Biomedical subjects

W M Koch

Publications and source records attributed to W M Koch.

At least 37 records · Page 2Linked to original sources

PubMed1999

Head and neck cancer in nonsmokers: a distinct clinical and molecular entity.

OBJECTIVES/HYPOTHESIS: Clinical and molecular patterns of head and neck squamous cell carcinoma (HNSCC) in nonsmokers and smokers may be different. Analysis of these patterns may improve understanding and management of this disease. STUDY DESIGN: three hundred five subjects were included (46 nonsmokers, 29 former smokers, and 230 smokers). Subsets were analyzed for p53 mutation, human papillomavirus (HPV), and loss of heterozygosity (LOH) at 10 chromosomal loci. METHODS: Clinical information was analyzed for common patterns of disease among the groups. The p53 gene was sequenced, and polymerase chain reaction was used to detect HPV DNA and LOH at two microsatellite markers for each loci. The chi2 test was used to assess differences in genetic alterations between groups, logistic regression to examine the independence of association of tobacco exposure with each alteration, and Kaplan Meier estimates and the log-rank statistic to assess differences in survival. RESULTS: Nonsmokers included a disproportionate number of women, oral cavity (especially tongue) tumors, and very young or old individuals. Smokers had more tumors of the larynx, hypopharynx, and floor of mouth. The rate of p53 mutation was much greater in smokers; the percentage with HPV was marginally lower. The percentage of LOH at 3p, 4q, and 11q13, and the overall average number of chromosomal losses, was significantly lower in nonsmokers' tumors. Survival did not vary with smoking or age. CONCLUSIONS: The clinical and genetic features of HNSCC are distinct between groups defined by tobacco use. Tumors of nonsmokers contain a lower frequency of common genetic alterations, suggesting that the underlying changes in these tumors may remain undiscovered.

Adolescent↗

PubMed1999

Second esophageal tumors in patients with head and neck squamous cell carcinoma: an assessment of clonal relationships.

Patients with squamous cell carcinoma of the head and neck (HNSCC) often develop second carcinomas elsewhere in the upper aerodigestive tract. Some of these paired tumors share a common origin, reflecting the ability of a single progenitor cell to replicate, expand, and populate contiguous regions of the upper aerodigestive tract-a process referred to as clonal expansion. The geographical limitations of clonal expansion, however, have not been adequately addressed. For example, it is not known whether a neoplastic clone from the oral cavity, pharynx, or larynx can migrate to the esophagus. We compared paired tumors from 16 patients with HNSCC and a second squamous cell carcinoma of the esophagus (ESCC) for patterns of allelic loss on chromosomal arms 3p, 9p, and 17p. Losses at these loci occur early during neoplastic transformation of the respiratory tract. In 14 cases (87%), the paired tumors had discordant patterns of allelic loss, suggesting that these tumors were not clonally related. Conversely, two (13%) of the 16 paired tumors had identical genetic alterations, which suggests clonal expansion as the mechanism underlying tumor multifocality. One clone spread from the hypopharynx into the cervical esophagus, and the other spread from the tonsil to the distal esophagus. Although most second ESCCs appear to arise as independent neoplasms, a clonal population of neoplastic cells is capable of traveling across substantial distances to give rise to second tumors at different anatomical sites.

Carcinoma, Squamous Cell↗

PubMed1998

Distinguishing second primary tumors from lung metastases in patients with head and neck squamous cell carcinoma.

BACKGROUND: In patients with head and neck squamous cell carcinoma (HNSCC), a squamous cell carcinoma (SCC) in the lung represents either another primary tumor or a metastasis. This distinction greatly influences patient prognosis and could guide treatment strategies, but the nature of a solitary lung nodule is often difficult to discern by use of standard clinical and histologic parameters. Comparison of genetic alterations in the tumors could resolve this dilemma. METHODS: We compared paired tumors from 16 patients with HNSCC and a solitary lung SCC for loss (i.e., deletion) of loci on chromosomal arms 3p and 9p. Losses at these loci occur early during neoplastic transformation of the respiratory tract. DNA from microdissected tumors and normal tissues was subjected to polymerase chain reaction-based microsatellite analysis. An effort was also made to distinguish primary lung cancers from lung metastases on the basis of clinical and histopathologic features. RESULTS: In most cases, comparison of genetic alterations clarified the relationship between the lung tumor and the primary HNSCC. The paired tumors from 10 patients had concordant patterns of loss at all loci suggesting metastatic spread, whereas three paired tumors had discordant patterns of loss at all loci suggesting independent tumor origin. These observations were supported by the clinical and pathologic findings. CONCLUSIONS/IMPLICATIONS: In patients with HNSCC and a solitary SCC in the lung, microsatellite analysis provides a rapid genetic approach for discerning clonal relationships. In such patients, we found that a solitary SCC in the lung more likely represents a metastasis than an independent lung cancer. Microsatellite analysis could potentially be applied to any patient with multiple tumors, where tumor relationships are not clear on clinical, radiographic, or even histopathologic grounds.

