Biomedical subjects

W K Hong

Publications and source records attributed to W K Hong.

At least 163 records · Page 9Linked to original sources

PubMed1997

Associations between cytochrome P4502E1 genotype, mutagen sensitivity, cigarette smoking and susceptibility to lung cancer.

Cytochrome P4502E1 (CYP2E1) is involved in the metabolic activation of carcinogenic N-nitrosoamines. We therefore assessed the genotype frequencies of PstI or RsaI CYP2E1 restriction fragment length polymorphisms and another susceptibility marker, mutagen sensitivity, in 137 lung cancer cases (92 African American and 45 Mexican American) and 206 controls (114 African American and 92 Mexican American) identified in a molecular epidemiological study of lung cancer. The CYP2E1 c1/c1 genotype was found in 86.7% of Mexican American cases, 70.6% of Mexican American controls, 89.1% of African American cases and 86.8% of African American controls. By multivariate analysis, this genotype was found to be associated with a 14.0-fold increased risk of lung cancer in Mexican Americans but not in African Americans; a 9.9-fold increased risk of lung cancer in Mexican American former smokers, but not in non-smokers or current smokers; a 15-fold increased risk of lung cancer in Mexican American males, but not in females. Patients with the susceptible genotype appeared to have developed cancer at an earlier age and with lower cigarette pack-year of exposure than did patients with the c1/c2 or c2/c2 genotypes. Stratified analysis suggested a greater than multiplicative interaction between cigarette smoking and CYP2E1 c1/c1 genotype, although not statistically significant. The odds ratios (ORs) for the CYP2E1 c1/c1 genotype, cigarette smoking and both risk factors combined were 1.3, 6.7 and 16.3, respectively. The association between CYP2E1 c1/c1 genotype and pack-years of smoking followed the same pattern. The interaction between mutagen sensitivity and CYP2E1 c1/c1 genotype was especially strong in former smokers (the ORs for the CYP2E1 c1/c1 genotype, mutagen sensitivity and both risk factors combined were 3.9, 5.4 and 23.0, respectively). Therefore, the data suggest that individuals who lack a c2 allele might be at higher risk for developing lung cancer.

Alleles↗

PubMed1997

Intratumoral genetic heterogeneity in primary head and neck squamous carcinoma using microsatellite markers.

We investigated intratumoral genetic variability using 13 of the most frequently altered microsatellite loci in primary head and neck squamous carcinoma to determine the extent and the implication of this feature on the interpretation of the genetic analysis of these tumors. DNA extracted from four spatially different samples of 17 prospectively resected specimens, in addition to matching normal mucosa, was tested. Overall, the highest incidence of loss of heterozygosity was noted at chromosomes 3p and 9p loci (70% in each). Chromosomes 8p and 17p loci showed 35% and 40% loss of heterozygosity, respectively. Loss of heterozygosity was homogeneously manifested in all different samples of tumors with these alterations. Microsatellite instability was noted in two (17%) tumors, one of which showed intratumoral heterogeneity. Our study indicates that single sample analysis may reflect the genetic alterations in a given primary head and neck squamous carcinoma using these markers.

Adult↗

PubMed1997

Maximum-tolerated dose defined for single-agent gemcitabine: a phase I dose-escalation study in chemotherapy-naive patients with advanced non-small-cell lung cancer.

