Prospective comparison of acute severe toxicities between smokers and non-smokers during radiotherapy for head and neck cancers.

BACKGROUND AND PURPOSE: The association between smoking and acute radiation toxicities of head and neck cancer (HNC) is currently unproven. The aim of the study was to compare the occurrence of acute severe toxicity between active and non-active smokers treated for HNC by radiotherapy. MATERIALS AND METHODS: A prospective monocentric cohort study included patients treated by (chemo)radiotherapy for HNC from January 2021 to January 2023. Smoking status was recorded. Patients underwent a medical exam weekly during the radiotherapy to report acute toxicities according to the Common Terminology Criteria for Adverse Effects system version 5.0. Primary endpoint was the occurrence of at least one grade ≥ 3 acute toxicity among mucositis, dysphagia and dermatitis. RESULTS: Among the 102 patients included, 27.4 % were active smokers, 58.8 % were former smokers and 13.7 % had never smoked. Regarding toxicity, 23.5 % (n = 24) patients experienced severe mucositis, 37.2 % (n = 38) severe dysphagia, 13.7 % (n = 14) severe dermatitis and 54.9 % (n = 56) experienced at least one of them. Occurrence of severe acute toxicity was not statistically associated with smoking during radiotherapy (64.3 % among active smokers versus 51.3 % among non-active smokers; p = 0.24). On multivariate analysis, concurrent chemotherapy (87.5 % vs 65.2 %; OR = 5.04 [1.64-15.52]; p = 0.004) and 2.12 Gy versus 2 Gy fractionation schedule (64.3 % vs 41.3 %; OR = 2.53 [1.09-5.90]; p = 0.03) were significantly associated with severe acute toxicity. CONCLUSION: This study did not find an association between smoking during radiotherapy for HNC and occurrence of severe acute toxicities.

Lack of referral for genetic counseling and testing in BRCA1/2 and Lynch syndromes: a nationwide study based on 240,134 consultations and 134,652 genetic tests.

Based on nationwide data from the French national cancer institute (INCa), we analyzed the evolution of cancer genetics consultations and testing over time, and the uptake of targeted tests in relatives of families with BRCA1/2 or MMR genes mutation. Genetic testing and consultations for familial high-risk individuals are exclusively funded and monitored by the INCa in France. All nationwide cancer genetics centers reported annually standardized parameters of activity from 2003 to 2011. The analysis included a total of 240,134 consultations and 134,652 genetic tests enabling to identify 32,494 mutation carriers. Referral for hereditary breast and ovarian cancer (HBOC) or colorectal cancer predisposition syndromes represented 59 % (141,639) and 23.2 % (55,698) consultations, respectively. From 2003 to 2011, we found a dramatic and steady increase of tests performed for BRCA1/2 (from 2,095 to 7,393 tests/year, P < 0.0001) but not for MMR genes (from 1,144 to 1,635/year, P = NS). The overall percentage of deleterious mutations identified in the probands tested was 13.8 and 20.9 % in HBOC and Lynch syndromes, respectively. Pooled analysis for BRCA1/2 and Lynch syndrome tests showed an inverse relationship between the percentage of mutation detected and the absolute number of tests performed over the time (overall Cochran-Armitage test for trend: P < 0.001). In families with BRCA1/2 or MMR identified mutations, there was an average number of 2.94 and 3.28 relatives performing targeted tests, respectively. This nationwide study shows a lack of referral and genetic testing in Lynch as compared to HBOC syndromes. Only a third of relatives of a proband with a predisposing mutation performed a targeted test. Enhanced information about benefit of genetic testing should be given to clinicians and patients for Lynch syndrome and relatives of a proband carrying an identified predisposing mutation.

Factors associated with Pap smear screening among French women visiting a general practitioner in the Rhône-Alpes region.