Adult↗

PubMed1998

Analysis of PTEN/MMAC1 alterations in aerodigestive tract tumors.

PTEN/MMAC1 is a candidate tumor suppressor gene recently identified at chromosomal band 10q23. It is mutated in sporadic brain, breast, and prostate cancer and in the germ line of patients with hereditary Cowden disease. We searched for genetic alterations of the PTEN/MMAC1 gene in 39 primary head and neck cancers (HNSCCs), 42 primary non-small cell lung cancers (NSCLCs), 80 pancreatic cancer xenografts, and 37 cell lines and xenografts from colon, lung, and gastric cancers. Microsatellite analysis revealed loss of heterozygosity at markers near the gene in 41% of primary HNSCCs, 50% of NSCLCs, and 39% of the pancreatic cancers. Three cases of HNSCCs displayed homozygous deletion involving the gene. We sequenced the entire coding region of the PTEN/MMAC1 gene in the remaining tumors displaying loss of heterozygosity and found one terminating mutation in a HNSCC sample. Thus, a second inactivation event was observed in 4 of 39 primary HNSCC cases. By use of a protein truncation assay, one terminating mutation was also identified in one of eight NSCLC cell lines. Our results suggest that PTEN/MMAC1 gene inactivation plays a role in the genesis of some tumor types.

Carcinoma, Non-Small-Cell Lung↗

PubMed1998

Gamma probe-directed biopsy of the sentinel node in oral squamous cell carcinoma.

OBJECTIVE: Management of the N0 neck in head and neck squamous cell carcinoma is an important issue for the head and neck surgeon. Experience with radionuclide-labeled colloid injection to identify a sentinel node in malignant melanoma suggests a high level of accuracy for this approach to identify microscopic metastasis when present. We set out to explore the feasibility of using the handheld gamma probe to identify radiolabeled sentinel nodes in oral squamous cell carcinoma. PATIENT POPULATION: Five individuals with N0 necks and accessible oral or oropharyngeal primary sites from a major tertiary referral center. METHODS: Radiolabel with unfiltered technetium Tc 99m sulfur colloid was injected in quadrants around the primary site followed by immediate dynamic lymphoscintigraphy. Open biopsy of the sentinel node was accomplished within 2 hours of injection after extirpation of the primary site. Regional or complete neck dissection was performed after sentinel node biopsy. RESULTS: Sentinel node biopsy accurately identified one or several nodes in 2 cases, including nodes containing metastatic cancer in 1. In the other 3 cases, the radiolabel failed to identify the sentinel node despite the presence of metastatic disease in the nodes at final pathologic study in 2. CONCLUSIONS: Detection and biopsy of the sentinel node are feasible for selected patients with oral head and neck squamous cell carcinoma with N0 necks. There is a potential savings of time, cost, and morbidity with this approach. However, several substantial problems were encountered with the technique in this limited series of patients. Establishing the reliability of lymphoscintigraphy in this setting would require testing in a much larger patient cohort. Our experience suggests that such an investment may not be warranted.

Adult↗

PubMed1998

Lack of BRCA2 alterations in primary head and neck squamous cell carcinoma.

