Martin English

Primary postoperative chemotherapy without radiotherapy for intracranial ependymoma in children: the UKCCSG/SIOP prospective study

BACKGROUND Over half of childhood intracranial ependymomas occur in children younger than 5 years. As an adjuvant treatment, radiotherapy can be effective, but has the potential to damage the childs developing nervous system at a crucial time-with a resultant reduction in IQ and cognitive impairment, endocrinopathy, and risk of second malignancy. We aimed to assess the role of a primary chemotherapy strategy in avoiding or delaying radiotherapy in children younger than 3 years with intracranial ependymoma. METHODS Between December, 1992, and April, 2003, we enrolled 89 children with ependymoma who were aged 3 years or younger at diagnosis, of whom nine had metastatic disease on pre-operative imaging. After maximal surgical resection, children received alternating blocks of myelosuppressive and non-myelosuppressive chemotherapy every 14 days for an intended duration of 1 year. Radiotherapy was withheld unless local imaging (ie, from the childs treatment centre) showed progressive disease. FINDINGS 50 of the 80 patients with non-metastatic disease progressed, 34 of whom were irradiated for progression. The 5-year cumulative incidence of freedom from radiotherapy for the 80 non-metastatic patients was 42% (95% CI 32-53). With a median follow-up of 6 years (range 1.5-11.3), overall survival for the non-metastatic patients at 3 years was 79.3% (95% CI 68.5-86.8) and at 5 years 63.4% (51.2-73.4). The corresponding values for event-free survival were 47.6% (36.2-58.1) and 41.8% (30.7-52.6). There was no significant difference in event-free or overall survival between complete and incomplete surgical resection, nor did survival differ according to histological grade, age at diagnosis, or site of disease. In 47 of 59 (80%) patients who progressed, relapse resulted from local control only. The median time to progression for the 59 patients who progressed was 1.6 years (range 0.1-10.2 years). The median age at irradiation of the whole group was 3.6 years (range 1.5-11.9). For the 80 non-metastatic patients, the 23 who achieved the highest relative dose intensity of chemotherapy had the highest post-chemotherapy 5-year overall survival of 76% (95% CI 46.6-91.2), compared with 52% (33.3-68.1) for the 32 patients who achieved the lowest relative dose intensity of chemotherapy. INTERPRETATION This protocol avoided or delayed radiotherapy in a substantial proportion of children younger than 3 years without compromising survival. These results suggest, therefore, that primary chemotherapy strategies have an important role in the treatment of very young children with intracranial ependymoma.

Predicting parenting stress in caregivers of children with brain tumours

The purpose of the study was to identify factors that contribute to parenting stress in caregivers of children diagnosed with brain tumours.

Noninvasive detection of glutamate predicts survival in pediatric medulloblastoma.

Purpose: Medulloblastoma is the most common malignant brain tumor occurring in childhood and is a significant cause of morbidity and mortality in pediatric oncology. More intense treatment strategies are recommended for patients displaying high-risk factors; however, considerable variation in outcome remains, indicating a need for improved predictive markers. In this study, 1H magnetic resonance spectroscopy (MRS) was used to investigate noninvasive molecular biomarkers of survival in medulloblastoma. Experimental Design: MRS was performed on a series of 35 biopsy-confirmed medulloblastoma cases. One case was excluded because of poor quality MRS. The prognostic value of MRS detectable biomarkers was investigated using Cox regression, retrospectively (N = 15). A subsequent validation analysis (N = 19) was also performed to reduce the chance of type I errors. Where available, high-resolution ex vivo MRS of biopsy tissue was used to confirm biomarker assignments. Results: The retrospective analysis revealed that creatine, glutamate, and glycine were markers of survival (P < 0.01). The validation analysis showed that glutamate was a robust marker, with a hazard ration (HR) of 8.0 for the full dataset (P = 0.0003, N = 34). A good correlation between in vivo and ex vivo MRS glutamate/total-choline was found (P = 0.001), validating the in vivo assignment. Ex vivo glutamate/total-choline was also associated with survival (P < 0.01). Conclusion: The identification of glutamate as a predictive biomarker of survival in pediatric medulloblastoma provides a clinically viable risk factor and highlights the importance of more detailed studies into the metabolism of this disease. Noninvasive biomarker detection using MRS may offer improved disease monitoring and potential for widespread use following multicenter validation. Clin Cancer Res; 20(17); 4532–9. ©2014 AACR.

Short echo time single voxel 1H magnetic resonance spectroscopy in the diagnosis and characterisation of pineal tumours in children

Magnetic resonance spectroscopy (MRS) has been successful in characterising a range of brain tumours and is a useful aid to non‐invasive diagnosis. The pineal region poses considerable surgical challenges and a major surgical resection is not required in the management of all tumours. Improved non‐invasive assessment of pineal region tumours would be of considerable benefit.

Infantile clivus chordoma without clivus involvement: case report and review of the literature

BackgroundWe present a giant clival chordoma with disseminated disease but without involvement of the clivus. To our knowledge, this is the youngest child and only the second case, presenting without base of skull involvement, in paediatric literature and the fourth reported case of a chordoma in a patient with tuberous sclerosis.DiscussionWe discuss the subtle presentation, difficulties in diagnosis and management and also review the literature.

