledge about the clinical course and best treatment options for patients with NF1-associated OPHG and diencephalic syndrome is still limited. All 3 patients showed good response to treatment with normalization of body mass index and decrease in tumor volume within 6 months.

Central nervous system tumors in children under 5 years of age: a report on treatment burden, survival and long-term outcomes.

PURPOSE: The challenges of treating central nervous system (CNS) tumors in young children are many. These include age-specific tumor characteristics, limited treatment options, and susceptibility of the developing CNS to cytotoxic therapy. The aim of this study was to analyze the long-term survival, health-related, and educational/occupational outcomes of this vulnerable patient population. METHODS: Retrospective study of 128 children diagnosed with a CNS tumor under 5 years of age at a single center in Switzerland between 1990 and 2019. RESULTS: Median age at diagnosis was 1.81 years [IQR, 0.98-3.17]. Median follow-up time of surviving patients was 8.39 years [range, 0.74-23.65]. The main tumor subtypes were pediatric low-grade glioma (36%), pediatric high-grade glioma (11%), ependymoma (16%), medulloblastoma (11%), other embryonal tumors (7%), germ cell tumors (3%), choroid plexus tumors (6%), and others (9%). The 5-year overall survival (OS) was 78.8% (95% CI, 71.8-86.4%) for the whole cohort. Eighty-seven percent of survivors > 5 years had any tumor- or treatment-related sequelae with 61% neurological complications, 30% endocrine sequelae, 17% hearing impairment, and 56% visual impairment at last follow-up. Most patients (72%) attended regular school or worked in a skilled job at last follow-up. CONCLUSION: Young children diagnosed with a CNS tumor experience a range of complications after treatment, many of which are long-lasting and potentially debilitating. Our findings highlight the vulnerabilities of this population, the need for long-term support and strategies for rehabilitation, specifically tailored for young children.

A single supratentorial high-grade neuroepithelial tumor with two distinct BCOR mutations, exceptionally long complete remission and survival.

Here, we present a patient with high-grade neuroepithelial tumors with mutations in the BCL6 corepressor BCOR (HGNET-BCOR), a rare, highly malignant brain tumor with poor prognosis. The patient underwent gross total tumor resection (GTR), high-dose chemotherapy, and, after local relapse, GTR, proton radiation, and chemotherapy. After a 7.5 year-long complete remission, the tumor recurred locally, was treated by GTR, and responded to temozolomide treatment. In addition to an internal tandem duplication in BCOR common to the majority of HGNET-BCOR cases, molecular analysis revealed a second BCOR mutation in this tumor: a frame shift mutation. The combination of these mutations was associated with relatively low BCOR expression compared to other HGNET-BCOR cases.

Management of Primary Tectal Plate Low-Grade Glioma in Pediatric Patients: Results of the Multicenter Treatment Study SIOP-LGG 2004.

BACKGROUND: Tectal plate low-grade gliomas (LGGs) most often present with increased intracranial pressure and sometimes as incidental findings from brain imaging. Prognostic factors predicting outcome are largely unknown. METHODS: From 2004 until 2012, 71 patients with tectal plate LGG from Germany and Switzerland were followed within the SIOP-LGG 2004 study. Median age at diagnosis was 9.7 (range: 0.1-17.5) years, and median follow-up time of surviving patients was 6.3 (interquartile range: 4.9-8.3) years. RESULTS: A total of 41 out of 71 patients received no tumor treatment (12 with and 29 without biopsy). The 10-year event-free survival (EFS) rate (± standard error ) for patients with an initial tumor volume of ≤3 cm3 was 56% (±7%), as opposed to 12% (±8%) for those with tumors >3 cm3 (p < 0.001). The 10-year EFS for patients without contrast enhancement on initial magnetic resonance imaging (MRI) was 52% (±9%), and for those with enhancement, it was 23% (±9%) (p = 0.003). The 10-year overall survival rate was 96% (±3%) (death due to disease, 1; ventriculoperitoneal shunt infection, 1). Sixty-three (89%) patients had at least one cerebrospinal fluid diversion procedure. CONCLUSIONS: More than half of patients were managed without tumor treatment. Favorable prognostic factors for EFS were small initial tumor volume (≤3cm3) and the absence of initial contrast enhancement on MRI. Overall survival was excellent.

