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1.  Secondary Chemoprevention of Barrett’s Esophagus With Celecoxib: Results of a Randomized Trial 
Barrett’s esophagus is a premalignant condition that is a risk factor for the development of esophageal adenocarcinoma, a disease whose incidence is rapidly increasing. Because aspirin and other nonsteroidal antiinflammatory drugs, such as celecoxib, may decrease the risk of developing esophageal cancer, we investigated the effect of long-term administration of celecoxib in patients with Barrett’s esophagus with dysplasia.
Chemoprevention for Barrett’s Esophagus Trial (CBET) is a phase IIb multicenter randomized placebo-controlled trial of celecoxib in patients with Barrett’s esophagus and low- or high-grade dysplasia. Patients were randomly assigned to treatment with 200 mg of celecoxib or placebo, both administered orally twice daily, and then stratified by grade of dysplasia. The primary outcome was the change from baseline to 48 weeks of treatment in the proportion of biopsy samples with dysplasia between the celecoxib and placebo arms. Secondary and tertiary outcomes included evaluation of changes in histology and expression levels of relevant biomarkers. All statistical tests were two-sided.
From April 1, 2000, through June 30, 2003, 222 patients were registered into CBET, and 100 of them with low- or high-grade Barrett’s dysplasia were randomly assigned to treatment (49 to celecoxib and 51 to placebo). After 48 weeks of treatment, no difference was observed in the median change in the proportion of biopsy samples with dysplasia or cancer between treatment groups in either the low-grade (median change with celecoxib = − 0.09, interquartile range [IQR] = − 0.32 to 0.14 and with placebo = − 0.07, IQR = − 0.26 to 0.12; P = .64) or high-grade (median change with celecoxib = 0.12, IQR = − 0.31 to 0.55, and with placebo = 0.02, IQR = − 0.24 to 0.28; P = .88) stratum. No statistically significant differences in total surface area of the Barrett’s esophagus; in prostaglandin levels; in cyclooxygenase-1/2 mRNA levels; or in methylation of tumor suppressor genes p16, adenomatous polyposis coli, and E-cadherin were found with celecoxib compared with placebo.
Administration of 200 mg of celecoxib twice daily for 48 weeks of treatment does not appear to prevent progression of Barrett’s dysplasia to cancer.
PMCID: PMC3755596  PMID: 17405999
2.  Selenomethionine Induced Transcriptional Programs in Human Prostate Cancer Cells 
The Journal of urology  2007;177(2):743-750.
We determined the effects of selenomethionine, the major organic selenium containing compound found in the diet and the form of selenium being used in the Selenium and Vitamin E Cancer Prevention Trial, on prostate cancer cells.
Materials and Methods
We assessed global transcript profiles of selenomethionine treated LNCaP using cDNA microarrays and compared them to those of cells treated with methylselenic acid, a direct precursor of methylselenol, which is the active form of selenium in vivo.
After treatment with selenomethionine 2,336 unique genes showed expression changes of at least 1.5-fold in at least 3 time points during 48 hours and 366 unique transcripts differed significantly between selenomethionine and methylselenic acid treated LNCaP. Approximately half of the 76 cell cycle regulated genes affected by selenomethionine were down-regulated and enriched for genes associated with the G2/M phase. Flow cytometry analysis showed that selenomethionine induced G2/M arrest in LNCaP at low concentrations. Selenomethionine also affected expression levels of 35 known androgen responsive genes and 18 of these transcripts showed changes that were the inverse of those seen after androgen stimulation. At high concentrations selenomethionine decreased prostate specific antigen promoter driven luciferase expression.
Selenomethionine modulates transcript levels of genes involved in a number of biological processes, including cell cycle/apoptosis androgen signaling, signal transduction and transcriptional regulation. Although the pathways affected paralleled in many ways those that are modulated by methylselenic acid, distinct differences in transcript patterns and effects on cell cycle regulation suggest that different selenium compounds could exert unique effects in prostate cells.
PMCID: PMC2729366  PMID: 17222674
prostate; prostatic neoplasms; selenomethionine; microarray analysis; gene expression
3.  Correlation Between Dysplasia and Ploidy Status in Oral Leukoplakia 
Head and Neck Pathology  2012;6(3):322-327.
Oral leukoplakia and other potentially malignant disorders (PMD) may progress to oral squamous cell carcinoma (OSCC). The gold standard for assessing the potential for malignant transformation remains histologic examination with the aim of grading the dysplastic changes. However, not all lesions with dysplasia will progress to OSCC. DNA ploidy has been suggested as a method to predict the clinical behaviour of PMD. This study reports on the use of high-resolution flow cytometry to determine the ploidy status of formalin-fixed, paraffin-embedded material from PMD compared to their dysplasia grade on histology. Aneuploidy was found in 13 % of mild, 31 % of moderate, and 54 % of severe dysplasia cases. This difference was statistically significant (p = 0.011). The differences in ploidy status were more significant when grouping the dysplasia into low-risk and high-risk categories (p = 0.008). These findings indicate that the ploidy status of PMD as determined by high-resolution flow cytometry may be of value in predicting biological behaviour in PMD such as leukoplakia.
PMCID: PMC3422580  PMID: 22430773
Leukoplakia; DNA ploidy; Dysplasia; Potentially malignant disorders; Oral mucosa; Flow cytometry
4.  Value of Second Pass in Loop Electrosurgical Excisional Procedure 
Journal of Korean Medical Science  2009;24(1):110-113.
