ZFTA (Zinc Finger Translocation Associated) Fusion in Supratentorial Ependymomas: Low Prevalence in South Asians and No Correlation with Survival.

BACKGROUND: Supratentorial ependymomas (STEs) are an aggressive group of ependymomas, topographically distinct from their posterior fossa and spinal counterparts. Zinc finger translocation associated (ZFTA) fusion-positive cases have been reported to account for the majority of STEs, although data on its association with poorer outcomes are inconsistent. MATERIALS AND METHODS: We assessed the prevalence of the ZFTA fusion by reverse-transcription polymerase chain reaction and fluorescence in situ hybridization in a cohort of 61 patients (68 samples) with STE. Our primary outcome was to determine the role of the ZFTA fusion on progression-free and overall survival of patients with STE. Our secondary objectives were to assess the impact of ZFTA fusion on nuclear factor (NF)-kB pathway signaling via surrogate markers of this pathway, namely COX-2, CCND1, and L1 cell adhesion molecule. RESULTS: ZFTA fusion was noted in 21.3% of STEs in our cohort. The presence of this rearrangement did not significantly impact the progression-free or overall survival of patients with STEs and was not associated with upregulation of markers of the NF-kB pathway. Only gross total resection was significantly associated with better progression-free survival. CONCLUSIONS: In contradiction to previous reports from across the world, the ZFTA fusion is far less prevalent among our population. It does not appear to drive NF-kB signaling or significantly affect outcomes. Gross total resection must be attempted in all cases of STE and adjuvant radiation and/or chemotherapy employed when gross total resection is not achieved.

Clinical impact of hypothalamic-pituitary disorders after conformal radiation therapy for pediatric low-grade glioma or ependymoma.

BACKGROUND: To determine the impact of hypothalamic-pituitary (HP) disorders on health outcomes in children and adolescents who received conformal radiation therapy (RT) for central nervous system tumors. PROCEDURE: Cohort study including 355 patients (age ≤25 years at diagnosis) treated with high-dose (50.4-59.4 Gy) RT using photons for low-grade glioma or ependymoma. Patients (median age, 6.4 years at RT) received systematic endocrine follow-up (median duration, 10.1 years; range, 0.1-19.6). Associations between HP disorders and adverse health outcomes were determined by multivariable analysis. RESULTS: Prevalence was 37.2% for growth hormone deficiency (GHD), 17.7% for gonadotropin deficiency (LH/FSHD), 14.9% for thyroid-stimulating hormone deficiency (TSHD), 10.3% for adrenocorticotropic hormone deficiency (ACTHD), and 12.6% for central precocious puberty (CPP). Hypothalamus mean dose ≥ 36 Gy was associated with higher odds of any deficiency. GHD was associated with short stature (OR 2.77; 95% CI 1.34-5.70), low bone mineral density (OR 3.47; 95% CI 1.16-10.40), and TSHD with dyslipidemia (OR 5.54; 95% CI 1.66-18.52). Patients with ACTHD and CPP had lower intelligence quotient scores, and memory scores were impaired in patients with GHD (P = 0.02). Treatment of GHD was not associated with increased risk for tumor recurrence, secondary tumors, or mortality. CONCLUSIONS: HP disorders occur frequently in patients receiving high-dose RT and are related to physical and neurocognitive well-being. Future studies are needed to assess whether further optimization of endocrine management yields better health outcomes.

A novel neuromodulation technique for the rehabilitation of balance and gait: A case study.

Cranial-nerve non-invasive neuromodulation (CN-NINM) through the tongue has been proposed as an adjuvant intervention to improve efficacy of rehabilitation. However, CN-NINM effects have only been explored in multiple sclerosis and stroke populations. In this report we used CN-NINM during a 2-week (2 × 1.5 h sessions daily) physiotherapy program for the rehabilitation of a 57 y/o woman presenting with balance and gait impairments after a surgical resection of a fourth ventricular ependymoma. Clinical and instrumented balance and gait assessments showed improved performance in all tests and without adverse effects This study shows the beneficial effects and feasibility of combined physiotherapy and CN-NINM in this patient.

