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Une categorie de crimes contre les enfants semble particulierement mediatisee, celle des deces des premieres vingt-quatre heures, perpetres en general par la mere et maintenant designes sous le terme de neonaticides. L’etude approfondie de 34 dossiers judiciaires de neonaticides et de la presse concernant ce sujet permet d’esquisser des pistes sur le statut actuel de ce crime tout a fait particulier, bien qu’il ne soit plus penalement specifie. Le travail de la justice face a ces morts violentes est decrypte au travers du contenu des dossiers, proces-verbaux, expertises, actes de procedure. Les donnees recueillies, de nature quantitative et qualitative, permettent de comparer les types de procedure judiciaire, les auteurs mis en cause et les peines qui leur sont infligees. Comme dans les autres pays ou une incrimination specifique n’est pas prevue par le code penal, les decisions varient considerablement, du classement sans suite, non-lieu ou acquittement, jusqu’a quinze annees de reclusion criminelle. L’article analyse les elements qui ont pu les influencer, parmi les autopsies, les expertises psychiatriques, les aveux de la mere, ou sa capacite a exprimer une culpabilite.

Background: However hormone receptor–positive, early-stage breast cancer is a disease with a long natural history and improved survival with 5-year adjuvant endocrine treatments. Yet late recurrence remains an important issue in adjuvant therapy. Predictors of late recurrence are not yet well characterized. Method: A total of 252 breast primary tumors were selected at the Netherlands Cancer Institute from retrospective series of ER+, HER2− breast cancer patients with a follow-up of at least 10 years. Gene expression analysis was performed using Agilent 4×44K microarrays. In order to identify genes associated to late survival differences, we used the survdiff function implemented in the R package survival and we set the parameter rho to −1 to give weight to the later part of the survival curve. The survdiff function was applied to each probe individually for DMFS time considering the probe as a covariate dichotomized into 2 groups (above and below the median expression across all samples). The parameter “strata” was used to stratify the 140 patients based on additional clinico-pathological parameters (Grade, Diameter, Lymph node status and MammaPrint), in order to find genes that add prognostic value to those parameters already known. This approach uses the distant-metastasis free survival (DMFS) time as a continuous variable. Results: After univariate analysis, MammaPrint, diameter, lymph node status and grade were significantly associated to late DMFS differences (Chi-square test p-values equal to 0.016, 0.004, In order to independently validate the prognostic power of these two genes, we tested their performance in the validation set of treated patients (n = 112) and in three publicly available datasets. In all datasets, the CH25H gene confirmed to be significantly associated to metastasis-free survival time in all tested series. Conclusions: These results might indicate that CH25H is an independent marker of late metastatic relapses. CH25H catalyzes the formation of 25-hydroxycholesterol from cholesterol, leading to repress cholesterol biosynthetic enzymes. In the last years, it is emerging that lipid metabolism plays an important role in breast cancer development and progression. Taken together, these findings make the CH25H gene a potential target for late metastasis control in breast cancer. These results warrant further prospective investigation and functional characterization of CH25H in this setting. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-09-05.

Modern challenges in oncology, in particular the advent of targeted therapies and personalized medicine, highlight the need for developing a consortium of comprehensive cancer centers to run clinical trials in rare, molecularly-defined populations, and implement high-throughput technologies for daily practice.

International audience; OBJECTIVES: To measure the extent and analyse the mechanisms of underestimation of neonaticides (infanticides in the first 24 h of life) and to identify characteristics of neonaticidal mothers. DESIGN: A retrospective study was carried out in 26 courts in three French regions covering 34.6% of all births in France. Included in the study were all cases of infants dying on their day of birth during a 5-year period (1996-2000) that were submitted to courts by the state prosecutor. Complete court case data cover 1996-2007. WHO-International Classification of Diseases cause of death codes assigned in the mortality statistics were compared to causes assigned by the courts. Analysis was carried out on the psychiatric assessments of the mothers. RESULTS: 27 cases of neonaticides were analysed. 17 mothers were identified. We observed sizeable underestimation of neonaticides in official mortality statistics (0.39 per 100 000 births vs 2.1 in our study). Mothers' median age was 26 years; one third had at least three children. More than half lived with the child's father. Two thirds were employed and did not differ significantly from women in the general population regarding occupation. These women appeared to have low self-esteem, be immature and dependent, but did not have frank mental illness. There was no true case of 'denial of pregnancy'. Contraception was not used. CONCLUSION: This study has implications for prevention in terms of contraception and appropriate targeting of vulnerable women. It encourages the development of case-control studies on maternal risk factors within the framework of the French birth cohort currently being established.

