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ABSTRACT: Objective The presence of regional metastases in patients with head and neck squamous cell carcinoma (HNSCC) is a common and adverse event associated with poor prognosis. The authors' recent work on human HNSCC tissues underlies Snail's role as a molecular prognostic marker for HNSCC. Snail positivity is significantly predictive of poorly differentiated, lymphovascular invasive, and regionally metastatic tumors. Here, the authors investigate the capacity of Snail to drive epithelial-mesenchymal transition (EMT) in human oral epithelial cell lines and its ability to confer drug resistance. Study Design Snail was overexpressed in HNSCC and oral epithelial cell lines. Anchorage independent growth assays, wound healing assays, invasion and migration assays, spheroid modeling, and cell survival assays were performed. Setting Academic tertiary medical center. Subjects and Methods Snail overexpressing HNSCC (OSC, Tu212, Tu686) and oral epithelial cell lines (HOK 16-B, OKF-6) were evaluated using assays for wound healing, invasion and migration, 3-dimensional growth, Western blot, and immunofluorescence. Results The overexpression of Snail in human HNSCC and oral epithelial cell lines drives EMT. The transfection of Snail confers the expression of a mesenchymal molecular signature, including downregulation of the epithelial adherens, such as E-cadherin and β-catenin, and induction of mesenchymal markers. Snail-overexpressing cell lines demonstrate rapid growth in Anchorage-independent growth assays, a decreased capacity to form tight spheroids, an increased resistance to erlotinib, and an increased capacity for invasion. Conclusion Snail controls the mesenchymal phenotype and drives erlotinib resistance in HNSCC cells. Snail may prove to be a useful marker in predicting epidermal growth factor receptor inhibitor responsiveness.
Otolaryngology Head and Neck Surgery 05/2012; 147(4):726-32. · 1.72 Impact Factor
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David Hu,
Ontario D Lau,
Linda Wang,
Guanyu Wang,
Dorthe Schaue,
Li Zhu,
Min Huang,
Yuan Lin,
Miranda Dennis,
Elliot Abemayor, David A Elashoff,
Steven M Dubinett,
William H McBride,
Sherven Sharma,
Ben Wu,
Maie A St John
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ABSTRACT: To evaluate the therapeutic efficacy of a novel modular polymer platform in the treatment of head and neck squamous cell carcinoma (HNSCC).
In vivo study.
Academic research laboratory. Subjects and
C3H/HeJ mice and SCID/beige mice were randomized to receive implantation of no polymer, plain polymer, plain polymer with local cisplatin injection, or cisplatin polymer. The 2 groups of mice implanted with cisplatin polymer or no polymer were further randomized to receive 4 Gy of external beam radiation for 4 days or no radiation. Tumor size was measured until the mice were humanely killed. At necropsy, the tumors were excised and weighed.
There was a significant reduction in tumor growth using this novel polymer platform. The cisplatin-secreting polymer effectively reduced human head and neck tumor growth in SCID mice by 17-fold and SCC VII/SF tumors in C3H/HeJ mice by more than 16-fold compared with the control, plain polymer, and plain polymer + intratumoral cisplatin injection groups (P = .01 for both). We also observed a statistically significant lower tumor weight in mice treated with cisplatin polymer and concomitant radiation compared with the radiation alone and control groups.
We demonstrate the efficacy of a novel polymer platform in delivering cisplatin to a partially resected SCC in a murine model. This polymer may represent a new therapeutic modality for patients with HNSCC. Once this polymer platform is optimized, we will plan for validation in the context of a prospective trial in patients with unresectable advanced or recurrent HNSCC.
Archives of otolaryngology--head & neck surgery 04/2012; 138(4):412-7. · 1.92 Impact Factor
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ABSTRACT: The aims of this study were to define a novel classification system of tumor perineural invasion (PNI) with respect to tumor/nerve involvement such as intratumoral (IT), peripheral, or extratumoral (ET) and to determine the prognostic significance of each of these histologic subcategories in patients with noncutaneous head and neck squamous cell carcinoma (HNSCC).
This study is a retrospective chart review and histologic analysis of patients with HNSCC in the setting of a tertiary care medical center.
A clinical chart review of 142 patients with HNSCC who underwent primary surgical treatment from January 2004 through December 2007 was performed. Clinical information collected included patient age, sex, alcohol and tobacco use, tumor location, TNM stage, postoperative adjuvant chemotherapy and/or radiation treatment, and patient outcome. For each case, PNI density, the distance of each PNI focus to the tumor edge, and size of the largest nerve involved were measured. Furthermore, PNI was subcategorized as IT, peripheral, or ET. A Cox regression analysis was performed to determine if PNI was related to regional disease recurrence. Kaplan-Meier survival analysis was also performed.