The aim of this study was to compare the rate of incomplete resection and treatment outcome of the second-pass technique with those of single-pass technique in loop electrosurgical excisional procedure (LEEP). From 1997 to 2002, 683 women were diagnosed as squamous dysplasia via LEEP in our institution. Age, parity, LEEP technique, grade of lesion, glandular extension, margin status, residual tumor and recurrence were obtained by reviewing medical records. Positive margin was defined as mild dysplasia or higher grade lesions at resection margin of the LEEP specimen. In women who underwent hysterectomy, residual tumor was defined as mild dysplasia or higher grade lesions in hysterectomy specimen. In women who did not underwent hysterectomy, Pap smear more than atypical squamous cells of undetermined significance or biopsy result more than mild dysplasia within two years after LEEP were regarded as cytologic or histologic recurrences, respectively. Treatment failure of LEEP was defined as residual tumor or histologic recurrence. The second-pass technique significantly reduced the endocervical margin positivity (odds ratio [OR], 0.36; 95% confidence interval [CI], 0.21-0.63). However, the second-pass technique did not reduce the treatment failure (OR, 0.62; 95% CI, 0.29-1.32). In conclusion, the second-pass technique markedly reduced the endocervical margin positivity, but did not reduce the treatment failure rate of LEEP.
PMCID: PMC2650991  PMID: 19270822
Second-Pass Technique; Cervical Intraepithelial Neoplasia; Loop Electrosurgical Excisional Procedure; Endocervical Margin Involvement; Conization
5.  mRNA expression of the DNA replication-initiation proteins in epithelial dysplasia and squamous cell carcinoma of the tongue 
BMC Cancer  2008;8:395.
The tongue squamous cell carcinomas (SCCs) are characterized by high mitotic activity, and early detection is desirable. Overexpression of the DNA replication-initiation proteins has been associated with dysplasia and malignancy. Our aim was to determine whether these proteins are useful biomarkers for assessing the development of tongue SCC.
We analyzed the mRNA expression of CDC6, CDT1, MCM2 and CDC45 in formalin-fixed, paraffin-embedded benign and malignant tongue tissues using quantitative real-time PCR followed by statistical analysis.
We found that the expression levels are significantly higher in malignant SCC than mild precancerous epithelial dysplasia, and the expression levels in general increase with increasing grade of precancerous lesions from mild, moderate to severe epithelial dysplasia. CDC6 and CDC45 expression is dependent of the dysplasia grade and lymph node status. CDT1 expression is higher in severe dysplasia than in mild and moderate dysplasia. MCM2 expression is dependent of the dysplasia grade, lymph node status and clinical stage. The expression of the four genes is independent of tumor size or histological grade. A simple linear regression analysis revealed a linear increase in the mRNA levels of the four genes from the mild to severe dysplasia and SCC. A strong association was established between CDC6 and CDT1, and between MCM2 and CDC45 expression. The nonparametric receiver operating characteristic analysis suggested that MCM2 and CDC45 had a higher accuracy than CDC6 and CDT1 for distinguishing dysplasia from tongue SCC.
These proteins can be used as biomarkers to distinguish precancerous dysplasia from SCC and are useful for early detection and diagnosis of SCC as an adjunct to clinicopathological parameters.
PMCID: PMC2648984  PMID: 19116018
6.  Methyl Selenocysteine: single-dose pharmacokinetics in men 
The recently published report of the SELECT evaluation of selenium and vitamin E provided strong evidence that selenium 200mcg/day in the form of selenomethionine does not protect selenium-replete men against prostate or any other cancer. This appears to refute the result of the much smaller Nutritional Prevention of Cancer (NPC) trial of selenium. Since SELECT did not test the NPC agent, is possible that the difference between the two trials stems partly from the use of different agents: selenomethionine in SELECT, selenized yeast in the NPC trial. One of the organic selenium forms suspected of having strong chemopreventive effects, and which may have been present in the NPC agent, is methyl selenocysteine. This study characterizes the single-dose pharmacokinetics of methyl selenocysteine.
PMCID: PMC3208773  PMID: 21846796
selenium; selenomethionine; methyl selenocysteine; chemoprevention; pharmacokinetics
7.  Class-specific herpes simplex virus antibodies in sera and cervical secretions from patients with cervical neoplasia: a multi-group comparison 
Epidemiology and Infection  1988;100(3):455-465.
Serum and cervical secretions were collected from patients with cervical dysplasia, carcinoma-in-situ (CIS), squamous cell carcinoma (cervical SCC), and controls with normal cervices, attending clinics within the West Lambeth Health District, London. Enzyme-linked immunosorbent assays were used to examine cervical secretory IgA (sIgA) and serum IgG and IgA antibodies to herpes simplex virus (HSV). Sexual and demographic factors were considered during data analysis, which involved fitting multiple linear or multiple logistic regressions to HSV antibody levels. Prevalence of sIgA-HSV and levels of serum antibodies to HSV in all groups were compared with those of gynaecology controls. Caucasian women with mild dysplasia had a significantly higher prevalence of sIgA-HSV. Serum IgG levels to HSV (IgG-HSV) were significantly elevated in women with mild dysplasia and severe dysplasia/CIS. Serum IgA levels to HSV1 (IgG-HSV1) were significantly higher in women with cervical SCC (after adjusting for smoking habits) and other genital tumours. Significantly higher levels of serum IgA to HSV2 (IgA-HSV2) were also found among Caucasian women with cervical SCC. The possible role of HSV as a co-factor in cervical carcinogenesis is discussed.
