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Richard V Smith

Publications and source records attributed to Richard V Smith.

9 recordsLinked to original sources
PubMed2017

Nonpromoter methylation of the CDKN2A gene with active transcription is associated with improved locoregional control in laryngeal squamous cell carcinoma.

We previously reported a novel association between CDKN2A nonpromoter methylation and transcription (ARF/INK4a) in human papillomavirus associated oropharyngeal tumors. In this study we assessed whether nonpromoter CDKN2A methylation in laryngeal squamous cell carcinomas (LXSCC) conferred a similar association with transcription that predicted patient outcome. We compared DNA methylation and ARF/INK4a RNA expression levels for the CDKN2A locus using the Illumina HumanMethylation27 beadchip and RT-PCR in 43 LXSCC tumor samples collected from a prospective study of head and neck cancer patients treated at Montefiore Medical Center (MMC). Validation was performed using RNAseq data on 111 LXSCC tumor samples from the Cancer Genome Atlas (TCGA). The clinical relevance of combined nonpromoter CDKN2A methylation and transcription was assessed by multivariate Cox regression for locoregional recurrence on a subset of 69 LXSCC patients with complete clinicopathologic data from the MMC and TCGA cohorts. We found evidence of CDKN2A nonpromoter hypermethylation in a third of LXSCC from our MMC cohort, which was significantly associated with increased ARF and INK4a RNA expression (Wilcoxon rank-sum, P&#xa0;=&#xa0;0.007 and 0.003, respectively). A similar association was confirmed in TCGA samples (Wilcoxon rank-sum test P&#xa0;<&#xa0;0.0001 for ARF and INK4a). Patients with CDKN2A hypermethylation or high ARF/INK4a expression were significantly less likely to develop a locoregional recurrence compared to those with neither of the features, independent of other clinicopatholgic risk factors (adjusted hazard ratio=0.21, 95% confidence interval:0.05-0.81). These results support the conclusion that CDKN2A nonpromoter methylation is associated with increased ARF and INK4a RNA expression, and improved locoregional control in LXSCC.

Carcinoma, Squamous Cell↗
PubMed2007

Phase II clinical trial of parenteral hydroxyurea and hyper-fractionated, accelerated external beam radiation therapy in patients with advanced squamous cell carcinoma of the head and neck: toxicity and efficacy with continuous ribonucleoside reductase inhibition.

BACKGROUND: Almost all concurrent chemoradiation regimens for head and neck are platinum based; however, cisplatin is associated with severe renal, oto-, and neurotoxicity. Hydroxyurea (HU) has been associated with fewer irreversible toxicities. We obtained HU in parenteral form to be administered continually during the radiation treatment. Intravenous HU promised better pharmacokinetics and cell cycle blockade. METHODS: Participants had biopsy-proven, untreated squamous cell carcinoma of the oral cavity, oropharynx (stage IV) and hypopharynx (stages II-IV). Radiation therapy consisted initially of 74.4 Gy administered in twice daily 1.2-Gy fractions. After 20 patients, the radiation dose was reduced to 60.0 Gy, and another 16 patients were enrolled. RESULTS: Patients received HU by Continuous Ambulatory Drug Delivery (CADD) pump on a daily x5 schedule during radiation therapy. Because of persistent long-term dysphagia, after 20 patients, the dose of external beam radiation therapy was reduced from 74 to 60 Gy, and the duration of concurrent HU was correspondingly reduced. The new regimen was much better tolerated. The median survival for the group as a whole was 30 months. Within this small study, there were no significant differences in survival, regional control, or local control between the 2 groups. CONCLUSIONS: Lower doses of concurrent parenteral HU and hyper-fractionated radiation therapy are tolerable and promising.

Aged↗
PubMed2006

Pilot study of mucosal genetic differences in early smokers and nonsmokers.

