Antony Michalski

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 childs 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.

Combined MYC and P53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease

Summary We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. Combined MYC family amplifications and P53 pathway defects commonly emerged at relapse, and all patients in this group died of rapidly progressive disease postrelapse. To study this interaction, we investigated a transgenic model of MYCN-driven medulloblastoma and found spontaneous development of Trp53 inactivating mutations. Abrogation of p53 function in this model produced aggressive tumors that mimicked characteristics of relapsed human tumors with combined P53-MYC dysfunction. Restoration of p53 activity and genetic and therapeutic suppression of MYCN all reduced tumor growth and prolonged survival. Our findings identify P53-MYC interactions at medulloblastoma relapse as biomarkers of clinically aggressive disease that may be targeted therapeutically.

Primitive neuroectodermal tumours: Anatomic location, extent of surgery, and outcome

BACKGROUND/PURPOSE Primitive neuroectodermal tumours (PNET) are rare tumours sharing similar histology, immunohistochemistry, and cytogenetics to Ewings sarcomas. The aim of the study was to document the effect of site of origin and the completeness of surgical excision on the outcome in infants and children with PNET. METHODS All patients (n = 26) with PNET treated in our hospital during the last 6 years were included in the study. The diagnosis was based on the histopathologic findings and a positive MIC2 antibody test. The tumours were classified according to the Intergroup Rhabdomyosarcoma Study III, and were treated according to the UKEESG protocol for Ewings Sarcoma. RESULTS Complete remission (CR) was achieved in 52% of the patients completing their chemotherapy. Overall, survival was 42% (11 of 26). Tumours from the paraspinal and scapula areas responded relatively well (CR, 83%), whereas abdominal PNET did not respond to treatment. Tumours arising from the head, neck, or chest had an intermediate prognosis (37% survival). Three of the 10 patients who had a complete excision of the tumour died of progressive disease. CONCLUSIONS Complete surgical excision reduced the risk of local recurrence but did not prevent metastatic spread. These data indicate that PNET have a worse prognosis and different favourable sites than other sarcomas. New treatment strategies are necessary for these rare tumours.

RAF gene fusions are specific to pilocytic astrocytoma in a broad paediatric brain tumour cohort

Brain tumours are the most common solid tumour in children and are the primary cause of cancer-related death in children and young adults [4, 6]. The most prevalent childhood brain tumours are low-grade gliomas, specifically pilocytic astrocytomas (PAs, WHO Grade I) [1]. PAs are slow-growing tumours which are often cystic, and may occur sporadically or in association with the genetic disorder Neurofibromatosis type 1. Several recent studies including our own have identified novel KIAA1549–BRAF and SRGAP3–RAF1 gene fusions in the majority of PAs tested [3, 7, 8, 12]. In these fusions, the N-terminal autoinhibitory domains of the RAF proteins are replaced by those of KIAA1549 or SRGAP3, resulting in constitutive activation of the ERK/MAPK pathway. A recent study has suggested that the KIAA1549–BRAF fusion is more common in PAs originating in the cerebellum [5]. In low-grade glioma without RAF gene fusions there is increasing evidence for activation of the ERK/MAPK pathway through alternative mechanisms, such as point mutation of KRAS or BRAF [2, 11, 13]. Despite the high frequency of RAF gene fusions in PAs, they have not been investigated in other types of paediatric brain tumours. In this study, we screened a new cohort of 74 paediatric brain tumours, with a range of different pathologies, for all known KIAA1549–BRAF and SRGAP3–RAF1 fusion variants. Access to tumours and clinical data was in accordance with Local Research Ethics Committee (LREC) regulations: Great Ormond Street Hospital LREC reference number 05/Q0508/153. Tumours were classified by diagnostic criteria defined by the World Health Organization (WHO) [10]. Total RNA was extracted from fresh frozen tissue samples using the miRNeasy mini kit (Qiagen, Crawley, UK) and reverse transcribed using the SuperScript First-Strand cDNA synthesis system (Invitrogen, Carlsbad, CA). KIAA1549–BRAF fusions were detected using previously described primers and techniques [3]. The primers used for detecting SRGAP3–RAF1 fusions were 50-TGG CAGTAACCTCATCACCA-30 (located in SRGAP3 exon 10) and 50-GGTTGGGTCGACAACCTTTA-30 (located in RAF1 exon 11). All fusions identified by PCR were confirmed by direct sequencing on a 3100 Genetic Analyzer capillary sequencer (Applied Biosystems, Foster City, CA). Electronic supplementary material The online version of this article (doi:10.1007/s00401-010-0693-y) contains supplementary material, which is available to authorized users.