PURPOSE: We conducted a phase I trial of the novel nucleoside analog, gemcitabine, in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC) to determine the maximum-tolerated dose and efficacy in this population. PATIENT AND METHODS: Eligibility requirements included stage III or IV NSCLC, performance status < or = 1, and no prior chemotherapy. Gemcitabine was administered as a 30-minute intravenous infusion weekly for 3 weeks every 4 weeks. We enrolled patients at doses that ranged from 1,000 to 2,800 mg/m2/wk (three patients per cohort). Responses were assessed after every two courses (8 weeks). RESULTS: We treated 33 chemotherapy-naive patients with stage III (n = 5) or IV (n = 28) NSCLC. Most had performance status 1, and 67% had adenocarcinoma. Eight of 32 assessable patients (25%) achieved a partial response. The projected median survival duration (all patients) is 49 weeks. The maximum-tolerated dose was 2,200 mg/m2/wk for 3 weeks every 4 weeks; dose-limiting toxicity was myelosuppression and reversible transaminase elevation. Other side effects were consistently mild. The maximum dose-intensity achieved with the first two cycles was 2,362 mg/m2/wk for 3 weeks every 4 weeks, which is a feasible phase II starting dose. CONCLUSION: This study estimates a phase II starting dose of gemcitabine in chemotherapy-naive patients to be 2,400 mg/m2/wk for 3 consecutive weeks every 4 weeks; this is much higher than that previously reported in heavily pretreated patients. Twenty-five percent of patients with advanced NSCLC achieved a partial response to gemcitabine. This significant activity in conjunction with a very favorable toxicity profile supports the further evaluation of gemcitabine in combination with other active agents.

Adult↗

PubMed1997

Retinoids in head and neck chemoprevention.

Over the last few years, we have witnessed tremendous progress in both basic and clinical research on retinoids. Preclinical studies have indicated the potential of retinoids in cancer prevention and therapy, but the actual successful application of retinoids in clinical chemoprevention trials has been the recent and exciting development in the field of retinoid research. Our understanding of the role of retinoids in normal developmental processes and the differentiation of normal and malignant cells, and the fundamental discovery of the nuclear retinoid receptors that act as transcription modulating factors regulating specific gene expression have been major advances in the field of basic retinoid research. Chemoprevention is the newest research approach in our efforts to control upper-aerodigestive tract cancers, which have one of the lowest cure rates among epithelial malignancies, and in which the occurrence of second primary tumors further burdens the dismal prognosis of patients. The efficacy of retinoids in the reversal of oral premalignant lesions and the prevention of second primary tumors has generated tremendous enthusiasm among retinoid researchers, particularly those in the field of chemoprevention. Current explorations of combinations of retinoids with biologic response modifiers such as alpha-interferon, as well as new receptor-selective retinoids, hold promise for the future.

Anticarcinogenic Agents↗

PubMed1997

Evidence of a retinoid signaling alteration involving the activator protein 1 complex in tumorigenic human bronchial epithelial cells and non-small cell lung cancer cells.

Retinoids, including retinol and retinoic acid derivatives, inhibit the growth of normal human bronchial epithelial (HBE) cells. Using a lung carcinogenesis model consisting of normal, immortalized, and tumorigenic HBE cells, we showed previously that, compared to normal HBE cells, the tumorigenic HBE cell line 11701 is resistant to the growth-inhibitory effects of all-trans-retinoic acid (t-RA). Retinoid receptor function is preserved in tumorigenic 11701 cells, suggesting that other retinoid signaling components are altered. The activator protein 1 (AP-1) complex is a component of the retinoid signaling pathway and has demonstrated importance in cellular growth and differentiation. Therefore, we investigated whether AP-1 is involved in a retinoid signaling defect in tumorigenic 11701 cells and in retinoid-resistant non-small cell lung cancer (NSCLC) cell lines. We found that t-RA treatment inhibited AP-1 transcriptional activity in normal HBE cells but not in tumorigenic 11701 cells nor in the NSCLC cell lines Calu-1, Calu-6, SKMES-1, and ChaGo K1. We sought mechanisms for this retinoid signaling alteration involving AP-1 in tumorigenic 11701 cells. Basal AP-1 transcriptional activity; AP-1 DNA-binding activity; and the mRNA levels of c-fos, the AP-1 coactivator Jun activation domain-binding protein 1, and the retinoid receptor corepressor, the silencing mediator for retinoid and thyroid hormone receptors (SMRT), were lower in tumorigenic 11701 cells than in normal HBE cells. Transient transfection of tumorigenic 11701 cells with c-fos or CREB binding protein, which is a coactivator of AP-1 and retinoid receptors, enhanced basal AP-1 transcriptional activity but did not alter the effects of t-RA on AP-1 transcriptional activity. These findings provide evidence of a retinoid signaling alteration involving AP-1 in tumorigenic 11701 and NSCLC cells. Furthermore, the inhibitory effect of t-RA on AP-1 transcriptional activity was not restored in tumorigenic 11701 cells by transfection of c-fos, silencing mediator for retinoid and thyroid hormone receptors, Jun activation domain-binding protein 1, or CREB-binding protein, suggesting the involvement of other transcriptional coregulators in this retinoid signaling defect.