Resume Une enquete, concue pour evaluer la satisfaction des patients traites dans un Centre de lutte contre le cancer (CLCC) quant a l'annonce du diagnostic de leur maladie et de son traitement et optimiser les pratiques actuelles, a ete conduite par le groupe des CLCC. Methodes Mille six cent six patients traites dans un CLCC ont participe a une enquete telephonique. Tous les patients en prise en charge initiale (i.e. hors rechute) dans chaque CLCC participant ont ete inclus pendant trois semaines. Ils ont ete interroges sur leur satisfaction quant a l'annonce du diagnostic et du traitement de leur maladie. Certains facteurs individuels, determinants potentiels de la satisfaction, ont ete pris en compte. L'etude a considere les resultats en termes d'excellence, ne considerant que les taux de patients tres satisfaits. Resultats La satisfaction globale (patients tres satisfaits) est de 77 % quant a la prise en charge dans le centre et de 63 % quant a la consultation initiale d'annonce (diagnostic et/ou proposition du traitement). Un modele etabli par analyse de regression ( partial least squares [PLS]) a identifie quatre dimensions principales et leurs contributions relatives a la satisfaction du patient : la relation du patient avec son medecin (64 %), la nature des informations transmises (14 % ; dimension fortement influencee par l'information sur le type, la duree et l'organisation pratique du traitement prevu), l'agenda (14 % ; dimension fortement influencee par le delai d'attente lors de la consultation d'annonce), l'accompagnement (8 % ; dimension influencee a part egale par l'information sur le soutien possible de la famille proche et le role des associations de patients ou groupes d'entraide). En outre, 90 % des patients etaient satisfaits du niveau de leur implication dans les discussions concernant leur prise en charge. Discussion Les patients atteints de cancer pris en charge (i.e. hors rechutes) dans les CLCC sont globalement tres satisfaits. Pour autant, des actions d'amelioration sont utiles ; le modele d'evaluation de la satisfaction elabore permet de comprendre les differentes composantes expliquant la satisfaction et d'analyser les resultats des centres de maniere comparative. Il a ete concu comme un outil d'evaluation permettant le benchmarking des composantes de la satisfaction afin d'ameliorer les pratiques et resultats dans ce domaine.

Exosomes are nanovesicles originating from late endosomal compartments and secreted by most living cells in ex vivo cell culture conditions. The interest in exosomes was rekindled when B-cell and dendritic cell-derived exosomes were shown to mediate MHC-dependent immune responses. Despite limited understanding of exosome biogenesis and physiological relevance, accumulating evidence points to their bioactivity culminating in clinical applications in cancer. This review focuses on the preclinical studies exploiting the immunogenicity of dendritic cell-derived exosomes (Dex) and will elaborate on the past and future vaccination trials conducted using Dex strategy in melanoma and non-small cell lung cancer patients. Cancer Res; 70(4); 1281–5

Seventy-six North African patients (most from Algeria) affected with nasopharyngeal carcinoma (NPC) have been studied for their HLA-A, -B, and -DR phenotypes and compared with a control North African population. Antigens HLA-A3, HLA-B5 and HLA-Bw15 were found more frequently in the NPC group than in the control group (30.3% vs 17.6%, 38.2% vs 24.4% and 9.2% vs 0.8%, respectively). HLA-Aw33, HLA-B14 and HLA-DR4 were less frequent in the patients than in the controls (3.9% vs 16.8%, 1.3% vs 16% and 13.2% vs 29.1%, respectively). After correction for the number of specificities tested, these differences were not statistically significant. They were, however, more striking when compared to normal Kabyles (Algerian Berbers), a major ethnical population in Algeria, with lower incidences of the HLA-B5 antigen and of the HLA-Aw33-B14 haplotype. This could suggest, in North Africa, either the existence of MHC-linked genes of resistance or susceptibility to NPC, in Berbers especially, or a preferential occurrence of NPC in non-Berbers. Antibody titers against the Epstein-Barr virus (EBV) associated early antigen (EA) and viral capsid antigen (VCA) have been measured. No correlation was observed between HLA phenotypes and the anti-EBV serological response of the patients.

