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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Squamous cell carcinoma of the head and neck is complicated by a second primary carcinoma of the head and neck, esophagus (the upper aerodigestive tract, or UADT), or lung in 10-40% of patients. Routine panendoscopy will identify a simultaneous second primary in 9-14% of the patients. Metachronous second cancers most often involve the esophagus or lung, whereas synchronous second cancers are more common in the head and neck as occult lesions. For the highest-risk subgroups, second primary cancers occur in 4% of patients per year. In cancer of the floor of the mouth the excess mortality rate is 5-6% per year. Risk is independent of stage of the first primary and the survival impact is the greatest in groups of patients with early-stage disease. Head and neck cancer almost always results from the heavy use of tobacco for many years, either with or without the concomitant heavy use of alcohol, and these same agents are directly responsible for the second cancers of the UADT and lung. All head and neck cancer patients should be advised to avoid these agents. The clinician must diagnose and treat second cancers to extend the survival of patients with a good prognosis for control of the initial head and neck cancer. We need further progress in eliminating the use of known carcinogens in these patients, paradigms for cost-effective diagnosis and treatment of second primary cancers, effective treatment of the head and neck primary cancer devoid of long-lasting tissue toxicities, effective chemopreventive agents to retard established processes of carcinogenesis that place the patient at continued risk after cigarette and alcohol use has been eliminated, and continued efforts to control the medical illnesses to which these patients are susceptible.
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PMID:Multiple primary cancer in patients with cancer of the head and neck: second cancer of the head and neck, esophagus, and lung. 267 75

Head and neck cancer remains a common cause of mortality and morbidity in the United States and throughout the world. In spite of advances in the management of patients with advanced disease, overall survival in this group remains poor. Furthermore, although cancer mortality is lower in patients with early-stage disease, treatment results in significant morbidity, and these patients also face the risk of developing a second primary tumor. Chemoprevention is an innovative approach to decrease overall cancer morbidity and mortality using substances that are capable of preventing cancer progression. Head and neck cancer is an excellent model for chemoprevention, as its biology is consistent with the two concepts important for the development of chemoprevention strategies: field cancerization and multistep carcinogenesis. Several classes of compounds have been evaluated in chemoprevention trials. The most frequently studied agents, the retinoids, were found frequently to induce remissions in patients with oral leukoplakia. Furthermore, retinoids prevented progression to malignancy in one randomized maintenance study. Other agents, including beta-carotene and vitamin E, have been found also to have activity in the management of oral leukoplakia. However, the clinical role of chemopreventive agents in reducing cancer mortality remains to be defined. Two studies, one in head and neck cancer and one in lung cancer, have shown the ability of retinoids to prevent the development of second primary tumors. Current large randomized trials are defining the effectiveness of these agents in reducing the mortality of aerodigestive tract tumors in individuals at high risk.
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PMID:Biology and chemoprevention of head and neck cancer. 805 3

Head and neck cancer is occurring in younger patients in certain areas of the world. The factors that contribute to this process remain poorly defined, emphasizing the need for continued investigations into head and neck carcinogenesis. One potential determinant of disease development may relate to the significance of the host's intrinsic capacity to detoxify carcinogens, ie, through the phase II enzyme family, glutathione-S-transferases. Those patients with deficient GST activity may be at greatest risk. Additionally, genetic studies have suggested that certain chromosomes may be more susceptible to tobacco-induced damage. Chromosome 3p has now been identified as frequently altered both within head and neck cancers as well as within tobacco-induced malignancies. Over the past year numerous reports have addressed potential biologic determinants of not only cancer development, but also its continued progression. These factors may include altered growth factors and their receptors, changes in cellular intermediate filaments such as increased cytokeratin 19, and the production of matrix metalloproteinases. Finally, investigations continue to provide new insight into mechanisms by which abnormal gene expression may govern response to therapy. Our growing understanding of the complexity of head and neck cancer biology reinforces the need for preventive strategies, including the role of both nutritional and behavioral interventions.
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PMID:Head and neck oncology research. 808 Aug 55

Head and neck cancer development has been proposed to represent a multistage process characterized by dysregulation of proliferation and differentiation and driven by an accumulation of genetic alterations in an anatomic field repeatedly exposed to carcinogens. To visualize the accumulation of genetic alterations during head and neck tumorigeneses and to determine the extent of the genetically altered field, we probed 25 squamous cell carcinomas of the head and neck and their adjacent premalignant lesions for numerical chromosome aberrations by nonisotopic, in situ hybridization using chromosome-specific centromeric DNA probes for chromosomes 7 and 17. Normal control oral epithelium from individuals free of cancer showed no chromosome polysomy (i.e., cells with > or = 3 chromosome copies), whereas histologically normal epithelium adjacent to the tumors showed squamous cells with polysomies for chromosomes 7 and 17. Moreover, the frequency of cells with polysomy increased as the tissues passed from histologically normal epithelium to hyperplasia to dysplasia to cancer. The finding of genotypic abnormalities in histologically normal and precancerous regions adjacent to the tumor supports the concept of field cancerization. The finding of progressive genetic changes as the tumor develops supports the concept of multistep carcinogenesis in the head and neck region. Such genotypic parameters could serve as biomarkers in the assessment of the risk of progression to malignancy and as intermediate end points in chemoprevention trials.
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PMID:Increased polysomies of chromosomes 7 and 17 during head and neck multistage tumorigenesis. 850 29