Childhood cancer survival in Switzerland (1976-2013): Time-trends and predictors.

Population-based studies on childhood cancer survival are key to monitor progress against cancer and to detect potential differences between regions and other subgroups in the population. We investigated time trends and factors associated with childhood cancer survival on a national level in Switzerland, from 1976 to 2013. We extracted data from the population-based Swiss Childhood Cancer Registry of 5,776 children (age 0-14 years) diagnosed with cancer from 1985 to 2014 in Switzerland. We calculated age-adjusted 5-year survival, defined the annual reduction in risk of death (ARR), and explored associations of survival with clinical and demographic factors. Overall, 5-year survival improved significantly, from 64% in 1976-1983 to 88% in 2004-2013. ARR over the whole period was 4% for all diagnostic groups, greatest for Hodgkin lymphomas (8%), ependymomas (6%), Burkitt's lymphomas (6%) and germ cell tumours (6%). Children treated in hospitals without specialised paediatric cancer centre for leukaemia (HR 12.9), lymphoma (HR 5.0) and neuroblastoma (HR 3.7) were at higher risk of death. In French-speaking Switzerland, risk of death was lower for lymphoma (HR 0.6), CNS tumours (HR 0.7) and neuroblastoma (HR 0.5). Children with migration background had a higher risk of death from all tumours except bone tumours. Childhood cancer survival significantly improved from 1976 to 2013, but there is room for further improvement. Survival rates varied by type of clinical treatment, language region and nationality. All paediatric cancer patients should be referred to a specialised paediatric cancer centre. Further research is needed to intervene and completely eliminate inequalities in survival.

Tropomyosin receptor kinase C (TrkC) expression in medulloblastoma: relation to the molecular subgroups and impact on treatment response.

PURPOSE: High messenger RNA (mRNA) expression of the tropomyosin receptor kinase C gene (TrkC) has been associated with favorable survival in medulloblastoma patients. Untested is whether it plays a role through modulating the response to therapy or whether it might be a surrogate marker for a favorable molecular subgroup. METHODS: The medulloblastoma-derived cell line DAOY was stably transfected to overexpress TrkC (clone DAOY-TrkC) and compared to a control (clone DAOY-EV, empty vector transfected). Cell viability (MTS assay) was tested after irradiation or incubation with chemotherapeutic drugs. Neuroradiologic response to postoperative chemotherapy or craniospinal irradiation (CSI) of medulloblastoma patients aged 3-21 years with postoperative residual disease treated within the consecutive trials HIT'91/HIT2000 was compared to TrkC mRNA expression in their tumor samples. Five well-characterized independent expression-profiling studies covering together 686 medulloblastoma patients were analyzed for TrkC levels according to the molecular subgroups. RESULTS: Cell viability of DAOY-TrkC compared to DAOY-EV was not different after exposure to increasing doses of irradiation, cisplatin, etoposide, or vincristine. While TrkC mRNA expression tended to be higher in non-responders (n = 5/19) to postoperative CSI (p = 0.03, ratio 15.5, 95% CI 9-267), this was the case in responders (n = 23/43) to chemotherapy (p = 0.04, ratio 6.1, 95% CI 1.1-35), both analyzed with Mann-Whitney U test (not significant after Bonferroni adjustment). The highest TrkC mRNA levels were found in the SHH subgroup across all expression-profiling studies. CONCLUSIONS: High TrkC mRNA expression appears to be frequent in the SHH subgroup and seems not to have a major effect on therapy responsiveness in medulloblastoma patients.

Pencil beam scanning proton therapy for pediatric intracranial ependymoma.