BACKGROUND: Global gene expression analysis is proving to be an important means of assessing human tumors and may identify key components of carcinogenesis or clinical prognosis. This technique has been successfully applied to head and neck squamous cell carcinoma (HNSCC) and thyroid carcinomas; however, little has been done to evaluate premalignant states. METHODS: Human buccal mucosal cells were sampled from smokers and nonsmokers using a noninvasive brush technique. The method was validated by assessing the quantity and quality of RNA obtained. The purified RNA was then assayed using cDNA microarrays containing 27,323 cDNA clones to examine the buccal mucosa in these patients for differences in gene expression patterns. Using unsupervised and supervised hierarchical clustering methods, we developed a gene profile signature for an initial training set of smokers and nonsmokers and then used this to predict smoking status in a subsequent test set of subjects. Selected genes were then cross-referenced with previously published gene sets found in HNSCC identified by our group. RESULTS: Nineteen subjects were used in this pilot analysis, 9 smokers and 10 nonsmokers. Smoking among the study group ranged from 1 to 60 pack years. RNA purified from buccal mucosal brushing demonstrated a high degree of similarity in gene expression profiles among independent samples. Through the application of supervised clustering techniques, we were able to identify 113 genes whose expression differed significantly between samples from smokers and nonsmokers (t test, P < .001). This expression signature was able to accurately predict who within the second set of subjects were smokers, with the exception of one person who had a minimal tobacco history and clustered with the nonsmokers. Cross-referencing data with that found in HNSCC, we were able to identify a tumor suppressor gene involved in the c-myc pathway (Mxi1) that was similarly under-expressed in smokers and cancer patients with progressive disease. CONCLUSIONS: Although the sample size was small in this preliminary dataset, our analysis revealed several groups of genes that were either over- or under-expressed in the smokers and which could be used to predict smoking exposure. Many of these represent genes of possible interest as early molecular markers for head and neck carcinogenesis.

Adult↗
PubMed2005

Molecular profiling of tumor progression in head and neck cancer.

OBJECTIVE: To assess gene expression changes associated with tumor progression in patients with squamous cell carcinoma of the oral cavity. DESIGN: A microarray containing 17 840 complementary DNA clones was used to measure gene expression changes associated with tumor progression in 9 patients with squamous cell carcinoma of the oral cavity. Samples were taken for analysis from the primary tumor, nodal metastasis, and "normal" mucosa from the patients' oral cavity. SETTING: Tertiary care facility. Patients Nine patients with stage III or stage IV untreated oral cavity squamous cell carcinoma. RESULTS: Our analysis to categorize genes based on their expression patterns has identified 140 genes that consistently increased in expression during progression from normal tissue to invasive tumor and subsequently to metastatic node (in at least 4 of the 9 cases studied). A similar list of 94 genes has been identified that decreased in expression during tumor progression and metastasis. We validated this gene discovery approach by selecting moesin (a member of the ezrin/radixin/moesin [ERM] family of cytoskeletal proteins) and one of the genes that consistently increased in expression during tumor progression for subsequent immunohistochemical analysis using a head and neck squamous cell carcinoma tissue array. CONCLUSION: A distinct pattern of gene expression, with progressive up- or down-regulation of expression, is found during the progression from histologically normal tissue to primary carcinoma and to nodal metastasis.

Carcinoma, Squamous Cell↗
PubMed2005

Use of becaplermin in the closure of pharyngocutaneous fistulas.

BACKGROUND: We report on the contribution of recombinant platelet-derived growth factor-BB (becaplermin) in treating recalcitrant postlaryngectomy fistulas in two patients with head and neck cancer. METHODS: Topical becaplermin was applied daily, with periodic wound assessment and photodocumentation. RESULTS: The two patients with persistent fistula refractory to conventional management have demonstrated rapid improvement after topical application of becaplermin. Each wound exhibited an exuberant granulation response, with a 50% decrease in the size of wound at 1 week. The patients experienced eventual closure, with none having local recurrence of their cancer at 2 years' follow-up. CONCLUSIONS: Becaplermin seems to be a promising addition to traditional methods of treatment for postlaryngectomy fistulas. In patients with delayed healing, future studies will be required to determine the overall efficacy of such biologic response modifiers in the treatment of pharyngocutaneous fistulas and other chronic wounds of the head and neck.

Administration, Topical↗
PubMed2004

Decreased short- and long-term swallowing problems with altered radiotherapy dosing used in an organ-sparing protocol for advanced pharyngeal carcinoma.