PMCID: PMC2249362  PMID: 2837405
8.  Expression of midkine in the early stage of carcinogenesis in human colorectal cancer 
British Journal of Cancer  1999;79(1):179-184.
It has been suggested that a heparin-binding growth factor, midkine (MK), plays an important role incarcinogenesis because of its frequent overexpression in various malignant tumours. To clarify whether or not MK contributes to theearly stage of carcinogenesis, we examined the status of MK mRNA in 20 adenomas with moderate- and severe-grade dysplasia, 28carcinomas and 28 corresponding normal tissues, by means of Northern blotting. The MK expression level was significantly moreelevated in adenomas than in normal tissues P< 0.001, unpaired Student's t -test). A difference wasalso observed between carcinomas and the corresponding normal tissues P< 0.04, paired Student's t-test). Moreover, MK immunostaining was positive in the adenomas with moderate- and severe-grade dysplasia and in the carcinomas,but not in mild-grade dysplasia or in normal tissues. These findings were in line with those on Western blotting. In three patientswith both adenomas with moderate- or severe-grade dysplasia and carcinomas, elevated MK expression was observed in the neoplasticlesions. This is the first report of the association of elevated MK expression with the early stage of carcinogenesis in humans. © 1999 Cancer Research Campaign
PMCID: PMC2362182  PMID: 10408712
carcinogenesis; colorectal adenoma; colorectal carcinoma; midkine; pleiotrophin
9.  A follow-up study of progression from dysplasia to squamous cell carcinoma with immunohistochemical examination of p53 protein overexpression in the bronchi of ex-chromate workers. 
British Journal of Cancer  1997;75(5):678-683.
Squamous cell carcinoma (SCC) of the bronchus is considered to develop from preneoplastic 'dysplasia', but reports of sequential observation of this dysplasia-carcinoma sequence in humans are very few. We followed four dysplastic lesions found in the bronchi of three ex-chromate workers by bronchoscopy and biopsy and found that all of them progressed to SCC. Of the four lesions, three were severe dysplasias at the first biopsy which progressed to SCCs in 7-13 months. The last one was a slight dysplasia at the first biopsy and showed progression of the atypia to carcinoma in 6 years and 10 months. An immunohistochemical analysis of the chronological change in p53 protein expression in these lesions and in normal ciliated epithelium taken from the surroundings was conducted in each case. Overexpression of p53 protein was observed in two of the severe dysplasias and the one slight dysplasia, as well as their eventual SCCs. However, no such change was apparent in one case of severe dysplasia or its eventual SCC. Normal epithelium was consistently negative. Our results provide direct proof of the dysplasia-carcinoma sequence and suggest that alteration in the expression of p53 protein might be an important early event which persists. Therefore, the immunohistochemical detection of p53 overexpression in biopsy specimens of bronchial epithelium might be useful for evaluation of preneoplastic lesions in high-risk group individuals and for early diagnosis of bronchial cancer.
PMCID: PMC2063337  PMID: 9043024
10.  Baseline Comorbidities in a Skin Cancer Prevention Trial in Bangladesh 
Epidemiologic research suggests that increased cancer risk due to chronic arsenic exposure persists for several decades even after the exposure has terminated. Observational studies suggest antioxidants exert a protective effect on arsenical skin lesions and cancers among those chronically exposed to arsenic through drinking water. This study reports on the design, methods, and baseline analyses from the Bangladesh Vitamin E and Selenium Trial (BEST), a population based chemoprevention study conducted among adults in Bangladesh with visible arsenic toxicity.
Materials and methods
BEST is a 2×2 full factorial double-blind randomized controlled trial of 7,000 adults having manifest arsenical skin lesions evaluating the efficacy of 6-year supplementation with alpha-tocopherol (100 mg daily) and L-selenomethionine (200 μg daily) for the prevention of non-melanoma skin cancer.
In cross-sectional analyses, we observed significant associations of skin lesion severity with male sex (female prevalence odds ratio (POR)=0.87; 95% CI=0.79–0.96), older age (aged 36–45 POR=1.27; 95% CI=1.13–1.42; aged 46–55 POR=1.44; 95% CI=1.27–1.64; and aged 56–65 POR=1.50; 95% CI=1.26–1.78 compared to aged 25–35), hypertension (POR=1.29; 95% CI=1.08–1.55), diabetes (POR=2.13; 95% CI=1.32–3.46), asthma (POR=1.55; 95% CI=1.03–2.32), and peptic ulcer disease (POR=1.20; 95% CI=1.07–1.35).
We report novel associations between arsenical skin lesions with several common chronic diseases. With the rapidly increasing burden of preventable cancers in developing countries, efficient and feasible chemoprevention study designs and approaches, such as employed in BEST, may prove both timely and potentially beneficial in conceiving cancer chemoprevention trials in Bangladesh and beyond.