BACKGROUND: To help prevent cervical cancer, three yearly opportunistic Pap smear screening is recommended in France for women aged 25-65 years. Pap smear screening coverage varies with age and socioeconomic level. The aim of this cross-sectional study was to identify factors associated with a low uptake of Pap smear screening among women with no limited access to healthcare. METHODS: We analyzed data from women aged 25-65 living in the Rhône-Alpes region who completed a self-administered questionnaire given to them by general practitioners between June and August 2008. The questionnaire covered knowledge about cervical cancer and its prevention as well as the women's history of Pap smear screening and other health-related behaviors. The relationship between low uptake of Pap smear screening--defined as not having had the test within the past 3 years--and a range of possible contributing factors was investigated using logistic regression. RESULTS: Of 1186 women with an intact uterus who completed the questionnaire, 89.1% said they had had a Pap smear within the past 3 years. On multivariate analysis, the 10.9% who had not were significantly more likely to live alone (1.76 [1.13-2.74]), to have no children (2.17 [1.31-3.62]), to have never used contraception (5.35 [2.98-9.62]), to have less knowledge about Pap smear screening (3.40 [1.55-7.49]), and to be unvaccinated against hepatitis B (0.55 [0.35-0.87]). CONCLUSION: Despite high overall compliance with Pap smear screening recommendations among women who consulted general practitioners, several factors were significantly associated with a low uptake of the service. Considering these factors may help to refine messages aimed at cervical cancer prevention.

Prognostic value of Dicer expression in human breast cancers and association with the mesenchymal phenotype.

BACKGROUND: Dicer, a ribonuclease, is the key enzyme required for the biogenesis of microRNAs and small interfering RNAs and is essential for both mammalian development and cell differentiation. Recent evidence indicates that Dicer may also be involved in tumourigenesis. However, no studies have examined the clinical significance of Dicer at both the RNA and the protein levels in breast cancer. METHODS: In this study, the biological and prognostic value of Dicer expression was assessed in breast cancer cell lines, breast cancer progression cellular models, and in two well-characterised sets of breast carcinoma samples obtained from patients with long-term follow-up using tissue microarrays and quantitative reverse transcription-PCR. RESULTS: We have found that Dicer protein expression is significantly associated with hormone receptor status and cancer subtype in breast tumours (ER P=0.008; PR P=0.019; cancer subtype P=0.023, luminal A P=0.0174). Dicer mRNA expression appeared to have an independent prognostic impact in metastatic disease (hazard ratio=3.36, P=0.0032). In the breast cancer cell lines, lower Dicer expression was found in cells harbouring a mesenchymal phenotype and in metastatic bone derivatives of a breast cancer cell line. These findings suggest that the downregulation of Dicer expression may be related to the metastatic spread of tumours. CONCLUSION: Assessment of Dicer expression may facilitate prediction of distant metastases for patients suffering from breast cancer.

Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations.

BACKGROUND: We have previously demonstrated that breast cancers associated with inherited BRCA1 and BRCA2 gene mutations differ from each other in their histopathologic appearances and that each of these types differs from breast cancers in patients unselected for family history (i.e., sporadic cancers). We have now conducted a more detailed examination of cytologic and architectural features of these tumors. METHODS: Specimens of tumor tissue (5-microm-thick sections) were examined independently by two pathologists, who were unaware of the case or control subject status, for the presence of cell mitosis, lymphocytic infiltration, continuous pushing margins, and solid sheets of cancer cells; cell nuclei, cell nucleoli, cell necrosis, and cell borders were also evaluated. The resulting data were combined with previously available information on tumor type and tumor grade and further evaluated by multifactorial analysis. All statistical tests are two-sided. RESULTS: Cancers associated with BRCA1 mutations exhibited higher mitotic counts (P = .001), a greater proportion of the tumor with a continuous pushing margin (P<.0001), and more lymphocytic infiltration (P = .002) than sporadic (i.e., control) cancers. Cancers associated with BRCA2 mutations exhibited a higher score for tubule formation (fewer tubules) (P = .0002), a higher proportion of the tumor perimeter with a continuous pushing margin (P<.0001), and a lower mitotic count (P = .003) than control cancers. CONCLUSIONS: Our study has identified key features of the histologic phenotypes of breast cancers in carriers of mutant BRCA1 and BRCA2 genes. This information may improve the classification of breast cancers in individuals with a family history of the disease and may ultimately aid in the clinical management of patients.

Neurofibromatosis and early onset of cancers in hMLH1-deficient children.