To assess the clinical outcome and late side effect profile of pencil beam scanning proton therapy (PT) delivered to children with intracranial ependymoma. Between July-2004 and March-2013, 50 patients with intracranial ependymoma (n = 46, grade 3) received involved-field PT at Paul Scherrer Institute (PSI). Median age at time of PT was 2.6 years (range 1.1-15.2). Thirty-six patients had infratentorial and 14 supratentorial ependymomas. Seventeen patients presented with macroscopic residual disease after subtotal resection before starting PT (8 with ≤1.5 cc and 9 with >1.5 cc residual tumor respectively). Forty-three (86 %) patients received post-operative chemotherapy before PT according to protocols; 44 (88 %) patients younger than 5 years required general anesthesia. Median prescribed dose was 59.4 Gy (RBE) (range 54-60) delivered in 1.8-2 Gy (RBE) per fraction. Late toxicity was assessed according to CTCAE v4.0. With a mean follow-up time of 43.4 months (range 8.5-113.7) seven patients experienced local failure (6 with infratentorial tumors and 1 with supratentorial tumor); four of the local failures were in patients with residual disease ≥1.5 cc at the time of PT and 3 without residual macroscopic disease. Five patients died from tumor progression. Actuarial 5-year Local Control rates were 78 ± 7.5 % and 5-year OS rates were 84 ± 6.8 %. Three patients developed grade ≥3 toxicity: 2 developed unilateral deafness (infratentorial tumors infiltrating into the internal acoustic canal), one patient developed a fatal brainstem necrosis. Repeated general anesthesia in children younger than 5 years was delivered without complications. Our data indicate the safety and the effectiveness of PT for pediatric ependymomas. Local control and survival rates are encouraging considering the high grade histology in 92 % of the patients and the number of patients with residual tumor ≥1.5 cc. The rates of late effects compare favorably with published photon-treated cohorts.

The Changing Landscape of Pediatric Low-Grade Gliomas: Clinical Challenges and Emerging Therapies.

Pediatric low-grade gliomas (PLGGs) are the most common brain tumors in children. Though histologically benign and associated with excellent outcome, patients with unresectable lesions--mostly young children with midline tumors--experience multiple progressions and are at increased risk for long-term neurological sequelae. PLGGs in children with underlying genetic predisposition syndromes--especially neurofibromatosis type 1 and tuberous sclerosis--have a distinct natural history and biology with important treatment implications. Given the complexity of medical issues, optimal management requires a large network of health care providers; treatment decisions must address both tumor control and potential side effects of the therapy. Current treatment strategies often fail to induce sustained tumor regression and many children require several lines of therapy, highlighting the need for novel therapies. Here, we review the current management of PLGG and discuss how new molecular targets--in particular alterations of the Ras/MAPK pathway--are rapidly changing our approach to PLGG.

Colostomy for Perianal Sepsis With Ecthyma Gangrenosum in Immunocompromised Children.

BACKGROUND: Perianal sepsis with ecthyma gangrenosum is a severe and potentially mutilating complication in immunocompromised children. Therapies include antimicrobial treatment, incision and drainage, generous tissue debridement, and skin transplantation. PROCEDURE: We describe 3 children with acute lymphoblastic leukemia having sepsis with Pseudomonas aeruginosa in febrile neutropenia and severe perianal infections treated relatively early with a protective colostomy. Indications for colostomy were nonhealing wounds, and ceaseless pain. RESULTS: All patients showed a rapid reduction of pain. Complete wound healing was seen in 2 patients, and considerable pain reduction and increased quality of life were seen in a third patient during palliative care. CONCLUSIONS: These results suggest that a protective colostomy should be considered early in the management of immunocompromised children with ecthyma gangrenosum.

CCDC26, CDKN2BAS, RTEL1 and TERT Polymorphisms in pediatric brain tumor susceptibility.

