Primary postoperative chemotherapy without radiotherapy for treatment of brain tumours other than ependymoma in children under 3 years: results of the first UKCCSG/SIOP CNS 9204 trial.

BACKGROUND: Radiotherapy is an effective adjuvant treatment for brain tumours arising in very young children, but it has the potential to damage the child's developing nervous system at a crucial time - with a resultant reduction in IQ leading to cognitive impairment, associated 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 malignant brain tumours other than ependymoma, the results of which have already been published. METHODS: Ninety-seven children were enrolled between March 1993 and July 2003 and, following diagnostic review, comprised: medulloblastoma (n=31), astrocytoma (26), choroid plexus carcinoma [CPC] (15), CNS PNET (11), atypical teratoid/rhabdoid tumours [AT/RT] (6) and ineligible (6). Following maximal surgical resection, chemotherapy was delivered every 14 d for 1 year or until disease progression. Radiotherapy was withheld in the absence of progression. FINDINGS: Over all diagnostic groups the cumulative progression rate was 80.9% at 5 years while the corresponding need-for-radiotherapy rate for progression was 54.6%, but both rates varied by tumour type. There was no clear relationship between chemotherapy dose intensity and outcome. Patients with medulloblastoma presented as a high-risk group, 83.9% having residual disease and/or metastases at diagnosis. For these patients, outcome was related to histology. The 5-year OS for desmoplastic/nodular medulloblastoma was 52.9% (95% confidence interval (CI): 27.6-73.0) and for classic medulloblastoma 33.3% (CI: 4.6-67.6); the 5-year EFS were 35.3% (CI: 14.5-57.0) and 33.3% (CI: 4.6-67.6), respectively. All children with large cell or anaplastic variants of medulloblastoma died within 2 years of diagnosis. The 5-year EFS for non-brainstem high-grade gliomas [HGGs] was 13.0% (CI: 2.2-33.4) and the OS was 30.9% (CI: 11.5-52.8). For CPC the 5-year OS was 26.67% (CI: 8.3-49.6) without RT. This treatment strategy was less effective for AT/RT with 3-year OS of 16.7% (CI: 0.8-51.7) and CNS PNET with 1-year OS of 9.1% (CI: 0.5-33.3). INTERPRETATION: The outcome for very young children with brain tumours is dictated by degree of surgical resection and histological tumour type and underlying biology as an indicator of treatment sensitivity. Overall, the median age at radiotherapy was 3 years and radiotherapy was avoided in 45% of patients. Desmoplastic/nodular sub-type of medulloblastoma has a better prognosis than classic histology, despite traditional adverse clinical features of metastatic disease and incomplete surgical resection. A subgroup with HGG and CPC are long-term survivors without RT. This study highlights the differing therapeutic challenges presented by the malignant brain tumours of early childhood, the importance of surgical approaches and the need to explore individualised brain sparing approaches to the range of malignant brain tumours that present in early childhood.

The 'unified hypothesis' of Geddes et al. is not supported by the data.

Inflicted head injury to the developing brain frequently results in serious disability. The pathogenesis of the neuraxial and ocular findings in infants believed to have suffered inflicted head injury remains the subject of considerable debate. Recent neuropathology studies of fatal cases of inflicted head injury and of a foetal/perinatal non-traumatic model have led to the proposal that there is a 'unified hypothesis', the essential feature of which is hypoxic brain swelling secondary to cervicomedullary injury. It has been suggested that less than violent forces may be involved and even that some cases may not be due to trauma at all. The purpose of this paper is to provide a critical review of the data upon which these suppositions are based on a background of what is already known. It is submitted that there are serious flaws in the methodology; the conclusions reached cannot logically be drawn from the data; and the 'unified hypothesis' is not supported by the evidence. On the basis of the data presented, it is also difficult to sustain the secondary hypothesis purporting to describe a minority cohort with 'infantile encephalopathy with subdural and retinal bleeding' of non-traumatic causation.

