Optimising the chick chorioallantoic membrane xenograft model of neuroblastoma for drug delivery.

BACKGROUND: Neuroblastoma is a paediatric cancer that despite multimodal therapy still has a poor outcome for many patients with high risk tumours. Retinoic acid (RA) promotes differentiation of some neuroblastoma tumours and cell lines, and is successfully used clinically, supporting the view that differentiation therapy is a promising strategy for treatment of neuroblastoma. To improve treatment of a wider range of tumour types, development and testing of novel differentiation agents is essential. New pre-clinical models are therefore required to test therapies in a rapid cost effective way in order to identify the most useful agents. METHODS: As a proof of principle, differentiation upon ATRA treatment of two MYCN-amplified neuroblastoma cell lines, IMR32 and BE2C, was measured both in cell cultures and in tumours formed on the chick chorioallantoic membrane (CAM). Differentiation was assessed by 1) change in cell morphology, 2) reduction in cell proliferation using Ki67 staining and 3) changes in differentiation markers (STMN4 and ROBO2) and stem cell marker (KLF4). Results were compared to MLN8237, a classical Aurora Kinase A inhibitor. For the in vivo experiments, cells were implanted on the CAM at embryonic day 7 (E7), ATRA treatment was between E11 and E13 and tumours were analysed at E14. RESULTS: Treatment of IMR32 and BE2C cells in vitro with 10 µM ATRA resulted in a change in cell morphology, a 65% decrease in cell proliferation, upregulation of STMN4 and ROBO2 and downregulation of KLF4. ATRA proved more effective than MLN8237 in these assays. In vivo, 100 µM ATRA repetitive treatment at E11, E12 and E13 promoted a change in expression of differentiation markers and reduced proliferation by 43% (p < 0.05). 40 µM ATRA treatment at E11 and E13 reduced proliferation by 37% (p < 0.05) and also changed cell morphology within the tumour. CONCLUSION: Differentiation of neuroblastoma tumours formed on the chick CAM can be analysed by changes in cell morphology, proliferation and gene expression. The well-described effects of ATRA on neuroblastoma differentiation were recapitulated within 3 days in the chick embryo model, which therefore offers a rapid, cost effective model compliant with the 3Rs to select promising drugs for further preclinical analysis.

Open versus needle biopsy in diagnosing neuroblastoma.

BACKGROUND: Open surgical biopsy is traditionally advocated prior to initiating therapy in UKCCLG neuroblastoma protocols. We report a single centre experience comparing the utility of open biopsy vs image guided needle biopsy in aiding the definitive diagnosis and risk stratification of neuroblastoma - (Shimada classification, MYCN expression, cytogenetics - 1p 11q, 17 q). METHODS: Medical records of all new cases of neuroblastoma presenting to a single UKCCLG centre during January 2002-July 2013 were examined. RESULTS: Thirty nine patients underwent a biopsy of primary tumour for neuroblastoma during the study. Twenty one children had open biopsy and eighteen cases had a needle biopsy. Staging of neuroblastoma revealed - stage 4 (n=26), stage 3 (n=7), stage 2 (n=3) and stage 4S (n=3). Sites of primary tumour were adrenal gland (n=20), abdomen (n=12), thoracic (n=4), abdomino-thoracic (n=2) and abdomino pelvic regions (n=1). All patients (open vs needle) had adequate tissue retrieved for histological diagnosis of neuroblastoma. One needle and one open biopsy case did not have MYCN status determined despite adequate tissue sampling. Seventeen patients (7 open and 10 needle biopsies) had 1p and 17q status reported in MLPA testing (Multiplex Ligation-dependent Probe Amplification). No single patient required a repeat tumour biopsy. Morbidity in the series was minimal with only one child - open biopsy group, requiring emergent laparotomy to control bleeding from an abdominal primary tumour. No complications were recorded with needle biopsy. CONCLUSIONS: Open and image guided needle biopsy appear to yield adequate tissue sampling for diagnosis, risk classification and staging of neuroblastoma. Further larger co-operative studies may usefully guide national and international protocols.