Pediatric thalamic tumors in the MRI era: a Canadian perspective.

BACKGROUND: Thalamic gliomas are rare. The natural history is unpredictable, and the optimal management of these tumors in children is poorly defined. The aim was to identify outcomes, prognostic factors, and response to various modalities of treatment in a relatively large population of pediatric thalamic tumors from many centers within a fairly homogeneous health care system. METHODS: We performed a Canadian multicenter retrospective review of pediatric thalamic tumors presenting during the MRI era (1989-2012). Radiology and pathology were reviewed by central independent reviewers. Paraffin shavings for RNA extraction were taken and tested for fusion events involving KIAA1549:BRAF. Tumors were classified as unilateral or bithalamic based on their origin on imaging. Univariate and multivariate analyses on factors influencing survival were performed. RESULTS: Seventy-two thalamic tumors were identified from 11 institutions. Females represented 53% of the study population, and the mean age at presentation was 8.9 years. Sixty-two tumors were unilateral and 10 bithalamic. Unilateral tumors had a greater propensity to grow inferiorly towards the brainstem. These tumors were predominantly low grade in comparison to bithalamic tumors which were high-grade astrocytomas. The 5-year overall survival was 61 ± 13% for unithalamic tumors compared to 37 ± 32% for bithalamic tumors (p = 0.097). Multivariate analysis indicated tumor grade as the only significant prognostic factor for unithalamic tumors. Six unilateral tumors, all low grade, were BRAF fusion positive. CONCLUSION: Unilateral and bilateral thalamic tumors behave differently. Surgical resection is an appropriate treatment option in unilateral tumors, most of which are low grade, but outcome is not related to extent of resection (EOR). Bilateral thalamic tumors have a poorer prognosis, but the occasional patient does remarkably well. The efficacy of chemotherapy and radiotherapy has not been clearly demonstrated. Novel therapeutic approaches are required to improve the prognosis for malignant unilateral thalamic tumors and bilateral thalamic tumors.

Ependymoma in adults: Local experience with an uncommon tumour.

This study reviews our tertiary hospital experience in an adult population of ependymoma patients. Ependymomas are uncommon tumours of the central nervous system (CNS) and the literature provides little information to guide management and predict prognosis. The prospectively maintained Australian Comprehensive Cancer Outcomes and Research Database of CNS tumours was searched for patients diagnosed with ependymomas at the Royal Melbourne Hospital between January 2008 and December 2013. A total of 39 adult patients with ependymoma were identified, including 13 with spinal myxopapillary ependymoma. The mean age at diagnosis was 44 years. All patients underwent surgical resection, 67% of whom had a gross macroscopic resection. Postoperative adjuvant radiotherapy was administered to 11 patients (30%), two (5%) died from progressive disease and seven (18%) developed recurrent disease. Our findings are consistent with the existing literature for patient demographics and the approach to treatment, whilst our clinical outcomes appear more favourable. This study provides the basis for further and necessary research, including determination of the molecular characterisation of these tumours and the identification of prognostic and predictive biomarkers and treatment targets.

Severe cyanide poisoning from an alternative medicine treatment with amygdalin and apricot kernels in a 4-year-old child.

BACKGROUND: The use of complementary and alternative medicine (CAM) is widespread in children with cancer and is poorly regulated. PATIENTS AND METHODS: Case report. RESULTS: We describe a case of severe cyanide poisoning arising from CAM use. A severely agitated, encephalopathic, unresponsive 4-year-old boy (initial Glasgow Coma Scale of 3) with a history of metastatic ependymoma was brought to our emergency department by ambulance services. Initial blood gas analysis demonstrated severe metabolic/lactic acidosis. On detailed questioning of the parents, the use of CAM including intravenous and oral "vitamin B 17" (amygdalin) and oral apricot kernel was reported. After administering sodium thiosulfate, rapid improvement in his medical condition with complete recovery without need for further intensive care treatment was seen. Serum cyanide level was markedly elevated. CONCLUSIONS: Cyanide poisoning can be the cause of severe encephalopathy in children receiving CAM treatment with substances containing cyanogenic glycosides.