We previously demonstrated that loss of 13q occurred in greater than 50% of primary head and neck squamous cell carcinomas. Although the minimal region of loss at 13q14.1-14.3 included the Rb1 gene, Rb1 inactivation was found to be rare. To further investigate possible targets of 13q loss in head and neck cancer, 32 primary tumors were fine mapped by microsatellite analysis with the use of 10 new markers spanning the minimal region. Twenty-one (66%) of 32 tumors displayed loss of heterozygosity and once again the minimal region of loss was confirmed to be 13q14.1-14.3. In addition to 6 monosomies, 11 tumors had regions of loss that either selectively deleted (one tumor) or stretched into the BRCA2 region 13q12-13 (10 tumors). Therefore we pursued investigation of the BRCA2 gene by a coupled transcription and translation assay of its largest exon (exon 11; 4932 base pairs) to detect functional truncations indicative of mutation in 37 primary head and neck tumors with 13q loss. These tumors included 17 of the 32 tumors recently analyzed and 20 other tumors with 13q loss from a previous study. Additionally, we performed the transcription and translation assay on five head and neck cancer cell lines. We found no alterations in exon 11 of the BRCA2 gene in any of the tumors or cell lines suggesting that perhaps another tumor suppressor gene on 13q is involved in head and neck cancer.

BRCA2 Protein↗

PubMed1998

Occult tonsillar carcinoma in the unknown primary.

OBJECTIVES: Evaluate effectiveness of routine tonsillectomy in the assessment of patients with squamous cell carcinoma of the neck of unknown primary, and evaluate outcomes of this group compared with patients without a primary identified initially. STUDY DESIGN: A retrospective review of the medical records of 37 patients presenting with an unknown primary tumor over a 10-year period. METHODS: Charts were reviewed for age and sex of patients, methods of evaluation and diagnosis, sites of tissues obtained on biopsy, N stage of disease, and presence of extracapsular spread. Recurrence and survival data were collected over a mean follow-up period of 34 months. RESULTS: All primary lesions discovered through pathologic evaluation arose from the tonsil (9/9), and all were detected in patients undergoing tonsillectomy in conjunction with direct laryngoscopy. None of the patients (0/9) with occult tonsillar carcinoma have had recurrence, in contrast to 60% (15/25) of remaining patients. Patients with tonsillar primary lesions demonstrated less extracapsular spread of disease (25%) than patients without tonsillar primaries (67%), despite similar N staging within the two groups. CONCLUSIONS: Occult tonsillar carcinoma accounts for the unknown primary more frequently than was previously recognized. Bilateral tonsillectomy is recommended to increase the detection yield and to capture the rare case of bilateral disease. A lower incidence of extracapsular spread and reduced recurrence rates in patients with unknown primary tumors presenting as occult tonsillar carcinoma may contribute to the improved prognosis observed in this group.

Adult↗

PubMed1997

Clinical and molecular aspects of squamous cell carcinoma of the head and neck in the nonsmoker and nondrinker.

Most molecular analyses of head and neck squamous cell carcinoma involve patients who have used tobacco and alcohol. The pathways involved in tumorigenesis in patients lacking these lifestyle risks may be quite different. Research involving rigorous epidemiologic and molecular methods is needed to identify the unique spectra of genetic alterations in subsets of the population. This review considers recent information on the accumulation of genetic changes in the typical head and neck squamous cell carcinoma population and several studies that attempt to analyze subsets of patients categorized by age, gender, and carcinogen exposure. Efforts to identify risk factors in nonsmoking and nondrinking head and neck squamous cell carcinoma patients are evaluated, including studies of family history, human papillomavirus, chromosome fragmentability, microsatellite instability, and carcinogen-metabolizing enzyme genotype.

Alcohol Drinking↗

PubMed1997

Impact of chromosome 14q loss on survival in primary head and neck squamous cell carcinoma.

We screened 73 primary head and neck squamous cell carcinoma (HNSCC) specimens for loss of heterozygosity (LOH) on chromosome 14q. Analysis of 20 polymorphic microsatellite markers identified 29 (40%) HNSCCs exhibiting LOH of 14q in at least one locus. Six tumors had probable monosomy of 14q, displaying allelic loss for all informative markers tested, and 23 demonstrated partial losses on 14q. Fine mapping with 1-10 additional markers revealed two poorly defined regions of loss (4-7 cM) at 14q13-21 and 14q31-32.1 in seven tumors. In 53 patients with previously untreated tumors treated with curative intent, LOH of 14q in these tumors correlated with poor survival. Compared to patients with tumors that retain heterozygosity of 14q, those with 14q LOH had a 3-fold increased risk of death in multivariate analysis (hazards ratio, 3.2; 95% confidence interval = 1.2-8.4). These data have confirmed a high frequency of chromosome 14q loss in HNSCC and suggest that LOH of any region on chromosome 14q is an indicator of poor outcome.