Wilms' tumor--lessons and outcomes--a 25-year single center UK experience.

Wilms' tumor (WT) is a common childhood renal cancer. A 25-year single center UK experience is reported. During 1985-2010, 97 children underwent immediate nephrectomy or delayed resection of tumor after chemotherapy. Survival, morbidity, and late effects following treatment are described. Tumor distribution was: Stage I, 25.7% (n = 25); Stage II, 24.7% (n = 24); Stage III, 26.8% (n = 26); Stage IV, 17.5% (n = 17); and Stage V, 5.2% (n = 5). Immediate nephrectomy was performed in 39% (n = 38) patients with elective delayed resection in 61% (n = 59) cases. Ten patients had cavotomy to excise tumor involving vena cava territory. Two cases required cardiopulmonary bypass. Tumor rupture was recorded in eight (8.5%) total operated cases-after immediate (n = 5/37), 13.5% vs delayed nephrectomy-(n = 3/57), 5.2%; X(2) P = .154. From 2001 onwards, one case of tumor rupture was recorded at this center after the universal adoption of UKW3 and SIOP guidelines advocating preoperative chemotherapy and delayed nephrectomy for all WT. Three treatment-related deaths occurred-hepatic veno-occlusive disease (n = 2) with actinomycin D and a single WT fatality due to vascular injury. Overall survival was 84.5% (82/97 cases). Two patients developed "late malignancies" -thyroid cancer and a basal cell carcinoma. This study demonstrates excellent survival for WT comparable with national outcomes and international cooperative studies. Adverse events with chemotherapy and surgery, including "late onset," second malignancies deserve special consideration.

Hyperfractionated Accelerated Radiotherapy (HART) with maintenance chemotherapy for metastatic (M1-3) Medulloblastoma--a safety/feasibility study.

BACKGROUND AND PURPOSE: To evaluate feasibility and toxicity of Hyperfractionated Accelerated Radiotherapy (HART) 1.24Gy b.i.d. followed by chemotherapy for M1-3 Medulloblastoma (MB). The aim of HART was to use hyperfractionation to improve therapeutic ratio combined with acceleration to minimise tumour cell repopulation during radiotherapy (RT). MATERIALS AND METHODS: Between February 2002 and May 2008, 34 eligible patients (22 male, 12 female) aged 3-15years (median 7) with metastatic MB (M1-9; M2-3, M3-22) received HART with a craniospinal radiotherapy (CSRT) dose of 39.68Gy followed by 22.32Gy boost to the whole posterior fossa and 9.92Gy metastatic boosts. The 8th and subsequent patients received vincristine (VCR) 1.5mg/m(2) weekly×8 doses over 8weeks starting during the 1st week of RT. Maintenance chemotherapy comprised 8 six-weekly cycles of VCR 1.5mg/m(2) weekly×3, CCNU 75mg/m(2) and cisplatin 70mg/m(2). RESULTS: Median duration of HART was 34days (range 31-38). Grade 3-4 toxicities included mucositis (8), nausea (10), anaemia (5), thrombocytopaenia (2), leucopaenia (24). With 4.5-year median follow-up, 3-year EFS and OS were 59% and 71%, respectively. Of 10 relapses, 1 was outside the central nervous system (CNS), 1 posterior fossa alone and 8 leptomeningeal with 3 also associated with posterior fossa. CONCLUSION: HART with or without VCR was well tolerated and may have a place in the multi-modality management of high-risk MB.

The potential impact of tumour biology on improved clinical practice for medulloblastoma: progress towards biologically driven clinical trials.