Time-dependent structural changes of the dentatothalamic pathway in children treated for posterior fossa tumor.

BACKGROUND AND PURPOSE: Injury to the dentatothalamic pathway that originates in the cerebellum has been suggested as a mechanism for neurologic complications in children treated for posterior fossa tumors. We hypothesized that time-dependent changes occur in the dentatothalamic pathway. MATERIALS AND METHODS: Diffusion tensor evaluation was performed in 14 children (median age, 4.1 years; age range, 1-20 years) who underwent serial MR imaging at 3T as part of routine follow-up after posterior fossa tumor resection with or without adjuvant therapy. Tensor metrics were obtained in the acute (≤1 week), subacute (1 to <6 months), and chronic (≥6 months) periods after surgery. We evaluated the following dentatothalamic constituents: bilateral dentate nuclei, cerebellar white matter, and superior cerebellar peduncles. Serial dentate nuclei volumes were also obtained and compared with the patient's baseline. RESULTS: The most significant tensor changes to the superior cerebellar peduncles and cerebellar white matter occurred in the subacute period, regardless of the tumor pathology or therapy regimen, with signs of recovery in the chronic period. However, chronic volume loss and reduced mean diffusivity were observed in the dentate nuclei and did not reverse. This atrophy was associated with radiation therapy and symptoms of ataxia. CONCLUSIONS: Longitudinal diffusion MR imaging in children treated for posterior fossa tumors showed time-dependent tensor changes in components of the dentatothalamic pathway that suggest evolution of structural damage with inflammation and recovery of tissue directionality. However, the dentate nuclei did not show tensor or volumetric recovery, suggesting that the injury may be chronic.

Intracranial ependymoma: long-term results in a series of 21 patients treated with stereotactic (125)iodine brachytherapy.

BACKGROUND: We evaluated the long-term outcome in patients harboring intracranial ependymomas treated with interstitial brachytherapy (IBT). METHODS: Twenty-one patients (M/F = 9/12; median age: 29 years; range: 8-70 years), diagnosed with intracranial ependymoma (1 WHO I, 11 WHO II, 9 WHO III) were treated with IBT using stereotactically implanted (125)Iodine seeds between 1987 and 2010, either primarily, as adjuvant therapy following incomplete resection, or as salvage treatment upon tumor recurrence. Sixteen of 21 patients underwent microsurgical resection prior to IBT; in 5 patients, IBT was performed primarily after stereotactic biopsy for histological diagnosis. The cumulative tumor surface dose ranged from 50-65 Gy treating a median tumor volume of 3.6 ml (range, 0.3-11.6 ml). A median follow-up period of 105.3 months (range, 12.7-286.2 months) was evaluated. RESULTS: Actuarial 2-, 5- and 10-years overall- and disease-specific survival rates after IBT were each 90% and 100% at all times for ependymomas WHO I/II, for anaplastic ependymomas WHO III 100%, 100%, 70% and 100%, 100%, 86%, respectively. The neurological status of seven patients improved, while there was no change in 12 and deterioration in 2 patients, respectively. Follow-up MR images disclosed a complete tumor remission in 3, a partial remission in 12 and a stable disease in 6 patients. Treatment-associated morbidity only occurred in a single patient. CONCLUSIONS: This study shows that stereotactic IBT for intracranial ependymomas is safe and can provide a high degree of local tumor control. Due to the low rate of side effects, IBT may evolve into an attractive alternative to microsurgery in ependymomas located in eloquent areas or as a salvage treatment.

Predicting the probability of abnormal stimulated growth hormone response in children after radiotherapy for brain tumors.