The role of genetic polymorphisms in pediatric brain tumor (PBT) etiology is poorly understood. We hypothesized that single nucleotide polymorphisms (SNPs) identified in genome-wide association studies (GWAS) on adult glioma would also be associated with PBT risk. The study is based on the Cefalo study, a population-based multicenter case-control study. Saliva DNA from 245 cases and 489 controls, aged 7-19 years at diagnosis/reference date, was extracted and genotyped for 29 SNPs reported by GWAS to be significantly associated with risk of adult glioma. Data were analyzed using unconditional logistic regression. Stratified analyses were performed for two histological subtypes: astrocytoma alone and the other tumor types combined. The results indicated that four SNPs, CDKN2BAS rs4977756 (p = 0.036), rs1412829 (p = 0.037), rs2157719 (p = 0.018) and rs1063192 (p = 0.021), were associated with an increased susceptibility to PBTs, whereas the TERT rs2736100 was associated with a decreased risk (p = 0.018). Moreover, the stratified analyses showed a decreased risk of astrocytoma associated with RTEL1 rs6089953, rs6010620 and rs2297440 (p trend = 0.022, p trend = 0.042, p trend = 0.029, respectively) as well as an increased risk of this subtype associated with RTEL1 rs4809324 (p trend = 0.033). In addition, SNPs rs10464870 and rs891835 in CCDC26 were associated with an increased risk of non-astrocytoma tumor subtypes (p trend = 0.009, p trend = 0.007, respectively). Our findings indicate that SNPs in CDKN2BAS, TERT, RTEL1 and CCDC26 may be associated with the risk of PBTs. Therefore, we suggest that pediatric and adult brain tumors might share common genetic risk factors and similar etiological pathways.

Ventricular Catheter Systems with Subcutaneous Reservoirs (Ommaya Reservoirs) in Pediatric Patients with Brain Tumors: Infections and Other Complications.

OBJECTIVE: This study aims to describe complications related to ventricular catheter systems with subcutaneous reservoirs (VCSR) (such as Ommaya reservoirs) in pediatric patients with brain tumors. METHODS: Retrospective analysis of consecutive patients with a total of 31 VCSR treated at the Children's University Hospital of Zurich, Switzerland. RESULTS: A total of 20 patients with a median age of 3.3 years at VCSR implantation received 31 VCSR. Overall, 19 complications in 11 patients were recorded: 7 patients had a VCSR-related infection with coagulase-negative staphylococci, 4 of these probably as a surgical complication and 3 probably related to VCSR use. Systemic perioperative prophylaxis was administered in 22 cases, and intraventricular vancomycin and gentamicin were given in 8 cases (none of which subsequently developed an infection). Other complications included wound dehiscence, catheter malplacement, and leakage of cerebrospinal fluid. Overall, 17 VCSR were explanted due to complications. CONCLUSION: Infections were the most frequent VCSR-related complication. In our own institution, the high rate of complications led to the definition of a bundle of measures as a standard operating procedure for VCSR placement and use. Prospective studies in larger patient collectives are warranted to better identify risk factors and evaluate preventive measures such as the administration of perioperative antibiotics and the use of antimicrobial coating of catheters.

Contrast-enhanced MRI of the temporomandibular joint: findings in children without juvenile idiopathic arthritis.

BACKGROUND: Contrast-enhanced magnetic resonance imaging (MRI) is highly sensitive for assessing temporomandibular joint (TMJ) involvement in juvenile idiopathic arthritis (JIA), but only sparse data exist on normal TMJ appearance in children. PURPOSE: To determine normal MRI appearance and enhancement pattern of pediatric TMJ as basis for diagnosing early arthritis. MATERIAL AND METHODS: In 27 children (age range, 1.2-16.8 years) without TMJ pathology undergoing head MRI, fat-saturated T2-weighted (T2W) and postcontrast fat-saturated T1-weighted (T1W) images sagittally aligned to the 54 TMJs, besides standard T1W and T2W images, were assessed for bony and soft tissue signal intensity (SI), the amount of perceptible joint fluid, and contrast enhancement (CE). RESULTS: Bone marrow SI and CE of the mandible were consistent with varying degrees of residual red marrow in 96% of joints. The mandibular condyles were mostly isointense to the ramus, but in 9% showed mild edema-like bone marrow SI and CE. Small amounts of intraarticular fluid were detected in 31% on T2W images without fat saturation and in 83% on T2W images with fat saturation as fine lines in the upper or lower joint compartment or as small dots in an articular recess. Seventy-nine percent of all TMJs showed intense joint enhancement on early images restricted to areas of intraarticular fluid. CONCLUSION: Small amounts of joint fluid with intense CE are a common MRI finding in TMJs of children without JIA and therefore should not be considered diagnostic for early arthritis.

