[Locally advanced unresectable pancreatic cancer: Induction chemoradiotherapy followed by maintenance gemcitabine versus gemcitabine alone: Definitive results of the 2000-2001 FFCD/SFRO phase III trial]. / Cancer du pancréas localement évolué non resécable : chimioradiothérapie d'induction suivie de chimiothérapie par gemcitabine contre chimiothérapie exclusive par gemcitabine : résultats définitifs de l'étude de phase III 2000-2001de la FFCD et de la SFRO.

PURPOSE: To compare chemoradiation with systemic chemotherapy to chemotherapy alone in locally advanced pancreatic cancer. PATIENTS AND METHODS: One hundred and nineteen patients with locally advanced pancreatic cancer, with World Health Organization performance status of zero to two were randomly assigned to either the induction chemoradiation group (60 Gy, 2 Gy/fraction; concomitant 5-fluoro-uracil infusion, 300 mg/m(2) per day, days 1-5 for 6 weeks; cisplatin, 20 mg/m(2) per day, days 1-5 during weeks 1 and 5) or the induction gemcitabine group (GEM: 1000 mg/m(2) weekly for 7 weeks). Maintenance gemcitabine (1000 mg/m(2) weekly, 3/4 weeks) was given in both arms until disease progression or toxicity. RESULTS: Overall survival was shorter in the chemoradiation than in the gemcitabine arm (median survival 8.6 [99% confidence interval 7.1-11.4] and 13 months [8,9,9-18], p=0.03). One-year survival was, respectively, 32 and 53%. These results were confirmed in a per-protocol analysis for patients who received 75% or more of the planned dose of radiotherapy. More overall grades 3-4 toxic effects were recorded in the chemoradiation arm, both during induction (36 versus 22%) and maintenance (32 versus 18%). CONCLUSION: This intensive induction schedule of chemoradiation was more toxic and less effective than gemcitabine alone.

Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000-01 FFCD/SFRO study.

BACKGROUND: The role of chemoradiation with systemic chemotherapy compared with chemotherapy alone in locally advanced pancreatic cancer (LAPC) is uncertain. PATIENTS AND METHODS: One hundred and nineteen patients with LAPC, World Health Organization performance status of zero to two were randomly assigned to either the induction CHRT group (60 Gy, 2 Gy/fraction; concomitant 5-fluorouracil infusion, 300 mg/m(2)/day, days 1-5 for 6 weeks; cisplatin, 20 mg/m(2)/day, days 1-5 during weeks 1 and 5) or the induction gemcitabine group (GEM: 1000 mg/m(2) weekly for 7 weeks). Maintenance gemcitabine (1000 mg/m(2) weekly, 3/4 weeks) was given in both arms until disease progression or toxicity. RESULTS: Overall survival was shorter in the CHRT than in GEM arm [median survival 8.6 (99% confidence interval 7.1-11.4) and 13 months (8.7-18.1), P = 0.03]. One-year survival was, respectively, 32% and 53%. These results were confirmed in a per-protocol analysis for patients who received 75% or more of the planned dose of radiotherapy. More overall grades 3-4 toxic effects were recorded in the CHRT arm, both during induction (36 versus 22%) and maintenance (32 versus 18%). CONCLUSION: This intensive induction schedule of CHRT was more toxic and less effective than gemcitabine alone.

Endoscopic screening for esophageal squamous-cell carcinoma in high-risk patients: a prospective study conducted in 62 French endoscopy centers.

