Showing papers by "William B. Armstrong published in 2010"

Development of the Bowman-Birk inhibitor for oral cancer chemoprevention and analysis of Neu immunohistochemical staining intensity with Bowman-Birk inhibitor concentrate treatment.

Abstract: Cancer chemoprevention is a rapidly evolving approach to reverse or inhibit carcinogenesis, and there is active interest in development of effective chemopreventive agents against head and neck cancers. The retinoids are archetypal chemopreventive agents for oral premalignant lesions. They have significant clinical effect, but widespread use is limited by significant clinical toxicity. The Bowman-Birk Inhibitor is one of several nontoxic compounds exhibiting both potent anticarcinogenic activity and minimal toxicity. The purposes of the study were to summarize the preclinical and clinical development of Bowman-Birk Inhibitor and a Bowman-Birk Inhibitor concentrate against oral premalignant lesions and to evaluate Neu immunohistochemical staining intensity for lesions and simultaneously obtained biopsy specimens of normal-appearing mucosa from the Phase IIa Bowman-Birk Inhibitor concentrate oral leukoplakia chemoprevention trial. Part I is a selected literature review. Part II is a retrospective analysis of pathological specimens prospectively obtained from the Phase IIa clinical trial of Bowman-Birk Inhibitor concentrate. Thirty-two sets of biopsy specimens from lesions and uninvolved oral mucosa before and after treatment with Bowman-Birk Inhibitor concentrate in doses ranging from 200 to 1066 chymotrypsin inhibitory units were examined in blinded fashion for Neu immunohistochemical staining intensity using the 3B-5 monoclonal antibody. Staining intensity scores among the lesion and control biopsy specimens before and after Bowman-Birk Inhibitor concentrate treatment were analyzed and compared with previously obtained values for serum Neu, oral mucosal cell Neu, protease activity, and clinical response to treatment. Mean Neu staining score was significantly higher in lesions compared with uninvolved mucosa (P <.001). Pretreatment staining scores for biopsy specimens of lesions and control biopsy specimens of normal-appearing tissues were correlated (Spearman correlation coefficient [r] = 0.375, P =.045), but no correlation between lesion and control biopsy specimen scores was evident after treatment. The change in Neu staining score with Bowman-Birk Inhibitor concentrate treatment in control site biopsy specimens demonstrated an inverse relationship of change in lesion area with Bowman-Birk Inhibitor concentrate treatment (Spearman r = -0.493, P <.007). Bowman-Birk Inhibitor concentrate shows promise to become an effective nontoxic chemopreventive agent based on results of extensive preclinical studies, and Phase I and Phase IIa clinical trials. Bowman-Birk Inhibitor concentrate has dose-related clinical activity against oral leukoplakia and modulates levels of Neu and protease activity. The current investigation identified increased Neu staining intensity in hyperplastic lesions compared with simultaneously obtained biopsy specimens of normal-appearing mucosa both before and after Bowman-Birk Inhibitor concentrate treatment. This finding supports prior observations that increased Neu expression is present in a subset of oral premalignant lesions and head and neck cancers. The trend of increased Neu staining score in control biopsy tissues of subjects exhibiting decreased lesion area following Bowman-Birk Inhibitor concentrate treatment raises questions about the mechanisms of Bowman-Birk Inhibitor concentrate action. One possible explanation is that Bowman-Birk Inhibitor stabilizes the extracellular domain of Neu, thereby preventing receptor truncation and internalization. Further study of modulation of Neu and protease activity by Bowman-Birk Inhibitor concentrate treatment may provide insights into the role of proteases and protease inhibitors in oral premalignant lesions and the mechanisms underlying Bowman-Birk Inhibitor concentrate effects. A Phase IIb randomized, placebo-controlled clinical trial to determine the clinical effectiveness of Bowman-Birk Inhibitor concentrate and further evaluate these candidate biomarkers is under way.

Optical coherence tomography of the larynx using the Niris system.