PMCID: PMC3953314  PMID: 23590571
dietary supplements; selenium; vitamin E; skin neoplasms; Bangladesh
11.  Serum 25(OH)-Vitamin D concentration and risk of esophageal squamous dysplasia 
Squamous dysplasia is the precursor lesion for esophageal squamous cell carcinoma (ESCC), and nutritional factors play an important role in the etiology of this cancer. Previous studies using a variety of measures of vitamin D exposure have reached different conclusions about the association between vitamin D and risk of developing esophageal cancer.
We measured serum 25-hydroxyvitamin D (25(OH)D) concentrations in a cross-sectional analysis of 720 subjects from Linxian, China, a population at high risk for developing ESCC. All subjects underwent endoscopy and biopsy and were categorized by presence or absence of histologic squamous dysplasia. We used crude and multivariate adjusted generalized linear models to estimate the relative risk (RR) and 95% confidence intervals (CI) for the association between squamous dysplasia and sex-specific quartiles of serum 25(OH)D concentration.
Two hundred and thirty (32%) of 720 subjects had squamous dysplasia. Subjects with dysplasia had significantly higher median serum 25(OH)D concentrations then subjects without dysplasia, 36.5 and 31.5 nmol/L respectively (Wilcoxon two-sample test p = 0.0004). In multivariate adjusted models, subjects in the highest compared to the lowest quartile were at significantly increased risk of squamous dysplasia, RR (95% CI) = 1.86 (1.35–2.62). Increased risks were similar when examined in men and women separately: Men RR (95% CI) = 1.74 (1.08–2.93); Women RR (95% CI) = 1.96 (1.28–3.18).
Higher serum 25(OH)D concentration was associated with significantly increased risk of squamous dysplasia. No obvious source of measured or unmeasured confounding explains this finding.
PMCID: PMC2812415  PMID: 17855710
Esophageal cancer; Squamous dysplasia; Vitamin D; Serum 25(OH)D; China
12.  Chemoprevention of Nonmelanoma Skin Cancer With Celecoxib: A Randomized, Double-Blind, Placebo-Controlled Trial 
Preclinical studies indicate that the enzyme cyclooxygenase 2 plays an important role in ultraviolet-induced skin cancers. We evaluated the efficacy and safety of celecoxib, a cyclooxygenase 2 inhibitor, as a chemopreventive agent for actinic keratoses, the premalignant precursor of nonmelanoma skin cancers, and for nonmelanoma skin cancers, including cutaneous squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs).
A double-blind placebo-controlled randomized trial involving 240 subjects aged 37–87 years with 10–40 actinic keratoses was conducted at eight US academic medical centers. Patients were randomly assigned to receive 200 mg of celecoxib or placebo administered orally twice daily for 9 months. Subjects were evaluated at 3, 6, 9 (ie, completion of treatment), and 11 months after randomization. The primary endpoint was the number of new actinic keratoses at the 9-month visit as a percentage of the number at the time of randomization. In an intent-to-treat analysis, the incidence of actinic keratoses was compared between the two groups using t tests. In exploratory analyses, we evaluated the number of nonmelanoma skin cancers combined and SCCs and BCCs separately per patient at 11 months after randomization using Poisson regression, after adjustment for patient characteristics and time on study. The numbers of adverse events in the two treatment arms were compared using χ2 or Fisher exact tests. All statistical tests were two-sided.
There was no difference in the incidence of actinic keratoses between the two groups at 9 months after randomization. However, at 11 months after randomization, there were fewer nonmelanoma skin cancers in the celecoxib arm than in the placebo arm (mean cumulative tumor number per patient 0.14 vs 0.35; rate ratio [RR] = .43, 95% confidence interval [CI] = 0.24 to 0.75; P = .003). After adjusting for age, sex, Fitzpatrick skin type, history of actinic keratosis at randomization, nonmelanoma skin cancer history, and patient time on study, the number of nonmelanoma skin cancers was lower in the celecoxib arm than in the placebo arm (RR = 0.41, 95% CI = 0.23 to 0.72, P = .002) as were the numbers of BCCs (RR = 0.40, 95% CI = 0.18 to 0.93, P = .032) and SCCs (RR = 0.42, 95% CI = 0.19 to 0.93, P = .032). Serious and cardiovascular adverse events were similar in the two groups.
Celecoxib may be effective for prevention of SCCs and BCCs in individuals who have extensive actinic damage and are at high risk for development of nonmelanoma skin cancers.
PMCID: PMC3001966  PMID: 21115882
13.  Progressive 3q Amplification Consistently Targets SOX2 in Preinvasive Squamous Lung Cancer 
Rationale: Amplification of distal 3q is the most common genomic aberration in squamous lung cancer (SQC). SQC develops in a multistage progression from normal bronchial epithelium through dysplasia to invasive disease. Identifying the key driver events in the early pathogenesis of SQC will facilitate the search for predictive molecular biomarkers and the identification of novel molecular targets for chemoprevention and therapeutic strategies. For technical reasons, previous attempts to analyze 3q amplification in preinvasive lesions have focused on small numbers of predetermined candidate loci rather than an unbiased survey of copy-number variation.
Objectives: To perform a detailed analysis of the 3q amplicon in bronchial dysplasia of different histological grades.
Methods: We use molecular copy-number counting (MCC) to analyze the structure of chromosome 3 in 19 preinvasive bronchial biopsy specimens from 15 patients and sequential biopsy specimens from 3 individuals.
