Hervé Brisse

The International Neuroblastoma Risk Group (INRG) Staging System: An INRG Task Force Report

PURPOSE The International Neuroblastoma Risk Group (INRG) classification system was developed to establish a consensus approach for pretreatment risk stratification. Because the International Neuroblastoma Staging System (INSS) is a postsurgical staging system, a new clinical staging system was required for the INRG pretreatment risk classification system. METHODS To stage patients before any treatment, the INRG Task Force, consisting of neuroblastoma experts from Australia/New Zealand, China, Europe, Japan, and North America, developed a new INRG staging system (INRGSS) based on clinical criteria and image-defined risk factors (IDRFs). To investigate the impact of IDRFs on outcome, survival analyses were performed on 661 European patients with INSS stages 1, 2, or 3 disease for whom IDRFs were known. RESULTS In the INGRSS, locoregional tumors are staged L1 or L2 based on the absence or presence of one or more of 20 IDRFs, respectively. Metastatic tumors are defined as stage M, except for stage MS, in which metastases are confined to the skin, liver, and/or bone marrow in children younger than 18 months of age. Within the 661-patient cohort, IDRFs were present (ie, stage L2) in 21% of patients with stage 1, 45% of patients with stage 2, and 94% of patients with stage 3 disease. Patients with INRGSS stage L2 disease had significantly lower 5-year event-free survival than those with INRGSS stage L1 disease (78% +/- 4% v 90% +/- 3%; P = .0010). CONCLUSION Use of the new staging (INRGSS) and risk classification (INRG) of neuroblastoma will greatly facilitate the comparison of risk-based clinical trials conducted in different regions of the world.

Magnetic resonance imaging of the fetus

Abstract Fetal magnetic resonance imaging (FMRI) has gained considerable interest during the last decade, especially in its intracranial applications. Due to its high soft-tissue contrast and presumed safety, FMRI should be accepted as a complementary technique in prenatal diagnosis, useful either to elucidate equivocal findings on routine US studies or to further delineate some pathological entities. Normal patterns of fetal brain maturation, as shown by FMRI, are described because they are of paramount importance to accurately evaluate intracranial diseases. To date, however, FMRI requires specialised facilities and should be considered as an evolving clinical research modality and performed within precise guidelines in a multidisciplinary approach to prenatal pathology.

Guidelines for imaging retinoblastoma: imaging principles and MRI standardization

Retinoblastoma is the most common intraocular tumor in children. The diagnosis is usually established by the ophthalmologist on the basis of fundoscopy and US. Together with US, high-resolution MRI has emerged as an important imaging modality for pretreatment assessment, i.e. for diagnostic confirmation, detection of local tumor extent, detection of associated developmental malformation of the brain and detection of associated intracranial primitive neuroectodermal tumor (trilateral retinoblastoma). Minimum requirements for pretreatment diagnostic evaluation of retinoblastoma or mimicking lesions are presented, based on consensus among members of the European Retinoblastoma Imaging Collaboration (ERIC). The most appropriate techniques for imaging in a child with leukocoria are reviewed. CT is no longer recommended. Implementation of a standardized MRI protocol for retinoblastoma in clinical practice may benefit children worldwide, especially those with hereditary retinoblastoma, since a decreased use of CT reduces the exposure to ionizing radiation.

Pattern of relapse and outcome of non-metastatic germinoma patients treated with chemotherapy and limited field radiation: the SFOP experience

Over the last two decades, chemotherapy has been introduced in protocols for patients with intracranial germinoma with the objective of reducing the volume and the dose of irradiation without compromising survival rates. The aim of this work is to critically analyze the pattern of relapse in a cohort of patients with nonmetastatic germinoma prospectively treated with chemotherapy followed by focal field radiation. Data of all germinoma patients registered in the French protocol for intracranial germ cell tumors between 1990 and 1999 were reviewed. The pattern of relapse, management, and outcome were analyzed in 10 of 60 patients who developed a recurrence after initial treatment. In 9 patients, the site of recurrence was local or loco-regional, notably in the periventricular area for 8. One patient only had isolated distant leptomeningeal relapse. The review of the sites of relapse suggests that most recurrences could have been avoided with a larger ventricular field of radiation. Treatment at first relapse included chemotherapy (10 patients), high-dose chemotherapy and stem cell transplant (8 patients), and/or radiation therapy (4 patients). Five patients experienced a second relapse. At a median follow-up of 72 months since the first relapse, 8 patients are alive in second or third remission. This review identified an excess of periventricular relapses when the focal field of radiation is used in the combined management of germinoma. These relapses are predominantly marginal or outside radiation fields. Ventricular field radiation appears a logical alternative to decrease the incidence of such relapses. Future trials should aim at better identifying patients who may benefit from local and ventricular radiation, respectively.