Head and neck cancer is a major worldwide health problem; it has been estimated that approximately 900,000 people were diagnosed with this disease in 1995. Patients are generally treated with surgery and/or radiation therapy. Treatment, especially of patients with early stage (I or II) head and neck squamous cell carcinoma, is often successful. A serious concern, however, is the fact that these patients subsequently develop second primary tumors at an annual rate of 4%-7%. Molecular analyses of premalignant and malignant tissues have produced strong evidence that clonal genetic alterations occur during the early stage of aerodigestive tract carcinogenesis. Although the roles of tobacco and diet in head and neck carcinogenesis have been the subjects of epidemiologic investigations for many years, it has only recently become possible to integrate information regarding genetic susceptibility factors into the development of comprehensive risk models for these cancers. The molecular and epidemiologic studies provide the foundation on which clinical trials can be designed to evaluate the role of retinoids and other compounds in the reversal of premalignancy and the prevention of second primary tumors (i.e., in chemoprevention). This translational approach has led to studies of the utility of intermediate end point markers, such as the nuclear retinoic acid receptors, in chemoprevention strategies. Given the rapid advances occurring in this area of research, it may soon be possible to use these biomarkers to identify patients who are most at risk for developing head and neck cancer and who are most likely to benefit from chemopreventive interventions.
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PMID:Molecular epidemiology and retinoid chemoprevention of head and neck cancer. 901

Head-and-neck cancer (HNC) patients have a high risk of developing second primary tumors of the upper aerodigestive tract, the main cause of death. Although the roles of tobacco and diet in multiple head-and-neck carcinogenesis have been thoroughly investigated, little is known about individual genetic susceptibility factors involved in this process. Genomic instability, reflecting the propensity and the susceptibility of the genome to acquire multiple alterations, could be considered a driving force behind multiple carcinogenesis. Mutation of the p53 tumor-suppressor gene has been proposed to play an important role in this process. Therefore, we evaluated the incidence of inherited p53 germ-line alteration(s) in a population of 24 consecutive HNC patients and their first-degree relatives affected by multiple malignancies as well as the occurrence of p53 somatic acquired mutation(s) in 16 cancers, including first and second primaries from 5 HNCs of the same group. Mutations in exons 4-11 of the p53 gene were investigated using SSCP-PCR analysis and DNA sequencing. Analysis was extended to the peripheral blood and cancer biopsies available from first-degree relatives of cancer-prone families with p53 germ-line mutations. p53 germ-line mutations were identified in the peripheral blood and corresponding cancers of 3 HNC patients who had multiple malignancies. The only missense mutation detected was mapped in exon 6; it is a GTG to GAG substitution with an amino acid change from Val to Glu at codon 197. The remaining 2 p53 germ-line mutations were single-nucleotide substitutions without amino acid change in exon 6 (codon 213, CGA to CGG) and in exon 8 (codon 295, CCT to CCC), respectively. These mutations were found in HNC patients with a family history of cancer. Abnormal expression of wild-type p53 protein in normal and pathological tissues from patients with the same sense single-nucleotide substitutions was detected by immuno-histochemistry.
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PMID:Multiple primary tumors of the upper aerodigestive tract: is there a role for constitutional mutations in the p53 gene? 1038 49

Molecular studies have revealed that microsatellite instability and loss of heterozygosity occurred in head-and-neck cancer, suggesting the involvement both of suppressor and of mutator pathways in head-and-neck carcinogenesis. There is evidence for relations between tumor phenotype and clinical parameters. Indeed, replication-error phenotype, characterized by microsatellite instability, was associated with decreased sensitivity to chemotherapeutic agents in cell lines. Loss of heterozygosity is a frequent mechanism of inactivation of tumor-suppressor genes, which might be implicated in resistance to chemotherapy. In head-and-neck cancer, chemosensitivity is inconstant, and no marker is available to predict response to treatment. In order to evaluate the role of tumor phenotype on resistance to chemotherapy, we analyzed 56 primary head-and-neck squamous-cell carcinomas collected at time of diagnosis and a sub-group of 23 resistant tumors collected after chemotherapy at 22 microsatellite loci. At time of diagnosis, only one tumor showed MSI-H phenotype. Loss of heterozygosity (LOH) was observed in 75% of tumors, indicating the dominant role of the suppressor in comparison with the mutator pathway in HNSCC carcinogenesis. No change in microsatellite patterns was observed after treatment, suggesting that chemotherapy did not select mismatch-repair-deficient clones. Univariate analyses showed that LOH at 9p or 17p was significantly associated with drug resistance. In a multivariate analysis, only LOH at 17p remains predictive of low response to chemotherapy, with a relative risk of 3.7 and 95% CI of 1.1-13, indicating that p53 alterations could play a role in chemotherapy resistance in HNSCC. Int. J. Cancer (Pred. Oncol.) 84:410-415, 1999.
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PMID:Microsatellite analysis and response to chemotherapy in head-and-neck squamous-cell carcinoma. 1040 95