OBJECTIVE: To determine the effect of a reduced radiotherapy dose on short- and long-term swallowing problems after organ-sparing treatment. DESIGN: Prospective case series. SETTING: Tertiary care referral center. PATIENTS: A consecutive sample of 29 patients with advanced oropharyngeal or hypopharyngeal cancer who were treated with intravenous hydroxyurea and concomitant hyperfractionated, accelerated radiotherapy. INTERVENTIONS: Initial experience with 74.4 Gy of radiation demonstrated severe long-term swallowing problems, prompting a dose reduction to 60.0 Gy. Eighteen patients were followed up for this study in the 74.4-Gy group, while 11 were in the 60.0-Gy group. MAIN OUTCOME MEASURES: Swallowing variables were assessed in both patient groups at 4 months and at 12 months following completion of therapy. RESULTS: Patient demographics and tumor characteristics were similar in each group, while significant differences were noted in the posttreatment clinical swallowing variables. Persistent severe odynophagia at 4 months (89% [16/18] vs 30% [3/10]) and at 12 months (64% [7/11] vs 11% [1/9]) was greater in the 74.4-Gy group (P =.002). Clinical signs of aspiration were also increased in the 74.4-Gy group, with 81% (13/16) vs 11% (1/9) at 4 months and 60% (6/10) vs 11% (1/9) at 12 months (P<.05). Most striking, however, was the incidence of long-term gastrostomy, with 78% (14/18) of patients receiving 74.4 Gy requiring gastrostomy feedings at 12 months compared with 18% (2/11) in the 60.0-Gy group (P =.002). Local control was unchanged by the altered dosing, with median follow-ups of 43.5 and 24.0 months in the 74.4-Gy and 60.0-Gy groups, respectively. CONCLUSION: Decreased radiation doses can maintain disease control and reduce treatment-related long-term swallowing complications.

Adult↗
PubMed2002

The digital camera in clinical practice.

The benefits of digital photography are certainly numerous and include rapid image production, easy and quick deletion of poor images, no need for film or its associated expenses, decreased costs for enlargements, ease of editing and image storage, effortless placement in presentations or publications. Many physicians believe that the benefits of digital images clearly outweigh any limitations that future technologic advances will minimize. Digital imaging allows for the seamless integration of all patient images (e.g., clinical, radiographic, pathologic) into the medical record. Additionally, manipulating these images with lighting, filters, of other processing techniques may encourage diagnostic advances (e.g., distinguishing between benign and malignant surface lesions). Some drawbacks, however, continue to exist, including cost of the hardware and software, continuously evolving technology, power consumption and battery usage, lower image resolution compared with 35-mm photography, and the need to have backup image files. With decreasing costs, improving resolutions, and enhanced capabilities, digital cameras will overcome these limitations rapidly.

Humans↗
PubMed2002

The significance of immunohistochemically demonstrated nodal micrometastases in patients with squamous cell carcinoma of the head and neck.

OBJECTIVES/HYPOTHESIS: Patients with primary squamous cell carcinoma of the head and neck have a relatively high risk of occult lymph node metastases. Pathological demonstration of these metastases may be difficult, and the detection of such occult metastases may identify patients who are at an increased risk for early recurrence or reduced survival. Immunohistochemistry may be applied in the identification of occult metastases that may be missed on routine (H&E) histological examination. The aim of the study is to determine the prevalence and prognostic significance of immunohistochemically identified micrometastases in squamous cell carcinoma of the head and neck. STUDY DESIGN: A retrospective analysis of neck dissection specimens having no evidence of metastatic disease. METHODS: Lymph nodes from neck dissections performed on 10 patients with squamous cell carcinoma of the head and neck without conventional histological evidence of nodal metastases were subsequently stained for cytokeratins by the monoclonal antibody cocktail AE1/AE3 to detect micrometastases. RESULTS: Occult micrometastases were found in the lymph nodes 5 of 10 patients examined. There was no association between the site of primary tumor, or T tage, and the presence of occult metastases. Three of five patients found to have occult metastases developed recurrence in the neck, whereas only one of five patients with no evidence of micrometastases had regional recurrence. There was no significant discrepancy in the patient survival rate. CONCLUSIONS: Metastatic tumor cells are frequently present in lymph nodes, even in patients without histological evidence of nodal metastases by conventional methods. The presence of micrometastases may identify patients at increased risk for recurrence and may indicate poorer prognosis. The true clinical significance of these occult metastases will be determined by a long-term follow-up.

Aged↗