There are important gaps in the health status of citizens across Europe, as measured by life expectancy, mortality or morbidity data (Report for the European Commission on the health status of the European Union, 2003). Among the main determinants of the major causes of mortality and morbidity, stated in this report, stands recurrently access to quality healthcare. There is a fundamental need to define quality indicators and set minimal levels of performance quality criteria for healthcare. There is a need to integrate research into healthcare and to provide patients with equity of access to such high quality care. Oncology is a speciality particularly suited to experimenting a first application of accreditation at European level. The Organisation of European Cancer Institutes is a growing network of cancer Centres in Europe. The focus of the OECI is to work with professionals and organisations with regard to prevention, care, research, development, patient's role and education. In order to fulfil its mission, the OECI initiated in 2002 an accreditation project with three objectives: • to develop a comprehensive accreditation system for oncology care, taking into account prevention, care, research, education and networking. • to set an updated database of cancer centres in Europe, with exhaustive information on their resources and activities (in care, research, education and management) • to develop a global labelling tool dedicated to comprehensive cancer centres in Europe, designating the various types of cancer structures, and the comprehensive cancer centres of reference and Excellence. An accreditation tool has been established, defining standards and criteria for prevention, care, research, education and follow-up activities. A quantitative database of cancer centres is integrated in the tool, with a questionnaire, that provides an overall view of the oncological landscape in OECI cancer centres in Europe. Data on infrastructures, resources and activities have been collected. This OECI accreditation tool will be launched in autumn 2008 for all cancer centres in Europe. It serves as a basis for the development of the labelling tool for cancer structures in Europe, with a focus on Comprehensiveness and Excellence labels. Quality assessment and improvement is a critical need in Europe and is addressed by the OECI for cancer care in Europe. Accreditation is a well accepted process and is feasible. Standards and criteria as well as an accreditation tool have been developed. The OECI questionnaire gives an accurate vision of cancer institutions throughout Europe, helping assessing the needs and providing standards. The accreditation project is a long-term complete and voluntary process with external and internal added value, an active process of sharing information and experience that should help the whole cancer community reach comprehensiveness and excellence.

Comprehensive Cancer Centres (CCCs) serve as critical drivers for improving cancer survival. In Europe, we have developed an Excellence Designation System (EDS) consisting of criteria to assess “excellence” of CCCs in translational research (bench to bedside and back), with the expectation that many European CCCs will aspire to this status., Highlights Assessing excellence of translational research is essential to improving its performance so that the time lag in bringing results of research to practice will be reduced.We have developed a set of excellence criteria that can help identify and designate Comprehensive Cancer Centres that perform excellent translational research. Examples of criteria are: organizational strategy; the depth of research programmes from bench to bedside and back; team science; commitment to collaboration; shared resources and critical patient mass.Assessment process requires a flexible peer‐review approach because excellent translational research can be found also in areas that are outside the scope of the assessment and/or the “typical” definition of translational research. The assessment framework was piloted in several cancer centres in Europe and is ready to be implemented.

International audience; Accoucher sans donner naissance : les néonaticides, des histoires tues Résumé A partir de l'étude de dossiers judiciaires de mères impliquées dans des néonaticides, soit des meurtres d'enfant dans leurs premières vingt-quatre de vie, nous démontrons en quoi naître implique et nécessite plus qu'un accouchement physiologique. En effet dans ces affaires, s'il y a bien grossesse, parfois même désirée et s'il y a bien accouchement au sens strictement physiologique du terme, la naissance d'un enfant n'advient pas. Faute d'une inscription symbolique au sein de sa famille, faute d'un accueil médiatisé, cet enfant n'aura-au mieux-qu'une reconnaissance juridique. Il semble que l'isolement, ressenti par des mères qui ont peur de leurs proches et gardent leur grossesse secrète, soit déterminant. Ainsi, naître est un processus éminent social qui nécessite que la mère ne se vive pas seule et puisse considérer les autres comme une adresse, un soutien, un recours.