Imaging of malignant tumours of the long bones in children: monitoring response to neoadjuvant chemotherapy and preoperative assessment

This review focuses on imaging of osteosarcoma and Ewing’s sarcoma of the long bones in children during preoperative neoadjuvant chemotherapy. Morphological criteria on plain films and conventional static MRI are insufficiently correlated with histological response. We review the contribution of dynamic MRI, diffusion-weighted MR and nuclear medicine (18FDG-PET) to monitor tumoural necrosis. MRI is currently the best method to evaluate local extension prior to tumour resection, especially to assess the feasibility of conservative surgery. Quantitative models in dynamic MRI and 18FDG-PET are currently being developed in order to find new early prognostic criteria, but for the time being, treatment protocols are still based on the gold standard of histological response.

Relevance of CT and MRI in retinoblastoma for the diagnosis of postlaminar invasion with normal-size optic nerve: a retrospective study of 150 patients with histological comparison

Background Detection of optic nerve invasion is mandatory in children primarily enucleated for retinoblastoma to ensure a free resection margin.Objective To assess the accuracy of CT and MRI for the detection of postlaminar invasion in normal-size nerves.Materials and methods A total of 150 patients enucleated for retinoblastoma were included. Imaging data (119 CT and 46 MRI) were retrospectively reviewed and compared with histological findings. Abnormal contrast enhancement of the optic nerve was used as diagnostic criterion for invasion. The associations between postlaminar invasion and several indirect signs were also assessed. Statistical analysis was performed with the Kruskal-Wallis and Fisher exact tests.Results Postlaminar invasion on histology was observed in 8% (12/150). The sensitivity, specificity, accuracy and negative and positive predictive values were 60%, 95%, 91%, 95% and 60% for MRI, and 0%, 100%, 94% and 94% (PPV not assessable) for CT, respectively. Tumour diameter was the only indirect radiological sign significantly associated with postlaminar optic nerve invasion (P=0.002).Conclusion Our results suggest that MRI is more relevant than CT for preoperative detection of optic nerve invasion in patients with retinoblastoma. Tumour diameter is the only indirect sign significantly associated with postlaminar invasion.

Opsoclonus-myoclonus in children associated or not with neuroblastoma.

OBJECTIVE To compare the clinical data at diagnosis, treatment and neurological outcome in 34 children with opsoclonus-myoclonus syndrome (OMS) associated with a detected neuroblastoma or not. STUDY DESIGN This is a multicentric retrospective study of 34 children presenting with OMS from four pediatric centers diagnosed between 1988 and 2008. RESULTS Twenty-two patients had OMS associated with a neuroblastoma. These patients all had neuroblastomas with favourable prognostic features; all underwent surgery, six received chemotherapy. Twelve children had OMS without a detected neuroblastoma. For OMS, the main treatment in all children was corticotherapy (n=33), but immunoglobulins (n=13), cyclophosphamide (n=4) and rituximab (n=4) were also given. In the 27 OMS patients with or without neuroblastoma whose follow up was greater than two years, the neurological outcome was evaluated: 59.3% had neurological sequelae, including motor, praxic and/or language sequelae (n=9), persistent ataxia (n=6) and moderate motor deficit (n=3). No significant difference in neurological outcome was noted between the two patient groups. CONCLUSION Our retrospective study provides further evidence that OMS with or without a detected neuroblastoma is the same disease, whose major challenges are the neurological sequelae. An international collaboration is required to improve the knowledge about OMS, the treatment and the outcome in this rare disorder.