BACKGROUND AND STUDY AIMS: The prevalence of esophageal squamous-cell carcinoma in high-risk patients and the advantages of systematic Lugol staining during esophagoscopy have not yet been evaluated in a large prospective study. In this study we aimed to assess the prevalence of this type of tumor in high-risk patients, to examine the role of Lugol staining in endoscopic screening for esophageal squamous-cell carcinoma, and to establish whether it is possible to identify a particularly high-risk group which would benefit from systematic screening. PATIENTS AND METHODS: A prospective study was undertaken in 62 endoscopy centers. A total of 1095 patients were enrolled, none of whom had any esophageal symptoms. These patients had presented with either a past history of or a recent head and neck or tracheobronchial squamous-cell carcinoma (group 1), with alcoholic chronic pancreatitis (group 2), with alcoholic cirrhosis (group 3), or were alcohol and tobacco addicts (group 4). The patients underwent a meticulous endoscopic examination of the esophagus, followed by Lugol staining. RESULTS: The prevalence of esophageal squamous-cell carcinoma was 3.2 %. The group 1 patients showed the highest prevalence of carcinoma (5.3 %) and the highest prevalence of dysplasia (4.5 %). Of the 35 carcinomas detected in the 1095 patients, seven (20 %) were early lesions, and 20 % were only detected after Lugol staining (P = 0.02). High-grade dysplasia was only observed in group 1 patients and two-thirds of these lesions were only diagnosed after Lugol staining. The overall prevalence of low-grade dysplasia was 2.4 %, and 77 % of these were detected only after Lugol staining (P < 0.001). CONCLUSIONS: Lugol dye staining increases the sensitivity of esophageal endoscopy for the detection of high-grade dysplasia and cancer. The prevalence of dysplasia and cancer reached 9.9 % in group 1, and we therefore believe that an endoscopic screening program could be justified for patients with head and neck or tracheobronchial cancer.

Detection of antibodies to polyomavirus SV40 in two central European countries.

Simian virus 40 (SV40) is significantly associated with some human cancers. However, the frequency of tumor-associated virus detection differs by geographic regions, so it is important to understand the status of SV40 infections in different populations. Poliovaccines potentially containing live SV40 were used in well-documented nationwide vaccination programs in Hungary and the Czech Republic that are reported here. We analyzed serum samples from periodic surveillance programs in those two countries for antibodies to SV40 using a specific plaque reduction neutralization assay. The prevalence of antibodies was between 1.3 and 8.7% in Hungary and from 1.0 to 4.0% in the Czech Republic. Females had a higher rate of antibodies than males, reaching in certain age groups 15.6% in Hungary and 8.3% in the Czech Republic. Antibodies to SV40 were found in similar proportions in both countries among persons not directly exposed to poliovaccines and subjects vaccinated in the era of SV40-free vaccines. Complexities and limitations of current serological approaches to epidemiological studies of SV40 in humans are discussed. These data suggest that SV40 may be present in these populations and emphasize the importance of follow-up studies to determine the pathogenesis of infections by this emerging human agent.

Wnt-1 and int-2 mammary oncogene effects on the beta-catenin pathway in immortalized mouse mammary epithelial cells are not sufficient for tumorigenesis.

Development of strategies for prevention of breast cancer development requires an understanding of the effects of mammary oncogenes on mammary cells at early stages in neoplastic transformation. As mammary oncogenes wnt-1 and int-2 affect different signal transduction pathways, we investigated their effects on established mouse mammary epithelial cell lines (MMECLs) reflecting early stages in tumorigenesis. Normal interactions between beta-catenin and E-cadherin were abrogated in all three immortalized MMECLs and the cells lacked beta-catenin-mediated transactivation activity, detectable using a reporter assay, suggesting that alterations in cell adhesion may be very early events in mammary tumorigenesis. Immortalized FSK4 and EL12 cells and hyperplastic TM3 cells were stably transfected with expression vectors encoding wnt-1 or int-2 or the control vector, and drug-selected pooled cells from each line were confirmed by reverse transcription-polymerase chain reaction to express the transfected oncogene; this expression persisted in the cells analysed in vitro and in vivo. Resultant phenotypic changes depended both on the oncogene and the target mammary cell line. In FSK4 cells, expression of wnt-1 or int-2 resulted in proliferative changes in vitro, including reduced contact inhibition, increased beta-catenin expression, and decreased p53 transcriptional activity, but neither oncogene conferred upon those cells the ability to produce tumors in vivo. EL12 cells were highly refractory to the effects of both oncogenes, with the only measurable changes being increased E-cadherin levels induced by both oncogenes and increased proliferation of the int-2-transfected cells in the absence of serum. Parental TM3 cells were phenotypically similar to wnt-1- or int-2-transfected FSK4 cells and displayed an increased rate of proliferation in vitro and markedly increased tumorigenicity in vivo following transfection with int-2 but not with wnt-1. These results suggest that wnt-1 signaling is redundant in the hyperplastic TM3 cells and indicate that wnt-1-induced effects in the immortalized FSK4 and EL12 cells were not sufficient to mediate a tumorigenic phenotype. This study showed that the wnt-1 and int-2 oncogenes have similar but distinguishable effects on immortalized MMECLs and that the genetic background of the mammary cells greatly influences the consequences of oncogene expression at early stages of cell transformation.