Hereditary nonpolyposis colon cancer is a common hereditary disorder caused by the germ-line mutations of DNA mismatch repair (MMR) genes, especially hMLH1 and hMSH2. We report here the first identification of human compounds with a homozygous inactivation of a MMR gene. In a typical hereditary nonpolyposis colon cancer family, MMR-deficient children conceived from matings between heterozygotes for a hMLH1 deleterious mutation exhibited clinical features of de novo neurofibromatosis type I and early onset of extracolonic cancers. This observation demonstrates that MMR deficiency is compatible with human development but may lead to mutations during embryogenesis. On the basis of clinical symptoms observed in MMR-deficient children, we speculate that the neurofibromatosis type 1 gene is a preferential target for such alterations.

Clinical relevance of CD44 cell-surface expression and N-myc gene amplification in a multicentric analysis of 121 pediatric neuroblastomas.

PURPOSE: In contrast to other human tumors, a repression of the cell-surface glycoprotein CD44 on neuroblastoma is a marker of aggressiveness that usually correlates to N-myc amplification. We thus compared the prognostic value of both markers in the initial staging of 121 children treated for neuroblastoma in collaborative institutions. METHODS: Frozen samples were analyzed by a rapid and well-standardized technique of immunostaining with monoclonal antibodies (MoAbs) against epitopes in the CD44 constant region. RESULTS: In this retrospective series, CD44 was expressed on 102 specimens and strongly correlated with favorable tumor stages and histology, younger age, and normal N-myc copy numbers. In univariate analysis, CD44 expression and normal N-myc were the most powerful markers of favorable clinical outcome (P < 10(-6) and chi 2 = 65.40 and P < 10(-6) and chi 2 = 42.56, respectively), but analysis of CD44 affords significant prognostic discrimination in subgroups of patients with or without N-myc-amplified tumors. In the subgroup of stage IV neuroblastomas, CD44 was the only significant prognostic marker (P < .02, chi 2 = 5.76), whereas N-myc status was not discriminant. In multivariate analysis of five factors, ie, N-myc amplification, CD44 expression, age, tumor stage, and histology, the only independent prognostic factors of event-free survival were CD44 expression and tumor stage. CONCLUSION: The analysis of CD44 cell-surface expression must be recommended as an additional biologic marker in the initial staging of the disease.

Impact of megatherapy on survival after relapse from stage 4 neuroblastoma in patients over 1 year of age at diagnosis: a report from the European Group for Bone Marrow Transplantation.

PURPOSE: Relapse from stage 4 neuroblastoma usually carries a poor prognosis. A retrospective study using the European Bone Marrow Transplant (EBMT) Solid Tumor Registry was undertaken to define the role of megatherapy (MGT) in relapsed patients. PATIENTS AND METHODS: After relapse, 33 boys and 15 girls with previous stage 4 neuroblastoma received intensification by MGT followed by either autologous (n = 42) or allogeneic (n = 6) bone marrow rescue in 11 European institutions. The median age at diagnosis was 47 months (range, 14 to 134) and the median interval from diagnosis to relapse was 16 months (range, 4 to 94). Thirty patients had received only conventional-dose primary treatments (group A), whereas 18 patients had previously received intensification with MGT (group B). The median follow-up time of the total group is 95 months (range, 25 to 185). RESULTS: The actuarial overall survival rate at 2 years after MGT for relapse is 27% for group A and 0% for group B (P = .02). Three adverse, independent prognostic factors were confirmed by multivariate analysis using the Cox proportional hazards regression model: an interval of less than 12 months between diagnosis and relapse (P < .0001), nonresponding or untreated relapse (P = .0002), and previous MGT during primary treatments (P = .055). None of the other variables analyzed, such as sex, age, bone or bone marrow involvement at diagnosis or at relapse, and type of MGT at relapse, influenced outcome in this patient cohort. CONCLUSION: Responding patients who relapse more than 12 months from diagnosis who had not received previous MGT appear to benefit from consolidation MGT. Relapse patients who do not fulfill these criteria gain no advantage from this cost-intensive procedure and should be treated differently.

High-dose therapy and autologous bone marrow transplantation in partial remission after first-line induction therapy for diffuse non-Hodgkin's lymphoma.