Phase II Study of Temozolomide in Relapsed or Refractory High-Risk Neuroblastoma: A Joint Société Française des Cancers de l’Enfant and United Kingdom Children Cancer Study Group–New Agents Group Study

PURPOSE To determine the response rate (RR) of neuroblastoma (NB) in children to temozolomide (TMZ), and evaluate the duration of response and tolerance of the drug in this patient population. PATIENTS AND METHODS A multicenter, phase II evaluation of an oral, daily schedule of TMZ (200 mg/m2/d x 5 days every 28 days) was undertaken in children with refractory or relapsed high-risk NB (metastatic or localized with Myc-N amplification). Response assessment was based on imaging with two-dimentional measurement of disease and meta-iodobenzylguanidine (MIBG) score. Activity was defined by a reduction in lesion size or isotope uptake at anytime. Methodology included a two-step design using Flemings method with a first step of 15 patients and a second of 10 additional patients if two to four responses had been observed in the first cohort. All data was centrally reviewed by a panel. RESULTS Twenty-five assessable patients were recruited over a 14-month period in 14 centers and received 94 cycles of chemotherapy. Twenty-three patients had metastatic NB either refractory (n = 9) or in relapse (n = 14). Grade 3 or 4 thrombocytopenia was the most frequent toxicity (16% of cycles). Myelosuppression resulted in treatment delays and dose reductions (24% and 21% of cycles, respectively). Response (complete response, very good partial response, or partial response) was observed in five patients (RR = 20% +/- 8%) with a median duration of 6 months and an objective or mixed response in five additional patients. CONCLUSION Temozolomide shows activity in heavily pretreated patients with NB, and deserves further evaluation in combination with another drug.

Imaging in unilateral Wilms tumour

Wilms tumour is one of the most common malignancies in children, with an excellent prognosis after therapy. There is a very diverse approach to treatment according to geographical location. This variation in therapeutic attitude toward Wilms tumour, particularly between the United States and Europe, has consequences for the choice of imaging modality at diagnosis. In Europe, the International Society of Paediatric Oncology (SIOP) treatment protocol is based on chemotherapy followed by surgery. Imaging (US, CT and MRI), clinical history and examination will help predict whether the findings are consistent with Wilms tumour. Furthermore, in the UK preoperative image-guided biopsy is advised to help identify the small group of patients who, despite typical imaging features of Wilms tumour, have other types of neoplasia that require alternative management. In the United States, the National Wilms Tumor Study (NWTS) advises surgery prior to chemo- and radiotherapy. Hence imaging must provide detailed anatomical information for surgical planning. This article discusses the role of imaging at diagnosis and the relative strengths and weaknesses of the available radiological techniques. We also focus on imaging the lung for metastatic disease and the consequences (to the patient’s ultimate outcome) of CT-diagnosed small pulmonary nodules and discuss the radiological diagnosis and consequences of tumour rupture present at diagnosis.

Assessment of organ absorbed doses and estimation of effective doses from pediatric anthropomorphic phantom measurements for multi-detector row CT with and without automatic exposure control.

This study was designed to measure organ absorbed doses from multi-detector row computed tomography (MDCT) on pediatric anthropomorphic phantoms, calculate the corresponding effective doses, and assess the influence of automatic exposure control (AEC) in terms of organ dose variations. Four anthropomorphic phantoms (phantoms represent the equivalent of a newborn, 1-, 5-, and 10-y-old child) were scanned with a four-channel MDCT coupled with a z-axis-based AEC system. Two CT torso protocols were compared: a first protocol without AEC and constant tube current-time product and a second protocol with AEC using age-adjusted noise indices. Organ absorbed doses were monitored by thermoluminescent dosimeters (LiF: Mg, Cu, P). Effective doses were calculated according to the tissue weighting factors of the International Commission on Radiological Protection (ICRP Publication 103). For fixed mA acquisitions, organ doses normalized to the volume CT dose index in a 16-cm head phantom (CTDIvol16) ranged from 0.6 to 1.5 and effective doses ranged from 8.4 to 13.5 mSv. For the newborn-equivalent phantom, the AEC-modulated scan showed almost no significant dose variation compared to the fixed mA scan. For the 1-, 5- and 10-y equivalent phantoms, the use of AEC induced a significant dose decrease on chest organs (ranging from 61 to 31% for thyroid, 37 to 21% for lung, 34 to 17% for esophagus, and 39 to 10% for breast). However, AEC also induced a significant dose increase (ranging from 28 to 48% for salivary glands, 22 to 51% for bladder, and 24 to 70% for ovaries) related to the high density of skull base and pelvic bones. These dose increases should be considered before using AEC as a dose optimization tool in children.