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Biomedical subjects

W K Hong

Publications and source records attributed to W K Hong.

At least 235 records · Page 13Linked to original sources
PubMed1994

Epidemiology, biology, and chemoprevention of aerodigestive cancer.

Cancers of the aerodigestive tract are a major cause of worldwide morbidity and mortality. Long term survival rates for these epithelial cancers have not improved substantially in the past 20 years despite intensive efforts to improve the prevention and therapy of these diseases. Therefore, new approaches are needed. One new investigative approach is chemoprevention, the chemical prevention of cancer. Chemoprevention studies in the upper aerodigestive tract have focused on the reversal of premalignant lesions and the prevention of second primary tumors. These chemoprevention efforts have resulted from an understanding of the multistep nature of epithelial carcinogenesis and the diffuse epithelial injury that results from carcinogen exposure. Ongoing research efforts are attempting to define these processes. The interaction between carcinogen exposure and host susceptibility in the development of cancers of the aerodigestive tract is being evaluated (e.g., with an assay of chromosomal sensitivity to the clastogen bleomycin). This review discusses several new aspects of the epidemiology, biology, and chemoprevention of aerodigestive tract carcinogenesis.

Biomarkers, Tumor↗
PubMed1994

Modulation by retinoic acid (RA) of squamous cell differentiation, cellular RA-binding proteins, and nuclear RA receptors in human head and neck squamous cell carcinoma cell lines.

The ability of all-trans-retinoic acid (RA) to modulate the growth and squamous differentiation of four head and neck squamous cell carcinoma cell lines (183, 886, 1483, and SqCC/Y1) was examined, and the relationship of their state of squamous differentiation and RA responsiveness to the expression of cytosolic RA-binding proteins (CRABPs), nuclear RA receptors (RARs), and retinoid X receptors (RXRs) was investigated. RA inhibited proliferation of all but the 183 cell line and suppressed squamous differentiation markers K1 keratin, type 1 transglutaminase, and involucrin mRNAs and proteins to varying degrees in 183, 1483, and SqCC/Y1 cells. Traces of CRABP-I mRNA were detected only in the 886 cells, whereas CRABP-II mRNA was detected in the other three cell lines. RA suppressed CRABP-II expression in SqCC/Y1 cells but had no effect on its expression in the other cell lines. All cell lines expressed mRNAs for RAR-alpha, RAR-beta, RAR-gamma, and RXR-alpha. The RAR-beta mRNA level was lowest in the SqCC/Y1 cells, and RXR-beta and RXR-gamma were not detected in any of the cell lines. RA treatment increased the levels of the three RAR mRNAs in most of the cell lines but had no effect on the RXR mRNAs. The CRABP-II mRNA level in SqCC/Y1 cells was lowest in cells grown in serum-free medium and increased when the cells were grown in medium with 5 or 10% serum. In contrast, the RXR-alpha mRNA level was inversely related to serum concentration. The results show that, in head and neck squamous cell carcinoma cells, there are no simple relationships among the expression of CRABPs, RARs, and RXRs and either squamous differentiation or response to RA-induced growth inhibition or suppression of squamous differentiation.

Carcinoma, Squamous Cell↗
PubMed1994

Differential expression of nuclear retinoid receptors in normal, premalignant, and malignant head and neck tissues.

Retinoids reverse premalignant lesions and inhibit the development of second primary cancers in patients with upper aerodigestive tract cancers. It is thought that these effects result from the ability of retinoids to restore normal cell growth and differentiation. Since nuclear retinoid receptors (RARs and RXRs) are the ultimate mediators of retinoid actions, alterations in their expression could lead to cancer development. To determine whether the expression of the mRNAs of the receptors is related to the development of head and neck squamous cell carcinoma (HNSCC), we used digoxigenin-labeled antisense riboprobes of RAR-alpha, RAR-beta, RAR-gamma, RXR-alpha, and RXR-beta for in situ hybridization to histological sections of specimens from 7 normal volunteers and 31 HNSCC patients. All 31 tissue specimens contained carcinomas, 16 also contained dysplastic lesions, 22 also contained hyperplastic lesions, 17 also contained adjacent normal tissue, and 6 contained all 4 types of tissue. All specimens from normal volunteers expressed the 5 receptors. Similar levels of RAR-gamma and RXR-alpha and RXR-beta mRNAs were detected in most of the adjacent normal, hyperplastic, dysplastic, and malignant tissues. RAR-alpha mRNA was detected in 94% of adjacent normal tissues and hyperplastic tissues, in 87% of dysplasias, and in 77% of HNSCCs. In contrast, RAR-beta mRNA was detected in about 70% of adjacent normal and hyperplastic lesions, and its expression decreased further to 56% of dysplastic lesions and to 35% of HNSCCs. The difference in RAR-beta level in carcinoma and adjacent normal tissues was significant (P < 0.05). These results indicate that the decreased expression of RAR-beta may be associated with HNSCC development.