Seventeen patients received high-dose therapy with autologous bone marrow transplantation (ABMT) when in partial response after induction therapy. There were 11 children and six adults between 3 and 57 years old. Twelve patients were determined to have high-grade lymphoma (ten Burkitt's and two lymphoblastic), and five had intermediate-grade diffuse lymphoma. Ten patients had surgically proven active disease in the abdomen, two had active disease in the bone marrow, and five persistent neurological symptoms. The time interval between diagnosis and ABMT was 2-10 months (median 4 months). Two patients died of progressive disease and two others died while in complete remission (CR) because of toxicity. Thirteen of 17 are still alive and disease free with a median observation time of 2 years. Morbidity was high with 6/17 life threatening reversible complications but overall survival is 75% at 24 months in a group of patients clearly defined as having a very bad prognosis in previous studies.

Response rate accuracy in oncology trials: reasons for interobserver variability. Groupe Français d'Immunothérapie of the Fédération Nationale des Centres de Lutte Contre le Cancer.

PURPOSE: We evaluated the impact of an evaluation committee (EC) on patients' overall response status in a large multicenter trial in oncology. We identified reasons for disagreements between investigators and the EC. MATERIALS AND METHODS: The Cancer Renal Cytokine (CRECY) study was a French multicenter trial that tested cytokine therapy in 489 patients with metastatic renal cell carcinoma. Objective response (OR) evaluation included medical imaging and was studied according to international guidelines. A blinded peer review of all responders and litigious cases was performed by an EC. RESULTS: Major disagreements occurred in 40% and minor disagreements in 10.5% of the reviewed files. The number of significant tumor responses was reduced by 23.2% after review by the EC. Reasons for disagreements included errors in tumor measurements, errors in selection of measurable targets, intercurrent diseases, and radiologic technical problems. These reasons for disagreements are analyzed and discussed. CONCLUSION: We conclude that all therapeutic trial results should be reviewed by peer analysis of all presumed responders by an EC. International guidelines for response evaluation should be updated by including more reliable methods of measurements and definition of minimal imaging procedures.

Early lymphopenia after cytotoxic chemotherapy as a risk factor for febrile neutropenia.

PURPOSE: Febrile grade four (ie, < or = 500/microL) neutropenia (FN) is a frequent life-threatening complication of cancer chemotherapy. Although its incidence correlates to the dose of chemotherapy, FN may occur after almost any cytotoxic regimen. At present, there is no predictive method to identify patients who will experience FN. PATIENTS AND METHODS: Univariate and multivariate analyses of risk factors for FN were performed on a retrospective cohort of 112 consecutive patients treated with various chemotherapy regimens. Two independent risk factors were identified by the logistic regression and used to create a risk model for FN. The validity of the model was tested in three distinct groups of patients: two prospective groups of patients treated in two institutions (Centre Léon Berard [CLB] and Institut G. Roussy [IGR]) and the group of patients with intermediate- or high-grade non-Hodgkin's lymphoma (NHL) treated with the doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) regimen between 1988 and 1992 at CLB. RESULTS: Within the retrospective group, 23 of 47 (49%) patients with lymphocyte counts < or = 700/microL at day 5 after chemotherapy experienced FN compared with seven of 65 (11%) of other patients (P = .00002). The type of chemotherapy (high dose v others) was also significantly correlated to FN (48% v 11%, P = .0003). Age, performance status, the number of previous chemotherapy cycles, or polymorphonuclear leukocyte (PMN) counts, were not significantly correlated to the incidence of FN in univariate analyses. Two independent risk factors were identified in the logistic regression: day 5 lymphocyte counts (beta = 1.97 +/- 0.53) and the type of chemotherapy regimen (beta = 1.91 +/- 0.53). The calculated probability to experience FN in patients with none, one, and both of these risk factors was 4.3%, 24.0%, and 68.8%, respectively. The validity of this model was tested in the three groups of patients used as validation samples. The observed incidences of FN in the above defined risk subgroups were 3%, 19%, and 67%, respectively, within the CLB prospective series and 6%, 19%, and 75% within the IGR prospective series. In the ACVBP group, the incidence of FN was 33% and 72%, respectively, in patients from the intermediate- and high-risk groups. In the two prospective groups and in the ACVBP series, the observed numbers of FN in the different risk groups did not differ significantly from those calculated by the model (P = .89, P = .86, and P = .72 for these three groups, respectively). CONCLUSION: Day 5 lymphocyte counts < or = 700/microL and the type of chemotherapy regimen enable oncologists to define subgroups of patients treated with chemotherapy as those with a high intermediate, and low risk of FN. These criteria could be used to select subjects in whom prophylactic measures for FN, in particular hematopoietic growth factors, should be proposed.

