Biomedical subjects

David G Pfister

Publications and source records attributed to David G Pfister.

24 records · Page 2Linked to original sources

PubMed2003

The role of novel oncogenes squamous cell carcinoma-related oncogene and phosphatidylinositol 3-kinase p110alpha in squamous cell carcinoma of the oral tongue.

PURPOSE: Amplification at chromosome 3q26.3 is a common and crucial event in head and neck squamous cell carcinoma (HNSCC), impacting significantly on tumor progression and clinical outcome. Two novel oncogenes, namely squamous cell carcinoma (SCC)-related oncogene (SCCRO) and PIK3CA (gene encoding phosphatidylinositol-3 kinase catalytic alpha-polypeptide), have been identified as targets of 3q26.3 amplification. This study aimed to delineate the role of SCCRO and PIK3CA in the pathogenesis of oral tongue SCC. EXPERIMENTAL DESIGN: The association between gene copy number for SCCRO and PIK3CA measured by fluorescence in situ hybridization and level of mRNA expression quantitated by real-time reverse transcription-PCR was assessed in a panel of human HNSCC cell lines. In addition, gene expression in 49 consecutive primary SCCs of the oral tongue was determined and correlated with clinicopathological characteristics and outcome. RESULTS: The mRNA level of SCCRO and PIK3CA was significantly correlated to the gene copy number in nine HNSCC cell lines. In addition, the expression level of SCCRO and PIK3CA was significantly greater in malignant tissues compared with those in histologically normal mucosae (2.17- and 2.46-fold, respectively; P < 0.001). Matched tumor normal control analysis revealed that 24.5 and 69.4% of patients expressed high levels of SCCRO and PIK3CA, respectively. Univariate analyses demonstrated that SCCRO overexpression correlated with nodal metastases (P = 0.05) and advanced stage (P = 0.02), whereas PIK3CA overexpression was associated with vascular invasion (P = 0.04). Only SCCRO overexpression was associated with disease-specific (P = 0.04) and overall survival (P = 0.02). Furthermore, SCCRO overexpression remained an independent predictor for cervical nodal metastasis on multivariate regression analysis (chi(2) likelihood ratio = 4.38; P = 0.04). CONCLUSIONS: Although both SCCRO and PIK3CA may play a role in the pathogenesis of oral tongue SCC through amplification at 3q26, SCCRO appears to be a significant predictor of regional metastasis and may be a marker for tumor aggressiveness and clinical outcome.

Adult↗

PubMed2002

American Society of Clinical Oncology technology assessment of pharmacologic interventions for breast cancer risk reduction including tamoxifen, raloxifene, and aromatase inhibition.

OBJECTIVE: To update an evidence-based technology assessment of chemoprevention strategies for breast cancer risk reduction. POTENTIAL INTERVENTIONS: Tamoxifen, raloxifene, aromatase inhibition, and fenretinide. OUTCOMES: Outcomes of interest include breast cancer incidence, breast cancer-specific survival, overall survival, and net health benefit. EVIDENCE: A comprehensive, formal literature review was conducted for relevant topics. Testimony was collected from invited experts and interested parties. The American Society of Clinical Oncology (ASCO) prescribed technology assessment procedure was followed. VALUES: More weight was given to published randomized trials. BENEFITS/HARMS: A woman's decision regarding breast cancer risk reduction strategies is complex and will depend on the importance and weight attributed to information regarding both cancer- and noncancer-related risks and benefits. CONCLUSIONS: For women with a defined 5-year projected breast cancer risk of > or= 1.66%, tamoxifen (at 20 mg/d for 5 years) may be offered to reduce their risk. Risk/benefit models suggest that greatest clinical benefit with least side effects is derived from use of tamoxifen in younger (premenopausal) women (who are less likely to have thromboembolic sequelae and uterine cancer), women without a uterus, and women at higher breast cancer risk. Data do not as yet suggest that tamoxifen provides an overall health benefit or increases survival. In all circumstances, tamoxifen use should be discussed as part of an informed decision-making process with careful consideration of individually calculated risks and benefits. Use of tamoxifen combined with hormone replacement therapy or use of raloxifene, any aromatase inhibitor or inactivator, or fenretinide to lower the risk of developing breast cancer is not recommended outside of a clinical trial setting. This technology assessment represents an ongoing process and recommendations will be updated in a timely matter. VALIDATION: The conclusions were endorsed by the ASCO Health Services Research Committee and the ASCO Board of Directors.