Carcinoma, Squamous Cell↗
PubMed1994

Dysregulation of epidermal growth factor receptor expression in premalignant lesions during head and neck tumorigenesis.

The development of head and neck cancer, believed to result from field cancerization and a multistep process of tumorigenesis, is often associated with an accumulation of genotypic and phenotypic alterations. The phenotypic changes could be the result of dysregulation of growth control genes such as epidermal growth factor receptor (EGFR). With the goal of identifying a potential biomarker of the multistep process of tumorigensis, we studied specimens of 36 head and neck squamous cell carcinomas from 5 different sites that contained normal epithelia and/or premalignant lesions adjacent to the tumors. Almost all of the individuals from whom these specimens were obtained had been exposed to first-hand smoking and/or alcohol consumption. Using a monoclonal anti-EGFR antibody for immunohistochemical analysis on paraffin-embedded sections with attached 886 cells for internal control, the levels of EGFR expression were assessed by image analysis. The relative staining intensity of EGFR in normal epithelia adjacent to tumors was 2-fold higher than that in normal control epithelium (P = 0.021), suggesting that, even in histologically normal epithelium, EGFR was already up-regulated in tissues surrounding tumors. These findings supported the theory of field cancerization in head and neck tumorigenesis. As tissue progressed from normal tissue adjacent to tumor to hyperplasia and to dysplasia, EGFR expression remained elevated. However, in the step from dysplasia to squamous cell carcinoma, EGFR expression was further and dramatically up-regulated (P = 0.01). Therefore, these results indicate that EGFR dysregulation happens in two steps, the moderate up-regulation of EGFR expression in normal epithelium adjacent to tumor and the further up-regulation of EGFR expression in the change from dysplasia to squamous cell carcinoma. In summary, the studies presented here indicate that EGFR dysregulation might be a useful marker for identifying individuals at risk of tumor development and an intermediate end point in chemoprevention trials.

Adult↗
PubMed1994

Thymoma. A retrospective study of 87 cases.

BACKGROUND: The authors retrospectively analyzed 87 patients with malignant thymoma treated at M.D. Anderson Cancer Center between 1951 and 1990. The analysis examined the clinical stages, histologic types, and treatment modalities and attempted to determine if chemotherapy had an impact on survival. METHODS: The patients were divided into three groups by their year of treatment and treatment modality. Patients treated between 1951 and 1975 were in Group I; patients treated between 1976 and 1980 were in Group II; and patients treated between 1981 and 1990 were in Group III. Most of the patients (18 [72%] in Group I; 16 [62%] in Group II; and 18 [50%] in Group III) had surgical resection alone or with radiotherapy. Patients with advanced-stage disease in Group I received single-agent chemotherapy, whereas patients with advanced-stage disease in Group II received a different, combination chemotherapy regimen, and those in Group III were treated primarily with cisplatin- and doxorubicin-based combination chemotherapy, e.g., the cyclophosphamide doxorubicin, and cisplatin with or without prednisone. The 17 patients treated with cisplatin with or without prednisone were separately evaluated for survival according to their response. RESULTS: Twenty-eight patients (5 [20%] in Group I; 6 [23%] in Group II; and 17 [47%] in Group III) received chemotherapy alone or after surgery or radiotherapy. The cisplatin with or without prednisone regimen was used in 17 Group III patients for initial treatment or for relapse. The overall response rate among the patients receiving the cisplatin with or without prednisone regimen was 64%; 6 (35%) had a complete response, and 5 (29%) had a partial response. Thirty-one (36%) of the 87 total patients had 45 recurrent tumors; the lung (29%), pleura (22%), and mediastinum (18%) were the most common sites of recurrence, whereas bone was the most common distant metastatic site. The 5-year survival rate was 70% in patients with Stage I disease, 71% in patients with Stage II or III disease, and 46% in patients with Stage IV disease. The 10-year survival rate was 70% in patients with Stage I disease, 47% in patients with Stage II or III disease, and 21% in patients with Stage IV disease. Statistical analysis indicated a significant difference among the survival rates of patients with noninvasive Stage I, invasive Stage II plus III (P = 0.033), and Stage II plus III and IV tumors (P = 0.056), but not between patients with Stage II or III tumors. Patients with a major response to the cisplatin with or without prednisone regimen had a significant survival improvement compared to those with no response (P = 0.002, log-rank test). CONCLUSIONS: Because thymoma is a chemosensitive tumor and frequently recurs in patients with Stage II or greater disease, chemotherapy carries a potential survival benefit and should be incorporated into the multimodality approach to prolong disease-free survival.