Neuroimaging for non-accidental head injury in childhood: a proposed protocol.

Non-accidental head injury (NAHI) is a major cause of neurological disability and death during infancy. Radiological imaging plays a crucial role in evaluating craniospinal injury, both for guiding medical management and the forensic aspects of abusive trauma. The damage sustained is varied, complex and may be accompanied by an evolving pattern of brain injury secondary to a cascade of metabolic and physiological derangements. Regrettably, many cases are poorly or incompletely evaluated leading to diagnostic errors and difficulties in executing subsequent child care or criminal proceedings. It is evident, from cases referred to the authors, that imaging protocols for NAHI are lacking (or only loosely adhered to, if present) in many centres throughout the U.K. Future research in this field will also be hampered if there is a lack of consistent and reliable radiological data. There is no nationally agreed protocol for imaging NAHI. We propose such a protocol, based upon a wide experience in the medical management of child abuse and extensive involvement in the medicolegal aspects of NAHI.

The role of neuroendoscopy in the management of brain tumours.

Neuroendoscopy is increasingly used in the management of brain tumours and tumour related hydrocephalus and this study reviews the efficacy of neuroendoscopic interventions in this unit in patients with brain tumours. A series of 87 neuroendoscopic operations carried out in 77 patients with brain tumours over a 6-year period is reported. The age range of the patients was from 5 months to 70 years (median 13 years). In 56 cases (64%) presentation was with a newly-diagnosed tumour and hydrocephalus. The majority of the remaining patients had varying degrees of worsening hydrocephalus on the background of a previously diagnosed tumour. Neuroendoscopic third ventriculostomy (NTV) was successful in relieving hydrocephalus in the short term in 63/66 cases (95%) and in the longer term in 55/66 cases (83%). Neuroendoscopic tumour biopsies were successful in providing a tissue diagnosis in 17/28 cases (61%) and four extensive and three partial resections of tumour were carried out. There were two deaths within 30 days of the procedure with only one of these, secondary to intraventricular haemorrhage, directly related to neuroendoscopy. Few significant complications were noted otherwise. For selected intraventricular and paraventricular tumours neuroendoscopy offers the opportunity to combine relief of hydrocephalus with tumour biopsy and sampling of CSF in a single procedure.

Treatment of Chiari malformation, syringomyelia and hydrocephalus by neuroendoscopic third ventriculostomy.

This short paper illustrates a case with cervical myelomeningocoele, a Chiari malformation (CM), hydrocephalus (HC) and cervical syringomyelia treated by neuroendoscopic third ventriculostomy (NTV) with resolution of both the hydrocephalus and the syrinx. Two similar cases are discussed. The technique is advocated for the treatment of such complex dysraphic conditions.

The intracranial complications of rhinosinusitis: can they be prevented?

OBJECTIVES/HYPOTHESIS: Reference textbooks on the intracranial complications of rhinosinusitis imply that many of the intracranial complications of rhinosinusitis can be prevented. We sought to examine whether or not this is true. STUDY DESIGN: A retrospective case series. METHODS: The study included 47 consecutive patients presenting with intracranial complications secondary to rhinosinusitis between 1992 to 1999 with a mean follow-up of 5 years and 1 month. RESULTS: The most common presenting symptoms of intracranial involvement were an altered mental state, headache, fever, seizure, vomiting, a unilateral weakness or hemiparesis, or a cranial nerve sign. These justify an urgent magnetic resonance imaging or computed tomography scan. The importance of imaging before a lumbar puncture cannot be overemphasized. Of particular note was the finding that 21 patients (45%) presented with a periorbital cellulitis or frontal swelling. Therefore, it does not follow that because a collection of pus presents anteriorly it precludes any intracranial involvement. More than half of our patients (55%) had visited their primary care physician with an upper respiratory tract infection and had been treated appropriately. Once any central symptoms or signs developed, there was little evidence of any significant delay in referral to our unit. Only six patients had a history of nasal disease, three having had recent sinus surgery and three having had nasal polyps. Nine patients had significant long-term morbidity, seven patients had epilepsy, one patient had dysphasia, and one patient had right arm weakness. The single death in our series was associated with a cavernous sinus thrombosis. CONCLUSIONS: The report emphasizes the need for surgeons to be alert to the diagnosis, particularly in patients with a periorbital abscess or frontal swelling. Sinus surgery has a role in obtaining pus for culture, as well as draining the sinus if it is in continuity with an intracranial collection. Intracranial infections secondary to rhinosinusitis occur sporadically and, although it appears that this cannot be prevented, early recognition and treatment are essential to reduce any subsequent morbidity or mortality.