Simian virus 40 regulatory region structural diversity and the association of viral archetypal regulatory regions with human brain tumors.

The regulatory region (RR) of simian virus 40 (SV40) contains enhancer/promoter elements and an origin of DNA replication. Natural SV40 isolates from simian brain or kidney tissues typically have an archetypal RR arrangement with a single 72-basepair enhancer element. A rare simpler, shorter SV40 RR exists that lacks a duplicated sequence in the G/C-rich region and is termed protoarchetypal. Occasionally, SV40 strain variants arise de novo that have complex RRs, which typically contain sequence reiterations, rearrangements, and/or deletions. These variants replicate faster and to higher titers in tissue culture; we speculate that such faster-growing variants were selected when laboratory strains of SV40 were initially recovered. SV40 strains with archetypal RRs have been found in some human brain tumors. The possible implications of these findings and a brief review of the SV40 RR structure are presented.

Increasing evidence for involvement of SV40 in human cancer.

SV40, a small DNA virus, is known to possess strong oncogenic potential. Millions of people were exposed to SV40 as an unknown contaminant of some early poliovaccines. This article briefly summarizes the increasing evidence of the association of SV40 with certain types of human cancer, including mesotheliomas and brain tumors. Unanswered questions pertaining to the pathogenesis of human infections by SV40 and the functional role of the virus in tumor development are noted. It is concluded that SV40 should be considered a candidate human tumor virus and that vigorous efforts to clarify the role of the virus in human disease should be supported.

Molecular characterization of SV40 DNA in multiple samples from a human mesothelioma.

BACKGROUND: Prolonged exposure to asbestos, a potent carcinogen, has been the generally accepted factor responsible for the development of human mesotheliomas. Recent reports documenting the detection of SV40 DNA in human mesotheliomas suggest the possibility that this known tumor virus may be an additional factor involved in the development of some tumors. METHODS: A detailed analysis was performed by polymerase chain reaction and DNA sequencing of the genetic characteristics of SV40 viral DNA detected in samples taken from multiple sites of a human mesothelioma. RESULTS: A single virus variant was detected within the tumor that encoded a novel variable region at the C-terminus of the large T-antigen oncoprotein. The viral regulatory region was predominantly archetypal in sequence (lacking duplications of the enhancer), typical of natural isolates. CONCLUSIONS: These data confirm previous reports from several laboratories showing an association of SV40 DNA with human mesotheliomas and provide the first evidence of a novel virus variant present in separated regions of a mesothelioma.

Simian virus 40, poliovirus vaccines, and human cancer: research progress versus media and public interests.

From 1955 through early 1963, millions of people were inadvertently exposed to simian virus 40 (SV40) as a contaminant of poliovirus vaccines; the virus had been present in the monkey kidney cultures used to prepare the vaccines and had escaped detection. SV40 was discovered in 1960 and subsequently eliminated from poliovirus vaccines. This article reviews current knowledge about SV40 and considers public responses to reports in the media. SV40 is a potent tumour virus with broad tissue tropism that induces tumours in rodents and transforms cultured cells from many species. It is also an important laboratory model for basic studies of molecular processes in eukaryotic cells and mechanisms of neoplastic transformation. SV40 neutralizing antibodies have been detected in individuals not exposed to contaminated poliovirus vaccines. There have been many reports of detection of SV40 DNA in human tumours, especially mesotheliomas, brain tumours and osteosarcomas; and DNA sequence analyses have ruled out the possibility that the viral DNA in tumours was due to laboratory contamination or that the virus had been misidentified. However, additional studies are necessary to prove that SV40 is the cause of certain human cancers. A recently published review article evaluated the status of the field and received much media attention. The public response emphasized that there is great interest in the possibility of health risks today from vaccinations received in the past.