International audience

Purpose: The aim of this multicenter trial was to evaluate the role of ovarian suppression in patients with early breast cancer previously treated with local surgery and adjuvant chemotherapy. Patients and methods: Nine hundred and twenty-six premenopausal patients with completely resected breast cancer and either axillary node involvement or histological grade 2 or 3 tumors were randomized after surgery to adjuvant chemotherapy alone (control arm) or adjuvant chemotherapy plus ovarian suppression (ovarian suppression arm). Ovarian suppression was obtained by either radiation-induced ovarian ablation or triptorelin for 3 years. The analyses were performed with Cox models stratified by center. Results: Median follow-up was 9.5 years. Mean age was 43 years. Ninety per cent of patients had histologically proven positive axillary nodes, 63% positive hormonal receptors and 77% had received an anthracycline-based chemotherapy regimen. Ovarian suppression was by radiationinduced ovarian ablation (45% of patients) or with triptorelin (48%). At the time of randomization, all patients had regular menses or their follicle-stimulating hormone and estradiol levels indicated a premenopausal status. The 10-year disease-free survival rates were 49% [95% confidence interval (CI) 44% to 54%] in both arms (P = 0.51). The 10-year overall survival rates were 66% (95% CI 61% to 70%) for the ovarian suppression arm and 68% (95% CI 63% to 73%) for the control arm (P = 0.19). There were no variations in the treatment effect according to age, hormonal receptor status or ovarian suppression modality. However, in patients

The proapoptotic protein apoptosis protein activating factor-1 (Apaf-1), which is normally located in the cytoplasm, can translocate to the nucleus before non-small cell lung carcinoma (NSCLC) cells manifest signs of apoptosis such as mitochondrial damage, caspase activation, or chromatin condensation. This may indicate a stage of imminent apoptosis. Importantly, we found that 24% (15 of 62) of resected stage I NSCLC (T1N0M0 or T2N0M0), manifested a marked nuclear localization of Apaf-1 (Apaf-1Nuc), as compared with the mostly cytoplasmic localization of Apaf-1 found in the remaining tumors (Apaf-1Cyt). After a median follow-up of 6.31 years, the actuarial 5-year overall survival rates were 89% (56–98%) in the Apaf-1Nuc group and 54% (36–71%) in the Apaf-1Cyt group (P = 0.039). No correlation between the subcellular localization of Apaf-1 and that of p53 and Hsp70 could be established. Thus, the subcellular location of Apaf-1 (but not that of p53 or Hsp70) constitutes an accurate prognostic factor for overall survival in NSCLC.

Contains fulltext : 58490.pdf (Publisher’s version ) (Closed access) Ideal vaccines should be stable, safe, molecularly defined, and out-of-shelf reagents efficient at triggering effector and memory Ag-specific T cell-based immune responses. Dendritic cell-derived exosomes could be considered as novel peptide-based vaccines because exosomes harbor a discrete set of proteins, bear functional MHC class I and II molecules that can be loaded with synthetic peptides of choice, and are stable reagents that were safely used in pioneering phase I studies. However, we showed in part I that exosomes are efficient to promote primary MHC class I-restricted effector CD8(+) T cell responses only when transferred onto mature DC in vivo. In this work, we bring evidence that among the clinically available reagents, Toll-like receptor 3 and 9 ligands are elective adjuvants capable of triggering efficient MHC-restricted CD8(+) T cell responses when combined to exosomes. Exosome immunogenicity across species allowed to verify the efficacy of good manufactory procedures-manufactured human exosomes admixed with CpG oligonucleotides in prophylactic and therapeutic settings of melanoma in HLA-A2 transgenic mice. CpG adjuvants appear to be ideal adjuvants for exosome-based cancer vaccines.