Adult↗

PubMed1996

An allelotype of papillary thyroid cancer.

Although papillary carcinoma accounts for approximately 70% of all thyroid cancers, preliminary studies of allelic loss have thus far not identified any areas of chromosomal deletion. We evaluated 30 papillary thyroid carcinomas for chromosomal loss/allelic imbalance by testing at least 2 microsatellite markers from every autosomal arm. Fifteen of the 30 tumors tested exhibited loss of heterozygosity/allelic imbalance (LOH/AI) at one or more loci. Chromosomal arms with frequent LOH/AI included 4q, 5p, 7p and 11p. An average of 1.1 chromosomal arms displayed LOH/AI in each individual tumor. Therefore, 4q, 5p, 7p and, to a lesser extent, 11p display significant LOH/AI in papillary thyroid cancer, which indicates the presence of putative tumor-suppressor gene loci at these chromosomal arms.

Alleles↗

PubMed1996

Detection of telomerase activity in oral rinses from head and neck squamous cell carcinoma patients.

Telomerase is a ribonucleoprotein that maintains telomere length and whose activity is associated with escape from cellular senescence. Telomerase activity has been found in germline, immortalized, and malignant tumor cells. Using a modified PCR-based assay for telomerase activity, 26 of 35 (80%) primary, fresh, head and neck squamous cell cancer specimens and 3 of 6 head and neck squamous dysplastic lesions possessed telomerase activity. In addition, 14 of 44 (32%) oral rinses from a separate group of head and neck squamous cell cancer patients contained detectable telomerase activity, whereas 1 of 22 (5%) oral rinses from normal control patients exhibited telomerase activity. Telomerase activity in oral rinses was compared with corresponding activity in paired primary tumor samples for 19 cases: 7 of 19 demonstrated activity in both tumor and oral rinse, 2 of 19 lacked activity in both tumor and oral rinse, 10 of 19 tumors demonstrated activity that could not be detected in corresponding oral rinses, and there were no examples of positive oral rinses with corresponding negative tumors. Although currently limited in its sensitivity, analysis of telomerase activity in oral rinses represents a novel method to detect the presence of cancer cells shed in the upper aerodigestive tract.

Carcinoma, Squamous Cell↗

PubMed1996

p53 mutation and locoregional treatment failure in head and neck squamous cell carcinoma.

BACKGROUND: The p53 gene (also known as TP53) may be the most common genetic target involved in the malignant transformation of human cells. Direct sequence analysis has demonstrated that alteration of this gene occurs in approximately 45% of head and neck squamous cell carcinomas. The consequences of p53 mutations in these cancers with respect to tumor behavior and patient survival have not been rigorously determined. PURPOSE: We evaluated the implications of p53 mutations in relation to the control of locoregional disease and overall survival following radiation therapy. METHODS: Data from 110 consecutive patients with invasive disease who were treated with primary radiation therapy (given with curative intent) or with adjuvant radiation therapy (following complete surgical extirpation of gross disease) were included in the analysis. A 1.8-kilobase fragment of the p53 gene encompassing exons 5-9 was amplified from the DNA of stored (frozen) tumor specimens; the amplified DNA was cloned and sequenced by use of standard techniques. Overall survival and locoregional disease-free survival after the completion of radiation therapy were estimated by the Kaplan-Meier method; survival comparisons were made by use of the logrank test or proportional hazards regression models. Reported P values are two-sided. RESULTS: Fortyeight (44%) of the 110 tumors had cells bearing p53 mutations. The risk of locoregional recurrence following either primary or adjuvant radiation therapy was significantly greater (i.e., the time to recurrence was shorter) for patients whose tumors contained mutant p53 genes (univariate model hazard ratio [HR] for p53 mutation versus wild-type = 2.2; 95% confidence interval [CI] = 1.2-4.1; P = .02). The presence of regional lymph node metastases (presence versus absence, HR = 2.0; 95% CI = 1.0-4.2; P = .05) and treatment type (primary radiation therapy versus surgery plus adjuvant radiation therapy, HR = 2.3; 95% CI = 1.2-4.3; P = .01) were also associated with greater risks of locoregional failure. The presence of p53 mutations and lymph node metastases and treatment with primary, as opposed to adjuvant, radiation therapy remained significant risk factors in multivariate regression analysis. No relationship was demonstrated between p53 status and overall survival (mutant versus wild-type, HR = 1.1; 95% CI = 0.6-2.1; P = .66); however, a relationship was shown for tumor stage and overall survival (stages III and IV [more advanced] versus stages I and II [less advanced], HR = 3.3; 95% CI = 1.0-10.8; P = .05). Mutation of the p53 gene was not associated with patient age, sex, tumor stage, primary tumor site, regional lymph node status, degree of tumor cell differentiation, or treatment method. CONCLUSIONS: Mutation of the p53 gene is associated with an increased risk of locoregional failure in patients with invasive head and neck squamous cell carcinoma who are treated with radiation therapy.