The effectiveness of neuroendoscopic interventions in children with brain tumours.

OBJECT: The purpose of this study was to review the efficacy of neuroendoscopic interventions in children with brain tumours and tumour-related hydrocephalus. METHODS: In all, 61 consecutive neuroendoscopic operations carried out in 53 children with brain tumours over a 6-year period were reviewed. The patients ranged in age from 5 months to 18 years (median 9 years). Forty of 61 presentations were with a newly diagnosed tumour and hydrocephalus - the remainder predominantly had a known tumour and worsening hydrocephalus. CONCLUSIONS: Neuroendoscopic third ventriculostomy (NTV) successfully relieved hydrocephalus in the short term in 45 of 47 cases and in the longer term in 39 of 47 cases. Neuroendoscopic biopsy provided definitive tissue diagnosis in 10 of 16 cases and 5 tumours were resected. There was 1 postoperative death, which not directly related to the neuroendoscopy and few significant complications otherwise. Neuroendoscopic methods allow effective immediate and longer term control of hydrocephalus as well as the opportunity for CSF sampling and tumour biopsy in selected cases.

The use of chemotherapy to facilitate surgical resection in pleomorphic xanthoastrocytoma: experience in a single case.

The use of noncytotoxic chemotherapy as an adjuvant treatment to permit resection of a pleomorphic xanthoastrocytoma (PXA) is described. A 6-year-old girl with a large right occipito-temporo-parietal lesion presented with signs and symptoms of raised intracranial pressure. An initial attempt at resection was halted because of excessive blood loss, and tumour embolisation was not feasible as no suitable vascular pedicle was identified. Two cycles of vincristine and carboplatin were given, and these decreased the vascularity of the tumour allowing subsequent complete macroscopic resection 9 weeks later. The use of chemotherapy to decrease the vascularity of the tumour by way of its antiangiogenic effects is discussed.

Separation of Notch1 promoted lineage commitment and expansion/transformation in developing T cells.

Notch1 signaling is required for T cell development. We have previously demonstrated that expression of a dominant active Notch1 (ICN1) transgene in hematopoietic stem cells (HSCs) leads to thymic-independent development of CD4(+)CD8(+) double-positive (DP) T cells in the bone marrow (BM). To understand the function of Notch1 in early stages of T cell development, we assessed the ability of ICN1 to induce extrathymic T lineage commitment in BM progenitors from mice that varied in their capacity to form a functional pre-T cell receptor (TCR). Whereas mice repopulated with ICN1 transduced HSCs from either recombinase deficient (Rag-2(-/)-) or Src homology 2 domain--containing leukocyte protein of 76 kD (SLP-76)(-/)- mice failed to develop DP BM cells, recipients of ICN1-transduced Rag-2(-/)- progenitors contained two novel BM cell populations indicative of pre-DP T cell development. These novel BM populations are characterized by their expression of CD3 epsilon and pre-T alpha mRNA and the surface proteins CD44 and CD25. In contrast, complementation of Rag-2(-/)- mice with a TCR beta transgene restored ICN1-induced DP development in the BM within 3 wk after BM transfer (BMT). At later time points, this population selectively and consistently gave rise to T cell leukemia. These findings demonstrate that Notch signaling directs T lineage commitment from multipotent progenitor cells; however, both expansion and leukemic transformation of this population are dependent on T cell-specific signals associated with development of DP thymocytes.