Background: A randomised trial was conducted comparing wide lumpectomy and breast irradiation with modified radical mastectomy. As the follow-up was long (mean duration 22 years), we analysed the variation in the effect of treatment over time. Patients and methods: The trial included 179 patients with a breast cancer measuring ≤2 cm at macroscopic examination. Eighty-eight patients had breast-conserving surgery and radiotherapy, and 91 underwent mastectomy. All patients had axillary dissection. The analyses were based on Cox models with time-dependent treatment effects. Results: The effect of treatment on death or metastasis did not vary with time. The risk of local recurrence was lower during the first 5 years for the breast-conserving surgery group as compared with the mastectomy group, but higher after 5 years (P = 10 –4 for a different treatment effect over time). Similar results were found in a database including 1847 patients with small breast tumours at diagnosis. In this analysis, late breast recurrences were also more frequent in the breast-conserving surgery group and this treatment effect was greater among younger patients (≤40 years at the time of diagnosis). Conclusions: Late breast recurrences were more frequently observed in younger patients treated with breastconserving treatment compared with those submitted to mastectomy. These results require confirmation in other randomised studies so that younger patients with early breast cancer can receive adequate counselling and so that a more stringent long-term follow-up policy can be adopted when breast-conserving treatment is

Purpose: To describe the pathologic characteristics and prognostic factors of primary breast sarcomas (PBSs). Patients and Methods: We reviewed the clinical records and pathologic slides of 83 women with PBS treated in our institution between 1954 and 1991, with a median follow-up of 7.8 years. The majority of patients had undergone surgical treatment. Results: The main histologic type was malignant fibrohistiocytoma (n = 57). For the whole population, the 10-year overall survival (OS) and disease-free survival (DFS) rates were 62% and 50%, respectively. For Fédération Nationale des Centres de Lutte Contre le Cancer grade 1, 2, and 3 tumors, the 10-year OS and DFS rates were 82% and 61%, 62% and 51%, and 36% and 25%, respectively (P = .00007 and .004, respectively). For tumors measuring less than 5 cm, 5 to 10 cm, and more than 10 cm, the 10-year OS and DFS rates were 76% and 66%, 68% and 55%, and 28% and 15%, respectively (P = .002 and .009, respectively). In the multivariate analysis, the tumor size and histologic grade were correlated with the 10-year DFS rate (P = .04 and .01, respectively), but only the histologic grade was correlated with OS (P = .01). Angiosarcoma was the only histologic type significantly associated with a poorer outcome in the multivariate analysis. Conclusion: PBSs have the same clinical history and prognostic factors as sarcomas arising at other sites. Therefore, it is legitimate to use a similar treatment strategy for PBS as for other sarcomas.

Summary Background Exosomes derived from tumours are small vesicles released in vitro by tumour cell lines in culture supematants. To assess the role of these exosomes in vivo, we examined malignant effusions for their presence. We also investigated whether these exosomes could induce production of tumour-specific T cells when pulsed with dendritic cells. Methods We isolated exosomes by ultracentrifugation on sucrose and D 2 O gradients of 11 malignant effusions. We characterised exosomes with Western blot analyses, immunoelectron microscopy, and in-vitro stimulations of autologous T lymphocytes. Findings Malignant effusions accumulate high numbers of membrane vesicles that have a mean diameter of 80 nm (SD 30). These vesicles have antigen-presenting molecules (MHC class-I heat-shock proteins), tetraspanins (CD81), and tumour antigens (Her2/Neu, Mart1, TRP, gp100). These criteria, including their morphological characteristics, indicate the similarities between these vesicles and exosomes. Exosomes from patients with melanoma deliver Mart1 tumour antigens to dendritic cells derived from monocytes (MD-DCs) for cross presentation to clones of cytotoxic T lymphocytes specific to Mart1. In seven of nine patients with cancer, lymphocytes specific to the tumour could be efficiently expanded from peripheral blood cells by pulsing autologous MD-DCs with autologous ascitis exosomes. In one patient tested, we successfully expanded a restricted T-cell repertoire, which could not be recovered carcinomatosis nodules. Interpretation Exosomes derived from tumours accumulate in ascites from patients with cancer. Ascitis exosomes are a natural and new source of tumour-rejection antigens, opening up new avenues for immunisation against cancers.

Cancer treatment is slowly shifting from an approach in which the tissue of origin and the histology were the guiding principles for the choice of chemotherapy towards a genotype-centric approach in which the changes in the cancer genome are used to select patients for treatment with highly selective and targeted drugs. This transition has all the hallmarks of a disruptive innovation and requires major adjustments in the way that cancer is diagnosed and treated. We discuss here the hurdles on the road ahead to a more personalized treatment of cancer.