Carcinoma, Squamous Cell↗

PubMed1996

Allelotype of salivary gland tumors.

To elucidate the genetic alterations that occur in salivary gland tumors, we screened every autosomal arm (and the X-chromosome) of 29 primary human salivary gland neoplasms (11 pleomorphic adenomas, 10 adenoid cystic carcinomas, 5 mucopidermoid carcinomas, and 3 carcinomas ex-mixed tumors) for allelic loss using 86 microsatellite markers. A minimum of two microsatellite markers were used per chromosomal arm to achieve informativity of at least 60% (excluding X). The pleomorphic adenomas demonstrated few areas of allelic loss; the most prominent chromosomal arm involved was 12q, lost in more than 35% of informative cases. The most significant allelic losses in adenoid cystic carcinoma were 1p, 2p, 6q, 17p, and 20p (>20% of informative cases) and 19q (40% of informative cases). Mucoepidermoid carcinoma showed 50% or greater loss at 2q, 5p, 12p, and 16q. Although losses at 9p, 3p, and 17p are common in squamous cell carcinoma of the head and neck, only the carcinoma ex-mixed tumors demonstrated loss at these loci, consistent with progression to a more aggressive phenotype. Salivary gland tumors display allelic loss patterns different from many other tumor types, suggesting distinct genetic pathways in the progression of these tumors.

Alleles↗

PubMed1995

Association between cigarette smoking and mutation of the p53 gene in squamous-cell carcinoma of the head and neck.

BACKGROUND: Although epidemiologic studies have long associated tobacco and alcohol use with the development of squamous-cell carcinoma of the head and neck, the molecular targets of these carcinogens have yet to be identified. We performed a molecular analysis to determine the pattern of mutations in the p53 gene in neoplasms from patients with squamous-cell carcinoma of the head and neck and a history of tobacco or alcohol use. METHODS: Sequence analysis of the conserved regions of the p53 gene was performed in tumor samples from 129 patients with primary squamous-cell carcinoma of the head and neck. We then used statistical analysis to identify any patient characteristics associated with mutation of the p53 gene. RESULTS: We found p53 mutations in 42 percent of the patients (54 of 129). Fifty-eight percent of the patients who smoked cigarettes and used alcohol (37 of 64; 95 percent confidence interval, 45 to 70 percent), 33 percent of the patients who smoked but abstained from alcohol (13 of 39; 95 percent confidence interval, 19 to 50 percent), and 17 percent of the patients who neither smoked nor drank alcohol (4 of 24, 95 percent confidence interval, 5 to 37 percent) had p53 mutations (P = 0.001). (Two patients used alcohol but did not smoke, and neither had a p53 mutation.) Furthermore, 100 percent of the mutations in the patients who neither drank nor smoked occurred at sites containing cytidine phosphate guanosine dinucleotides (potentially representing endogenous mutations) within the p53 gene (5 of 5 mutations; 95 percent confidence interval, 48 to 100 percent), whereas only 23 percent of those in cigarette smokers consisted of such changes (12 of 53 mutations; 95 percent confidence interval, 12 to 36 percent; P = 0.001). CONCLUSIONS: In our study, a history of tobacco and alcohol use was associated with a high frequency of p53 mutations in patients with squamous-cell carcinoma of the head and neck. Preliminary evidence linked cigarette smoking to p53 mutations at nonendogenous mutation sites. Our findings suggest a role for tobacco in the molecular progression of squamous-cell carcinoma of the head and neck and support the epidemiologic evidence that abstinence from smoking is important to prevent head and neck cancer.

