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Background. DNA ploidy analysis has been investigated as a prognostic indicator in prostate cancer. Most of the data is derived from retrospective studies using paraffin-embedded tissue. This method has drawbacks related to the quality of DNA histograms and uncontrolled data collection. Methods. DNA ploidy analysis of freshly resected prostatic tissue was prospectively compared with conventional prognostic variables in 97 men treated with radical prostatectomy for localized prostate cancer. Results. Regarding the patients, 31.9% were African American and 66% had pathologic Stages C or D1 disease. Only 9.6% of patients with Stages A2 and B had a prostate-specific antigen (PSA) value greater than 10 ng/ml, whereas 97% of patients with PSA values greater than 20 ng/ml had pathologic Stages C and D1.PSA levels correlated with Gleason score (P = < 0.05); 51% and 100% of patients with Gleason score 5-7 and 8-10, respectively, had PSA values greater than 10 ng/ml. Twenty-two patients (23%) had DNA aneuploid tumors. Comparisons of mechanical to enzymatic cell suspensions indicated that DNA aneuploidy was better preserved in mechanical cell preparations. DNA ploidy correlated with pathologic stage (P = < 0.05) and Gleason score (P = < 0.05). Fifteen of 79 patients (18.9%) with Gleason score 5-7 had DNA aneuploid tumors versus 71.4% of patients with Gleason score 8-10. PSA groups correlated with ploidy status (P = 0.01). Although the majority of patients (19 of 22) with DNA aneuploid tumors had elevated preoperative PSA levels, none had a PSA value greater than 50 ng/ml. Conclusions. DNA ploidy analysis correlated with established prognostic indicators in prostate cancer; however, its independent correlation with natural history and treatment outcome must be established for it to have an effect on therapeutic decisions.

While flow cytometry is useful in screening human cancers for chromosome abnormalities, only karyotyping is the definitive test. Karyotyping requires the growth of living cells from a biopsy or blood sample. The test demands skill and patience, and is generally not suitable for mass screening. Nevertheless, the cases of two patients with dedifferentiated chondrosarcoma illustrate that the karyotype provides information that is not available by other techniques. Chondrosarcomas are the second most common form of bone cancer. They usually affect older patients and generally occur as slow-growing low-grade cartilaginous growths. However, about 10 percent of chondrosarcomas lose their differentiated state (dedifferentiation) and become poorly differentiated aggressive high-grade cancers with a poor prognosis. Fresh chondrosarcoma tissue was obtained from two patients at surgery. Flow cytometric analysis was performed on both specimens; one was found to have the normal diploid chromosome complement, while the other was found to have a pathological aneuploid complement. Karyotyping was performed on cells and revealed abnormalities within the cells of both specimens. While numerous abnormalities were observed in both specimens, the aneuploid specimen was cytogenetically more complex, as would be expected. However, one defect was common to the chondrosarcoma cells from both patients. This common feature consisted of breaks in the short arm of chromosome 1. These breaks revealed themselves as a deletion in one chromosome homolog and recombination in the other. In both patients, the deletion and recombination occurred at the same chromosome band, in the region of 1p36. This same region is lost in neuroblastoma (a malignant cancer that usually affects infants and children) and has been shown to be involved in myxoid chondrosarcoma. It is not yet known if the 1p36 break will prove to be a consistent finding in these tumors. However, the same break occurring in both patients cannot be attributed only to coincidence; investigation of the genes near the 1p36 point is likely to reveal interesting mechanisms of the malignant transformation of cells. (Consumer Summary produced by Reliance Medical Information, Inc.)

Purpose:This is a pilot study to identify changes in gene and protein expressions after treatment with docetaxel in cisplatin‐resistant head and neck squamous cell carcinoma (HNSCC).

Abstract Objective : Clinical parameters such as grade, size and/or location of the tumor are good predictors of outcome in patients with astrocytoma. The objective of this study was to determine whether DNA content parameters have a prognostic significance for this group of tumors.

Objective:The objective of this project was to determine the mechanisms in which docetaxel enhances Ad‐p53 tumor suppressive effects in head and neck cancer.

Objective:To determine the genetic differences between African Americans (AA) and Non‐African Americans (NAA) with head and neck squamous cell carcinoma (HNSCC).

PurposeTo characterize in vivo features of HPV‐immortalized and carcinogen transformed oral keratinocytes.

To identify molecular markers for the progression of head-and-neck squamous cell carcinoma (HNSCC), we used RNA arbitrarily primed (RAP) PCR to determine the qualitative and quantitative differences in gene expression between normal epithelial cells, those derived from dysplastic oral mucosa and invasive and metastatic HNSCC. Three differentially expressed DNA fragments (RAP20, RAP21, RAP26) that were upregulated in a tumor cell line (T45) were identified as being regions of the γ2 subunit of human laminin-5. Northern blot analysis of total cellular RNA revealed overexpression of these transcripts in 6 of 7 HNSCC cell lines compared with normal epidermal keratinocytes. In contrast, no differences were observed in HeLa (cervical carcinoma) or HCT116 (colon carcinoma) cells. Immunostaining of HNSCC cells derived from primary (HN4) and metastatic (HN12) tumors indicated elevated levels of endogenous laminin-γ2 protein. Furthermore, HNSCC tissues demonstrated strong laminin-γ2 staining, particularly in the peripheral basaloid cells of tumor islands at the invasion front. In contrast, only minimal staining of laminin-γ2 was detected in basal cells of the normal epithelium. The data indicate that laminin-γ2 is frequently overexpressed in HNSCCs and derivative cell lines and that its overexpression is likely to be useful as a marker of head-and-neck squamous malignancy. © 2002 Wiley-Liss, Inc.