Among the 142 patients, 37 (26%) had disease progression. The maximum extent of PNI was significantly correlated with disease-free survival on multivariate analysis (P = .019) and was also significantly related to disease-free survival when T stage (P = .017), N stage (P = .021), and T and N stages (P = .02) were added to the Cox regression model. Kaplan-Meier analysis demonstrated a trend toward increased disease-free survival of PNI negative and IT/peripheral PNI compared with ET PNI.
Perineural invasion is correlated with nodal status and T stage and is related to disease-free survival. It can be subcategorized as IT, peripheral, or ET. This novel classification system has important implications with regard to clinical outcome and may help define a cohort of patients that may require more aggressive management.
American journal of otolaryngology 12/2011; 33(2):212-5. · 0.77 Impact Factor
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ABSTRACT: The purpose of the study was to evaluate the treatment results of adenoid cystic carcinoma (ACC) of the airway at a single institution during a 30-year period.
All cases of ACC of the airway over a 30-year period at one tertiary care institution were reviewed retrospectively. The demographics, treatment modalities, pathologic characteristics, and outcomes were evaluated.
Eleven patients were treated for ACC of the airway with an age range of 25 to 72 years (median, 48 years). Six patients presented with ACC in the larynx, and 5 patients had ACC of the trachea. All patients underwent surgical excision and radiation; 9 of 11 patients had postoperative external beam radiation, 1 patient had preoperative external beam radiation, and the remaining patient had postoperative neutron beam therapy. Four patients with tracheal ACC and none with laryngeal ACC had microscopic or grossly positive margins after surgery (P = .048). Eighty percent of patients had perineural invasion on pathology. Two patients with tracheal ACC had local recurrence of disease, which occurred at 1 and 10 months postoperatively. One patient with laryngeal ACC died of distant metastatic disease at 16 months. Follow-up varied from 4 to 168 months (median, 31 months).
We report high disease-free survival rates for ACC of the airway in patients who underwent definitive surgical resection followed by postoperative radiation. There is a higher risk for local recurrence and positive surgical margins with distal tracheal location. Distant disease ultimately determines survival.
American journal of otolaryngology 09/2011; 33(2):226-31. · 0.77 Impact Factor
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ABSTRACT: Despite advances in treatments, lung cancer has been the leading cause of cancer-related deaths in the United States for the past several decades. Recent findings from the National Lung Screening Trial reveal that low-dose helical computed tomography (CT) scan screening of high-risk individuals reduces lung cancer mortality. This suggests that early detection is of key importance to improving patient outcome. However, of those screened with CT scans, 25% had positive scans that require further follow-up studies which often involve more radiation exposure and invasive tests to reduce false positive results. The purpose of this study was to identify candidate plasma biomarkers to aid in diagnosis of lung cancer in at-risk individuals. We found increased expression of the CXC chemokine connective tissue-activating peptide (CTAP)-III from plasma specimens of lung cancer patients compared to at-risk control subjects. Identification of the peptide was confirmed by the addition of an anti-NAP-2 antibody that recognizes CTAP-III and NAP-2. We also quantified and verified the increased levels of plasma CTAP-III with ELISA in patients with lung cancer (mean ± SD, 1859 ± 1219 ng/mL) compared to controls (698 ± 434 ng/mL; P<0.001). Our findings demonstrate elevated plasma levels of CTAP-III occur in lung cancer patients. Further studies are required to determine if this chemokine could be utilized in a blood-based biomarker panel for the diagnosis of lung cancer.
American Journal of Translational Research 05/2011; 3(3):226-33.
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ABSTRACT: To analyze outcomes in patients with squamous cell carcinoma (SCCA) of the tonsil from the years 1998 to 2006. To assess factors that may affect disease-specific survival, such as patient characteristics and/or treatment modality.
National Cancer Institute's Surveillance Epidemiology and End Results (SEER) program.
The SEER database was used to perform a population-based cohort analysis for patients diagnosed with SCCA of the tonsil from 1998 to 2006. Disease-specific survival was correlated with sex, age, ethnicity, year of diagnosis, and treatment modality in a univariate Cox proportional hazards analysis and a multiple Cox-regression model with and without interaction effect.
Applied inclusion criteria resulted in 8378 patients. Of this patient cohort, 80% were male and 85% were white. The mean patient age at diagnosis was 58.1 years. On univariate and multivariate analyses, ethnicities other than white carried a significantly higher rate of disease-specific death (hazard ratio = 1.71, P < .001). Each additional year of age at the time of diagnosis carried approximately a 4% increase in likelihood of disease-specific death. With each passing year of time at diagnosis, patients carried a decreased risk of disease-specific death (P < .001); this value was significant in all 3 statistical models. Patients who underwent external-beam radiation had a higher likelihood of disease-specific survival with each passing year at time of diagnosis.