Adolescent↗
PubMed1994

Retinoid chemoprevention studies in upper aerodigestive tract and lung carcinogenesis.

Chemoprevention is a clinical strategy to block or reverse carcinogenesis before the development of invasive cancer. Studies of chemoprevention in the lungs and upper aerodigestive tract have relied on the field carcinogenesis hypothesis, which predicts that diffuse epithelial injury will result from exposure of that epithelium to carcinogens. This hypothesis is supported by the frequent occurrence of multiple primary tumors within the exposed field. In addition, the understanding of carcinogenesis as a multistep process supports the use of interventions in damaged epithelium before the development of clinically invasive cancer. Current efforts are focused on applying to chemoprevention studies the increasing knowledge of the molecular events in carcinogenesis. In our program, clinical trials in lung and head and neck chemoprevention have focused on individuals with evidence of field carcinogenesis, i.e., a history of previous epithelial cancer or the presence of premalignant lesions. These trials include studies to develop clinically applicable intermediate markers of carcinogenesis and large Phase III trials to evaluate the efficacy of the retinoid isotretinoin in preventing second primary tumors following head and neck or lung cancers.

Anticarcinogenic Agents↗
PubMed1994

Activation of p53 gene expression in premalignant lesions during head and neck tumorigenesis.

With the goal of identifying a potential intermediate biomarker in the multistep process of head and neck cancer development, we conducted immunohistochemical analyses for p53 expression in 33 patients with head and neck squamous cell carcinomas whose tissue sections contained adjacent normal epithelium, hyperplastic, and/or dysplastic lesions. Fifteen of 33 (45%) squamous cell carcinomas of the head and neck expressed p53, but none of four normal control patients (cancer-free nonsmokers) expressed detectable p53 in oral mucosa specimens. To determine when p53 expression is initiated during head and neck tumorigenesis, we examined the normal and premalignant lesions adjacent to the tumors. Five of 24 (21%) samples of normal epithelium adjacent to tumors, 7 of 24 (29%) samples of hyperplasia, and 9 of 20 (45%) samples of dysplasia expressed p53. Quantitative image analysis demonstrated not only a gradual increase in the amount of p53 expression as tissue abnormalities progressed but also a topological change in expression. Whereas p53 expression, when present, was limited to the basal layer in normal epithelium adjacent to tumor, the expression of p53 expanded into the parabasal and superficial layers in hyperplasia and dysplasia. We conclude that p53 expression can be altered in very early phases of head and neck tumorigenesis. Thus, it may be an excellent candidate for risk assessment and may serve as an intermediate biomarker in chemoprevention trials.

Base Sequence↗
PubMed1994

Phase II study of carboplatin and edatrexate (10-EdAM) with leucovorin rescue for patients with recurrent squamous cell carcinoma of the head and neck.

Recurrent squamous cell carcinoma of the head and neck is poorly responsive to chemotherapy in most patients; therefore, the development of new approaches is essential. Edatrexate is a new antifolate with improved preclinical antitumor activity when compared to methotrexate. The purpose of this study was to define the feasibility and efficacy of combining edatrexate with another active single agent, carboplatin in chemotherapy-naive recurrent disease. Carboplatin was given as an outpatient on day 1 at a dosage based on the formula: Dose (mg/m2) = (0.091) (creatinine clearance) (body surface area) (desired percentage change in platelet count) + 86. Edatrexate (80 mg/m2) was given on days 1, 8, and 15 of a 21 day cycle. Calcium leucovorin 15 mg was given orally every 6 h for 4 doses after edatrexate. Of the 26 patients entered on the study, 1 was invaluable for toxicity or response and 3 patients were evaluable for toxicity only. Grade 3 or 4 neutropenia occurred in 2 patients each, and grade 3 or 4 thrombocytopenia occurred in 2 and 4 patients, respectively. Grade 3 stomatitis occurred in only two patients. Overall, major responses occurred in 2 of 22 evaluable patients (9%). The combination of carboplatin and edatrexate was not superior to the results expected with either agent alone.