Antineoplastic Agents, Hormonal↗

PubMed2002

Alteration of p53 pathway in squamous cell carcinoma of the head and neck: impact on treatment outcome in patients treated with larynx preservation intent.

PURPOSE: To identify the role of p53 pathway alteration(s) as predictors of treatment outcome in patients with advanced, resectable, squamous cell carcinoma (SCC) of the larynx and pharynx treated with larynx preservation (LP) intent. PATIENTS AND METHODS: Seventy-one patients treated on two consecutive LP protocols were studied based on availability of representative tissues. We analyzed the expression pattern of p53, its upstream regulator mdm2, and downstream transcriptional target p21/WAF1 by immunohistochemistry. Positive phenotype was defined as >or= 20% of tumor cells showing nuclear immunoreactivity. Results were correlated with treatment outcomes. RESULTS: Positive phenotype was observed in 35 (49%) of 71 cases for p53, in 52 (74%) of 70 for mdm2, and in 37 (54%) of 68 for p21. There was no correlation between p53 phenotype and p21 nuclear accumulation. The mdm2-negative phenotype was most predictive of major response at the primary tumor site (P =.088). p53-positive phenotype was associated with worse local control with LP (LCLP; 49% v 23%, P =.053) and inferior overall survival (OS; 51% v 29%, P =.017) at 5 years. On Cox regression analysis, p53-positive phenotype predicted inferior OS (P =.033) and showed a trend for worse LCLP (P =.102). When analyzed in a multivariate model as continuous variables, p53 showed a stronger correlation with inferior OS (P <.01), and mdm2 was associated with worse OS (P <.01). CONCLUSION: Among the three markers studied, our data support p53 phenotype as the most informative predictor of unfavorable outcomes in the LP setting, and suggest a role for mdm2 phenotype that requires further exploration. Our analysis does not support a p53-dependent mechanism for p21 expression. Prospective and larger studies are necessary before integration of these molecular markers as part of molecular staging and predictors for organ preservation or other outcomes.

Adult↗

PubMed2002

Amplification of the 3q26.3 locus is associated with progression to invasive cancer and is a negative prognostic factor in head and neck squamous cell carcinomas.

Amplification of the 3q26-q27 has a high prevalence in squamous cell carcinomas of mucosal origin, including those originating in the head and neck region. To elucidate its role as a prognostic tool in head and neck squamous cell carcinoma, a yeast artificial chromosome (YAC) contig spanning the entire 3q26-27 region was constructed. The minimal region of amplification was refined within a 1- to 2-Mb genomic segment contained within three overlapping, nonchimeric YAC clones using sequential fluorescent in situ hybridization analysis. These YAC clones containing the apex of amplification were used to develop a two-color fluorescence in situ hybridization assay and applied to the detection of 3q copy numbers in interphase nuclei on archival tumor tissue from 29 cases of normal mucosa, 20 of premalignant mucosa, and 50 of invasive head and neck squamous cell carcinomas. The presence of 3q amplification increased from 3% in normal mucosa to 25% in premalignant mucosa and 56% in invasive cancers (P < 0.01). In invasive tumors, low-level 3q amplification (3 to 4 X copy number) was identified in 18 of 50 primary head and neck cancers and high-level amplification (>4 X copy number) in 10 of 50 cases. With a median follow-up of 82.5 months, an increasing proportion of recurrences (32%, 72%, and 90%; P = 0.003) and cancer-related deaths (14%, 44%, and 70%; P = 0.006) were seen in patients with normal 3q copy number, low-level amplification, and high-level amplification, respectively. The 3-year disease-free (69%, 56%, and 10%; P = 0.001) and cause-specific (94%, 83%, and 40%; P = 0.01) survivals also decreased from normal copy number to low-level and high-level amplification. Only high-level amplification at 3q remained a significant prognostic variable on multivariate analysis including common prognostic predictors for both disease-free (relative risk, 5.1; 95% confidence interval = 1.9 to 13.9) and cause-specific survival (relative risk, 7.6; 95% confidence interval = 1.9 to 29.6). The findings suggest that the 3q copy number status is an important marker for tumor progression and prognostication in patients with head and neck squamous cell carcinoma.