Medulloblastoma is the most common malignant brain tumour of childhood and accounts for around 10% of all childhood cancer deaths. Despite recent improvements in survival rates, the delivery of individualised therapies based on disease-risk remains a major goal; intensified treatment for poor-risk disease, whilst reducing therapy for favourable-risk cases, with the overall aim of maximising survival whilst minimising late effects. Current clinical indices for the prediction of disease course are imprecise, however a series of molecular and histopathological biomarkers have been identified recently, which may allow a more accurate prediction of disease outcome (e.g., beta-catenin status as a favourable-risk marker, MYC gene amplification and large-cell histology as high-risk markers). Pan-European clinical trials being planned for medulloblastoma by the SIOP Brain tumour group will assess the stratification of patients using molecular and histological biomarkers, alongside clinical indices, to select favourable, standard and high-risk treatment groups. This selection will underpin two concurrent trials; PNET 5, which will test whether treatment can be reduced for a favourable-risk disease sub-group, with the aim of maintaining survival rates while reducing late-effects, and PNET 6, which will aim to improve survival rates in the standard-risk group. The implementation of these trials presents important new logistical challenges within routine practice, involving (i) the development of quality-controlled sample collection and handling systems across multiple treatment centres, including the mandatory ascertainment of fresh-frozen tumour material, and (ii) the delivery of standardised central biomarker analysis and histopathological review, within the approximately 30-day post-surgical window, prior to the selection and commencement of adjuvant therapy. Feasibility studies to establish these systems are underway across SIOP Europe national groups. Their success will require a coordinated approach by the entire multidisciplinary team, including neurosurgeons, oncologists and neuropathologists, with the common aim of facilitating targeted delivery of individualised risk-adapted therapies for children with medulloblastoma.

Impact of radiotherapy parameters on outcome for patients with supratentorial primitive neuro-ectodermal tumours entered into the SIOP/UKCCSG PNET 3 study.

BACKGROUND AND PURPOSE: To evaluate the impact of radiotherapy (RT) parameters on outcome in the SIOP/UKCCSG study of pre-RT chemotherapy for Supratentorial Primitive Neuro-ectodermal Tumours. METHODS AND MATERIALS: Sixty-two patients aged 2.9-16.6 (median 6.4 years) were eligible. Forty-eight (77%) had non-pineal sites and 14 (23%) had pineal sites. Eleven were randomized to RT alone (6) and five to pre-RT Vincristine, Etoposide, Carboplatin and Cyclophosphamide. Fifty-one were not randomized, 15 receiving RT alone and 36 receiving pre-RT chemotherapy. Craniospinal RT (CSRT) 35 Gy/21 fractions were followed by 20 Gy/12 fractions to primary tumour. RESULTS: Mean CSRT dose was 34.7 Gy and mean total primary dose was 53.4 Gy for those who received radiotherapy. Of 30 relapses, 18 (60%) were local only and 5 (16.7%) were combined local and leptomeningeal. There was no significant impact on Overall Survival (OS) or Event-Free Survival (EFS) of surgery-RT interval for patients treated by pre-RT chemotherapy or RT alone, or duration of RT (completing within 50 days). Planning films were received for 42/54 (77.8%) patients. Fourteen (33%) had one or more targeting deviations (10 cribriform fossa, 11 base of skull). There was a statistically significant increase in the risk of recurrence for patients with cribriform fossa targeting deviations (p=0.033), but not for patients with base of skull targeting deviations (p=0.242). There was no statistically significant difference in OS (p=0.0598) or EFS (p=0.0880) for patients who had one or more targeting deviations compared to those who had none. CONCLUSIONS: This study has not demonstrated a statistically significant impact of radiotherapy duration or targeting deviations on OS or EFS, possibly due to small patient numbers. However, multi-institutional SPNET trials should incorporate quality assurance programs including analysis of relapse pattern in relation to primary target volume coverage.

Diagnosis, incidence, and outcomes of suspected typhlitis in oncology patients--experience in a tertiary pediatric surgical center in the United Kingdom.