Measurements and Main Results: We demonstrate that no low-grade lesions, but all high-grade lesions, have 3q amplification. None of seven low-grade lesions progressed clinically, whereas 8 of 10 patients with high-grade disease progressed to cancer. We identify a minimum commonly amplified region on chromosome 3 consisting of 17 genes, including 2 known oncogenes, SOX2 and PIK3CA. We confirm that both genes are amplified in all high-grade dysplastic lesions tested. We further demonstrate, in three individuals, that the clinical progression of high-grade preinvasive disease is associated with incremental amplification of SOX2, suggesting this promotes malignant progression.
Conclusions: These findings demonstrate progressive 3q amplification in the evolution of preinvasive SQC and implicate SOX2 as a key target of this dynamic process.
PMCID: PMC2902760  PMID: 20299530
bronchial dysplasia; squamous lung cancer; gene amplification; molecular copy-number counting; SOX2
14.  Immunohistochemical evaluation of oral epithelial dysplasia using cyclin-D1, p27 and p63 expression as predictors of malignant transformation 
To evaluate the degree of expression of cyclin-D1, p27 and p63 in mild, moderate and severe dysplasia using immunohistochemical evaluation in order to illustrate their prognostic value and attempt to propose a molecular grading system for oral epithelial dysplasia.
Materials and Methods:
The analysis included thirty cases of mild, moderate and severe dysplasia from Department of Oral and Maxillofacial Pathology, Saveetha Dental College, Chennai after a critical review of the Hematoxylin and Eosin (H and E) stained sections. They were subjected to immunohistochemical evaluation using the markers cyclin-D1, p27 and p63. The assessment of the expression based on staining intensity and distribution of immunohistochemical staining of the various markers was analyzed followed by statistical analysis.
A highly significant increase in the expression of cyclin-D1 (P < 0.000) and p63 (P < 0.001) and a moderately significant decrease in the expression of p27 (P < 0.012) with the increasing severity of dysplasia was observed in our study.
The result of our research affirms the fact that the increase in the expression of markers of cell cycle regulators such as cyclin D1, decrease in the expression of cell cycle inhibitors like p27 and increased expression of p63 in parallel with the increasing severity of dysplasia, emphasizes the use of immunohistochemical markers cyclin D1, p27 and p63 as prognostic markers for better understanding the behaviour of these potentially malignant disorders aiming towards proposing a molecular grading system for oral epithelial dysplasia to enable timely management prior to their possible malignant transformation.
PMCID: PMC3783779  PMID: 24082731
Cyclin-D1; immunohistochemistry; leukoplakia; oral epithelial dysplasia; p27; p63
15.  Prognostic Value of Combined Aquaporin 3 and Aquaporin 5 Overexpression in Hepatocellular Carcinoma 
BioMed Research International  2013;2013:206525.
Background. Aquaporin (AQP) 3 and AQP 5 are involved in tumorigenesis and tumor progression of several tumor types. Aim. To investigate expression patterns and clinical significance of AQP3 and AQP5 in hepatocellular carcinoma (HCC). Methods. Immunohistochemistry was performed to detect the expression of AQP3 and AQP5 in HCC tissues. Results. Immunohistochemistry analysis showed the increased expression of AQP3 and AQP5 protein levels in HCC tissues compared with their adjacent nonneoplastic tissues (both P < 0.001). In addition, combined AQP3 and AQP5 protein expression was significantly associated with serum AFP (P = 0.008), tumor stage (P = 0.006), and tumor grade (P = 0.006). Moreover, HCC patients highly expressing both AQP3 and AQP5 proteins had worse 5-year disease-free survival and 5-year overall survival (P = 0.002 and 0.005, resp.). Furthermore, the Cox proportional hazards model showed that combined AQP3 and AQP5 protein expression was an independent poor prognostic factor for both 5-year disease-free survival (P = 0.009) and 5-year overall survival (P = 0.01) in HCC. Conclusion. Our data suggest for the first time that the aberrant expression of AQP3 and AQP5 proteins may be strongly related to tumor progression and prognosis in patients with HCC. The overexpression of AQP3 in combination with upregulation of AQP5 may be an unfavorable prognostic factor for HCC.
PMCID: PMC3810059  PMID: 24224160
16.  Genomic imbalances in precancerous tissues signal oral cancer risk 
Molecular Cancer  2009;8:50.
Oral cancer develops through a series of histopathological stages: through mild (low grade), moderate, and severe (high grade) dysplasia to carcinoma in situ and then invasive disease. Early detection of those oral premalignant lesions (OPLs) that will develop into invasive tumors is necessary to improve the poor prognosis of oral cancer. Because no tools exist for delineating progression risk in low grade oral lesions, we cannot determine which of these cases require aggressive intervention. We undertook whole genome analysis by tiling-path array comparative genomic hybridization for a rare panel of early and late stage OPLs (n = 62), all of which had extensive longitudinal follow up (>10 years). Genome profiles for oral squamous cell carcinomas (n = 24) were generated for comparison. Parallel analysis of genome alterations and clinical parameters was performed to identify features associated with disease progression. Genome alterations in low grade dysplasias progressing to invasive disease more closely resembled those observed for later stage disease than they did those observed for non-progressing low grade dysplasias. This was despite the histopathological similarity between progressing and non-progressing cases. Strikingly, unbiased computational analysis of genomic alteration data correctly classified nearly all progressing low grade dysplasia cases. Our data demonstrate that high resolution genomic analysis can be used to evaluate progression risk in low grade OPLs, a marked improvement over present histopathological approaches which cannot delineate progression risk. Taken together, our data suggest that whole genome technologies could be used in management strategies for patients presenting with precancerous oral lesions.