Aged↗

PubMed2002

A phase II trial of bryostatin-1 in patients with metastatic or recurrent squamous cell carcinoma of the head and neck.

Bryostatin-1 is a macrocyclic lactone that has been shown to modulate Protein Kinase C activity and has demonstrated antitumor activity in vitro and in vivo. Fifteen patients with metastatic or recurrent squamous cell carcinoma of the head and neck were treated with bryostatin-1 at a dose of 25 mcg/m2 by continuous intravenous infusion over 24 hours once weekly for three weeks followed by a break week to complete a four-week cycle. There were no major objective responses in the 14 evaluable patients. One patient with nasopharynx cancer had disease stabilization for 4 months prior to being removed from the study due to medical issues. This clinical benefit corresponded to a radiographic decrease in metabolic activity on positron emission tomograpy (PET) scan as well as molecular evidence of tumor apoptosis in a poly[ADP-ribose] polymerase (PARP) cleavage assay. Bryostatin-1 is not recommended for use as a single agent for the treatment of squamous cell head and neck cancer. Further investigation is warranted to determine the strength of the correlation between bryostatin-1 activity and PARP cleavage as a surrogate molecular marker of apoptosis.

Adult↗

PubMedDate not supplied

Double-blind, placebo-controlled, randomized trial of granulocyte-colony stimulating factor during postoperative radiotherapy for squamous head and neck cancer.

UNLABELLED: To evaluate the ability of granulocyte-stimulating factor to decrease mucositis during postoperative radiotherapy for stage II-IV squamous head and neck cancer in a randomized, double-blind, placebo-controlled trial. METHODS: After undergoing complete resection, patients were randomized to receive granulocyte-colony stimulating factor or placebo by daily subcutaneous injection during radiotherapy (63 Gy, 1.8 Gy/day). Patients undergoing prior radiotherapy or chemotherapy were excluded from the study. The primary outcome was the need for percutaneous endoscopic gastrostomy placement. Severity of mucositis was a secondary outcome. RESULTS: Forty-one patients were enrolled (132 planned). The study closed after slow accrual. Patient characteristics were as follows (granulocyte-colony stimulating factor vs placebo): median age, 59 versus 54 years; pT4, 16% versus 23%; pN2/3, 68% versus 59%; stage IV, 79% versus 68%. Forty patients were evaluable for planned outcomes. Patients in the granulocyte-colony stimulating factor arm showed trends toward lower rates of percutaneous endoscopic gastrostomy placement (0% vs 14%, P = 0.2) and severity of mucositis (P = 0.13), and had shorter mean radiotherapy duration (48.4 +/- 4.32 days vs 51.6 +/- 1.84 days, P = 0.005). Overall survival was significantly greater in the granulocyte-colony stimulating factor arm (hazard ratio, 0.37; P = 0.037). DISCUSSION: Granulocyte-colony stimulating factor during radiotherapy was feasible and led to significantly shorter radiotherapy duration and trends toward less percutaneous endoscopic gastrostomy placement and mucositis. The unanticipated improvement in survival outcomes warrants further hypothesis-driven investigation and validation.

Aged↗