Cytokines in metastatic renal cell carcinoma: is it useful to switch to interleukin-2 or interferon after failure of a first treatment? Groupe Français d'Immunothérape.

PURPOSE: Interleukin-2 (IL-2) and interferon alfa-2a (IFNalpha2a) have some antitumor activity in metastatic renal cell carcinoma either alone or in combination. To determine whether either of these cytokines might be efficient after failure of the other, we analyzed a series of patients treated with either IL-2 or IFNalpha2a as second-line treatment after failure of the other cytokine. PATIENTS AND METHODS: We recently performed a large multicenter study to determine the respective efficacy of IL-2, IFNalpha2a, or combined treatment in renal cell carcinoma. In this study, patients who progressed on the single-arm treatment could receive the other cytokine in a cross-over trial. IL-2 was administered as a continuous intravenous infusion for 5 days (18 x 10(6) IU/m(2)/d), and IFNalpha2a was administered three times weekly at 18 x 10(6) IU. RESULTS: A total of 113 patients with progressive disease after first-line treatment received either IFNalpha2a (n = 48) or IL-2 (n = 65). Toxicity during second-line treatment was similar to that observed during first-line treatment. Only four partial responses were observed (one with IFNalpha2a and three with IL-2). All partial responders had a performance status of 0 and lung metastases. Moreover, three of these four patients had stable disease or had responded to first-line therapy. Only one patient with confirmed disease progression after receiving IL-2 subsequently responded to IFNalpha2a. CONCLUSION: Cross-over after failure of IL-2 or IFNalpha2a is poorly efficient in metastatic renal cell carcinoma, especially when progression has been clearly documented.

LMCE3 treatment strategy: results in 99 consecutively diagnosed stage 4 neuroblastomas in children older than 1 year at diagnosis.

PURPOSE: To tailor postinduction therapy for stage 4 neuroblastoma in children who are older than 1 year at diagnosis according to status after induction. PATIENTS AND METHODS: From March 1987 to December 1992, 99 patients who were consecutively admitted were included in the Lyon-Marseille-Curie East of France (LMCE)3 strategy. After induction with the French Society of Pediatric Oncology NB87 regimen and surgery, patients who were in complete remission immediately proceeded to consolidation therapy with vincristine, melphalan, and fractionated total-body irradiation (VMT). All other patients underwent a postinduction strategy before VMT, either an additional megatherapy regimen or further chemotherapy with etoposide/carboplatin. RESULTS: The progression-free survival (PFS) is 29% at 7 years from diagnosis, which compares favorably with that of a similar cohort of 72 patients previously reported by our group (LMCE1; PFS of 20% at 5 years and 8% at 14 years, P =.004). In the multivariate analysis, only age younger than 3 years at diagnosis (P =.0085) and achievement of complete or very good partial remission after NB87 and surgery (P =.00024) remained significant. The PFS of the 87 patients who were included in the postinduction strategy was significantly better than that of the comparable 62 patients on the LMCE1 study (32% v 11% at 7 years; P =.005). CONCLUSION: The progressive improvements in the LMCE results over the last 10 years suggest that improvements in supportive care measures and increases in each component of this strategy (induction, postinduction, consolidation) may all contribute to increased survival rates.

Multivariate analysis of risk factors in stage 4 neuroblastoma patients over the age of one year treated with megatherapy and stem-cell transplantation: a report from the European Bone Marrow Transplantation Solid Tumor Registry.