Neuroendoscopic third ventriculostomy for hydrocephalus in adults: report of a single unit's experience with 63 cases.

BACKGROUND: Neuroendoscopic third ventriculostomy (NTV) is becoming a first line treatment for hydrocephalus in this center. Its use in a consecutive series of adults is reported. METHOD: Initially a retrospective data collection after 7 months becoming prospective studying all patients who underwent NTV in this center. The adults (17 years or older) have been studied. RESULTS: Sixty-three patients met the criteria for inclusion: 38 male, 25 female. Mean age at first NTV 37.5 years. There was an 80% success rate (i.e., no further therapy for the hydrocephalus required). Follow-up was for a mean of 3.1 years. The largest subgroup were patients with third ventricular tumours (35%), of whom 86% were successfully treated. Mean time to failure for the whole series was 8.5 months (range immediate--30 months). Complications occurred in 17.5%; those deemed serious in 11%. There were three deaths (4.7%) within 30 days of the procedure. There were six other deaths during follow-up, five because of tumour progression and one because of pneumonia. CONCLUSIONS: This procedure lends itself to the treatment of hydrocephalus in adults and appears to be more successful than in young children. It is efficacious in both previously shunted and non shunted patients. It is now the first-line treatment for noncommunicating hydrocephalus in this center and also for patients with shunt failure who are anatomically suitable, having cerebrospinal fluid spaces large enough to admit the endoscope. The complication and mortality rates compare favorably with those for shunts.

Notch1 regulates maturation of CD4+ and CD8+ thymocytes by modulating TCR signal strength.

Notch signaling regulates cell fate decisions in multiple lineages. We demonstrate in this report that retroviral expression of activated Notch1 in mouse thymocytes abrogates differentiation of immature CD4+CD8+ thymocytes into both CD4 and CD8 mature single-positive T cells. The ability of Notch1 to inhibit T cell development was observed in vitro and in vivo with both normal and TCR transgenic thymocytes. Notch1-mediated developmental arrest was dose dependent and was associated with impaired thymocyte responses to TCR stimulation. Notch1 also inhibited TCR-mediated signaling in Jurkat T cells. These data indicate that constitutively active Notch1 abrogates CD4+ and CD8+ maturation by interfering with TCR signal strength and provide an explanation for the physiological regulation of Notch expression during thymocyte development.

Differential requirement for SLP-76 domains in T cell development and function.

The hematopoietic cell-specific adaptor protein, SLP-76, is critical for T cell development and mature T cell receptor (TCR) signaling; however, the structural requirements of SLP-76 for mediating thymopoiesis and mature T cell function remain largely unknown. In this study, transgenic mice were generated to examine the requirements for specific domains of SLP-76 in thymocytes and peripheral T cells in vivo. Examination of mice expressing various mutants of SLP-76 on the null background demonstrates a differential requirement for specific domains of SLP-76 in thymocytes and T cells and provides new insight into the molecular mechanisms underlying SLP-76 function.

Immature CD4+CD8+ thymocytes do not polarize lipid rafts in response to TCR-mediated signals.

TCR-mediated stimulation induces activation and proliferation of mature T cells. When accompanied by signals through the costimulatory receptor CD28, TCR signals also result in the recruitment of cholesterol- and glycosphingolipid-rich membrane microdomains (lipid rafts), which are known to contain several molecules important for T cell signaling. Interestingly, immature CD4(+)CD8(+) thymocytes respond to TCR/CD28 costimulation not by proliferating, but by dying. In this study, we report that, although CD4(+)CD8(+) thymocytes polarize their actin cytoskeleton, they fail to recruit lipid rafts to the site of TCR/CD28 costimulation. We show that coupling of lipid raft mobilization to cytoskeletal reorganization can be mediated by phosphoinositide 3-kinase, and discuss the relevance of these findings to the interpretation of TCR signals by immature vs mature T cells.