Base Composition↗

PubMed1995

Molecular assessment of histopathological staging in squamous-cell carcinoma of the head and neck.

BACKGROUND: Surgical oncologists rely heavily on the histopathological assessment of surgical margins to ensure total excision of the tumor in patients with head and neck cancer. However, current techniques may not detect small numbers of cancer cells at the margins of resection or in cervical lymph nodes. METHODS: We used molecular techniques to determine whether clonal populations of infiltrating tumor cells harboring mutations of the p53 gene could be detected in histopathologically negative surgical margins and cervical lymph nodes of patients with squamous-cell carcinoma of the head and neck. RESULTS: We identified 25 patients with primary squamous-cell carcinoma of the head and neck containing a p53 mutation who appeared to have had complete tumor resection on the basis of a negative histopathological assessment. In 13 of these 25 patients, molecular analysis was positive for a p53 mutation in at least one tumor margin. In 5 of 13 patients with positive margins by this method (38 percent), the carcinoma has recurred locally, as compared with none of 12 patients with negative margins (P = 0.02 by the log-rank test). Furthermore, molecular analysis identified neoplastic cells in 6 of 28 lymph nodes (21 percent) that were initially negative by histopathological assessment. CONCLUSIONS: Among specimens initially believed to be negative by light microscopy, a substantial percentage of the surgical margins and lymph nodes from patients with squamous-cell carcinoma of the head and neck contained p53 mutations specific for the primary tumor. Patients with these positive margins appear to have a substantially increased risk of local recurrence. Molecular analysis of surgical margins and lymph nodes can augment standard histopathological assessment and may improve the prediction of local tumor recurrence.

Aged↗

PubMed1995

Squamous cell carcinoma of the head and neck in the elderly.

OBJECTIVE: While squamous cell carcinoma of the head and neck (HNSCC) most commonly affects individuals in the fifth to seventh decades of life, it occasionally arises in older patients. Biologic and epidemiologic factors of HNSCC in elderly patients have been investigated to shed light on the process of neoplastic transformation in that population. DESIGN: The medical records of patients with new onset of HNSCC presenting between 1988 and 1993 were reviewed retrospectively. SETTING: Tertiary-care hospital-based clinic. PATIENTS: Eighty-one individuals who developed HNSCC of the upper aerodigestive tract after their 75th birthday constituted the study group. A control group consisting of 102 patients who developed HNSCC between the ages of 40 and 70 years was also analyzed. MAIN OUTCOME MEASURE: Information about each individual's tobacco and ethanol exposure, family history of cancer, history of second primary cancer, treatment provided, and current disease status were derived from the medical record. The presence or absence of p53 gene mutation was tabulated for a subset of individuals in both the elderly and the middle-aged groups. RESULTS: The elderly patients had a significantly lower degree of alcohol and tobacco exposure, but a significantly higher rate of second primary cancers, especially in sites outside the upper aerodigestive tract. There was no difference in the incidence of cancer in first-degree relatives in the two groups. These findings were interpreted in light of results from our laboratory examining the incidence of p53 gene mutation in a large number of patients with HNSCC. A significantly higher percentage of tumors from the younger group contained a p53 gene mutation. Major surgery was an integral part of the treatment plan for most of the older patient group despite their advanced age. CONCLUSIONS: These findings suggest that HNSCC arising after the seventh decade of life less frequently involves a genetic change commonly found in younger patients. Heavy carcinogen exposure and p53 gene mutations are present less often in elderly individuals, whereas this group appears to be more susceptible to multiple cancers. The precise biologic factors involved in neoplastic transformation in this older population await discovery. Since aggressive therapy can be successfully tolerated by many elderly patients, an individualized approach to treatment is advocated.

Adult↗

PubMed1995

Chemoradiotherapy for organ preservation in oral and pharyngeal carcinoma.

