Véronique Mosseri

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

PURPOSE Because current approaches to risk classification and treatment stratification for children with neuroblastoma (NB) vary greatly throughout the world, it is difficult to directly compare risk-based clinical trials. The International Neuroblastoma Risk Group (INRG) classification system was developed to establish a consensus approach for pretreatment risk stratification. PATIENTS AND METHODS The statistical and clinical significance of 13 potential prognostic factors were analyzed in a cohort of 8,800 children diagnosed with NB between 1990 and 2002 from North America and Australia (Childrens Oncology Group), Europe (International Society of Pediatric Oncology Europe Neuroblastoma Group and German Pediatric Oncology and Hematology Group), and Japan. Survival tree regression analyses using event-free survival (EFS) as the primary end point were performed to test the prognostic significance of the 13 factors. RESULTS Stage, age, histologic category, grade of tumor differentiation, the status of the MYCN oncogene, chromosome 11q status, and DNA ploidy were the most highly statistically significant and clinically relevant factors. A new staging system (INRG Staging System) based on clinical criteria and tumor imaging was developed for the INRG Classification System. The optimal age cutoff was determined to be between 15 and 19 months, and 18 months was selected for the classification system. Sixteen pretreatment groups were defined on the basis of clinical criteria and statistically significantly different EFS of the cohort stratified by the INRG criteria. Patients with 5-year EFS more than 85%, more than 75% to < or = 85%, > or = 50% to < or = 75%, or less than 50% were classified as very low risk, low risk, intermediate risk, or high risk, respectively. CONCLUSION By defining homogenous pretreatment patient cohorts, the INRG classification system will greatly facilitate the comparison of risk-based clinical trials conducted in different regions of the world and the development of international collaborative studies.

Prognostic factors of breast recurrence in the conservative management of early breast cancer: A 25-year follow-up☆

Between 1960 and 1980, 518 patients with T1, T2, N0, N1a, invasive breast cancer were treated by limited surgery at Institute Curie with (183 patients) or without (335 patients) axillary node dissection, followed by radiation therapy to breast and nodes. Median follow-up was 8.6 years (1.3 to 25 years). Fifty-six breast recurrences occurred, including 49 breast recurrences alone, 3 simultaneous breast and node recurrences, and 4 simultaneous breast recurrences and metastasis. Five-year, 10-year, and 15-year actuarial risks of breast recurrences were 7 +/- 1%, 11 +/- 1.5%, and 18 +/- 3%, respectively. Univariate analysis of 14 clinical and pathological prognostic factors revealed that local control in breast was significantly impaired by young age, premenopausal status, inadequate gross surgical excision, extensive ductal in situ component, and endolymphatic extension. On multivariate analysis with a Cox regression model, the most important contributors to local breast control in order of importance were age (p less than 10(-4), relative risk = 2.44), adequacy of surgery (p = 0.003, relative risk = 2.78), and endolymphatic extension (p = 0.03, relative risk = 2.98). The 5-year actuarial survival rate following breast recurrence was 73%, and was significantly worse when breast recurrence occurred in the first 3 years after treatment: 44% versus 87%, respectively (p less than 0.01). This study confirms the relationship between young age and low breast control rates, and demonstrates the importance of adequate initial surgical procedures. It emphasizes the adverse prognosis of early breast recurrences as compared to the relatively favorable outcome of late recurrences.