Abstract: Optical coherence tomography (OCT) is an emerging imaging modality that combines a low-coherence light source and an interferometer to produce cross-sectional high-resolution images of living tissues.1 OCT works analogously to ultrasonography but instead of sound uses near-infrared light to discern variation in tissue optical properties. Clinical OCT devices have an axial resolution of approximately 10 µm and a maximum depth penetration of 2 to 3 mm, although 1 to 2 mm is more typical because most biologic tissues are turbid.2 This technology has been widely used in ophthalmology for examination of the retina, cornea, and macula3–5 and as a guide in cataract surgery.6 OCT has been evaluated in other specialties, including dermatology, cardiology, pulmonology, gastroenterology, urology, and neurology, although primarily using research OCT systems designed and constructed by specialists in photonic technologies at academic medical centres.7–12 In the head, neck, and upper aerodigestive tract, clinical OCT has focused on examination of the larynx, with one goal: to distinguish benign from microinvasive cancer that has violated the integrity of the basement membrane (BM).2,13–18 Some work has focused on using OCT to perform image-guided therapy of the larynx, although the results have been mixed.19 It has also been used coupled to a surgical microscope, allowing hands-free OCT simultaneously with microscopic visualization of the vocal cords.20 More recently, we pioneered the use of OCT to image both the neonatal and the pediatric airway with the aim of examining changes in the subglottis following prolonged intubation.21,22 OCT has also been used to image the middle ear and thyroid gland.23–26 The oral cavity has been studied comprehensively using OCT and is reviewed elsewhere.24,25,27–33 Outside of ophthalmology, most clinical OCT studies have involved the use of systems designed and built by research groups focused on enhancing the resolution, image acquisition rates, and functionality of this nascent imaging modality. Until recently, there has not been a commercially available turnkey OCT system for use in the head and neck, and most studies to date have used research devices designed and constructed in university optics laboratories. At University of California Irvine, we have had an active OCT research program at the Beckman Laser Institute and Medical Clinic for over 15 years, with over 7 years of clinical experience on OCT imaging in the head and neck in human subjects. Our investigations to date have used only OCT systems designed and constructed in our laboratories. The objective of this study was to present our experience with using the first commercially available OCT device designed to image the larynx among other applications and to compare its use with our previous experience in over 200 patients using research OCT systems.

Intraoperative Use of OCT in Endocrine Surgery

Abstract: OBJECTIVE: Clinical trials have suggested suppression of EGFR pathway results in improved response to radiotherapy. AKT is a component of the phosphatidylinositol-3 kinase pathway that is downstream of the EGF receptor. Here we perform a preclinical assessment of the augmentation effect of AKT inhibitor on radiotherapy for head and neck squamous cell carcinoma. METHOD: Ex vivo ATP analysis on human tissue samples was performed to measure metabolic activity. Treatment groups were classified as control, AKT inhibitor, cetuximab and AKT i cetuximab. Nude mice with human SCC1-flank tumor xenografts were treated with combination treatments of 120 mg/kg AKT inhibitor, 10 mg/kg cetuximab, and 2 Gy radiation. Tumor size was assessed after each treatment using a pair of digital calipers. RESULTS: Ex vivo treatment with an AKT inhibitor alone significantly reduced ATP metabolic activity in human tissue specimens compared to control (64%, p 0.04). Combination treatment with cetuximab further enhanced this effect (29%, p 0.01). In vivo SCC1 flank tumor xenografts in Nude mice were significantly smaller following 2 weeks combination treatment with AKT i, cetuximab and radiation (15 mm) compared to control (102 mm, p 0.02) or radiation monotherapy (56 mm, p 0.05). CONCLUSION: Inhibition of the AKT pathway augments treatment with cetuximab on ex vivo human tissue and combination treatment with cetuximab and radiation in vivo.

Ectopic Intratracheal Thyroid Causing Airway Obstruction

Abstract: INTRODUCTION: Thyroid ectopia can be found at the site of thyroid origin in the floor of the mouth, or anywhere along its path of embryological descent, thus reflecting the normal migration of thyroid progenitor cells. The most frequent sites of ectopic thyroid tissue are lingual, sublingual, thyroglossal and laryngotracheal, with ectopic intratracheal thyroid (EITT) accounting for a small minority of these cases. EITT represents approximately 1% of all primary endotracheal tumors (1). First noted by Ziemssen in 1875, there have been at least 130 cases of EITT described (2). Most cases have been reported from the endemic goiter regions of the world, and commonly detected in the third to fifth decades of life (3,4). Approximately 75% of EITT are associated with orthotopic goiters (3,4).