BACKGROUND: Typhlitis is clinically defined by the triad of neutropenia, abdominal pain, and fever. Radiologic evidence of colonic inflammation supports the diagnosis. We report a single United Kingdom tertiary center experience with management and outcome of typhlitis for 5 years. METHODS: Hospital computerized records were screened for ultrasound or computerized tomographic scan requests for abdominal pain for all oncology inpatients (2001-2005). Retrospective case note analysis was used to collect clinical data for patients with features of typhlitis. RESULTS: The incidence of typhlitis among oncology inpatients was 6.7% (40/596) among oncology inpatients and 11.6% (40/345) among those on chemotherapy. Eighteen children had radiologically confirmed typhlitis, and 22 had clinical features alone. Most (93%) patients responded to conservative management. Eighteen children had a variable period of bowel rest, including 12 patients who were supported with total parenteral nutrition. Three patients had laparotomy that revealed extensive colonic bowel necrosis (1), perforated gastric ulcer (1), and a perforated appendix (1). A single child died of fulminant gram-negative sepsis without surgical intervention. CONCLUSIONS: The diagnosis of typhlitis was based on clinical features, supported by radiologic evidence in almost half of the study group. Surgical intervention should be reserved for specific complications or where another surgical pathologic condition cannot reasonably be ruled out.

Successful treatment of central nervous system juvenile xanthogranulomatosis with cladribine.

Juvenile xanthogranulomatosis (JXG) is an uncommon histiocytic disease that is usually limited to the skin. Here we describe an infant with systemic JXG including a central nervous system (CNS) lesion. He was initially treated with prednisolone and vinblastine but developed an idiosyncratic reaction to prednisolone that was discontinued. The lesion then failed to respond to vinblastine monotherapy. Treatment with cladribine (2-chlorodeoxyadenosine) was subsequently successful with radiological resolution of the CNS lesion.

Sacrococcygeal teratoma--a 25-year experience in a UK regional center.

BACKGROUND: Sacrococcygeal teratoma (SCT) is uncommon (1:35,000-1:40,000 newborns). We report a 25-year single-center experience with a focus on late effects. METHODS: Surgical and tumor registries identified patients with SCT between 1977 and 2001. Perinatal data, associated anomalies, operative findings, histology, and survival were recorded. Continence was assessed clinically. Urodynamics and anorectal manometry were performed as indicated. RESULTS: Thirty-three patients (28 females) were treated for SCT. Before 1988, 2 of 18 were diagnosed antenatally compared with 8 of 15 between 1988 and 2001. Ten babies were delivered by cesarean birth. Seven children presented after the neonatal period. Surgery comprised tumor excision with coccygectomy. Histology was benign in 26 (79%), malignant in 6 (18%), and immature in a single patient. Presentation beyond the newborn period was associated with malignant disease and poorer outcome. Overall survival was 94%. Neuropathic bladder or bowel disturbance was identified in 7 of 20 patients on long-term follow-up. CONCLUSIONS: Antenatal diagnosis of SCT appears to be increasing. Parental counseling should include the continence problems that may follow removal of even benign tumors. Resection by surgical oncologists and reconstruction by colorectal specialists may improve function. Follow-up by oncologists, surgeons, and urologists remains an important part of SCT management.

Analysis of patients with supratentorial primitive neuro-ectodermal tumours entered into the SIOP/UKCCSG PNET 3 study.