Therapies targeting activated oncogenes have been associated with several successes in the last decades that are described in this review, together with their limits and related unsolved questions. Most of the tumours will eventually develop drug resistance potentially due to intratumor heterogeneity and selection of additional molecular events. Moreover, studies in the field of molecular characterisation of cancers have shown that most tumors include large number of rare genomic events. Developing new drugs requires the use of large-scale molecular screening programs to enrich phase I/II trials with patients presenting the genetic alterations to treat them with the appropriate drug(s). Administering one single drug will incur in non-durable results, so the future is to cleverly combine drugs. Development of personalized immunotherapeutics and/or anti-angiogenic agents could change the natural history of several cancers. Finally, other systems including DNA repair and metabolism have become targetable. These considerations justify the development of molecular medicine with the characterisation of each tumour to assess defects in all the systems previously mentioned to propose a unique combination of therapies to each patient. Current drug development is clearly not appropriate, and studies with drugs given in relevant combinations should be favoured by new relationships between academia and industry. New organisational and medico-economics approaches are required to minimize the financial burden of personalized medicine by considering the foreseen decrease of the costs of new technologies, and the money saved by avoiding the use of many costly, useless but nonetheless toxic treatments given after failure of standard therapy.

International audience

International audience

International audience

Given the broad expression of H-2 class Ib molecules on hematopoietic cells, antigen presentation pathways among CD1d expressing cells might tightly regulate CD1d-restricted natural killer T (NKT) cells. Bone marrow–derived dendritic cells (BM-DCs) and not adherent splenocytes become capable of triggering NK1.1+/T cell receptor (TCR)int hepatic NKT cell activation when (a) immature BM-DCs lack H-2Db−/− molecules or (b) BM-DCs undergo a stress signal of activation. In such conditions, BM-DCs promote T helper type 1 predominant CD1d-restricted NKT cell stimulation. H-2 class Ia–mediated inhibition involves more the direct H-2Db presentation than the indirect Qa-1b pathway. Such inhibition can be overruled by B7/CD28 interactions and marginally by CD40/CD40L or interleukin 12. These data point to a unique regulatory role of DCs in NKT cell innate immune responses and suggest that H-2 class Ia and Ib pathways differentially control NKT cell recognition of DC antigens.

Injuries cause a substantial part of mortality, morbidity and disability world-wide and are responsible for more years of life lost than other nosological entities. The etiology of injuries is mult...

Resume La recherche epidemiologique en sante mentale de l’enfant est peu developpee en France, comme l’atteste le tres petit nombre de publications, notamment en langue francaise. Cet article vise a montrer l’apport de l’epidemiologie a la connaissance de la pathologie mentale de l’enfant, principalement dans sa composante d’epidemiologie descriptive (la plus developpee actuellement), mais aussi dans ses dimensions d’epidemiologie explicative et evaluative. On a donc mene ici une reflexion methodologique sur les techniques utilisees, leur interet et leurs limites, en s’appuyant sur des exemples concrets issus de la litterature internationale. On constate, par exemple, l’extreme disparite des chiffres de prevalence de desordres psychiatriques, du fait notamment de problemes de diversite dans les definitions utilisees, et dans les lieux et techniques de recueil des donnees (outils de depistage et classifications diagnostiques notamment). Seules les etudes menees dans des echantillons representatifs de la population generale permettent une evaluation fiable de la frequence, mais elles sont lourdes et couteuses, de meme que les etudes longitudinales, et tout particulierement les suivis de cohortes de naissances, dont l’interet principal est de permettre l’identification, des la petite enfance, de facteurs predictifs de troubles mentaux. Des domaines entiers sont a developper, tels que l’epidemiologie genetique en pathologie mentale, les essais therapeutiques ou l’evaluation de programmes d’intervention. L’approche epidemiologique peut permettre l’evaluation des besoins en services, l’identification de « groupes a risques » et une approche scientifique des facteurs explicatifs. Dans les pays tels que la France ou la quasi-totalite des enfants est scolarisee a trois ans, il faut faire de l’ecole un lieu de depistage precoce, ce qui suppose un considerable renforcement des moyens et une politique innovante de formation des personnels de sante, notamment dans le domaine de la sante mentale.