A mammary-specific model demonstrates the role of the p53 tumor suppressor gene in tumor development.

Although alterations in the p53 tumor suppressor gene are detected frequently in human breast cancers, mammary tumors are observed infrequently in p53(null) mice. This has led to the suggestion that absence of p53 alone is not sufficient for induction of mammary tumors. However, early death of p53(null) mice from thymic lymphomas may obscure tumor phenotypes that would develop later. Therefore, p53(null) mammary epithelium was transplanted into cleared mammary fat pads of wild type p53 BALB/c hosts to allow long-term analysis of mammary tumor phenotypes. Five treatments were compared for their effects on tumor incidence in hosts bearing transplants of p53(null) and p53wt mammary epithelium. The treatment groups were: (1) untreated; (2) continuous hormone stimulation with pituitary isografts; (3) multiple pregnancies; (4) DMBA alone; and (5) DMBA+pituitary isografts. The tumor incidences in p53(null) vs p53wt mammary transplants for each treatment group were 62% vs 0%, 100% vs 0%, 68% vs 0%, 60% vs 4% and 91% vs 14%, respectively. The mammary tumors that developed in the p53(null) mammary epithelium were all adenocarcinomas and were frequently aneuploid. These data demonstrate that the absence of p53 is sufficient to cause development of mammary tumors and that hormonal stimulation enhances the tumorigenicity of p53(null) mammary epithelium to a greater extent than DMBA exposure alone. This model provides an in situ approach to examine the molecular basis for the role of p53 in the regulation of mammary tumorigenesis.

Viral carcinogenesis: revelation of molecular mechanisms and etiology of human disease.

The RNA and DNA tumor viruses have made fundamental contributions to two major areas of cancer research. Viruses were vital, first, to the discovery and analysis of cellular growth control pathways and the synthesis of current concepts of cancer biology and, second, to the recognition of the etiology of some human cancers. Transforming retroviruses carry oncogenes derived from cellular genes that are involved in mitogenic signalling and growth control. DNA tumor viruses encode oncogenes of viral origin that are essential for viral replication and cell transformation; viral oncoproteins complex with cellular proteins to stimulate cell cycle progression and led to the discovery of tumor suppressors. Viral systems support the concept that cancer development occurs by the accumulation of multiple cooperating events. Viruses are now accepted as bona fide etiologic factors of human cancer; these include hepatitis B virus, Epstein-Barr virus, human papillomaviruses, human T-cell leukemia virus type I and hepatitis C virus, plus several candidate human cancer viruses. It is estimated that 15% of all human tumors worldwide are caused by viruses. The infectious nature of viruses distinguishes them from all other cancer-causing factors; tumor viruses establish long-term persistent infections in humans, with cancer an accidental side effect of viral replication strategies. Viruses are usually not complete carcinogens, and the known human cancer viruses display different roles in transformation. Many years may pass between initial infection and tumor appearance and most infected individuals do not develop cancer, although immunocompromised individuals are at elevated risk of viral-associated cancers. Variable factors that influence viral carcinogenesis are reviewed, including possible synergy between viruses and environmental cofactors. The difficulties in establishing an etiologic role for a virus in human cancer are discussed, as well as the different approaches that proved viral links to cancer. Future directions for tumor virus studies are considered.

Molecular evidence of simian virus 40 infections in children.

Recent studies have detected simian virus 40 (SV40) DNA in certain human tumors and normal tissues. The significance of human infections by SV40, which was first discovered as a contaminant of poliovirus vaccines used between 1955 and 1963, remains unknown. The occurrence of SV40 infections in unselected hospitalized children was evaluated. Polymerase chain reaction and DNA sequence analyses were done on archival tissue specimens from patients positive for SV40 neutralizing antibody. SV40 DNA was identified in samples from 4 of 20 children (1 Wilms' tumor, 3 transplanted kidney samples). Sequence variation among SV40 regulatory regions ruled out laboratory contamination of specimens. This study shows the presence of SV40 infections in pediatric patients born after 1982.