The SIOP PNET 3 study was designed to determine whether 10 weeks of moderately intensive chemotherapy given after surgery and before radiotherapy (RT) would improve the outcome for patients with primitive neuroectodermal tumours (PNETs) compared with RT alone. Patients with a histological diagnosis of supratentorial PNET (StPNET) and no radiological evidence of metastatic disease were initially eligible for randomisation to either chemotherapy followed by craniospinal RT 35 Gy in 21 fractions with a boost of 20 Gy in 12 fractions to the primary site, or RT alone. In respect of the increasing recognition that StPNET were high-risk tumours, randomisation for this group closed in November 1999. This analysis includes both randomised and non-randomised patients with StPNET entered into the study database. Sixty-eight patients aged 2.9-16.6 years (median 6.5 years) were included in the analysis (chemotherapy+RT: 44, RT alone: 24). Fifty-four patients (79%) had a non-pineal and 14 (21%) a pineal site. At a median follow-up of 7.4 years, for all patients overall survival (OS) at 3 and 5 years was 54.4% and 48.3%, respectively. Event-free survival (EFS) at 3 and 5 years was 50.0% and 47.0%, respectively. There was no statistically significant difference in OS or EFS according to treatment received. OS (P=0.05) and EFS (P=0.03) were significantly better for patients with pineal primary sites. EFS for pineal tumours were 92.9% at 3 years and 71.4% at 5 years and for non-pineal primaries 40.7% at 3 years and 40.7% at 5 years. This study confirmed the relatively good survival for non-metastatic pineal PNETs but poor survival of non-pineal StPNETs. There was no evidence that pre-radiation chemotherapy improved outlook. Future treatment programs should be directed at the particular natural history of these tumours, to further define prognostic factors and to explore further biological characteristics.

Outcome for patients with metastatic (M2-3) medulloblastoma treated with SIOP/UKCCSG PNET-3 chemotherapy.

The aim of this study was to determine the outcome for patients with Chang stage M2-3 medulloblastoma (MB) treated with surgery and pre-radiotherapy (RT) chemotherapy (CT). Between 1992 and 2000, 68 patients aged 2.8-16.4 years (median 7.8 years) with M2-3 MB were treated with CT comprising vincristine, etoposide, carboplatin and cyclophosphamide. For 61 patients, CT was followed by craniospinal RT 35 Gy/21 fractions with a posterior fossa (PF) boost, 20 Gy/12 fractions. Twenty-four (35%) irradiated patients received a metastatic boost (mean dose to metastases 47.4 Gy, range 40.0-55.1 Gy). With 7.2-years of median follow-up, overall survival (OS) rates at 3 and 5 years were 50.0% (95% Confidence Interval (CI): 38.1-61.9%) and 43.9% (95% CI: 32.0-55.7%), respectively, event-free survival (EFS) rates at 3 and 5 years were 39.7% (95% CI: 28.1-51.3%) and 34.7% (95% CI: 23.2-46.2%), respectively. Univariate analysis did not demonstrate an impact of age, gender, M stage, extent of resection, RT duration or metastatic boost. For patients commencing RT within 110 days of surgery, EFS was significantly (P=0.04) worse than for those who commenced RT later than this. Response to pre-RT CT was assessable from institutional reports for 44 (65%) patients, and 17 (39%) had a complete response (CR), 15 (34%) a partial response (PR), 4 (9%) stable disease (SD) and 8 (18%) progression. Although CT improved outcome for M0-1 patients in the primitive neuroectodermal tumour (PNET-3) randomised study, and resulted in a high response rate in this study, there has been no apparent improvement in outcome for M2-3 patients when compared with earlier multi-institutional series. Newer approaches such as more intensive CT and RT need to be explored.

Factors influencing early failure of central venous catheters in children with cancer.

BACKGROUND: The authors report the results of a prospective, multicenter, multidisciplinary study of central venous catheters (CVCs) in pediatric oncology patients analyzing factors involved in early failure. METHODS: Information was collected from parent-held records on the fate of 824 devices inserted over a 20-month period, 415 of which were no longer in situ. RESULTS: Within the first 7 weeks after insertion, there were 66 failures, all occurring in external lines. Accidental dislodgement was the principal reason for CVC failure (44 of 66, 67%). Detailed analysis of the reason for failure of this large subgroup showed 11 factors individually associated with early dislodgement, of which, 4 were independently associated with failure by multivariate analysis. These 4 variables were the use of multilumen catheters, the absence of a skin exit site suture, platelet transfusion at the time of insertion, and patient age less than 2 years. CONCLUSIONS: This study confirms the multiple influences on successful CVC usage. Our analysis supports the principle of only using multilumen lines when clinically essential. The findings also support the inception of randomized studies of fixation, particularly in infants.