Population analysis based on the SEER database reveals increased disease-specific survival from tonsillar SCCA in more recent years. This may be because of earlier diagnosis, an increase in less aggressive subtypes of SCCA, and more effective treatment modalities.
Otolaryngology Head and Neck Surgery 03/2011; 145(2):236-41. · 1.72 Impact Factor
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ABSTRACT: Previous studies have shown Snail expression integral to the epithelial-mesenchymal transition during tumor progression. However, its behavior in clinical head and neck squamous cell carcinomas (HNSCCs) is yet undefined. We therefore sought to (1) investigate clinical and histopathologic characteristics of Snail-positive HNSCC and (2) understand the link between Snail and other commonly used HNSCC tumor markers.
A retrospective case-control study was conducted.
This study was conducted in a large-scale academic center.
Of 51 consecutive HNSCC, 42 surgical resections were included.
Two separate pathologists performed standard histopathologic reviews along with immunohistochemistries (Snail, E-cadherin, p16, epidermal growth factor receptor [EGFR]) and in situ hybridization (human papilloma virus [HPV]). Medical review for all cases was performed.
Twenty-two (52%) of 42 cases stained 4+ Snail (>75% staining). The remaining 20 cases were considered negative. Snail was strongly inversely related to E-cadherin expression (ρ = -0.69, P < .001), but statistically independent from HPV, p16, or EGFR expression. Snail(+) tumors were equally represented from each anatomic subsite. Snail(+) tumors were strongly associated with poor differentiation (P < .001) and basaloid classification (P = .004). Snail(+) tumors were also strongly associated with lymphovascular invasion (P = .02), but not perineural invasion. Ultimately, 11 (50%) of 22 of Snail(+) tumors demonstrated positive nodal metastasis and 11 (79%) of 14 node-positive cases were Snail(+) (P = .02).
This pilot study provides promising evidence of Snail' role as a molecular prognostic marker for HNSCC. Snail positivity is significantly predictive of poorly differentiated, lymphovascular invasive, as well as regionally metastatic tumors. Because Snail positivity appears independent of HPV, p16, and EGFR expression, Snail may prove to improve upon these markers' predictive limitations.
American journal of otolaryngology 03/2011; 33(1):6-13. · 0.77 Impact Factor
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ABSTRACT: The Editorial Response listed above, which did not appear in the print journal, was retracted by the Editors of the Journal of Andrology with the consent of the authors because the significant delay in processing the Editorial Response has rendered the information contained in it not currently relevant. The Editors extend their apologies to the authors and to the scientific community.
Journal of Andrology 12/2010; · 2.97 Impact Factor
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ABSTRACT: We examine radiographic profile patterns using clustering algorithms to assess progression rates at set time intervals in a rheumatoid arthritis (RA) observational study. Hands/feet radiographic scores were analyzed for 190 early, seropositive RA patients with ≥ 3 radiographic observations from a prospective cohort. Assessments at 6 months, 1 year, and yearly thereafter were requested for demographic, therapeutic, functional, laboratory, radiographic, and clinical data. Progression rates for the total sharp scores [erosion (E)+joint space narrowing (JSN)] were interpolated for intervals of 0 to 6 months, 6 month-1 year, 1-2 years, and 2-3 years past first radiographic observation. Patients were grouped on their sets of rates by K-median clustering algorithms, and categorical group membership was regressed onto baseline characteristics using multinomial models. The number of clusters was determined using one-way MANOVA, and baseline differences across clusters by Kruskal-Wallis tests. The median RA duration was 6.1 months, mean age 52 years, median disease activity score (DAS) 4.6, mean radiographic observations 4.6 (range 3-8) for this mostly female (77%), Caucasian (78%) sample. 3 patterns were determined: increasing (n = 41; 22%), increasing then decreasing (n = 41; 22%), and flat (n = 108; 57%). High baseline C-reactive protein was associated with a worsening radiographic progression (p < 0.005), as were HAQ-DI (p = 0.07), JSN (p < 0.01), and E (p = 0.03). Our conclusions are that radiographic progression patterns graphically supplement traditional linear rates, and are flexible to use in both clinical and observational studies. The identified clusters and rates may correspond better with clinical status and treatment over the disease course than linear progression rates alone.
Contemporary clinical trials 11/2010; 32(2):160-8. · 1.51 Impact Factor
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ABSTRACT: To further understanding of treatment of papillary thyroid carcinoma (PTC).
The Surveillance, Epidemiology, and End Results Program database was searched for patients who had undergone surgery for PTC.
Areas covered by Surveillance, Epidemiology, and End Results population-based registries.
Patients who had undergone PTC surgery between January 1, 1988, and December 31, 2001, were included in the study.
Disease-specific survival (DSS) and overall survival (OS).