We have examined the ability of γ-irradiation and bleomycin to induce apoptosis in a model system consisting of cell lines derived from naturally occurring human head-and-neck squamous-cell carcinomas with contrasting p53 status and expression levels of pro- and anti-apoptotic molecules. Following exposure to γ-irradiation (20 Gy) or bleomycin (3.5 μM) for 0 to 96 hr, cells expressing either transcriptionally inactive mutant p53 (HN6) or a truncated p53 molecule (HN19) underwent apoptosis, as assessed by fluorescence-activated cell sorting and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling, in contrast to cells that express wild-type p53 (HN30), suggesting that apoptosis induced by these agents occurs by p53-independent mechanisms. Apoptosis in HN6 and HN19 cells was preceded by a G2/M cell-cycle block, as analyzed by DNA content and BrdU staining. In contrast, HN30 cells remained blocked in both G1 and G2/M and failed to re-enter the cell cycle. Levels of Bcl-2 were elevated in 3 of 10 cell lines, and only marginal differences were observed for Bcl-xL. Pro-apoptotic proteins bax and Bcl-xS were detectable in normal keratinocytes and 4 tumor cell lines. Bax-δ (16 kDa) was highly represented in normal keratinocytes, and levels of bak were variable between cell lines. Elevated expression of Bcl-2 failed to protect HN19 cells from either γ-irradiation or bleomycin-induced apoptosis. Our data support the existence of p53- and Bcl-2–independent pathways regulating apoptosis in keratinocytes and suggest that efficacy of either radiotherapy or bleomycin treatment for oral squamous-cell neoplasms may not, therefore, be influenced solely by endogenous p53 status. Int. J. Cancer 88:737–743, 2000. © 2000 Wiley-Liss, Inc.

Objective/Hypothesis: We examined whether p53 gene mutations were predictive of clinical behavior in laryngeal cancer. Study Design: Retrospective study of 45 patients with laryngeal cancer from 1985 to 1997. Methods: DNA was extracted from tumor tissue and subject to polymerase chain reaction single‐strand conformational polymorphism (PCR‐SSCP) as well as DNA sequencing. The clinical outcome was correlated to the presence or absence of a p53 mutation. Results: The p53 gene was analyzed by direct DNA sequencing and was found to be mutated in 33% (15/45) of patients. The presence of a p53 mutation was associated with a significant improvement in overall survival (80% vs. 43%, P< .03) and a trend toward improved disease‐free survival (87% vs. 60%, P= .08). When other prognostic factors were adjusted, multivariate analysis revealed a trend toward improvement in overall survival as well as disease‐free survival. Conclusion: Depending on the location of a p53 mutation, the suppressive functions or clinical outcome may or may not be affected. Fifty‐three percent of mutations were detected in nonconserved regions as opposed to 17% as reported in colon cancer. In colon cancer, mutations in conserved regions of the p53 gene predicted a poorer survival, whereas nonconserved gene mutations were not predictive. In our group of patients, p53 mutations predicted a better prognosis, which may be due to a large proportion of mutations that lie within nonconserved areas. The predictive power of p53 gene mutations may depend on functional loss and inactivation of highly conserved areas and must be tested in a prospective trial.

Progressive deregulation of the cell-division cycle is thought to contribute to the establishment and progression of neoplasia. Previously, we have documented the in vivo inactivation of p16^INK4A, an inhibitor of G1 cyclin-dependent kinases, in squamous cell carcinomas of the head and neck region. In the present study, we extend these findings by examining the expression and functional activity of cyclin-dependent kinases (CDKs) and their regulatory subunits using a model system of cell lines derived from squamous cell carcinomas. Increased activity of CDK4 and 6 was universal in tumor cells compared with normal keratinocytes, reflecting over-expression of either or both kinases. In contrast to other studies, over-expression of cyclin D1, a regulatory subunit of CDK4 and 6, was not observed. Increased activity of CDK2 was less frequent and was related to over-expression of cyclin A and/or E. All tumor cell lines showed increased expression of proliferating cell nuclear antigen compared to normal keratinocytes. Four SCC cell lines, including one tumor-metastasis pair derived from a single patient, failed to express the p15^INK4B transcript. Western blot analysis of cell lysates revealed normal or reduced levels of p27^KIP1 in tumor cells compared to normal keratinocytes. However, failure to express wild-type p53 was not reflected by lower levels of p21^WAF1. Our data suggest that cell-cycle deregulation is likely to occur by multiple mechanisms during the genesis of head and neck squamous cell carcinomas. Furthermore, p16^INK4A is likely to be the primary target for inactivation on chromosome 9p21 in these tumors as p15^INK4B loss occurs less frequently. Int. J. Cancer 73:551–555, 1997. © 1997 Wiley-Liss, Inc.