Diagnosing relapse in children's brain tumors using metabolite profiles

BACKGROUND Malignant brain tumors in children generally have a very poor prognosis when they relapse and improvements are required in their management. It can be difficult to accurately diagnose abnormalities detected during tumor surveillance, and new techniques are required to aid this process. This study investigates how metabolite profiles measured noninvasively by (1)H magnetic resonance spectroscopy (MRS) at relapse reflect those at diagnosis and may be used in this monitoring process. METHODS Single-voxel MRS (1.5 T, point-resolved spectroscopy, echo time 30 ms, repetition time 1500 ms was performed on 19 children with grades II-IV brain tumors during routine MRI scans prior to treatment for a suspected brain tumor and at suspected first relapse. MRS was analyzed using TARQUIN software to provide metabolite concentrations. Paired Students t-tests were performed between metabolite profiles at diagnosis and at first relapse. RESULTS There was no significant difference (P > .05) in the level of any metabolite, lipid, or macromolecule from tumors prior to treatment and at first relapse. This was true for the whole group (n = 19), those with a local relapse (n = 12), and those with a distant relapse (n = 7). Lipids at 1.3 ppm were close to significance when comparing the level at diagnosis with that at distant first relapse (P = .07, 6.5 vs 12.9). In 5 cases the MRS indicative of tumor preceded a formal diagnosis of relapse. CONCLUSIONS Tumor metabolite profiles, measured by MRS, do not change greatly from diagnosis to first relapse, and this can aid the confirmation of the presence of tumor.

The oral health needs of children after treatment for a solid tumour or lymphoma

BACKGROUND With increasing survival rates for childhood cancer, late effects are of growing importance. Oral health is central to general health, level of nutrition, quality of life, and is significant in the holistic care of children during cancer therapy. HYPOTHESIS The oral health needs of children treated for solid tumours/lymphoma will be greater than the general population, groups will differ according to tumour and treatment. DESIGN One hundred and twenty patients, 0-17 years, under follow-up from 01/07/06 to 07/02/07 were investigated for caries, opacities, microdontia, and gingivitis. Analysis was performed with stratification according to tumour and treatment. Comparisons made with the UK 2003 Child Dental Health Survey. RESULTS The neuroblastoma group and high-dose chemotherapy with stem-cell rescue (HDCSCR) therapy group had increased caries of the primary teeth. Chi-squared analysis revealed a statistically significant relationship (P < 0.03) between the age at receipt of chemotherapy (<3.5 years) and the presence of microdont teeth. CONCLUSION Oral health care is important for all patients particularly those with a neuroblastoma, or who received HDCSCR. Patients should be advised about the possibility of microdontia in the permanent dentition following chemotherapy under 3.5 years.

The UK Experience of a Treatment Strategy for Pediatric Metastatic Medulloblastoma Comprising Intensive Induction Chemotherapy, Hyperfractionated Accelerated Radiotherapy and Response Directed High Dose Myeloablative Chemotherapy or Maintenance Chemotherapy (Milan Strategy)

Historically, the 5‐year overall survival (OS) for metastatic medulloblastoma (MMB) was less than 40%. The strategy of post‐operative induction chemotherapy (IC) followed by hyperfractionated accelerated radiotherapy (HART) and response directed high dose chemotherapy (HDC) was reported in a single center study to improve 5‐year OS to 73%. We report outcomes of this strategy in UK.

Estimation of renal function and its potential impact on carboplatin dosing in children with cancer

Renal function-based carboplatin dosing is used routinely in paediatric oncology clinical practice. It is important that accurate assessments of renal function are carried out consistently across clinical centres, a view supported by recently published British Nuclear Medicine Society (BNMS) guidelines for measuring glomerular filtration rate (GFR). These guidelines recommend the use of a radioisotope method for GFR determination, with between two and five blood samples taken starting 2 h after radioisotope injection and application of the Brochner-Mortensen (BM) correction factor. To study the likely impact of these guidelines, we have investigated current practices of measuring GFR in all 21 Childrens Cancer and Leukaemia Group (CCLG) paediatric oncology centres in the United Kingdom. This information was used to evaluate the potential impact on renal function-based carboplatin dosing using raw 51Cr-EDTA clearance data from 337 GFR tests carried out in children with cancer. A questionnaire survey revealed that between two and four samples were taken after isotope administration, with BM and Chantler corrections used in 38% (8/21) and 28% (6/21) of centres, respectively. A change from Chantler to BM correction, based on the BNMS guidelines, would result in a >10% decrease in carboplatin dose in at least 15% of patients and a >25% decrease in 2% of patients. A greater proportion of patients would have an alteration in carboplatin dose when centres not using any correction factor implement the BM correction. The increase in estimated 51Cr-EDTA half-life observed by omitting the 1 h sample decreases carboplatin dose by >10% in 23–52% of patients and by >25% in 3% of patients. This study highlights current variations in renal function measurement between clinical centres and the potential impact on carboplatin dosing. A standard methodology for estimating GFR should be followed to achieve uniform dosing in children with cancer.

Peripheral primitive neuroectodermal tumor with postchemotherapy neuroblastoma-like differentiation.

We report the case of an 11-year-old girl with a retroperitoneal tumor in the left upper quadrant. The girl was admitted to hospital with weight loss and a painless abdominal mass that on biopsy was diagnosed as a peripheral primitive neuroectodermal tumor/Ewing sarcoma (pPNET/EWS) of the soft tissue. The patient underwent chemotherapy followed by surgical resection of the tumor 5 months after diagnosis. The posttreatment residual viable tumor showed a morphologic appearance resembling a neuroblastoma. Interphase and metaphase fluorescent in situ hybridization (FISH) studies performed on the pretreatment and posttreatment samples showed the presence of a t(11;22) rearrangement resulting in EWSR1/FLI1 gene fusion consistent with pPNET/EWS in both specimens. This case is unusual in the sense of showing the typical gene fusion for pPNET/EWS both in the pretherapy sample with the typical morphological appearance of this tumor and in the posttherapy specimen showing neural differentiation suggestive of a neuroblastoma.