Abstract CN02-05: Phase IIb randomized clinical chemoprevention trial of a soybean-derived compound (Bowman-Birk inhibitor concentrate) for oral leukoplakia

Abstract: Introduction: Epidemiologic observations have suggested a protective effect of soybeans against a number of epithelial cancers including oral malignancies and by inference precursor lesions such as leukoplakia. Several compounds in soybeans have shown activity in preclinical models; we have focused our studies on BBI (Bowman-Birk inhibitor), which is active against the protease chymotrypsin. Our phase I trial demonstrated a very low toxicity profile and a 31% response rate in a 1-month nonrandomized study that was associated with favorable modulation of protease activity and neu oncogene in exfoliated buccal mucosal cells (EBMC). Methods: An intent-to-treat(ITT) randomized placebo (Quaker mass harina, a corn flour)-controlled, double-blind clinical trial of a soybean concentrate (C) of BBI (600 C.I. units) was performed in a multinstitutional investigation (7 sites). The study duration was 6 months and included pre/interim/postevaluation of lesions sizes and pre/post photographic assessments and oral mucosa biopsies(with post central pathology review) of the involved area(s). Intermediate biomarkers (IBM) included serial measurements of EBMC neu protein (ng/mg) and protease (Delrfu/min/ug protein) and serum neu protein (ng/ml). 325 patients underwent preliminary screening and 148 per protocol eligible were enrolled. Of these, 132 were randomized and 105 completed 6 months on study. All data on lesion sizes, photo judgments, and pathology indications of degree of abnormality or change in abnormality were entered into SAS datasets and subjected to 100% verification against the crf forms by the statistician. The several IBM measurements were converted from the original Microsoft Excel sheets into SAS data sets, and subject to spot checks against the original spreadsheets. Similarly, host-factor information from the questionnaires was spot checked against the original records. In all cases, the primary, per-protocol analyses was ITT. The per-protocol, intent-to-treat cohort, and all other categorizations of study participants will also be described with appropriate descriptive summary measures. Results: The ITT data set is composed of all those with valid, two-dimensional measurements on all lesions observed at both the randomization and 6-month visit. 89 evaluable patients met these criteria: 43 in the treatment and 46 in the placebo group. For the BBIC group, the mean relative percent change in total lesion area was −20.6% and for the placebo group −17.1%. Clinical responses for the 89 patients were: four showed a complete response (4.5%), 22 showed a partial response (25%), 53 showed stable disease (60%), and 10 showed disease progression (11.2%). For the drug group the CR+PR(>50% change) was 27.91% and for placebo group 30.43%. Neither the lesion size nor response comparisons demonstrated differences between the two groups that were significantly different (p>0.05). Photos of the same lesion at baseline and at the 6-month exam were available for 91 participants. Five qualified reviewers made judgments of the degree of change in abnormality on a seven-point scale, blinded to study arm and timepoint of photos. For mean comparison scores, 1 was substantial improvement over time, 4 indicated no change and 7 meaning much worse decline over time. Preliminary assessments of 77% of the patients having pre/post photos indicates that there were no significant differences between the placebo and treatment groups. Conclusion: BBIC is not effective as a chemoprevention agent for the management of oral leukoplakia. Central pathology review by two reviewers is near completion, but is unlikely to affect this conclusion. Final measurements of the three biomarkers should be available by the time of presentation and subanalysis will be presented for the two groups and for the patients who seemed to have had a clinical response. Citation Information: Cancer Prev Res 2010;3(12 Suppl):CN02-05.

The effectiveness of chemoprevention agents is underestimated when lesion sizes are rounded.