Blotting, Northern↗

PubMed1997

Comparison of p53 immunoreactivity in fresh-cut versus stored slides with and without microwave heating.

Because of technical problems in immunohistochemical staining of archival material, antigens can be masked or lost. A recent study reported diminished p53 immunoreactivity in slides that had been sectioned from parafinn-embedded tissue blocks and stored at room temperature. To investigate this issue, we performed immunohistochemical staining with use of a p53 monoclonal antibody (DO7) in 13 head and neck squamous cell carcinoma (HNSCC) and 13 non-small-cell lung carcinomas. The fresh-cut and stored slides were simultaneously stained with and without the use of a microwave heating (MWH) technique, and we compared the results of p53 immunostaining. The stored slides were sectioned from paraffin blocks 4 to 25 years old and kept at room temperature for 6 to 48 months. The slides were blindly evaluated for percentage of positivity and staining intensity. Twelve HNSCCs and six lung carcinomas showed p53 positivity. The stored slides showed a considerable decrease in staining intensity (P = 0.039), compared with fresh-cut slides. The difference in the percentage of positivity between the stored and fresh-cut slides was statistically significant, but the mean value of the difference was only 3.6%, which might not be meaningful for semiquantitation of immunostaining. MWH greatly enhanced staining intensity and percentage of positivity for both stored and fresh-cut slides. When MWH was applied, no significant difference in staining intensity (P = 0.063) was detected in fresh-cut versus stored slides, but the difference in the percentage of positivity was statistically significant (mean value, 3.1%). Individual cases showed a consistent p53 status regardless of the MWH treatment, storage duration, or age of the blocks. This study demonstrated a considerable decrease in p53 immunoreactivity in stored slides. Because the MWH successfully retrieved the p53 antigen without causing a change in p53 status, stored slides combined with an MWH antigen retrieval technique in a metal-containing solution should provide p53 immunostaining results similar to those from fresh-cut slides, as long as staining intensity is not a sole study parameter.

Carcinoma, Non-Small-Cell Lung↗

PubMed1997

Identifying and recruiting healthy control subjects from a managed care organization: a methodology for molecular epidemiological case-control studies of cancer.

Case-control studies with stringent matching criteria require large pools of healthy subjects from which to select matched controls. This paper describes a successful method of identifying a large pool of potential control subjects to participate in two molecular epidemiological case-control studies of lung cancer, each enrolling 400 case subjects and 400 control subjects. These studies are not population based, and the study base is not well-defined. Therefore, potential control subjects are being identified and recruited through 20 area clinic sites of a large multispecialty health maintenance organization. Because the research focus is driven by genetic hypotheses and we are controlling for multiple smoking-related variables, representativeness is of lesser concern. To identify potential control subjects, a one-page questionnaire is distributed to patients in the waiting room to assess contact information as well as data relevant to the case-control matching process. An average of 2,228 questionnaires are returned monthly toward a target pool of 40,000; of these, 59% of the respondents fulfill eligibility criteria as a control subject for one of the studies and are not averse to being contacted in the future for the purpose of research. When compared to former smokers and never smokers, current smokers in the control population were least likely to refuse further contact. A collaborative arrangement with a managed care organization offers a feasible mechanism through which researchers can access a large, ethnically diverse population of potential control subjects.

Adolescent↗

PubMed1997

Management strategies for recurrent non-small cell lung cancer.