Hepatitis C virus infection risk factors in patients admitted in hospital emergency departments in Picardy. Value of oriented screening based on recommendations of the 'Direction Générale de la Santé'.

OBJECTIVE AND DESIGN: Oriented hepatitis C virus (HCV) screening on the basis of transfusion, previous or current parenteral drug addiction, invasive procedures, and in family members of patients with hepatitis C, was recommended in France by the 'Direction Générale de la Santé' (DGS). The aim of this study was to estimate the frequency of these risk factors in patients admitted in hospital emergency departments in Picardy. METHODS: Between 1 June and 31 July 1996, physicians of the emergency units of seven hospitals in Picardy were asked to question admitted patients about risk factors mentioned in the DGS recommendations, and to suggest a screening test when at least one of these risk factors was present. RESULTS: Among 1648 patients, 68.7% had at least one of these risk factors. Screening was accepted by 723 patients, 58.7% of those with at least one risk factor, and more than 70% of those with history of transfusion and/or drug addiction. It was immediately performed in 451, and 2.4% had anti-HCV antibodies. The prevalence of anti-HCV antibodies was 1.5% in patients without history of transfusion or drug addiction and 7.9% in those with at least one of these two risk factors. CONCLUSION: Oriented screening based on transfusion or drug addiction history seems to have better efficiency than the screening policy recommended by the DGS. Poor reliability of answers about medical history was observed probably because of stress related to emergency circumstances. A screening test proposed to patients with these major risk factors by their usual physician would be probably more efficient.

Expression of MDM2 during mammary tumorigenesis.

The MDM2 oncoprotein encodes a 90 kDa nuclear phosphoprotein capable of abrogating the growth suppressive functions of p53 and pRb tumor suppressor proteins by direct interaction. Alternative splicing of MDM2 protein coding sequences has been documented during tumor progression in human ovarian and bladder carcinomas. The aim of this study was to determine whether alternative splicing of MDM2 occurs during breast tumorigenesis in mice and humans and whether protein coding sequences were affected. Specimens representing normal and malignant breast tissues from the murine D2 mammary tumor model system and human breast carcinomas were examined. Three distinct mdm2 mRNA transcripts of 3.3, 1.6 and 1.5 kb were detected in normal and malignant murine mammary tissues by Northern blot analysis using a full-length mdm2 cDNA probe. Additional Northern blot analysis using a probe derived from exon 12 of murine mdm2 demonstrated that the 1.5 and 1.6 kb transcripts lack sequences encoding the C-terminus of the protein. No evidence of internal deletions of protein coding sequences of mdm2 was detected in any of the normal mammary tissues or D2 murine mammary tumors examined by reverse transcription PCR (RT-PCR). Three distinct MDM2 transcripts of 6.7, 4.7 and 1.9 kb were detected in malignant human breast tissue by Northern blot analysis using a cDNA probe specific for the complete open reading frame of human MDM2. However, a cDNA probe specific for the last exon of human MDM2 hybridized only to the 6.7 and 4.7 kb transcripts, demonstrating that the 1.9 kb transcript lacked protein coding sequences contained in exon 12. Similarly, no internal deletions were detected in a panel of malignant human breast tissues using RT-PCR and analogous primers within human MDM2. Therefore, breast tumors differ from other solid tumors reported previously in that no internal deletions of MDM2 protein coding sequences were observed. However, the data document the presence of multiple MDM2 mRNA transcripts in both normal and malignant breast tissues. A subset of MDM2 transcripts were shown to lack the last exon which contains sequences coding for the RING and zinc fingers and domains which are targets for caspase-3 mediated proteolytic degradation and are required to target p53 for proteosomal degradation.

Polyomaviruses and human tumors: a brief review of current concepts and interpretations.

Polyomaviruses are small DNA viruses that typically establish persistent but inapparent infections of their natural hosts, although cytolytic disease may develop if the host becomes immunocompromised. Most polyomaviruses have the ability to induce tumor formation when introduced into certain foreign hosts and are considered oncoviruses. Some polyomaviruses, including those that infect humans, have occasionally been detected in cancerous tissue of their natural hosts. This article briefly reviews the biology of polyomaviruses and explores issues pertaining to the significance of association of polyomaviruses with human tumors.