PMCID: PMC2726119  PMID: 19627613
17.  In vivo Optical Coherence Tomography Imaging of Preinvasive Bronchial Lesions 
Optical coherence tomography (OCT) is an optical imaging method that can visualize cellular and extracellular structures at and below tissue surface. The objective of the study was to determine if OCT could characterize preneoplastic changes in the bronchial epithelium identified by autofluorescence bronchoscopy.
Experimental Design
A 1.5-mm fiberoptic probe was inserted via a bronchoscope into the airways of 138 volunteer heavy smokers participating in a chemoprevention trial and 10 patients with lung cancer to evaluate areas that were found to be normal or abnormal on autofluorescence bronchoscopy. Radial scanning of the airways was done to generate OCT images in real time. Following OCT imaging, the same sites were biopsied for pathologic correlation.
A total of 281 OCT images and the corresponding bronchial biopsies were obtained. The histopathology of these areas includes 145 normal/hyperplasia, 61 metaplasia, 39 mild dysplasia, 10 moderate dysplasia, 6 severe dysplasia, 7 carcinoma in situ, and 13 invasive carcinomas. Quantitative measurement of the epithelial thickness showed that invasive carcinoma was significantly different than carcinoma in situ (P = 0.004) and dysplasia was significantly different than metaplasia or hyperplasia (P = 0.002). In addition, nuclei of the cells corresponding to histologic results became more discernible in lesions that were moderate dysplasia or worse compared with lower-grade lesions.
Preliminary data suggest that autofluorescence bronchoscopy – guided OCT imaging of bronchial lesions is technically feasible. OCT may be a promising nonbiopsy tool for in vivo imaging of preneoplastic bronchial lesions to study their natural history and the effect of chemopreventive intervention.
PMCID: PMC2849640  PMID: 18381938
18.  High-Dose Ursodeoxycholic Acid Is Associated With the Development of Colorectal Neoplasia in Patients With Ulcerative Colitis and Primary Sclerosing Cholangitis 
Some studies have suggested that ursodeoxycholic acid (UDCA) may have a chemopreventive effect on the development of colorectal neoplasia in patients with ulcerative colitis (UC) and primary sclerosing cholangitis (PSC). We examined the effects of high-dose (28–30 mg/kg/day) UDCA on the development of colorectal neoplasia in patients with UC and PSC.
Patients with UC and PSC enrolled in a prior, multicenter randomized placebo-controlled trial of high-dose UDCA were evaluated for the development of colorectal neoplasia. Patients with UC and PSC who received UDCA were compared with those who received placebo. We reviewed the pathology and colonoscopy reports for the development of low-grade or high-grade dysplasia or colorectal cancer.
Fifty-six subjects were followed for a total of 235 patient years. Baseline characteristics (including duration of PSC and UC, medications, patient age, family history of colorectal cancer, and smoking status) were similar for both the groups. Patients who received high-dose UDCA had a significantly higher risk of developing colorectal neoplasia (dysplasia and cancer) during the study compared with those who received placebo (hazard ratio: 4.44, 95% confidence interval: 1.30–20.10, P=0.02).
Long-term use of high-dose UDCA is associated with an increased risk of colorectal neoplasia in patients with UC and PSC.
PMCID: PMC3168684  PMID: 21556038
19.  Human telomerase RNA component (hTERC) gene amplification detected by FISH in precancerous lesions and carcinoma of the larynx 
Diagnostic Pathology  2012;7:34.
Gain of 3q26 is frequently observed in squamous cell carcinomas of mucosal origin, including those originating in the head and neck region. The human telomerase RNA component (hTERC) gene, which is located on chromosome 3q26, encodes for an RNA subunit of telomerase that maintains the length of telomeres through cellular divisions, and is activated in malignant diseases. The present study was designed to detect hTERC amplification in laryngeal lesions and evaluate whether this might serve as a supportive biomarker in histopathological analysis for in the diagnosis of laryngeal lesions.
Fluorescent in situ hybridization (FISH) was applied on formalin-fixed paraffin-embedded blocks of 93 laryngeal specimens, including 14 normal epithelium (NE), 15 mild dysplasia (Md), 18 moderate dysplasia (MD), 16 severe dysplasia (SD), 9 carcinoma in situ (CIS), and 21 invasive carcinoma (IC)).
By histopathologic examination, hTERC amplification rates in NE, Md, MD, SD, CIS and IC cases were 0% (0/14), 13.33% (2/15), 72.22% (13/18), 81.25% (13/16), 100% (9/9) and 100% (21/21), respectively. Amplification of hTERC was significantly associated with histopathologic diagnosis (P < 0.0001). The percentage of hTERC amplification in patients with MD, SD, CIS, and IC was significantly higher than those with NE or Md (P < 0.0001). The number of cells with abnormal signals increased and the abnormal signal patterns were diversified with increasing severity of laryngeal dysplasia (P < 0.0001).