Prognostic Value of Tumor-Infiltrating CD4+ T-Cell Subpopulations in Head and Neck Cancers

Purpose: CD4+ T cells play a central role in initiating and maintaining anticancer immune responses. However, regulatory CD4+CD25+ T cells which express Foxp3 have also been shown to inhibit antitumor effector T cells. In view of these heterogeneous CD4+ T-cell populations, this study was designed to determine the prognostic value of various tumor-infiltrating CD4+ T-cell populations in head and neck squamous cell carcinoma. Experimental Design: Eighty-four newly diagnosed untreated patients with histologically proven primary head and neck squamous cell carcinoma were included in this study. Double or triple immunofluorescence staining was done to assess and quantify the activated CD4+CD69+ T cells, regulatory CD4+Foxp3+ T cells, and mixed CD4+CD25+ T cells comprising both activated and regulatory T cells. Results: On univariate analysis, high levels of tumor-infiltrating CD4+CD69+ T cells were correlated with both better locoregional control (P = 0.01) and longer survival (P = 0.01). Infiltration by regulatory Foxp3+CD4+ T cells was positively associated with a better locoregional control of the tumor. Multivariate analysis showed that the only significant prognostic factors related to locoregional control were T stage (P = 0.02) and CD4+Foxp3+ T-cell infiltration of the tumor (P = 0.02). In the Cox multivariate analysis, only two variables influenced overall survival probability: T stage (P = 0.036) and CD4+CD69+ T-cell infiltration (P = 0.017). Conclusion: This study shows that tumor-infiltrating activated CD4+CD69+ T cells are associated with a good prognosis in head and neck squamous cell carcinoma. In addition, regulatory Foxp3+CD4+ T cells are positively correlated with locoregional control may be through down-regulation of harmful inflammatory reaction, which could favor tumor progression.

Overall Genomic Pattern Is a Predictor of Outcome in Neuroblastoma

PURPOSE For a comprehensive overview of the genetic alterations of neuroblastoma, their association and clinical significance, we conducted a whole-genome DNA copy number analysis. PATIENTS AND METHODS A series of 493 neuroblastoma (NB) samples was investigated by array-based comparative genomic hybridization in two consecutive steps (224, then 269 patients). RESULTS Genomic analysis identified several types of profiles. Tumors presenting exclusively whole-chromosome copy number variations were associated with excellent survival. No disease-related death was observed in this group. In contrast, tumors with any type of segmental chromosome alterations characterized patients with a high risk of relapse. Patients with both numerical and segmental abnormalities clearly shared the higher risk of relapse of segmental-only patients. In a multivariate analysis, taking into account the genomic profile, but also previously described individual genetic and clinical markers with prognostic significance, the presence of segmental alterations with (HR, 7.3; 95% CI, 3.7 to 14.5; P < .001) or without MYCN amplification (HR, 4.5; 95% CI, 2.4 to 8.4; P < .001) was the strongest predictor of relapse; the other significant variables were age older than 18 months (HR, 1.8; 95% CI, 1.2 to 2.8; P = .004) and stage 4 (HR, 1.8; 95% CI, 1.2 to 2.7; P = .005). Finally, within tumors showing segmental alterations, stage 4, age, MYCN amplification, 1p and 11q deletions, and 1q gain were independent predictors of decreased overall survival. CONCLUSION The analysis of the overall genomic pattern, which probably unravels particular genomic instability mechanisms rather than the analysis of individual markers, is essential to predict relapse in NB patients. It adds critical prognostic information to conventional markers and should be included in future treatment stratification.

Contralateral breast cancer: annual incidence and risk parameters.

PURPOSE To screen for factors that might predict the risk of developing metachronous contralateral breast cancer (CBC), taking into account the influence of local or distant recurrence, and to assess the annual incidence of CBC. PATIENTS AND METHODS Of 4,748 women with invasive unilateral breast cancer, clinical stage I to IIIa, treated between 1981 and 1987, 282 metachronous CBCs were diagnosed. Due to competing risks between the occurrence of CBC and other events, several options for multivariate analysis were considered. RESULTS The median follow-up time was 80 months (range, 1 to 158). The cumulative rate of CBC was 4.1% +/- 0.3% at 5 years, and the annual incidence rate of CBC increased slowly, while the risk of local recurrence and metastases decreased after the fourth year. Whichever model we chose, age less than 55 years (relative risk [RR] = 1.40) at the time of diagnosis of the first breast cancer, as well as the presence of lobular type carcinoma (RR = 1.50), was associated with an increased risk of developing a tumor in the contralateral breast. Adjuvant chemotherapy significantly decreased (RR = 0.54) the risk of CBC. CONCLUSION Lobular histology and age less than 55 years are found to increase the risk of CBC, while adjuvant chemotherapy significantly decreased the risk of CBC. The progressive rise in the annual incidence rates of CBC, together with the absence of a link between clinical prognostic factors of the first cancer and CBC, suggested that CBC can be considered as a second primary breast cancer.