Because the benefit of first-line chemotherapy for non-small cell lung cancer (NSCLC) may be marginal, the use of chemotherapy in the second-line setting for the patient who has failed primary platinum-containing chemotherapy (PCC) is similarly debatable. The most experience with second-line chemotherapy for NSCLC is with docetaxel. Two identical studies enrolled 88 good performance status (PS) patients with NSCLC resistant or refractory to prior PCC. The partial response rate was 17%, median survival was 39 weeks, and the 1-year survival rate was 40% (compared with historical controls who had median and 1-year survivals of 16 weeks and 16% [P = .003]). Second-line activity of paclitaxel is less clearly defined: three trials are negative, two are equivocal, and one is positive. Comparison of these studies is difficult, however, because of varying drug doses/schedules, small sample sizes, and/or incomplete data. Median and 1-year survivals (available in two studies) were 17 weeks and 16%. Other agents active against NSCLC have been disappointing in the secondline setting, including vinorelbine, irinotecan, vindesine, mitomycin, and etoposide. In conclusion, docetaxel (and perhaps paclitaxel) may offer some benefit to NSCLC patients whose disease has failed initial PCC. However, the routine use of second-line chemotherapy with a taxane should probably be limited to patients with PS of 0 or 1 only.

Antineoplastic Agents↗

PubMed1997

Correlates of mutagen sensitivity in patients with upper aerodigestive tract cancer.

Although tobacco and alcohol use are the major determinants of upper aerodigestive tract carcinogenesis, not all smokers develop cancer. This phenomenon is due to individual variation in genetic susceptibility to carcinogens. One explanation may be differences in mutagen sensitivity (as measured by the in vitro bleomycin-induced mutagen sensitivity assay) in patients with squamous cell carcinoma of the upper aerodigestive tract. Antioxidant supplementation has also been shown to decrease DNA damage and thus may also inhibit carcinogenesis. In this study, we examined whether smoking, alcohol intake, and dietary antioxidant intake were correlated with mutagen sensitivity. The 612 patients evaluated are part of an ongoing multicenter Phase III trial of 13-cis retinoic acid for the prevention of second primary tumors. We found that patients with pharyngeal cancers were more likely than patients with oral cavity or larynx cancers to be mutagen sensitive. There were no significant differences in the distribution of mutagen sensitivity by sex or alcohol use. Never smokers were significantly more likely (61.1%) to be mutagen sensitive than current smokers (35.6%). Dietary consumption of the micronutrients alpha-carotene, beta-carotene, lutein, lycopene, and vitamin C was not correlated with mutagen sensitivity. Therefore, we suggest that mutagen sensitivity is an independent marker of cancer risk not affected by other known risk factors.

Adult↗

PubMed1997

Recent advances in paclitaxel-containing chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck.

Current chemotherapeutic approaches to recurrent or metastatic head and neck cancer have yielded response rates of 10% to 20% for single agents and 30% to 40% for combination chemotherapy. Median survival for patients with recurrent or metastatic disease treated with single agents or combination chemotherapy is between 4 and 6 months. Investigation of new drugs, therefore, has high priority among clinicians and researchers. One new agent that has been effective as single-agent therapy is paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ). We tested the combination of paclitaxel, ifosfamide, and cisplatin in recurrent or metastatic head and neck cancer. The starting dose of paclitaxel was 175 mg/m2 as a 3-hour infusion on day 1, ifosfamide 1 g/m2 as a 2-hour infusion on days 1 to 3, and cisplatin 60 mg/m2 via 2-hour infusion on day 1. This schedule was repeated every 3 weeks. Sixty-five patients were entered into the study and 62 patients are currently evaluable for response and toxicity in the phase I and phase II portions of this study. We observed 10 (16%) complete responses and 24 (39%) partial responses. The overall response rate was 55% in phases I/II of this interim analysis. In the phase II part alone, we have observed eight (16%) complete responses and 22 (44%) partial responses to date among 50 evaluable patients. Median survival times were 8.9 months for all patients and 9.7 months for patients in the phase II part of the study. Preliminary results demonstrate significant antitumor activity in patients with recurrent or metastatic head and neck cancer. The paclitaxel/ifosfamide/cisplatin regimen was well tolerated. Chemotherapy with paclitaxel/ifosfamide/cisplatin should be tested as an induction regimen in patients with locally advanced head and neck cancer. It also warrants testing in a randomized setting to compare it with a standard regimen, such as the combination of 5-fluorouracil and cisplatin.