PURPOSE: To develop a mathematical model utilizing more readily available measures than stimulation tests that identifies brain tumor survivors with high likelihood of abnormal growth hormone secretion after radiotherapy (RT), to avoid late recognition and a consequent delay in growth hormone replacement therapy. METHODS AND MATERIALS: We analyzed 191 prospectively collected post-RT evaluations of peak growth hormone level (arginine tolerance/levodopa stimulation test), serum insulin-like growth factor 1 (IGF-1), IGF-binding protein 3, height, weight, growth velocity, and body mass index in 106 children and adolescents treated for ependymoma (n=72), low-grade glioma (n=28) or craniopharyngioma (n=6), who had normal growth hormone levels before RT. Normal level in this study was defined as the peak growth hormone response to the stimulation test≥7 ng/mL. RESULTS: Independent predictor variables identified by multivariate logistic regression with high statistical significance (p<0.0001) included IGF-1 z score, weight z score, and hypothalamic dose. The developed predictive model demonstrated a strong discriminatory power with an area under the receiver operating characteristic curve of 0.883. At a potential cutoff point of probability of 0.3 the sensitivity was 80% and specificity 78%. CONCLUSIONS: Without unpleasant and expensive frequent stimulation tests, our model provides a quantitative approach to closely follow the growth hormone secretory capacity of brain tumor survivors. It allows identification of high-risk children for subsequent confirmatory tests and in-depth workup for diagnosis of growth hormone deficiency.

Cervical ependymoma in a male adolescent with neck and back pain.

OBJECTIVE: This case study addresses the clinical presentation, imaging manifestations, and management of an intramedullary ependymoma in an adolescent who presented for chiropractic evaluation with severe neck and back pain. The atypical manifestations of this disorder are emphasized. CLINICAL FEATURES: A 16-year-old male adolescent presented with severe neck and back pain and diffuse paresthesia extending into the dorsum of the forearm and wrist bilaterally. Magnetic resonance imaging revealed an intramedullary mass extending from C1 to C7. Biopsy of this lesion indicated a grade III intramedullary ependymoma. INTERVENTION AND OUTCOME: The patient underwent a successful resection of the tumor with minimal neurological deficit. At 4 months after resection, the follow-up examination yielded minimal discomfort in the neck and upper back, however there was severe cervical kyphosis. Postoperative magnetic resonance imaging revealed no evidence of intramedullary lesion. CONCLUSION: Although it is a rare and slow growing neoplasm, early detection is critical for optimal postoperative functional outcome that is directly related to the preoperative functional status.

TENS and FES for sensory impairment and gait dysfunction following removal of spinal cord ependymoma--a case report.

BACKGROUND: Sensory deficits are commonly reported following the resection of spinal cord tumours. The use of transcutaneous electrical nerve stimulation (TENS) as augmented sensory input is described in the research literature but rarely in the clinical literature. Functional electrical stimulation (FES) is used for people with motor impairments rather than sensory impairments. METHOD AND RESULTS: This case report describes the use of TENS and FES for a patient with severe sensory loss and mild weakness in the right leg following the removal of an intramedullary spinal cord tumour. The patient was able to walk more quickly and more confidently when using TENS and FES in combination. She consistently reported greater benefits from TENS alone compared to FES alone and continued to use TENS delivered via a sock electrode at six months after surgery. CONCLUSION: The use of TENS as a sensory stimulus was an invaluable component of this patient's treatment, allowing her to engage in a more challenging balance and gait programme at an earlier stage in her rehabilitation. Combining FES with TENS was also useful and allowed treatment to address motor and sensory impairments concurrently during functional activity.

EGFR tyrosine kinase inhibition radiosensitizes and induces apoptosis in malignant glioma and childhood ependymoma xenografts.

Malignant gliomas and childhood ependymomas have a high rate of treatment failure. Epidermal growth factor receptor (EGFR) activation has been implicated in the tumorigenesis and radioresistance of many cancers, including brain tumors. Therefore, combining EGFR targeting with irradiation is a potentially attractive therapeutic option. We evaluated the tyrosine kinase inhibitor gefitinib for its antitumor activity and potential to radio-sensitize in vivo in two xenograft models: an EGFR amplified glioma and an EGFR expressing ependymoma, both derived from primary tumors. When administered at 100 mg/kg for 5 consecutive days, gefitinib-induced partial tumor regression in all treated EGFR amplified IGRG88 glioma xenografts. The addition of 1 Gy of irradiation prior to gefitinib administration resulted in 5 complete and 4 partial regressions for the 9 treated tumors as well as a significant tumor growth delay of 33 days for the combined treatment compared to 19 days for each therapy alone, suggesting additive antitumor activity. Tumor regression was associated with inhibition of AKT and MAPK pathways by gefitinib. In contrast, the ependymoma IGREP83 was sensitive to irradiation, but remained resistant to gefitinib. Combined treatment was associated with inhibition of radiation-induced MAPK phosphorylation and significant induction of apoptotic cell death though radiation-induced AKT phosphorylation was maintained. Depending on the scheduling of both therapies, a trend towards superior antitumor activity was observed with combined treatment. Thus, EGFR targeting through tyrosine kinase inhibition appears to be a promising new approach in the treatment of EGFR-driven glioma, particularly in combination with radiation therapy.