OBJECTIVES: To use concurrent chemoradiotherapy as primary treatment for resectable head and neck squamous cell carcinoma to (1) demonstrate the feasibility of an organ preservation approach for nonlaryngeal sites; (2) evaluate the toxic reactions and response to a new combination of two platinum compounds; and (3) monitor the effect of therapy on oral and pharyngeal function. DESIGN: Case series, a prospective single-armed trial. SETTING: Tertiary referral center. PATIENTS: Twenty-two patients with head and neck squamous cell carcinoma of the oral cavity, oropharynx, and hypopharynx for whom surgery would significantly compromise function were entered in this trial. INTERVENTION: Standard fractionation external-beam radiation therapy (2 Gy/Fx; total, 70 Gy) was given during a 9-week period, including a 2-week break after 40 Gy, concurrently with eight weekly doses of carboplatin and three doses of cisplatin (100 mg/m2) at 3-week intervals. A biopsy was performed 12 weeks after the completion of chemoradiotherapy to assess clinical response. All patients presenting with nodes greater than 3 cm had planned neck dissection. MAIN OUTCOME MEASURES: Tumor response, toxic reactions, survival, and oral and pharyngeal function. RESULTS: Overall complete response was 86%. Estimated overall 2-year survival was 64%, and disease-specific survival was 71% (median follow-up time, 25 months). Five patients have died of disease and two of unrelated causes. Treatment was completed by all, with toxic reactions including myelosuppression, mucositis, and dysphagia. Half of the patients required gastrostomy. CONCLUSIONS: Concurrent chemoradiotherapy using two platinum analogues was tolerated with good local control and survival. Notable dysphagia was common. This study provides pilot data for randomized clinical trials to confirm the usefulness of chemoradiotherapy for nonlaryngeal organ preservation.

Adult↗

PubMed1995

Interferon gamma enhances lymphokine-activated killer cell adhesion but not lysis of head and neck squamous cell carcinoma.

OBJECTIVES: To determine if treatment with recombinant human interferon gamma (rHuIFN-gamma) increases the adhesion to, and lysis of, head and neck squamous cell carcinoma (SCC) cells by lymphokine-activated killer (LAK) and peripheral blood mononuclear (PBM) effector cells in vitro and to evaluate the role of cell surface adhesion molecules in these processes. DESIGN: Two human SCC cell lines, JHU-020-SCC and JHU-022-SCC, were used. Lymphokine-activated killer cells were generated by interleukin-2 stimulation of PBM cells obtained from the hemapheresis blood donor packs of healthy individuals. Adhesion assays were performed to assess the level of binding of both effector populations to SCC cells, which were treated with either fresh media or rHuIFN-gamma (100 U/mL). Binding was measured by flow cytometric detection of effector cells labeled with fluorescein-conjugated anti-CD45 monoclonal antibody. Monoclonal antibodies to the cell adhesion molecules HLA-DR, lymphocyte function-associated antigen 1, and intercellular adhesion molecule 1 were used in blocking experiments to determine their contribution to the process of effector-SCC cell adhesion. Cytotoxicity experiments were performed using a colorimetric assay to determine the cytotoxic response generated by LAK and PBM cells against SCC cells, with and without prior rHuIFN-gamma treatment of the tumor cells. MAIN OUTCOME MEASURES: Effector cell binding level and percent cytotoxicity of SCC cells. RESULTS: Recombinant human interferon gamma treatment of JHU-020-SCC cells resulted in increased adhesion to both LAK cells and PBM cells (P < .001). The presence of anti-lymphocyte function-associated antigen 1 antibody resulted in elimination of the enhanced adhesion seen with rHuIFN-gamma pretreatment of SCC cells (P =.03), but antibody to intercellular adhesion molecule 1 and HLA-DR did not reduce the level of effector binding. The greatest cytotoxic response against both JHU-020-SCC and JHU-022-SCC was seen with LAK cells (P < or = .001). Pretreatment of tumor targets by rHuIFN-gamma (100 U/mL) resulted in no enhancement of cytotoxic response by either LAK or PBM cells; at the effector-target ratio of 30:1, there was a significant decrease in LAK cell-mediated cytotoxic response against rHuIFN-gamma-treated SCC cells (P < or = .02). CONCLUSIONS: Recombinant human interferon gamma treatment of head and neck SCC cells does increase binding of both LAK cells and PBM cells to tumor cells, in part via the lymphocyte function-associated antigen 1 ligand mechanism. The cytotoxic effect mediated by LAK cells against head and neck SCC cells is reduced after rHuIFN-gamma treatment, suggesting that the activity of this cytokine may be more important in regulating antigen-specific cytotoxic response mediated by cytotoxic T-lymphocytes.

Antineoplastic Agents↗