Adult↗

PubMed1997

Polyamine measurements in the uterine cervix.

Cervical cancer remains a significant health problem. New strategies based on the molecular aspects of cervical carcinogenesis are needed. Chemoprevention represents a novel strategy for cervical cancer prevention. Our group plans phase I and II trials using alpha-difluoromethylornithine, a suicide inhibitor of ornithine decarboxylase and potent antiproliferative chemopreventive agent. We conducted a study to identify which polyamines in tissue could best serve as surrogate endpoint biomarkers for future trials. Thirty patients with biopsy-proven cervical intraepithelial neoplasia grade 3 underwent colposcopically directed biopsies of normal and abnormal areas of the uterine cervix for analysis of polyamine synthesis biomarkers. Statistically significant differences were found in the ornithine decarboxylase value and the spermidine:spermine ratio between normal and abnormal areas of the cervix. In general, the ranges in measurements varied widely. Differences in polyamine synthesis biomarkers between colposcopically normal and abnormal areas can be demonstrated. However, studies using polyamine synthesis biomarkers in the cervix would require large numbers of patients to achieve significance.

Cervix Uteri↗

PubMed1997

Phase I clinical and pharmacological study of liposome-entrapped NDDP administered intrapleurally in patients with malignant pleural effusions.

cis-Bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II) (NDDP) is a lipophilic non-cross-resistant platinum compound formulated in large multilamellar liposomes (1-3 micrometer). The maximum tolerated dose (MTD) of liposomal-entrapped NDDP (L-NDDP) administered i.v. in humans is 300 mg/m2, and myelosuppresion is the dose-limiting toxicity. L-NDDP administered i.p. is absorbed slowly from the peritoneal cavity of rats. Recently, i.p. cisplatin has been shown to be superior to i.v. cisplatin in improving the survival of patients with ovarian carcinoma and minimal residual disease. We conducted a Phase I study to determine the MTD, side effects, kinetics of absorption into the systemic circulation, and preliminary antitumor activity of L-NDDP administered intrapleurally in patients with free-flowing malignant pleural effusions. Twenty-one patients were treated with escalating doses of L-NDDP by intrapleural administration over 30 min every 21 days. Fourteen patients had adenocarcinoma of the lung, 5 patients had malignant pleural mesothelioma (MPM), and 2 patients had ovarian carcinoma. The dose-limiting toxicity of L-NDDP was chest pain secondary to chemical pleuritis, which was severe in three of four patients treated at 550 mg/m2. The MTD was 450 mg/m2. At this dose, the only toxicity observed was grade 1-2 nausea and vomiting presenting 6-8 h after drug administration. Neither myelosuppression nor nephrotoxicity was observed. Loculation of residual pleural fluid with continued decrease over a period of weeks to months was observed in seven patients; in one of these patients (MPM), the pleural effusion disappeared without evidence of recurrence for 19 + months, and in six patients (three adenocarcinoma of the lung, two MPM, and one ovarian carcinoma), the pleural effusion was reduced by >50% for 5+, 10+, 18+, 8, 5+, and 2+ months. Plasma pharmacokinetic studies showed that the absorption of L-NDDP from the pleural cavity was rapid during the first 2 h, with levels becoming steady (bioavailable or free platinum) or increasing slowly (total plasma platinum) between 6 and 24 h after administration. Urinary excretion was negligible (1-3%). We conclude that: (a) the MTD of intrapleural L-NDDP is 50% higher than the MTD after i.v. administration; (b) intrapleural L-NDDP causes mild nausea and vomiting and no myelosuppression at the MTD; and (c) the absorption of L-NDDP into the systemic circulation is much slower than that of the parent compound cisplatin. Because of the favorable depot effect, lack of systemic toxicity, and control of the pleural effusion in three of five patients with MPM, a disease similar to ovarian carcinoma in that it tends to remain confined to a body cavity, a Phase II study of intrapleural L-NDDP administered in patients with MPM is in progress.