Cerebellar tumour presenting with pathological laughter and gelastic syncope.

There is no report of patients in whom pathological laughter, a rare condition characterized by uncontrollable episodes of laughter usually triggered by unrelated stimuli, was ever closely associated with a loss of consciousness overtly linked with the onset of such uncontrollable laughter, also referred to as a gelastic syncope. A 53-year-old man presented with a 4-month history of syncope following intense and uncoordinated laughter. Physical and neurological examination was normal and the patient had no other typical cerebellar signs. We found a mass in the cerebellar vermis abutting the floor of the fourth ventricle, which upon histological examination after surgery proved to be an ependymoma. We emphasize that pathological laughter and gelastic syncope could represent unique and sole features of a cerebellar disorder.

[Intracranial ependymomas in adult patients. Prognostic factors, place of surgery and complementary treatment]. / Ependymomes intracrâniens de l'adulte. Facteurs pronostiques, place de la chirurgie et du traitement complémentaire.

Prognostic factors and optimal therapy for adult intracranial ependymoma are still debated. Available data has been generally collected from retrospective and heterogeneous series including pediatric and spinal cases in particular. The goal of this article is to review and discuss the prognostic factors and the various therapeutic strategies suggested in the literature in light of prognostic and decision making features delineated from a multicentric study conducted in France.

Ependymoma of the spinal cord presenting in a chiropractic practice: 2 case studies.

OBJECTIVE: The purpose of this study is to discuss the cases of 2 patients with previously undiagnosed primary spinal cord tumors presenting in a private chiropractic clinical setting. An overview of treatment and outcome for an ependymoma at T12-L1 and L1-L2 is discussed. CLINICAL FEATURES: One patient was a 46-year-old Hispanic woman with 3 to 4 years of intermittent backache that usually resolved with conservative care but failed to do so during an acute episode. Lower motor neuron signs, including bowel and bladder dysfunction, were revealed upon clinical assessment. The second patient, a 38-year-old white man under routine treatment, had no lower motor neuron signs or symptoms. INTERVENTION AND OUTCOME: Both patients were referred, one to a local hospital emergency department and the other directly to a neurosurgeon. Both underwent surgery. Upon returning home, the first patient received follow-up treatment primarily consisting of radiation therapy. Follow-up telephone interviews (3, 6, 12, 24, and 40 months) revealed the patient doing well. The second case did not require radiation therapy and was doing well at 4, 10, 12, and 18 months; the patient returned for unrelated treatment 1 year after the surgery. CONCLUSION: These cases show that with a careful history and patient examination, enough clinical data may be gathered to make an accurate health care determination under various conditions. It also illustrates the importance of interprofessional cooperation for various disciplines of health care providers regardless of training or specialty.

Intracranial retrograde dissemination in filum terminale myxopapillary ependymomas.

Myxopapillary ependymomas (ME) are considered benign tumours (WHO grade I) of the central nervous system with long term survival rates and a tendency to local recurrence. However an aggressive course has occasionally been described, leading to CSF dissemination and even systemic metastases. We describe the case of a 23-year-old man diagnosed with intracranial subarachnoid dissemination of a filum terminale ME three years after the initial diagnosis. We have performed a careful review of the literature on CSF dissemination in ME and finally propose treatment of these cases.

Value of 123I-IMT SPECT for diagnosis of recurrent non-astrocytic intracranial tumours.