Novel molecular subgroups for clinical classification and outcome prediction in childhood medulloblastoma: a cohort study

Summary Background International consensus recognises four medulloblastoma molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGrp3), and group 4 (MBGrp4), each defined by their characteristic genome-wide transcriptomic and DNA methylomic profiles. These subgroups have distinct clinicopathological and molecular features, and underpin current disease subclassification and initial subgroup-directed therapies that are underway in clinical trials. However, substantial biological heterogeneity and differences in survival are apparent within each subgroup, which remain to be resolved. We aimed to investigate whether additional molecular subgroups exist within childhood medulloblastoma and whether these could be used to improve disease subclassification and prognosis predictions. Methods In this retrospective cohort study, we assessed 428 primary medulloblastoma samples collected from UK Childrens Cancer and Leukaemia Group (CCLG) treatment centres (UK), collaborating European institutions, and the UKCCSG-SIOP-PNET3 European clinical trial. An independent validation cohort (n=276) of archival tumour samples was also analysed. We analysed samples from patients with childhood medulloblastoma who were aged 0–16 years at diagnosis, and had central review of pathology and comprehensive clinical data. We did comprehensive molecular profiling, including DNA methylation microarray analysis, and did unsupervised class discovery of test and validation cohorts to identify consensus primary molecular subgroups and characterise their clinical and biological significance. We modelled survival of patients aged 3–16 years in patients (n=215) who had craniospinal irradiation and had been treated with a curative intent. Findings Seven robust and reproducible primary molecular subgroups of childhood medulloblastoma were identified. MBWNT remained unchanged and each remaining consensus subgroup was split in two. MBSHH was split into age-dependent subgroups corresponding to infant (<4·3 years; MBSHH-Infant; n=65) and childhood patients (≥4·3 years; MBSHH-Child; n=38). MBGrp3 and MBGrp4 were each split into high-risk (MBGrp3-HR [n=65] and MBGrp4-HR [n=85]) and low-risk (MBGrp3-LR [n=50] and MBGrp4-LR [n=73]) subgroups. These biological subgroups were validated in the independent cohort. We identified features of the seven subgroups that were predictive of outcome. Cross-validated subgroup-dependent survival models, incorporating these novel subgroups along with secondary clinicopathological and molecular features and established disease risk-factors, outperformed existing disease risk-stratification schemes. These subgroup-dependent models stratified patients into four clinical risk groups for 5-year progression-free survival: favourable risk (54 [25%] of 215 patients; 91% survival [95% CI 82–100]); standard risk (50 [23%] patients; 81% survival [70–94]); high-risk (82 [38%] patients; 42% survival [31–56]); and very high-risk (29 [13%] patients; 28% survival [14–56]). Interpretation The discovery of seven novel, clinically significant subgroups improves disease risk-stratification and could inform treatment decisions. These data provide a new foundation for future research and clinical investigations. Funding Cancer Research UK, The Tom Grahame Trust, Star for Harris, Action Medical Research, SPARKS, The JGW Patterson Foundation, The INSTINCT network (co-funded by The Brain Tumour Charity, Great Ormond Street Childrens Charity, and Children with Cancer UK).

Potential Prognostic Factors of Relapse-Free Survival in Childhood Optic Pathway Glioma: A Multivariate Analysis

There is still no consensus on the natural history and optimal management of optic pathway gliomas (OPG) in children. In order to tackle optimal management issues, we need to clearly understand the prognostic and confounding factors affecting relapse of OPG. We propose the use of the Cox proportional hazards (PH) model in a retrospective study of childhood OPG of 69 children seen from 1977 to 1994. We have developed a comprehensive model capable of multivariate analyses and handling time-dependencies. Our studies showed that relapse-free survival improves with increasing age, the presence of neurofibromatosis 1 (NF1), and chemotherapy and radiotherapy (p < 0.0005). Sex, tumor position and surgery do not significantly affect survival. Older children with NF1 have extremely good prognosis. We noted behavior that departs from the strictly proportional hazards model, but results were inconclusive.

Treatment of recurrent central nervous system primitive neuroectodermal tumours in children and adolescents: Results of a Children’s Cancer and Leukaemia Group study

BACKGROUND The treatment of previously irradiated patients with recurrent central nervous system primitive neuroectodermal tumours (PNETs) is a considerable challenge. A study was undertaken to attempt to improve the outcome for such patients using a high dose chemotherapy (HDCT) based strategy. METHODS Between 2000 and 2007, 40 patients with relapsed medulloblastoma (MB) and 5 with relapsed supratentorial PNETs (StPNETs) were accrued. All but one had received prior craniospinal radiotherapy. Patients were initially treated with cyclophosphamide (4 g/m(2)) together with surgery or local radiotherapy where appropriate. If complete or near complete remission was achieved, the patient proceeded to receive two sequential courses of HDCT with stem cell rescue. The first course consisted of thiotepa (900 mg/m(2)) and the second carboplatin (AUC 21). RESULTS All five patients with StPNET died of tumour progression with a median OS of 0.4 years. Nineteen of the 40 patients with relapsed MB underwent surgery. Radiotherapy was administered to eight patients. All patients received at least one course of cyclophosphamide. Only 22 MB patients progressed to the HDCT phase; 10 patients received thiotepa only and 12 thiotepa and carboplatin. At a median follow-up of 7.4 years (Range 2.8-8.2 years), only three MB patients are still alive, one following a further relapse. Three and 5 year OS was 22.0% and 8.2%, respectively and 3 and 5 year EFS was 14.6% and 8.7%, respectively. CONCLUSION This national study based on a strategy including a particular tandem HDCT regimen showed no benefit for previously irradiated patients with relapsed StPNET and very limited benefit for patients with relapsed medulloblastoma.