Adenocarcinoma↗

PubMed1997

Accumulation of p53 protein and retinoic acid receptor beta in retinoid chemoprevention.

Although retinoids have proven to be effective as chemopreventive agents in reversing premalignant oral lesions and preventing second primary tumors, their mechanisms of chemopreventive efficacy in clinical settings have not been established. To better define this mechanism, we studied p53 protein and retinoic acid receptor beta (RAR-beta) expression in 52 baseline biopsy samples taken from premalignant oral lesions. We then studied p53 expression in 39 matched samples and RAR-beta expression in 38 matched samples before and after treating them with isotretinoin. The study results were then compared with clinical responses. To detect p53 protein expression, 4-micrometer sections of formalin-fixed, paraffin-embedded tissue specimens were used for immunohistochemical analysis with a monoclonal anti-p53 antibody, and levels of p53 expression were recorded with a labeling index (LI). Expression of RAR-beta mRNA was determined using nonradioactive in situ hybridization, and the staining intensity of RAR-beta mRNA was semiquantitated using scores from 0 (no expression) to 3+ (highest expression). p53 protein was detected in 85% of all lesions. High p53 protein expression (LI >/= 0.2) was detected in 25% of the lesions at baseline and in 18% of the lesions after isotretinoin therapy. The clinical response was 65% for lesions having low p53 expression (LI < 0.2) and 27% for lesions having high p53 expression (P = 0.027). Expression of RAR-beta mRNA was detected in 40% of the patients at baseline and increased to 90% of the patients after isotretinoin therapy (P < 0. 001). Seventy-two percent of the patients having low p53 expression had no RAR-betamRNA expression at baseline, whereas 22% of the patients having high p53 expression had no RAR-beta expression, which suggests that patients having low p53 expression tended to lose RAR-beta mRNA expression in their tissues. Eighty-three percent of patients having low p53 expression had up-regulation of RAR-beta mRNA after isotretinoin therapy, compared with 22% of patients with high p53 expression (P = 0.003). We correlated baseline p53 protein expression with RAR-beta modulation and clinical responses to isotretinoin therapy. The patients with low p53 protein expression at baseline and up-regulation of RAR-beta after isotretinoin therapy achieved a 70% rate of major response. The patients with low p53 protein expression and either no change or down-regulation of RAR-beta or with high p53 expression and up-regulation of RAR-beta had a response rate of 50%. The patients with high p53 protein expression and either no change or down-regulation of RAR-beta had a response rate of only 14% to isotretinoin therapy. The basic mechanisms underlying the association between clinical responses and these two biomarkers need to be explored.

Adult↗

PubMed1996

Telomerase activity in head and neck squamous cell carcinoma and adjacent tissues.

The primary function of telomerase is the synthesis of telomeric DNA, which is the main pathway by which telomere length is maintained in the human germline and stem cells. Activation of telomerase is associated with elongation of telomeres and cell immortalization. Recently, telomerase activity has been detected in tissues from many human cancers but not in the majority of normal tissues, suggesting that telomere stabilization and telomerase activation may play a role in tumorigenesis. To explore telomerase activity in head and neck neoplastic and preneoplastic tissues, we studied 16 head and neck squamous cell carcinoma (HNSCC) cell lines and 60 specimens from 29 patients with HNSCC for telomerase activity. We precisely compared telomerase activity with histological features in adjacent tissue sections. We detected telomerase activity in 16 of 16 (100%) HNSCC cell lines, 26 of 29 (90%) invasive tumors, 7 of 7 (100%) dysplastic lesions, and 5 of 5 (100%) hyperplastic lesions, whereas 0 of 17 normal tissues or 2 hyperkeratotic lesions had detectable telomerase activity. Our data indicate that activation of telomerase activity is frequent in HNSCC and may occur early in the tumorigenesis process. The reactivation of telomerase may be a useful marker for cancer risk assessment in the oral cavity.