Chemopreventives are chemicals that prevent the formation of cancers such as oral cancer. They can take the form of nutrients or synthetic molecules, and their fundamental characteristic is that they do not produce disease processes that would result in debilitating symptoms. Current evidence indicates that they function by modifying the oxidative state of transforming cells. Biomarkers can take the form of genetic and molecular indicators, which characterize the function of chemopreventives and cancer processes such as oral carcinogenesis. Biomarkers cannot provide all the required information for risk assessment or possible activity of the chemopreventives. Other methods, such as epidemiological analyses and techniques, must be used to enhance our understanding of the risk for oral cancer in human populations. One common epidemiologic method, the questionnaire, helps to determine the use and carcinogenic potential of tobacco and alcohol during oral carcinogenesis. Genetic and molecular changes in human patient populations may result in a reduction in the number and function of tumor suppressor genes. If these changes are to be assessed, the tissues (e.g., buccal mucosa) must be accessible and harvested in a reliable and consistent manner for the acquisition of DNA, mRNA, and protein. Oral tissues provide sufficient quantities of these molecules and, under stringent conditions, the quality required for the isolation of these molecular constituents. In conjunction with epidemiologic techniques, various genotypic polymorphisms, such as glutathione-S-transferase (GSTM1) or cytochrome P450 (CYP450A1), have indicated a loss in carcinogen detoxification or the processing of internal growth control signals. Biomarkers are composed of a large diverse group of genetic and molecular structures. Some of these biomarkers are indicators for programmed cell death (PCD), while others describe malignant tumor growth. Many of these classes of molecules are oxidative-responsive (e.g., tumor suppressor p53, Bcl-2, growth factors, immune-derived proteins, and death-inducing molecules) and induce PCD by triggering a cascade of cysteine proteases and regulators (e.g., caspases, death receptors). This pathway results in cell-cycle alterations and DNA fragmentation. It is hoped that a detailed knowledge of the processes involved in malignant transformation will better define the biomarker-screening tools for oral cancer. These tools will enhance our ability to predict the incidence of cancer, detect early malignant change, and quantitate chemoprevention during oral carcinogenesis. Chemopreventives such as the retinoids have already demonstrated their ability to suppress potential malignant changes in pre-malignant oral leukoplakias and decrease the incidence of second head-and-neck cancer primaries. It is our hope that this review will increase investigators' interest in developing new screening and detection systems for oral cancer.
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PMID:Biomarkers and molecular epidemiology and chemoprevention of oral carcinogenesis. 1068 2

Head and neck cancer is an important public health problem worldwide, accounting for approximately 40,400 new cancer cases and 12,300 cancer deaths annually in the US. Although early-stage disease is often curable with surgery or radiotherapy, the majority of patients present with advanced disease in which despite advances in combined modality therapy the outcomes have not dramatically improved. Furthermore, patients cured of their initial early-stage head and neck squamous cell carcinoma are at high risk for development of second primary tumors, which pose the main threat to survival. An alternative approach in reducing the incidence and thus mortality associated with these cancers is chemoprevention, the use of agents to reverse, halt, or delay carcinogenesis. The carcinogenesis process in head and neck cancer results from a dysregulation of cellular proliferation, differentiation, and cell death resulting from field-wide exposure of the upper aerodigestive tract to tobacco smoking. Newly acquired knowledge in the field of tumor biology and of the genetic changes underlying carcinogenesis through the use of new molecular technology represents the basis on which chemoprevention efforts should be based.
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PMID:Carcinogenesis of head and neck cancer and the role of chemoprevention in its reversal. 1084 Nov 96

Vitamin A, its physiologic metabolites, and synthetic derivatives (retinoids) have been shown to have protective effects against the development of certain types of cancer. In addition, pharmacologic amounts of retinoids have been used with some success in the treatment of a few human tumors. The chemoprevention effect of retinoids is most likely exerted at the tumor-promotion phase of carcinogenesis. Retinoids block tumor promotion by inhibiting proliferation, inducing apoptosis, inducing differentiation, or a combination of these actions. Clinically, isotretinoin (13-cis-retinoic acid) significantly decreases the incidence of second primary tumors in patients with head-and-neck cancer and reduces appearance of non-melanoma skin cancer in patients with xeroderma pigmentosum. Retinoic acid has proved to be an effective treatment for promyelocytic leukemia. However, retinoid resistance limits its use as a single agent. Clinical trials are in progress to determine the efficacy of retinoids in treating other types of cancer such as neuroblastoma and breast carcinoma. The development of receptor-selective retinoids and selective inhibitors of retinoid metabolism may lead to further use of retinoids in both chemoprevention and treatment of cancer.
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PMID:Recent advances in the use of vitamin A (retinoids) in the prevention and treatment of cancer. 1111 36


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