Prophylaxis of acute chemotherapy-induced nausea and vomiting in children with cancer: what is the evidence?

BACKGROUND: Nausea and vomiting are preventable side effects of cancer chemotherapy for children. Antiemetics are essential, especially as treatment becomes more intensive. Many drugs are available, but adequate evidence-based recommendations are lacking. We aimed (1) to consider an evidence-based approach for pharmacological prophylaxis of chemotherapy-induced nausea and vomiting (CINV) in children, and (2) to compare this approach with antiemetic prescribing in two paediatric oncology centres. PROCEDURE: Relevant publications (Medline, Embase, CancerLit:1966-2002) were critically evaluated using pre-defined criteria. Evidence-based statements summarising their findings were formulated, and evidence basis proposed. Current prescribing practice was then compared with this evidence basis in Welsh children under 16 receiving chemotherapy at Llandough Hospital, Cardiff or Alder Hey Children's Hospital, Liverpool between 1 January 2001 and 31 December 2001. RESULTS: Of 213 studies retrieved, 82 provided evidence. Our evidence basis recommends combination 5HT3-antagonist/corticosteroid for highly emetogenic chemotherapy, 5HT3-antagonist alone for moderate emetogenicity, and no antiemetic for other chemotherapy. Forty-four children in Cardiff (0.6-16.9 yrs) and 14 in Liverpool (0.8-16.2 yrs) were included in the audit. Differences in prescribing practice between the centres were not significant. In 109/159 (69%) of chemotherapy courses (35, 87 and 100% of high, moderate and low emetogenicity, respectively), antiemetics were selected in accordance with evidence basis. Seventy percent of prescribed doses were as evidence basis recommended. CONCLUSIONS: We present an evidence basis for prescribing prophylactic antiemetics to children undergoing chemotherapy. Prescribing practices in these two centres treating Welsh children were similar. Both differed from the evidence basis we propose. Deviations were greatest for regimens of high emetogenicity, where effective emetic control is most crucial.

Impact of radiotherapy parameters on outcome in the International Society of Paediatric Oncology/United Kingdom Children's Cancer Study Group PNET-3 study of preradiotherapy chemotherapy for M0-M1 medulloblastoma.

PURPOSE: To analyze the impact of radiotherapy (RT) parameters on outcome in a randomized study of pre-RT chemotherapy for M0-M1 medulloblastoma. METHODS AND MATERIALS: Patients were randomized to RT alone or RT preceded by chemotherapy with vincristine, etoposide, carboplatin, and cyclophosphamide. RT consisted of craniospinal RT, 35 Gy in 21 fractions, followed by a posterior fossa (PF) boost of 20 Gy in 12 fractions. The accuracy of cribriform fossa, skull base, and PF field placement was assessed. RESULTS: Between 1992 and 2000, 217 patients were randomized, of whom 179 were eligible for analysis. At a median follow-up of 5.4 years, the 3- and 5-year overall survival rate was 79.5% and 70.7%, respectively. The 3- and 5-year event-free survival (EFS) rate was 71.6% and 67.0%, respectively. EFS was significantly better for the chemotherapy plus RT group (3-year EFS rate 78.5% vs. 64.8%, p = 0.0366). Overall survival and EFS were significantly better for patients completing RT within 50 days compared with those taking >50 days to complete RT (3-year overall survival rate 84.1% vs. 70.9%, p = 0.0356, 3-year EFS rate 78.5% vs. 53.7%, p = 0.0092). Multivariate analysis identified the use of chemotherapy (p = 0.0248) and RT duration (p = 0.0100) as predictive of better EFS. Planning films were reviewed for 131 (74.4%) of 176 patients. Sixty-five (49.6%) had no targeting deviations and 58 (44.3%) had one or more deviations. PF recurrence occurred in 11 (34.4%) of 32 with a PF targeting deviation compared with 13 (16.3%) of 80 without (p = 0.043). No statistically significant impact of other targeting deviations on recurrence risk or EFS were found. CONCLUSION: The results of this study have confirmed the importance of the duration of RT for medulloblastoma. Also, attention to detail when planning RT is important, as illustrated in the case of PF field placement.