Tumor-Associated CSF MicroRNAs for the Prediction and Evaluation of CNS Malignancies.

Cerebrospinal fluid (CSF) is a readily reachable body fluid that is reflective of the underlying pathological state of the central nervous system (CNS). Hence it has been targeted for biomarker discovery for a variety of neurological disorders. CSF is also the major route for seeding metastases of CNS malignancies and its analysis could be informative for diagnosis and risk stratification of brain cancers. Recently, modern high-throughput, microRNAs (miRNAs) measuring technology has enabled sensitive detection of distinct miRNAs that are bio-chemicallystable in the CSF and can distinguish between different types of CNS cancers. Owing to the fact that a CSF specimen can be obtained with relative ease, analysis of CSF miRNAs could be a promising contribution to clinical practice. In this review, we examine the current scientific knowledge on tumor associated CSF miRNAs that could guide diagnosis of different brain cancer types, or could be helpful in predicting disease progression and therapy response. Finally, we highlight their potential applications clinically as biomarkers and discuss limitations.

MicroRNA signatures as biomarkers and therapeutic target for CNS embryonal tumors: the pros and the cons.

Embryonal tumors of the central nervous system represent a heterogeneous group of childhood cancers with an unknown pathogenesis; diagnosis, on the basis of histological appearance alone, is controversial and patients' response to therapy is difficult to predict. They encompass medulloblastoma, atypical teratoid/rhabdoid tumors and a group of primitive neuroectodermal tumors. All are aggressive tumors with the tendency to disseminate throughout the central nervous system. The large amount of genomic and molecular data generated over the last 5-10 years encourages optimism that new molecular targets will soon improve outcomes. Recent neurobiological studies have uncovered the key role of microRNAs (miRNAs) in embryonal tumors biology and their potential use as biomarkers is increasingly being recognized and investigated. However the successful use of microRNAs as reliable biomarkers for the detection and management of pediatric brain tumors represents a substantial challenge. This review debates the importance of miRNAs in the biology of central nervous systemembryonal tumors focusing on medulloblastoma and atypical teratoid/rhabdoid tumors and highlights the advantages as well as the limitations of their prospective application as biomarkers and candidates for molecular therapeutic targets.

Significance and therapeutic value of miRNAs in embryonal neural tumors.

Embryonal tumors of the nervous system are the leading cause of childhood cancer-related morbidity and mortality. Medulloblastoma, supratentorial primitive neuroectodermal tumors, atypical teratoid/rhabdoid tumor and neuroblastoma account for more than 20% of childhood malignancies and typify the current neural embryonal tumor model in pediatric oncology. Mechanisms driving the formation of these tumors point towards impaired differentiation of neuronal and neuron-associated cells during the development of the nervous system as an important factor. The importance of microRNAs (miRNAs) for proper embryonic cell function has been confirmed and their aberrant expressions have been linked to tumor development. The role of miRNAs in controlling essential regulators of key pathways implicated in tumor development makes their use in diagnostics a powerful tool to be used for early detection of cancer, risk assessment and prognosis, as well as for the design of innovative therapeutic strategies. In this review we focus on the significance of miRNAs involved in the biology of embryonal neural tumors, delineate their clinical significance and discuss their potential as a novel therapeutic target.

Apparent diffusion coefficient of pediatric cerebellar tumors: a biomarker of tumor grade?