The value of single-photon emission tomography (SPECT) using iodine-123-alpha-methyl-tyrosine (IMT) for the diagnosis of recurrent or residual gliomas is well established. In the current study we investigated whether IMT-SPECT could also be useful in the follow-up of brain metastases and other intracranial tumours of non-astrocytic origin. The study included 22 patients with suspected recurrent intracranial tumours of non-astrocytic origin (12 brain metastases, one supratentorial primitive neuroendocrine tumour (PNET), one rhabdoid tumour, two clivus chordomas, three ependymomas, two pituitary tumours, one anaplastic meningioma) who had previously been treated by surgery and/or radio/chemotherapy. SPECT results were correlated with clinical and MRI follow-up data. The study was true positive in 13 patients, true negative in five, false positive in one and false negative in three patients. Notably, all false negative findings were <13 mm. The resulting sensitivity of the IMT-SPECT was 81%. We concluded that the IMT-SPECT is a promising complementary imaging tool for the detection of recurrences of non-astrocytic intracranial tumours and their distinguishing from treatment-induced changes. The limitation of the IMT-SPECT is its low sensitivity for the detection of small lesions.

Osteopenia in children who have undergone posterior fossa or craniospinal irradiation for brain tumors.

OBJECTIVES: To determine lumbar spine and total body bone mineral density (BMD) in pediatric patients who have undergone cranial or craniospinal irradiation for posterior fossa tumors, specifically medulloblastoma and ependymoma and to analyze the association between degree of osteopenia and factors that may affect BMD. METHODS: Retrospective and prospective data collection included medical record review and examination, including pubertal, dietary, and activity assessment. Lumbar spine and total body BMD were measured by means of dual energy x-ray absorptiometry. Patients were routinely observed by the endocrinology department, and hormone deficiencies were corrected promptly. A subset of patients received calcium and vitamin D supplementation and underwent repeat BMD measurement 1 year later. RESULTS: Of 24 patients aged 4 to 20 years, 11 of whom were male, recruited from 1996 through 1999, 19 had medulloblastoma. All 19 underwent craniospinal radiotherapy plus a boost to the posterior fossa (mean +/- SD of 5410 +/- 130 rad [54.1 +/- 1.3 Gy] to the posterior fossa, mean +/- SD of 3470 +/- 460 rad [34.7 +/- 4.6 Gy] to the whole brain and spinal axis), and 8 of 19 underwent chemotherapy. The remaining 5 patients had ependymoma and underwent irradiation to the posterior fossa only (mean +/- SD of 5680 +/- 720 rad [56.8 +/- 7.2 Gy]). Therefore, there were 3 treatment groups: craniospinal irradiation and chemotherapy, only craniospinal irradiation, and only posterior fossa irradiation. Bone mineral studies were performed a mean +/- SD of 5.42 +/- 3.23 years after therapy. Our patients had lower total body BMD (mean z score, -0.47; 95% confidence interval, -0.85 to -0.09) and lumbar spine BMD (mean z score, -1.27; 95% confidence interval, -1.81 to -0.73) as compared with those of the the general population. There was no significant difference in mean lumbar spine BMD between patients in the 3 groups. Our patients consumed a diet deficient in vitamin D and calcium (mean +/- SD 53.6% +/- 24.1% and 70.0% +/- 37.4% of the amount recommended, respectively). Of 7 patients who underwent measurements 1 year later, 5 had in increase in BMD that was parallel to normal curves, with no compensatory increase. Four patients were hypothyroid, 6 were growth hormone deficient, and 6 were both. All hormones were replaced, with the exception of growth hormone in 1 patient. By using regression analysis, the factors that affected lumbar spine BMD, protectively in both cases, were calcium intake (beta = 0.015, 95% confidence interval, 0.001-0.029) and female sex (beta = 1.422, 95% confidence interval, 0.456-2.388). CONCLUSIONS: Children who have undergone irradiation for posterior fossa tumors have diminished total body and lumbar spine BMD, as compared with those of the general population. This reduction was similar within all 3 treatment groups, which suggests that chemotherapy did not play a major role and that localized irradiation may have systemic effects. This population often has balance and gait problems, so the risk of falling, coupled with osteopenia, may place them at considerably increased risk of fractures.