PURPOSE: The European Bone Marrow Transplantation (EBMT) Solid Tumor Registry (STR) contains detailed information on children with advanced neuroblastoma who, after standard-dose induction chemotherapy and surgery, received myeloablative megatherapy (MGT) followed by stem-cell transplantation (SCT). This data base was analyzed to identify factors that predict event-free survival (EFS). PATIENTS AND METHODS: Eligibility criteria were stage IV neuroblastoma, age over 1 year at diagnosis, and no relapse before MGT/SCT. Between February 1978 and July 1992, 549 patients were registered by 36 European transplant centers. The median age at diagnosis was 36 months (range, 13 to 216 months) and the male-female ratio was 1:45. Before MGT, 157 patients were in complete remission (CR), 156 in very good partial remission (VGPR), and 208 in partial remission (PR), whereas 24 had had only a minor response (MR). One hundred ten of 546 patients had undergone two successive MGT procedures. The median observation time was 60 months (range, 12 to 187 months). RESULTS: Actuarial EFS is 26% at 5 years. Multivariate analysis by the Cox proportional hazards regression model included 529 patients with complete data sets. After adjustment for treatment duration before MGT and double MGT procedures, two adverse, independent risk factors that influenced EFS were identified: (1) persisting skeletal lesions before MGT as defined by technetium (99TC) scans and/or meta-iodobenzylguanidine (mIBG) scans (P = .004) and (2) persisting bone marrow involvement before MGT (P = .03). CONCLUSION: After induction treatment, persisting skeletal disease as defined above and persisting bone marrow involvement may be predictive of a particularly poor outcome. Physicians may consider this an additional important tool to decide the patient's management.

[HNPCC syndrome (hereditary non polyposis colon cancer): identification and management]. / Le syndrome HNPCC (hereditary non polyposis colon cancer): identification et prise en charge.

BACKGROUND: The hereditary non-polyposis colon cancer (HNPCC) syndrome is an inherited condition defined by clinical and genealogical information, known as Amsterdam criteria. In about 70% of cases, HNPCC syndrome is caused by germline mutations in MMR genes, leading to microsatellite instability of tumor DNA (MSI phenotype). Patients affected by the disease are at high risk for colorectal and endometrial carcinomas, but also for other organs tumors. HNPCC syndrome is responsible for 5% of colorectal cancers. MAJOR ASPECTS: The lack of sensitivity of Amsterdam criteria in recognizing patients carrying a MMR germline mutation led to an enlargement of these criteria for the recruitment of possible HNPCC patients, and to a two-steps strategy, asking first for a tumor characterization according to MSI phenotype, especially in case of early-onset sporadic cases. FURTHER DEVELOPMENTS: The identification of germline MMR mutations has no major consequence on the cancer treatments, but influences markedly the long-term follow-up and the management of at-risk relatives. Gene carriers will enter a follow-up program regarding their colorectal and endometrial cancer risks; other organs being at low lifetime risk, no specific surveillance will be proposed.

Indication and limits of megatherapy and bone marrow transplantation in high-risk neuroblastoma: a single centre analysis of prognostic factors.

76 patients with high risk neuroblastoma were treated with one (41 patients) or two consecutive courses (35 patients) of megatherapy. Autologous bone marrow transplantation was scheduled after each megatherapy. Univariate analysis confirmed two prognostic factors in this heterogeneous study population: no bone lesions before megatherapy and age at diagnosis of less than 2 years with 5-year progression-free survival rates of 51% (P < 0.0007) and 53% (P < 0.025), respectively. Both factors were shown to be of independent prognostic significance using the Cox proportional hazard model. Identification of prognostic factors should help to define the interest and limits of megatherapy. We consider that elective megatherapy followed by innovative treatments appears justified in patients with persisting bone disease. In contrast, megatherapy has to be re-evaluated for patients showing a more favourable response pattern and/or young age, ideally in a randomised, prospective trial.

Metastatic medulloblastoma: the experience of the French Cooperative M7 Group.

A retrospective analysis was performed to determine the outcome of children with metastatic medulloblastoma given a standardised treatment programme. Of 68 consecutive patients treated in the French M7 protocol for medulloblastoma, 23 presented with metastatic disease. They were uniformly treated with surgery, and the same protocol of chemotherapy and craniospinal radiotherapy. The 7-year relapse-free survival rate is 43% for metastatic patients compared to 68% for patients with localised disease. Survival did not correlate with age, sex, location of metastases, extent of initial surgery and the dose of radiation therapy on the posterior fossa. Survival did correlate with the dose to the cranial field with a threshold dose of 30 Gy. Patients with metastatic disease have a worse prognosis and require more aggressive therapies at initial presentation. The prognostic impact of the different sites of metastatic disease requires further evaluation in cooperative studies.