BACKGROUND: The role of diffusion weighted imaging (DWI) to reliably differentiate tumor types and grades in pediatric cerebellar tumors is controversial. We aimed to clarify the discrepancy reported in previous articles. PROCEDURES: We retrospectively evaluated the apparent diffusion coefficient (ADC) values of the enhancing, solid parts of cerebellar tumors and correlated the absolute tumor ADC values and cerebellar and thalamic ratios with histology in a cohort of children with cerebellar tumors. RESULTS: Twenty-four children (12 females) were included in the study. The median age at pre-surgical MRI was 10 years (range 29 days-18.5 years). Absolute ADC values (mean 1.49, SD 0.25 vs. 0.63 ± 0.18), cerebellar (2.04 ± 0.33 vs. 0.83 ± 0.25), and thalamic ratio (1.98 ± 0.35 vs. 0.79 ± 0.23) were significantly higher in low- than in high-grade tumors (P < 0.0001). Absolute ADC values and cerebellar and thalamic ratios were significantly higher in low-grade astrocytomas than in MBs. Overlap was seen for WHO grade II and III ependymomas. One hundred percent specific cutoff ADC values of >1.2 × 10(3) and <0.8 × 10(-3) mm(2) /s were established for low- and high-grade tumors. CONCLUSION: ADC analysis of the solid, contrast enhancing components of pediatric cerebellar tumors may facilitate differentiation between various tumor histologies.

Isolated intraspinal juvenile xanthogranuloma in an infant presenting as acute paraplegia.

Juvenile xanthogranuloma is a histiocytic proliferative disease that predominantly affects the skin. Extracutaneous involvement is rare. We present the case of a 6-month-old infant with acute paraplegia. Magnetic resonance imaging showed an intraspinal extradural mass at midthoracic level with marked compression of the spinal cord. Complete tumor removal was achieved by emergency surgery and was followed by complete neurologic recovery. Histologic examination led to the diagnosis of a juvenile xanthogranuloma. To the best of our knowledge, an isolated intraspinal juvenile xanthogranuloma in the first 12 months of life has not been described before.

Surgical resection of pediatric skull base meningiomas.

PURPOSE: Meningiomas in children are rare, especially those located at the skull base. In this study, we report our experience of meningioma surgery in the pediatric population and compare our findings of skull base (SB) versus non-skull base (NSB) meningiomas. METHODS: From our database of 724 surgically treated meningioma patients at the University Hospital, Zurich between 1995 and 2010, 12 patients under 18 years of age were identified. Data for those patients was retrospectively collected through chart review. A descriptive comparison between SB and NSB meningiomas was undertaken to determine statistical significance. RESULTS: In all 12 children (seven males, five females; mean age 12.2 ± 4.3 years), surgical removal of the meningioma was performed microsurgically with a mean follow-up of 53 months (range 12-137 months). Of the 12 tumors, six were located in the SB and six in the NSB. Comparing SB to NSB lesions, the mean age was 11 ± 3.8 versus 14 ± 4.6 years, male/female gender distribution was 5:1 compared to 1:5, mean tumor size was 7.5 ± 6.2 versus 26 ± 15.8 cm(2) (p = 0.03), and mean surgery time was 347 versus 214 min. While WHO grade was similar for both groups, the Simpson grade revealed more extensive resection for NSB meningiomas. The Glasgow Outcome Scale at last follow-up was favorable for both groups. CONCLUSIONS: Meningioma surgery was safe with favorable outcomes. SB meningiomas were significantly smaller in size, were less likely to undergo complete resection, and had a predilection for younger, male patients.

Pediatric papillary tumors of the pineal region: to observe or to treat following gross total resection?

INTRODUCTION: Papillary tumors of the pineal region (PTPR) are rare brain tumors characterized by frequent local recurrences. Standardized treatment strategies are not yet defined. CASE REPORT: We present the case of a 3-year-old girl diagnosed with PTPR. Due to her young age, adjuvant radiotherapy was omitted after gross total tumor resection. Thirty-six months later, local tumor recurrence occurred. Considering the possible risks of secondary surgery, the recurrent tumor was irradiated with proton radiotherapy. Three months later, the tumor showed near-complete remission. DISCUSSION: Based on this experience and other pediatric case reports from the literature, local radiotherapy might be suggested also after complete tumor resection.