The hTERC amplification is important in the development of laryngeal squamous cell carcinoma (LSCC). FISH detection of hTERC amplification may provide an effective approach in conjunction with histopathologic evaluation for differential diagnosis of laryngeal lesions.
Virtual Slides
The virtual slide(s) for this article can be found here:
PMCID: PMC3359179  PMID: 22463766
Laryngeal carcinoma; Human telomerase RNA component gene; Amplification; Fluorescent in situ hybridization
20.  p53 Overexpression in laryngeal squamous cell carcinoma and dysplasia 
Clinical Molecular Pathology  1995;48(4):M194-M197.
Aim—To investigate the expression of p53 protein in invasive squamous cell carcinoma (SCC) of the larynx and dysplasia in relation to histological grade and tobacco smoking.
Method—Paraffin wax embedded tissue sections from 41 cases of invasive SCC of the larynx, 28 cases of dysplasia and 14 control laryngeal biopsy specimens were studied immunohistochemically using two anti-p53 monoclonal antibodies (DO7 and 1801). The Streptavidin/horseradish peroxidase method was used after microwave antigen retrieval and a semiquantitative method was applied to assess the extent of p53 expression.
Results—Of the cases of invasive SCC of the larynx, 78% (32/41), regardless of histological grade, overexpressed p53 compared with only 30% (eight of 28) of cases of mild dysplasia. A gradual increase in p53 expression from mild to severe dysplasia (60%) was observed, and only three of 14 control biopsy specimens of laryngeal nodules showed occasional weakly positive basal cells.
Conclusion—The gradual increase in p53 expression from mild to severe dysplasia to invasive SCC indicates that p53 overexpression is an early event in laryngeal carcinogenesis which may lead to invasive malignancy. p53 overexpression may be related to environmental factors as most of the patients smoked tobacco. Microwave postfixation may be essential for the reliable detection of p53.
PMCID: PMC407961  PMID: 16696005
p53; squamous cell carcinoma; dysplasia; larynx
21.  Inter-observer Agreement in Laryngeal Pre-neoplastic Lesions 
Head and Neck Pathology  2010;4(4):276-280.
In this series, laryngeal preneoplastic lesions were evaluated by the classifications of the World Health Organization (WHOC), Ljubljana (LC) and squamous intraepithelial neoplasia (SINC) by multiple observers. The inter-observer agreement (IA) by WHOC for laryngeal lesions had been previously evaluated, but to the best of our knowledge, there are no data for LC and SINC. H&E stained slides from 42 laryngeal biopsies were evaluated by fourteen participants according to WHOC and LC, and SINC was additionally applied by 6. The results were analyzed statistically. The diagnoses which were favored by most participants for each case, according to WHOC, were as follows: squamous cell hyperplasia (n = 5; 12%), mild dysplasia (n = 11; 26.2%), moderate dysplasia (n = 12; 28.6%), severe dysplasia (n = 7; 16.7%), carcinoma in situ (n = 5; 12%), and invasive squamous cell carcinoma (n = 2; 4.8%). There was a significant difference between the participants for all three classifications; some participants gave lower or higher scores than the others. The mean correlation coefficients (MCC) of the participants were higher for WHOC compared to LC (0.55 ± 0.15 and 0.48 ± 0.14, respectively). The mean linear-weighted kappa (wKappa) values of participants were not significantly different (0.42 ± 0.10, 0.41 ± 0.12 and 0.37 ± 0.07 for WHOC, LC and SINC, respectively). The kappa values in this series are in agreement with those in previous literature for WHOC, and the similar results obtained for LC and SINC are novel findings. Although the MCC of WHOC was higher, as the wkappa was not significantly different, the findings in this series are not in favor of any of the classifications for better IA for pre-neoplastic laryngeal lesions.
PMCID: PMC2996497  PMID: 20857246
Inter-observer agreement; Larynx; Pre-neoplastic lesions; World Health Organization classification; Ljubljana classification; Squamous intraepithelial neoplasia classification
22.  Modeling using baseline characteristics in a small multicenter clinical trial for Barrett’s esophagus 
Utilizing data obtained during a multicenter investigation, this paper illustrates how the use of covariates and careful modeling techniques can be useful in assessing whether a negative outcome from a small multicenter clinical trial could be due to imbalance in baseline characteristics. The Chemoprevention for Barrett’s Esophagus Trial (CBET) was a phase IIb, multicenter, randomized, placebo-controlled trial of celecoxib in patients with Barrett’s esophagus. The primary outcomes for the original study were the proportion of biopsy samples exhibiting dysplasia in the celecoxib and placebo groups. The secondary and tertiary outcomes included histologic change and measurements of biologically relevant markers, including COX-1 and –2 mRNA, prostanoid levels, and methylation of tumor suppressor genes p16, APC, and E-cadherin. The original study reported no significant differences in primary, secondary or tertiary outcomes. In this paper, we focus on the results of one of the secondary measures, quantitative endoscopy (QE).
The study utilizes data from 56 patients in the CBET for whom baseline (BL) QE and one-year follow-up QE (F04) studies were performed. Of these, 29 were treated with celecoxib (200 mg twice daily for a minimum of 48 weeks) and 27 received the placebo. These patients are segmented as to the presence or absence of circumferential, tongues or islands of Barrett’s.