Abstract: Change in the area of premalignant lesions is an end point in estimating the efficacy of chemopreventive agents. When examiners round measurements of lesion length and width, they introduce variability, which perturbs the relative percent change in lesion area and, consequently, the percent of subjects showing a clinical response. We use simulations to illustrate the resulting bias when the agent under test is effective in reducing lesion area. We simulated 500 oral leukoplakia lesions per run, with 2,500 runs at each of five levels of agent effectiveness, namely, true relative percent reduction in area of 25%, 45%, 50%, 55%, and 75%. Realistic values of lesion lengths and widths were generated randomly and then rounded to the nearest multiple of five. The product is the distribution of mean relative percent change in lesion area and the corresponding percent of subjects showing a clinical response. Even the fifth percentile of the distribution of mean relative percent change in lesion area consistently underestimated the true value, by about 6 percentage points. The percent showing a clinical response was underestimated by 50%, 37%, and 11% for true values of reduction in lesion area of 50%, 55%, and 75%, respectively. This could easily double the required sample size for a modest phase II study. We suggest that it is cost-effective to train observers of lesion length and width to eschew rounding of measurements in the chemoprevention setting.

CO2 laser transoral laser microsurgery of head and neck cancer: lessons learned over ten years

Abstract: Background CO2 transoral laser microsurgery (TLM) is an emerging technique for the management of laryngeal cancer and other head and neck malignancies. This technique has become more widely used by head and neck surgeons progressively replacing traditional open surgical procedures because it is better at preserving organ function with lower overall morbidity. The CO2 laser is coupled to a micromanipulator and microscope, which provides enhanced tumor visualization and the ability to perform precise tissue cuts, obtain excellent hemostasis, and avoid damaging the surrounding tissues and structures that are transected during open surgical procedures. Objectives To summarize our experience using the CO2 laser for the transoral resection of head and neck cancer, and discuss strategies and solutions for situations encountered during laser resections. Material and methods The basic principles and approach of performing TLM using CO2 laser for different otolaryngologic malignancies will be discussed. The benefits of using CO2 TLM over traditional surgery, common complications, and different settings used depending on the location of the tumor and as well as the several lessons learned over the years will also be discussed. Conclusion CO2 laser is the best-suited laser for TLM in treatment of head and neck cancer. Over the years the improved instrumentation, demonstration of oncologic effectiveness, clinical experience using TLM and decreased morbidity has led to an increased utilization of TLM by head and neck surgeons. Successful surgery requires adequate visualization, precise cutting, controlled depth of tissue penetration, and ability to obtain tissue hemostasis. The full spectrum of laser power settings, spot sizes and energy pulse delivery modes is utilized to resect mucosa, fat, muscle, connective tissue and cartilage while avoiding inadvertent damage to nerves and large vessels, and obtaining adequate hemostasis.

Emerging applications for OCT in the head and neck

Abstract: Objectives: To describe the current and promising new applications of Optical Coherence Tomography (OCT) as a helpful tool when imaging the different sites in the head and neck. We used the OCT Niris system, which is the first commercially available OCT device for applications outside the field of ophthalmology. Methods: OCT images were obtained of normal, benign, premalignant and malignant lesions in different areas of the head and neck. The OCT imaging system has a tissue penetration depth of approximately 1-2mm, a scanning range of 2mm and a spatial depth resolution of approximately 10-20μm. Imaging was performed using a flexible probe in two different settings, the outpatient clinic and the operating room. Results: High-resolution cross-sectional images from the larynx were obtained with the patient awake, without the need for general anesthesia, under direct visualization with a flexible fiberoptic endoscope. The OCT probe was inserted through the nasal cavity and placed in slight contact with the laryngeal tissue. In the ears, cholesteatoma was differentiated from inflamed middle ear mucosa by the different hyperintensity. In the neck, normal as well as different pathologies of the thyroid were identified. Conclusions: This system is non invasive and easy to incorporate into the operating room setting as well as the outpatient clinic. It requires minimal set-up and only one person is required to operate the system. OCT has the distinctive capability to obtain highresolution images, and the microanatomy of different sites can be observed. OCT technology has the potential to offer a quick, efficient and reliable imaging method to help the surgeon not only in the operating room but also in the clinical setting to guide surgical biopsies and aid in clinical decision making of different head and neck pathologies, especially those arising form the larynx.