Adult↗
PubMed1994

Phase I/II study of cisplatin, 5-fluorouracil and alpha-interferon for recurrent carcinoma of the head and neck.

Current chemotherapy regimens have failed to demonstrate a significant impact on the overall survival of patients with recurrent head and neck cancer; therefore, new agents or combinations of agents are necessary to improve outcome. Alpha-interferon potentiates the activity in vitro of both agents of one of the most active regimens currently available, cisplatin and 5-fluorouracil. The purpose of the current study was to evaluate the feasibility and efficacy in patients with recurrent head and neck cancer of adding alpha-interferon to cisplatin 14 mg/m2 daily and 5-fluorouracil 700 mg/m2 daily for 5 days. No significant toxicity occurred with alpha-interferon at dose level 0, 1 x 10(6) units/m2 daily for five days. Of four patients treated at dose level +1, alpha-interferon 3 x 10(6) units/m2, two developed prolonged grade III neutropenic following the fourth course. One of three patients developed grade IV thrombocytopenia and 6 of 13 courses at this dose level resulted in grade III neutropenia. A phase II study was performed in 19 patients with cisplatin 17 mg/m2/day, 5-fluoruracil 700 mg/m2/day and alpha-interferon 3 x 10(6) units/m2/day. During the phase II study grade III neutropenia occurred in 6 patients and grade IV neutropenia in another patient during at least one course. Grade III and IV thrombocytopenia occurred in one patient each during the phase II study. Overall, major responses occurred in 7 or 23 patients (30%): 5 in phase I and 2 in phase II. In conclusion, the addition of alpha-interferon to cisplatin and 5-fluorouracil is feasible, but does not appear to increase response rates in recurrent head and neck cancer.

Adult↗
PubMed1994

Phase II clinical trial of didemnin B in previously treated small cell lung cancer.

Didemnin B (NSC 325319), a cyclic depsipeptide isolated from a Carribean sea tunicate, exhibited potent antitumor activity in preclinical studies. After determining the maximum tolerated dose in our previous phase I/II trial, we conducted a phase II study of this drug in patients with previously treated small cell lung cancer; the starting dose was 6.3 mg/m2 intravenously over 30 min every 28 days. The major side effects were in the neuromuscular system and included severe muscle weakness, myopathy and/or myotonia by electromyography, and elevation of creatine phosphokinase and aldolase levels. We also observed modest increases in bilirubin and alkaline phosphatase levels. There were minimal hematologic toxic effects. No response was observed among 15 evaluable patients, leading us to conclude that didemnin B was toxic but inactive in patients with previously treated small cell lung cancer at the stated dose and schedule. A review of the literature revealed no significant antitumor activity in cancers of the colon, breast, ovaries, cervix, or lung (non-small cell) or in renal cell carcinoma. Further clinical trials for didemnin B may not be warranted at the stated dose and schedule.

Adult↗
PubMed1994

Detection of nuclear retinoic acid receptor mRNA in histological tissue sections using nonradioactive in situ hybridization histochemistry.

Nuclear retinoic acid receptors (RARs) function as ligand-activated trans-acting transcription factors and mediate the effects of retinoids on gene expression, cell growth, and differentiation. Determination of the receptors' expression in premalignant and malignant lesions may provide prognostic value and direct the selection of receptor-specific retinoids in cancer prevention or treatment. We describe a sensitive and practical in situ hybridization method for the analysis of RARs in tissue sections of fixed and embedded surgical specimens. Digoxigenin-labeled antisense and sense RNA probes were prepared for nuclear RAR-alpha, RAR-beta, and RAR-gamma. The specificity of the probes for their respective receptor mRNAs was demonstrated by Northern blot hybridization to total RNA extracted from murine and human cells. Optimal conditions for in situ localization of the RAR mRNA were established using cultured tumor cells, and these conditions were then used for the detection of RAR mRNA in formalin-fixed, paraffin-embedded sections of surgical specimens from human tumors. The hybridization stain was detected in the cytoplasm (where it was expected to be localized) and not seen in the cell nucleus. This method provides a rapid detection procedure with good resolution that allows one to clearly distinguish strongly and weakly stained cells. A comparison of receptor expression in head and neck squamous carcinoma specimens and in adjacent normal tissues revealed a significant decrease in the level of RAR-beta mRNA in the tumor cells.

Animals↗