Hyperfractionated Versus Conventional Radiotherapy Followed by Chemotherapy in Standard-Risk Medulloblastoma: Results From the Randomized Multicenter HIT-SIOP PNET 4 Trial

PURPOSE To compare event-free survival (EFS), overall survival (OS), pattern of relapse, and hearing loss in children with standard-risk medulloblastoma treated by postoperative hyperfractionated or conventionally fractionated radiotherapy followed by maintenance chemotherapy. PATIENTS AND METHODS In all, 340 children age 4 to 21 years from 122 European centers were postoperatively staged and randomly assigned to treatment with hyperfractionated radiotherapy (HFRT) or standard (conventional) fractionated radiotherapy (STRT) followed by a common chemotherapy regimen consisting of eight cycles of cisplatin, lomustine, and vincristine. RESULTS After a median follow-up of 4.8 years (range, 0.1 to 8.3 years), survival rates were not significantly different between the two treatment arms: 5-year EFS was 77% ± 4% in the STRT group and 78% ± 4% in the HFRT group; corresponding 5-year OS was 87% ± 3% and 85% ± 3%, respectively. A postoperative residual tumor of more than 1.5 cm(2) was the strongest negative prognostic factor. EFS of children with all reference assessments and no large residual tumor was 82% ± 2% at 5 years. Patients with a delay of more than 7 weeks to the start of RT had a worse prognosis. Severe hearing loss was not significantly different for the two treatment arms at follow-up. CONCLUSION In this large randomized European study, which enrolled patients with standard-risk medulloblastoma from more than 100 centers, excellent survival rates were achieved in patients without a large postoperative residual tumor and without RT treatment delays. EFS and OS for HFRT was not superior to STRT, which therefore remains standard of care in this disease.

Surgical Risk Factors in Primary Surgery for Localized Neuroblastoma: The LNESG1 Study of the European International Society of Pediatric Oncology Neuroblastoma Group

PURPOSE Although tumor resection is the mainstay of treatment for localized neuroblastoma, there are no established guidelines indicating which patients should be operated on immediately and which should undergo surgery after tumor reduction with chemotherapy. In an effort to develop such guidelines, the LNESG1 study defined surgical risk factors (SRFs) based on the imaging characteristics. PATIENTS AND METHODS A total of 905 patients with suspected localized neuroblastoma were registered by 10 European countries between January 1995 and October 1999; 811 of 905 patients were eligible for this analysis. RESULTS Information on SRFs was obtained for 719 of 811 patients; 367 without and 352 with SRFs. Of these 719 patients, 201 patients (four without and 197 with SRFs) underwent biopsy only. An attempt at tumor excision was made in 518 patients: 363 of 367 patients without and 155 of 352 patients with SRFs (98.9% v 44.0%). Complete excision was achieved in 271 of 363 patients without and in 72 of 155 patients with SRF (74.6% v 46.4%), near-complete excision was achieved in 81 and 61 patients (22.3% v 39.3%), and incomplete excision was achieved in 11 and 22 patients (3.0% v 14.2%), respectively. There were two surgery-related deaths. Nonfatal surgery-related complications occurred in 45 of 518 patients (8.7%) and were less frequent in patients without SRFs (5.0% v 17.4%). Associated surgical procedures were also less frequent in patients without SRFs (1.6% v 9.7%). CONCLUSION The adoption of SRFs as predictors of adverse surgical outcome was validated because their presence was associated with lower complete resection rate and greater risk of surgery-related complications. Additional studies aiming to better define the surgical approach to localized neuroblastoma are warranted.