The response of interest is total affected area at one year (Total F04); affected area at baseline (Total BL) is used as a covariate.
Controlling for complexity and clinic, there is a significant treatment effect. In addition, there is significant evidence that the area of Barrett’s involvement decreased for patients in the treatment group.
That there was a decrease for the celecoxib over the placebo group adds to the body of evidence that relates COX-2 specific inhibitors and cancer incidence.
PMCID: PMC3779362  PMID: 19013259
Barrett’s esophagus; Covariate modeling; Chemoprevention; Quantitative endoscopy
23.  Pulmonary preinvasive neoplasia 
Journal of Clinical Pathology  2001;54(4):257-271.
Advances in molecular biology have increased our knowledge of the biology of preneoplastic lesions in the human lung. The recently published WHO lung tumour classification defines three separate lesions that are regarded as preinvasive neoplasia. These are (1) squamous dysplasia and carcinoma in situ (SD/CIS), (2) atypical adenomatous hyperplasia (AAH), and (3) diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). SD/CIS is graded in four stages (mild, moderate, severe, and CIS), based upon the distribution of atypical cells and mitotic figures. Most airways showing SD/CIS demonstrate a range of grades; many epithelia are hard to assess and the reproducibility of this complex system remains to be established. Detailed criteria are, however, welcome and provide an objective framework on which to compare various molecular changes. Alterations in gene expression and chromosome structure known to be associated with malignant transformation can be demonstrated in CIS, less so in dysplasias, but also in morphologically normal epithelium. The changes might be sequential, and their frequency and number increase with atypia. Less is known of the "risk of progression" of SD/CIS to invasive "central" bronchial carcinoma. It may take between one and 10 years for invasion to occur, yet the lesion(s) may be reversible if carcinogen exposure ceases.
AAH may be an important precursor lesion for peripheral "parenchymal" adenocarcinoma of the lung: the "adenoma" in an adenoma–carcinoma sequence. There is good morphological evidence that AAH may progress from low to high grade to bronchioloalveolar carcinoma (BAC; a non-invasive lesion by definition). Invasion then develops within BAC and peripheral lung adenocarcinoma evolves. The molecular events associated with this progression are not well understood and studies are hampered by a lack of clear criteria to distinguish high grade AAH from BAC. Nonetheless, as with SD/CIS, the patterns of expression of tumour associated genes are consistent with neoplastic progression. We have little idea of the incidence of AAH in the normal or "smoking" populations. It is found more frequently in cancer bearing lungs, especially in those with adenocarcinoma, and is more common in women. No data are available on the risk of progression of AAH. DIPNECH is an exceptionally rare lesion associated with the development of multiple carcinoid tumours. Almost nothing is known of its biology.
Knowledge of these lesions will be crucial in the design and understanding of lung cancer screening programmes, where it is likely that the morphological and, more importantly perhaps, the molecular characteristics of these lesions will provide useful targets for detection and possibly even treatment.
Key Words: lung cancer • preneoplasia • carcinogenesis
PMCID: PMC1731391  PMID: 11304841
24.  Predictors of Progression in Barrett’s Esophagus: Current Knowledge and Future Directions 
Barrett’s esophagus is the strongest risk for esophageal adenocarcinoma (EAC), a malignancy with persistently poor long-term outcomes. EAC is thought to develop through progression of metaplasia to dysplasia to invasive carcinoma. Identification of factors predicting progression to EAC would help in focusing surveillance, chemoprevention or ablation at those deemed to be at highest risk of progression. We performed a comprehensive review of the literature and summarized current evidence on risk factors for progression in subjects with known BE. Clinical and demographic factors (age, male gender, length of BE segment) are associated with modestly increased odds of progression to EAC in some studies. Biomarkers such as aneuploidy and p53 loss of heterozygosity have been associated with increased risk of progression to high-grade dysplasia and / or EAC in single center prospective cohort studies. Promising newer techniques and markers have been recently reported with the potential to help risk stratify BE subjects. Development of a comprehensive BE risk progression score comprised of both clinical and biomarker variables should be the ultimate goal and can be achieved by multicenter prospective collaborative efforts. Though challenging, creation of such a score has the potential to improve outcomes and make the management of patients with BE more cost effective.
PMCID: PMC3408387  PMID: 20104216
25.  Squamous differentiation in carcinoma in situ of the cervix uteri 
Journal of Clinical Pathology  1967;20(1):7-14.
Cervical biopsies from 97 women with malignant cells in cervical scrape smears have been studied. Forty-eight patients had invasive squamous carcinoma, and 49 had intraepithelial lesions. Of these, six had dedifferentiated carcinoma in situ, nine had the differentiated lesions generally known as `severe dysplasia', and 29 had both; the severity of the dysplasia remained doubtful in five patients.
The `severe dysplasia' was compared with invasive carcinoma. A cellular analysis of the biopsies showed that the two categories have a number of features in common, chiefly the presence of atypical and normal mitoses, nucleoli, horn cells, and giant cells. The stratification of the epithelium in `severe dysplasia' is invariably abnormal and the architecture closely resembles that of invasive carcinoma. The cells in the smears from `severe dysplasia' are similar to those in invasive carcinoma.
It is suggested on the basis of these observations that a `severe dysplasia' should be interpreted as a differentiated carcinoma in situ.
PMCID: PMC473413  PMID: 6016890

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