Results of a randomized study of preradiation chemotherapy versus radiotherapy alone for nonmetastatic medulloblastoma: The International Society of Paediatric Oncology/United Kingdom Children's Cancer Study Group PNET-3 Study.

PURPOSE: To determine whether preradiotherapy (RT) chemotherapy would improve outcome for Chang stage M0-1 medulloblastoma when compared with RT alone. Chemotherapy comprised vincristine 1.5 mg/m2 weekly for 10 weeks and four cycles of etoposide 100 mg/m2 daily for 3 days, and carboplatin 500 mg/m2 daily for 2 days alternating with cyclophosphamide 1.5 g/m2. PATIENTS AND METHODS: Patients aged 3 to 16 years inclusive were randomly assigned to receive 35 Gy craniospinal RT with a 20 Gy posterior fossa boost, or chemotherapy followed by RT. RESULTS: Of 217 patients randomly assigned to treatment, 179 were eligible for analysis (chemotherapy + RT, 90 patients; RT alone, 89 patients). Median age was 7.67 years, and median follow-up was 5.40 years. Overall survival (OS) at 3 and 5 years was 79.5% and 70.7%, respectively. Event-free survival (EFS) at 3 and 5 years was 71.6% and 67.0%, respectively. EFS was significantly better for chemotherapy and RT (P =.0366), with EFS of 78.5% at 3 years and 74.2% at 5 years compared with 64.8% at 3 years and 59.8% at 5 years for RT alone. There was no statistically significant difference in 3-year and 5-year OS between the two arms (P =.0928). Multivariate analysis identified use of chemotherapy (P =.0248) and time to complete RT (P =.0100) as having significant effect on EFS. CONCLUSION: This is the first large multicenter randomized study to demonstrate improved EFS for chemotherapy compared with RT alone. It is anticipated that this regimen could reduce ototoxicity and nephrotoxicity compared with cisplatin-containing schedules. The importance of avoiding interruptions to RT has been confirmed.

Papillary endothelial hyperplasia associated with cortical dysplasia.

We report a unique case of papillary endothelial hyperplasia (PEH) presenting as a subcortical mass lesion intimately associated with focal cortical dysplasia (CD) and consider a possible causal relationship. A 6-year old girl presented with a 6-month history of a painless, frontoparietal skull "bump" associated with slowly progressive localised bossing followed by a 4-month history of absence attacks. Magnetic resonance imaging (MRI) revealed an adjacent parietal enhancing mass lesion beneath abnormal appearing cortex. A haemorrhagic vascular lesion with histology consistent with that of papillary endothelial hyperplasia was completely resected. Biopsies of the adjacent cortex showed CD. The patient has been symptom free post-surgery for 12 months with no MRI evidence of recurrence. Intracranial PEH is very rare and, in contrast to extracranial examples, half of the reported cases lacked a demonstrable vascular origin. Given that CD may be associated with intrinsic capillary hypervascularity, vascular malformations and tumours (e.g. dysembryoplastic neuroepithelial tumour) of a potential hypervascular or haemorrhagic nature, the association between PEH and CD may not be incidental. The abnormal vascularity not uncommonly found in CD may predispose to haemorrhage and/or thrombosis, the organisation of which may rarely be complicated by PEH. Alternatively, PEH and CD may both represent local, independent complications of a pre-existing vascular event or trauma.