BAC array CGH distinguishes mutually exclusive alterations that define clinicogenetic subtypes of gliomas

The pathological classification of gliomas constitutes a critical step of the clinical management of patients, yet it is frequently challenging. To assess the relationship between genetic abnormalities and clinicopathological characteristics, we have performed a genetic and clinical analysis of a series of gliomas. A total of 112 gliomas were analyzed by comparative genomic hybridization on a BAC array with a 1 megabase resolution. Altered regions were identified and correlation analysis enabled to retrieve significant associations and exclusions. Whole chromosomes (chrs) 1p and 19q losses with centromeric breakpoints and EGFR high level amplification were found to be mutually exclusive, permitting identification of 3 distinct, nonoverlapping groups of tumors with striking clinicopathological differences. Type A tumors with chrs 1p and 19q codeletion exhibited an oligodendroglial phenotype and a longer patient survival. Type B tumors were characterized by EGFR amplification. They harbored a WHO high grade of malignancy and a short patient survival. Finally, type C tumors displayed none of the previous patterns but the presence of chr 7 gain, chr 9p deletion and/or chr 10 loss. It included astrocytic tumors in patients younger than in type B and whose prognosis was highly dependent upon the number of alterations. A multivariate analysis based on a Cox model shows that age, WHO grade and genomic type provide complementary prognostic informations. Finally, our results highlight the potential of a whole‐genome analysis as an additional diagnostic in cases of unclear conventional genetic findings.

Standard-Risk Medulloblastoma Treated by Adjuvant Chemotherapy Followed by Reduced-Dose Craniospinal Radiation Therapy: A French Society of Pediatric Oncology Study

OBJECTIVE The primary objective of this study was to decrease the late effects of prophylactic radiation without reducing survival in standard-risk childhood medulloblastoma. PATIENTS AND METHODS Inclusion criteria were as follows: children between the ages of 3 and 18 years with total or subtotal tumor resection, no metastasis, and negative postoperative lumbar puncture CSF cytology. Two courses of eight drugs in 1 day followed by two courses of etoposide plus carboplatin (500 and 800 mg/m(2) per course, respectively) were administered after surgery. Radiation therapy had to begin 90 days after surgery. Delivered doses were 55 Gy to the posterior fossa and 25 Gy to the brain and spinal canal. RESULTS Between November 1991 and June 1998, 136 patients (median age, 8 years; median follow-up, 6.5 years) were included. The overall survival rate and 5-year recurrence-free survival rate were 73.8% +/- 7.6% and 64.8% +/- 8.1%, respectively. Radiologic review showed that 4% of patients were wrongly included. Review of radiotherapy technical files demonstrated a correlation between the presence of a major protocol deviation and treatment failure. The 5-year recurrence-free survival rate of patients included in this study with all optimal quality controls of histology, radiology, and radiotherapy was 71.8% +/- 10.5%. In terms of sequelae, 31% of patients required growth hormone replacement therapy and 25% required special schooling. CONCLUSION Reduced-dose craniospinal radiation therapy can be proposed in standard-risk medulloblastoma provided staging and radiation therapy are performed under optimal conditions.

Serum interleukin 6 and C-reactive protein levels correlate with resistance to IL-2 therapy and poor survival in melanoma patients.

Interleukin 6 and C-reactive protein (CRP) were determined prior to IL-2 therapy in sera from metastatic melanoma patients. Patients with elevated serum IL-6 (> 20 pg ml-1) and/or CRP (> 10 mg l-1) levels were associated with resistance to IL-2 therapy. A correlation between high serum IL-6 levels and a shorter median survival was also observed.