Aged↗

PubMed1996

Does induction chemotherapy have a role in the management of nasopharyngeal carcinoma? Results of treatment in the era of computerized tomography.

PURPOSE: To assess the outcomes of patients with nasopharyngeal carcinoma (NPC) whose treatment was determined by computerized tomography (CT) and/or magnetic resonance imaging staging and to analyze the impact of induction chemotherapy and accelerated fractionated radiotherapy. METHODS AND MATERIALS: The analysis is based on 122 of 143 previously untreated patients with NPC treated with radiation therapy at The University of Texas M. D. Anderson Cancer Center between 1983 and 1992. Excluded were 4 patients treated with palliative intent, 4 children, 12 patients not staged with CT, and 1 patient who died of a cerebrovascular accident prior to completion of treatment. The stage distribution was as follows: AJCC Stage I-2, Stage II-7, Stage III-12, Stage IV-101; Tl-15, T2-33, T3-22, T4-52; N0-32, N1-10, N2-47, N3-32, Nx-1. Fifty-nine (48%) patients had squamous cell carcinoma; 63 (52%) had lymphoepitheliomas, undifferentiated NPC or poorly differentiated carcinoma, NOS (UNPC). Sixty-seven patients (65 with Stage IV disease) received induction chemotherapy. Fifty-eight patients (24 of whom had induction chemotherapy) were treated with the concomitant boost fractionation schedule. The median follow-up for surviving patients was 57 months. RESULTS: The overall actuarial 2- and 5-year survival rates were 78 and 68%, respectively. Forty-nine patients (40%) had disease recurrence. Thirty-three (27%) had local regional failures; 19 at the primary site only, 8 in the neck and 6 in both. Local failure occurred in 31% of patients staged T4 compared to 13% of T1-T3 (p = 0.007). Sixteen patients failed at distant sites alone. Among Stage IV patients the 5-year actuarial rates for patients who did and did not receive induction chemotherapy were as follows: overall survival: 68 vs. 56% (p = 0.02), freedom from relapse: 64 vs. 37% (p = 0.01), and local control: 86 vs. 56% (p = 0.009). The actuarial 5-year distant failure rate in patients with UNPC who were treated with induction chemotherapy and controlled in the primary and neck was 13%. In patients who did not receive chemotherapy, the actuarial 5-year local control rates for patients treated with concomitant boost or conventional fractionation were 66 and 67%, respectively. CONCLUSIONS: While not providing conclusive evidence, this single institution experience suggests that neoadjuvant chemotherapy for Stage IV NPC patients improves both survival and disease control. Recurrence within the irradiated volume was the most prevalent mode of failure and future studies will evaluate regimens to enhance local regional control.

Adolescent↗

PubMed1996

Frequent abnormalities of FHIT, a candidate tumor suppressor gene, in head and neck cancer cell lines.

Loss of heterozygosity at the short arm of chromosome 3 occurs frequently in head and neck squamous cell carcinoma (HNSCC). FHIT, a candidate tumor suppressor gene, was recently identified at 3p14.2, and abnormalities of the gene were found in several types of human cancers. To investigate a potential role of the FHIT gene in HNSCC, we examined 16 HNSCC cell lines from 11 patients for abnormalities of the gene by using microsatellite analysis, reverse transcription-PCR, sequencing, and Southern blot analysis. We found that 13 of 16 (81%) cell lines exhibit loss of heterozygosity at 3p14.2. Seven cell lines from six individuals exhibited abnormal transcription patterns, including lack of a FHIT transcript in three lines and shortened transcripts in four lines. A further examination of coding sequences of FHIT in all lines with FHIT transcripts revealed a deletion of exon 4 in one line, a deletion of exons 5 to 7 in one line, and a deletion of exons 5 to 7 plus multiple small insertions between exons 4 and 8 in two lines derived from a primary tumor and a metastasis in the same individual. These results indicate that FHIT may have been inactivated in six cell lines from five (45%) individuals. We also observed two common polymorphism sites at codons 88 and 98 of the gene. These data indicate that abnormal transcription of the FHIT gene is common in HNSCC cell lines; however, other tumor suppressor gene(s) may reside at the same chromosomal region.