During the last 50 years, clinical cancer research has often been criticized for employing an oversimplified or "magic bullet" approach to finding the cause of human cancer and defining its treatment. More importantly, with the acquisition of more detailed knowledge, investigators have often tended to "lose the forest for the trees" and now risk losing the "trees for the leaves." The most important "forest," in the study of human cancer, is the accumulation of observations that result from a careful study of the natural histories and treatment outcomes of patients with these diseases. Although inherently obvious, it is often forgotten that, by definition, the most relevant natural or designed experiments in human cancer occur in human beings. A new term, translational research, has been coined to emphasize the importance of the study of human cancer within the framework of observations pertinent to the natural history and treatment outcome of patients.

5-fluorouracil (FUra) is one of the most frequently used drugs in cancer treatment, particularly in combination with other agents. Its activity when administered as an infusion rather than a bolus has led to a renewed and increased use. A cardiotoxicity that mimics ischemia has been associated with the administration of FUra in cancer patients. This cardiotoxicity may manifest itself as: (a) dysrythmias with and without cardiorespiratory symptoms (b) ECG changes with and without cardiorespiratory symptoms (c) cardiorespiratory symptoms with and without ECG changes (d) acute myocardial infarct; symptoms and ECG changes (e) ventricular dysfunction (f) cardiogenic shock and (g) sudden death. Several case studies which illustrate the cardiotoxic sequelae that may be associated with the use of this drug are discussed. The incidence, contributing factors, risk factors and mechanisms underlying this phenomenon are undetermined. No appropriate recommendations for monitoring patients or for predicting those patients that will develop such toxicity while receiving FUra can be made at present. Prospective studies to determine the true incidence, spectrum and mechanisms causing this syndrome are ongoing and required for its understanding and prevention.

Patients with squamous cell cancers of the head and neck (SCCHN) vary tremendously in their natural history and treatment outcome even amongst subgroups where the clinical and morphological parameters are similar. The ability to pretherapeutically identify individual patients and patient subgroups that differ in these regards would greatly facilitate clinical and basic science cancer research in this tumor. DNA content parameters are simple and accurate intermediate markers of a tumor's biology and reflect the fundamental process associated with the development of malignancy, chromosomal aneuploidy. In patients with SCCHN, DNA content parameters have been shown to be highly predictive of the natural history of the tumor and treatment outcome. They are also useful as intermediate markers for the study of the underlying molecular-genetic properties and processes responsible for the biological differences seen in these cancers. DNA content parameters therefore serve as fundamental ‘translational’ bridges in clinical and laboratory research in patients with SCCHN.

Because of the poor results of standard therapy in patients with locally advanced head and neck cancers, chemotherapy is increasingly used to improve the outcome of these patients. In resectable disease, chemotherapy is being investigated before definitive treatments, after surgery, concurrent with postoperative radiotherapy, after radiotherapy, and for possible laryngeal salvage. In unresectable cancers, chemotherapy before, concurrent with, and following radiotherapy is being investigated.

Twenty-nine patients with persistent, recurrent and/or metastatic squamous cell carcinoma of the head and neck were treated daily for five days at three-week intervals with topotecan 1.5 mg/m2. Four patients received prior chemotherapy, 23 prior surgery and 29 prior radiation therapy. Of the 29 eligible patients, 8 patients were not evaluable for response and were assumed to be non-responders. Of the remaining 21 évaluable patients, there were zero responses (0%, 95% confidence interval [0,.12]). The most common toxicities were myelosuppression, dyspnea and malaise/fatigue/lethargy. Topotecan has limited activity in advanced head and neck cancer with this dose and schedule.

• Regional metastases are a major determinant in the treatment outcome of patients with squamous cell carcinoma of the head and neck. Metastases do not respond as well to cytotoxic therapy as do primary tumors. DNA diploid tumors or tumor components also respond poorly to intermittent cytotoxic therapy. In our series of 497 patients with squamous cell carcinoma of the head and neck, the percentage of pure DNA diploid tumors and the mean DNA indexes in 497 primary tumors and 82 regional metastases were 34% and 1.54 and 50% and 1.34, respectively. Paired comparisons were performed in 61 patients and revealed a statistically significant increase in the frequency of DNA diploid tumors (27.4% to 41.2%) in associated lymph node metastases. The clinical observation that patients with squamous cell carcinoma of the head and neck and regional lymph node metastases have a poorer prognosis and a poorer response to cytotoxic therapy may in part be explained by the increased incidence of DNA diploid tumors in their regional lymph nodes, and the poorer response of such tumors to cytotoxic therapy.(Arch Otolaryngol Head Neck Surg. 1992;118:185-187)