Evaluation of CD44 prognostic value in neuroblastoma: comparison with the other prognostic factors.

CD44 gene products are potential markers of aggressiveness in different tumour models, a result which prompted us to study clinical neuroblastoma (NB) specimens. CD44 expression was determined by immunostaining of 52 tumour samples from newly diagnosed NB with a monoclonal antibody (J173) directed against an epitope common to all CD44 isoforms. CD44 immunoreactivity was detected in 37 of the tumours (71%). CD44 was expressed in all 22 NBs with favourable prognoses (stages 1, 2 or 4S), but only 50% (15/30) of advanced NB (stages 3 and 4) (P < 10(-4)), suggesting that the absence, rather than the overexpression, of CD44 is a signal of tumour aggressiveness. The cumulative progression-free survival was significantly longer in patients with CD44 positive tumours compared with patients with CD44 negative tumours (P < 10(-5)). More importantly, progression-free survival was also significantly higher in CD44 positive patients within the high-risk group (P < 0.01). In univariate analysis, we tested the prognostic value of tumour expression of CD44 in comparison with tumour stage, age, tumour histology, and presence or absence of amplification of the MYCN protooncogene. All five measures had significant prognostic value. The expression of CD44 and the absence of MYCN amplification were the most powerful predictors of a favourable outcome. In a multivariate analysis of these measures, CD44 expression and tumour stage were the only independent prognostic factors for the prediction of patient survival. NB is the first clinical model described in which tumour aggressiveness correlates with repression rather than stimulation of CD44 expression. We recommend the use of CD44 as an additional biological marker in the initial staging of NB.

Clinical relevance of CD44 cell surface expression and MYCN gene amplification in neuroblastoma.

This multicentric analysis of tumours obtained from 140 patients with neuroblastoma confirms that the lack of CD44 expression is a highly significant factor of poor prognosis and, as previously published in multivariate analysis of the four factors, i.e. MYCN amplification, CD44 expression, age and tumour stage, CD44 expression and tumour stage were the only independent prognostic factors of event-free survival (Combaret et al., J Clin Oncol 1996, 14, 25-34). Furthermore, CD44 analysis affords significant prognostic discrimination in subgroups of patients with or without MYCN amplified tumours, both in low-stage neuroblastomas and high-grade neuroblastomas. In the subgroup of patients with low-stage neuroblastoma and the stage 4 subgroup, CD44 was the only independent prognostic factor for the prediction of event-free survival in a multivariate analysis. In conclusion, CD44 is one of the most powerful factors for predicting clinical outcome in neuroblastoma at the time of initial staging.

1070 myeloablative megatherapy procedures followed by stem cell rescue for neuroblastoma: 17 years of European experience and conclusions. European Group for Blood and Marrow Transplant Registry Solid Tumour Working Party.

1070 myeloablative procedures followed by stem cell rescue for neuroblastoma are reviewed. These 1070 procedures are part of the European Group for Blood and Marrow Transplant (EBMTG) registry from the last 17 years (in 4536 patients). In 1070 neuroblastoma patients, survival at 2 years was 49%, at 5 years, 33% and relapses were observed as late as 7 years post-BMT (bone marrow transplant). However, 5-year survivors after megatherapy with BMT for stage 4 disease do have an 80% chance of becoming a long-term survivor. When BMT had been used in first complete response (CR1) no salvage was possible, whereas 15% survivors may be seen if BMT is used for the first time at relapse. Infants with stage 4 neuroblastoma had a 17% toxic death rate and indication in this group is exceptional and not recommended. In a matched cohort (17 allogeneic and 34 autologous), autologous stem cell rescue (SCR) was shown to be at least equal to allogeneic SCR. Multivariate analysis of clinical prognostic factors in children with stage 4 disease over 1 year showed that event-free survival was mainly influenced by two adverse factors before the megatherapy procedure: persisting skeleton lesions (99Tc and/or mIBG scan positive) as well as persisting bone marrow (BM) involvement.