Replication-defective adenoviruses are arousing growing interest as both gene therapy and vaccine vectors. In a phase I clinical trial designed to evaluate the feasibility and tolerance of recombinant adenovirus (rAd)mediated gene transfer, we previously demonstrated that a single intratumoral injection of 10(9) PFU of rAd encoding the beta-galactosidase protein (Ad-beta-Gal) induced strong short-term (1-3 months) humoral, helper (Th1 type) and cytotoxic T cell responses specific for the transgene product in patients with advanced lung cancer. The purpose of the present study was to evaluate the persistence of long-lasting immunity to the transgene protein and in parallel, to assess patient immunocompetence revealed by responses to recall antigens (tetanus toxoid, purified protein derivative), viral pathogens (Epstein-Barr virus, influenza virus), and allogeneic antigens in mixed lymphocytic reactions. The beta-Gal-specific proliferative response declined rapidly in patients with progressive disease, as did responses to the other antigens. In contrast, a long-lasting proliferative response to beta-gal was maintained in an immunocompetent patient in complete remission 2 years after an injection of 108 PFU of Ad-beta-Gal. Anti-beta-Gal humoral (IgG and IgA) responses persisted notably, as did responses to TT and poliomyelytic antigens. While T cell effector cytotoxic responses specific for the viral peptides plummeted, the frequency of anti-beta-Gal CTL precursors remained particularly high, thus attesting to major immunization. Despite the impact of both advanced disease and chemotherapy on immunocompetence, we show the long-term persistence of immunity to the transgene protein vectorized by rAd.

In vivo transfer of wild-type (wt) p53 gene via a recombinant adenovirus has been proposed to induce apoptosis and increase radiosensitivity in several human carcinoma models. In the context of combining p53 gene transfer and irradiation, we investigated the consequences of adenoviral-mediated wtp53 gene transfer on the cell cycle and radiosensitivity of a human head and neck squamous cell carcinoma line (SCC97) with a p53 mutated phenotype. We showed that ectopic expression of wtp53 in SCC97 cells resulted in a prolonged G1 arrest, associated with an increased expression of the cyclin-dependent kinase inhibitor WAF1/p21 target gene. A transient arrest in G2 but not in G1 was observed after irradiation. This G2 arrest was permanent when exponentially growing cells were transduced by Ad5CMV- p53 (RPR/INGN201) immediately after irradiation with 5 or 10 Gy. Moreover, levels of cyclins A2 and B1, which are known to regulate the G2/M transition, dramatically decreased as cells arrived in G2, whereas maximal levels of expression were observed in the absence of wtp53. In conclusion, adenoviral mediated transfer of wtp53 in irradiated SCC97 cells, which are mutated for p53, appeared to increase WAF1/p21 expression and decrease levels of the mitotic cyclins A2 and B1. These observations suggest that the G2 arrest resulted from a p53-dependent premature inactivation of the mitosis promoting factor. © 2000 Cancer Research Campaign

Latent membrane protein 1 (LMP1) is an Epstein-Barr virus (EBV) protein expressed in EBV-transformed B lymphocytes and in approximately 50% of nasopharyngeal carcinomas (NPCs). LMP1 signaling involves several cellular signaling intermediates, especially TNF receptor-associated factors (TRAFs). We have shown previously that LMP1 is highly concentrated in a cell fraction called glycosphingolipid-rich membrane complexes (GSL complexes). We report here that parallel accumulation of LMP1 and TRAF3, but not TRAF1 or TRADD, was observed in GSL complexes from lymphoblastoid and LMP1-positive NPC cells. In contrast, TRAF3 was not concentrated in GSL complexes from LMP1-negative cells. Binding of LMP1 and TRAF3 in GSL complexes was demonstrated in lymphoblastoid and NPC cells, by co-immunoprecipitation with both anti-LMP1 and anti-TRAF3 antibodies.

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A unique class of IFN-producing killer dendritic cells (IKDC) resembling natural killer cells has been defined that can recognize and lyse tumor cells through a tumor necrosis factor–related apoptosis-inducing ligand–dependent mechanism. IKDC may mediate the host-dependent antitumor activity of Gleevec/STI571 and other therapeutics that can inhibit the c-kit tyrosine kinase. IKDC represent an important new component of the innate immune system responding to cancer. [Cancer Res 2007;67(3):851–3]