Alternative Splicing↗

PubMed1996

Reduced DNA repair capacity in lung cancer patients.

Although lung cancer is the paradigm of a tobacco-induced malignancy, host-specific factors modulate susceptibility to tobacco carcinogenesis. Variations in DNA repair may influence the rate of removal of DNA damage and of fixation of mutations. To test the hypothesis that genetically determined DNA repair capacity (DRC) modulates lung cancer susceptibility, we conducted a pilot case-control study of 51 patients with newly diagnosed, previously untreated lung cancer and 56 controls identified from local community centers and frequency matched to the cases on age, sex, and ethnicity. The subjects were ascertained and interviewed for an ongoing molecular epidemiological investigation of lung cancer susceptibility. We measured DRC in the subjects' peripheral blood lymphocytes by using the host-cell reactivation assay, which measures cellular reactivation of a reporter gene damaged by exposure to 75 microM benzo(a)pyrene diol epoxide. The mean level of DRC in cases (3.3%) was significantly lower than that in controls (5.1%) (P < 0.01). Only nine cases (18%) had DNA repair levels greater than the median value of repair in the controls. This median level of DRC in controls was used as the cutoff value for calculating the odds ratios. After adjustment for age, sex, ethnicity, and smoking status, the cases were five times more likely than the controls to have reduced DRC (odds ratio, 5.7; 95% confidence interval, 2.1-15.7). Younger cases (< 65 years) and smokers were more likely than controls to have reduced DRC. These findings suggest that individuals with reduced DRC are at an increased risk of developing lung cancer.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗

PubMed1996

Benzo(a)pyrene diol epoxide-induced chromosomal aberrations and risk of lung cancer.

Benzo(a)pyrene is considered a classic DNA-damaging carcinogen and is one of a multitude of polycyclic aromatic hydrocarbons commonly found in tobacco smoke and in the ambient environment. In this report, we describe the characteristics of chromosomal aberrations induced in vitro by activated benzo(a)pyrene diol epoxide (BPDE) in lymphocyte cultures of 172 normal individuals ages 19-95 years and present the analysis of a pilot case-control study of 33 lung cancer patients and 96 selected controls without history of cancer and frequency matched on age (50-85 years) to the cases. The BPDE-induced chromosomal aberrations were predominantly single chromatid breaks, with few isochromatid breaks or exchange figures. In the 172 normal subjects, the frequencies of both spontaneous and BPDE-induced chromatid breaks were not correlated with age, sex, ethnicity, or tobacco use. However, the frequency of BPDE-induced chromatid breaks was significantly correlated with the frequency of spontaneous chromatid breaks (r = 0.19, P < 0.05). In addition, Hispanics had significantly higher mean BPDE-induced chromatid breaks than did non-Hispanic whites (P < 0.01). From the case-control analyses, the frequency of BPDE-induced chromosomal aberrations was significantly higher in cases (mean, 0.67 breaks/cell) than in controls (mean, 0.41 breaks/cell; P < 0.0001). An adjusted odds ratio of 6.53 (95% confidence interval, 3.74-11.4) for lung cancer was associated with increased frequency of these chromosomal aberrations. The higher rate of BPDE-induced chromosomal aberrations may be due to inefficient DNA repair. These findings warrant additional molecular epidemiological studies. The BPDE mutagen sensitivity assay will facilitate epidemiological studies of genetic susceptibility to smoking-related cancers.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