Lack of T-cell responses following autologous tumour lysate pulsed dendritic cell vaccination, in patients with relapsed osteosarcoma.

BackgroundImmunotherapy using autologous dendritic cell (DC) vaccination has not been systematically evaluated in osteosarcoma. We therefore conducted a phase I trial to assess feasibility, safety and tumour-specific immune responses in patients with relapsed disease.Patients and methodsOf 13 recruited patients with relapsed osteosarcoma, 12 received 3 weekly vaccines of autologous DCs matured with autologous tumour lysate and keyhole limpet haemocyanin (KLH), to a maximum of 6 vaccinations. An additional 3 paediatric patients afflicted with other tumour types and with relapsed disease received vaccines generated with identical methodology. Immune responses were assessed using an ELISpot assay for the detection of interferon gamma, whilst interleukin-2 and granzyme B were additionally assessed in cases where interferon-γ responses were induced.ResultsIn total 61 vaccines, of homogeneous maturation phenotype and viability, were administered with no significant toxicity. Only in 2 out of 12 treated osteosarcoma cases was there an induction of specific T-cell immune response to the tumour, whilst a strong but non-specific immune response was induced in 1 further osteosarcoma patient. Immune response against KLH was induced in only 3 out of 12 osteosarcoma patients. In contrast, three additional non-osteosarcoma patients showed significant T-cell responses to vaccine.ConclusionWe have shown the strategy of DC vaccination in relapsed osteosarcoma is safe and feasible. However, significant anti-tumour responses were induced in only 2 out of 12 vaccinated patients with no evidence of clinical benefit. Comparison of results with identically treated control patients suggests that osteosarcoma patients might be relatively insensitive to DC-based vaccine treatments.

Medulloblastoma as a first presentation of fanconi anemia.

Fanconi anemia is a chromosomal instability syndrome associated with certain congenital abnormalities, defective hemopoiesis, and an increased risk of developing acute myeloid leukemia and some solid tumors. The diagnosis can be made at birth if congenital abnormalities are present but is often made in childhood when hematologic complications develop. The authors report a case of Fanconi anemia diagnosed in a child with no congenital abnormalities and normal bone marrow who first presented with a cerebellar medulloblastoma. The authors discuss diagnostic and therapeutic implications for such malignancies in Fanconi anemia.

Futile care in oncology: when to stop trying

The idea that some medical interventions may be ‘futile’, and so should not to be attempted by the responsible physician, is a traditional one. However, in the late 1960s, our increasing recognition of principles that respected patient autonomy and authority over treatment, eclipsed this ‘paternalistic’ perspective for some time. Only in the past decade has the concept of futile treatment, and the physician authority that this implies, seen a resurgence as a legitimate ethical perspective. Nearly all of the more recent discussions have focused on the use of cardiopulmonary resuscitation (CPR). This is understandable, since CPR is the only intervention requiring an order not to provide. Until very recently, this was a decision which always required the patient’s or surrogate’s consent, at least in the USA. Physicians had to obtain consent not to use CPR, even when they were sure of its uselessness. This lead to conflicts between the demands of patients or families for CPR, and the physician’s (or other medical staff’s) reluctance to provide it. Two sorts of arguments support the physician’s authority to say “no” to such demands by patients and their families. The first, and most central, rests on the claim that patients’ ‘rights of autonomy’, which are by now well established in law and ethics, are negative rights, not positive ones. They include the right to refuse a recommended treatment, or to choose among the treatment options on offer. However, there can be no general right to demand whatever intervention the patient might choose, since this would make it impossible for health professionals to practise with integrity. They could be forced to provide interventions which would violate the most fundamental duties defining the character of the profession – in particular, the duty to help rather than hurt. This right to professional integrity is reflected in everyday medical practice; it is not the cardiac patient, for example, who decides whether he or she is a candidate for a bypass. It is the surgeons who must consider the moral weight of the possibility that the patient’s death might be by their hand. The second argument concerns how to properly enable the exercise of patient autonomy. Making choices is important to us when real alternatives are at stake – ie when what we choose will significantly affect our interests. The ‘autonomy’ that is offered to patients or their surrogates is a