Of the total 22,724 patients with PTC, 5964 patients underwent lobectomy. There were 2138 total and 471 disease-specific deaths. Controlling for tumor size, multivariate analysis revealed no survival difference between patients who had undergone total thyroidectomy and those who had undergone lobectomy. Increased tumor size, extrathyroidal extent, positive nodal status, and increased age displayed significantly worse DSS and OS (P < .001). Histologically, follicular PTC subtype did not affect DSS or OS. Patients who had received radioactive iodine had poorer DSS but improved OS. Patients undergoing external beam radiation therapy had poor DSS (hazard ratio, 4.48; 95% confidence interval, 3.30-6.06; P < .001) and OS (1.71; 1.42-2.07; P < .001).
The results of this study compel us to reinvestigate the current PTC surgical recommendations of total thyroidectomy based on tumor size because this may not affect survival across all populations. In addition, the current use of external beam radiation therapy for the treatment of PTC should be reexamined.
Archives of otolaryngology--head & neck surgery 11/2010; 136(11):1055-61. · 1.92 Impact Factor
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ABSTRACT: Human papilloma virus (HPV) and p16INKa (p16) positivity in head and neck squamous cell carcinomas (HNSCCs) is currently thought to be an encouraging prognostic indicator. However, the histopathologic changes responsible for this behavior are poorly understood. It is our objective to elucidate these histopathologic characteristics to help define the clinical utility of these markers.
Retrospective cohort study.
71 HNSCC tumors between July 1, 2008 and August 30, 2009 were examined for HPV, p16, and epidermal growth factor receptor (EGFR). Specified pathologic features were examined: perivascular invasion (PVI), perineural invasion (PNI), grade of squamous differentiation, basaloid classification.
HPV and p16 had no direct impact on perineural or perivascular invasion. However, HPV and p16 were strongly predictive of poorly differentiated tumors, as well as basaloid squamous cell carcinoma (SCCA) (P < .001). Additionally, upon multivariate analysis, HPV(+) and p16(+) tumors had an increased risk of nodal metastasis (HPV: odds ratio [OR] = 23.9 (2.2, 265.1) p = .01; p16: OR = 6.5 (1.4, 31.2) p = .02; PVI: OR = 6.0 (1.6, 22.8) p < .01). The area under the curve (AUC) of receiver operating characteristic (ROC) curves demonstrated improved predictive value for lymph node metastasis above standard H&E histopathologic features (76.7%) for both HPV (83.2%) and p16 (81.3%) individually.
HPV(+) and p16(+) are highly predictive for poorly differentiated tumors and basaloid SCCA. Additionally, HPV and p16 positivity demonstrate superior predictive value for lymph node metastasis above standard H&E histopathologic features. Although exact recommendations should be tempered by considerations of primary tumor subsite, T-stage, and depth of invasion, head and neck multidisciplinary teams should strongly consider aggressive lymph node treatment for any HPV(+) or p16(+) tumor.
The Laryngoscope 09/2010; 120(9):1788-94. · 1.75 Impact Factor
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Mariam Dohadwala,
Guanyu Wang,
Eileen Heinrich,
Jie Luo,
Ontario Lau,
Hubert Shih,
Qahera Munaim,
Gina Lee,
Longsheng Hong,
Chi Lai,
Elliot Abemayor,
Michael C Fishbein, David A Elashoff,
Steven M Dubinett,
Maie A St John
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ABSTRACT: To determine the role of ZEB1 in the inflammation-induced promotion of the epithelial-mesenchymal transition (EMT) in head and neck squamous cell carcinoma (HNSCC).
A molecular biology study. Real-time quantitative reverse-transcriptase polymerase chain reaction (RT-PCR), Western blot analysis, and immunohistochemical staining of human HNSCC tissue sections were used to determine how inflammation affects the transcriptional repressor, ZEB1.
An academic hospital laboratory.
Relative ZEB1 RNA levels were determined by RT-PCR, and protein expression was evaluated in situ by immunohistochemical staining of human HNSCC tissue sections.
IL-1beta-treated HNSCC cell lines demonstrated a significant decrease in E-cadherin mRNA and an increase in the mRNA expression of the transcriptional repressor ZEB1. IL-1beta exposure led to enhanced ZEB1 binding at the chromatin level, as determined by chromatin immunoprecipitation assays (ChIP). An inverse relationship between ZEB1 and E-cadherin was demonstrated in situ by immunohistochemical staining of human HNSCC tissue sections.
Our recent investigations indicate that inflammatory mediators are potent regulators of EMT in HNSCC. This is the first report indicating the role of ZEB1 in the inflammation-induced promotion of EMT in HNSCC. This newly defined pathway for transcriptional regulation of E-cadherin in HNSCC has important implications for targeted chemoprevention and therapy.
Otolaryngology Head and Neck Surgery 05/2010; 142(5):753-9. · 1.72 Impact Factor
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Haoling H Weng,
Veena K Ranganath,
Dinesh Khanna,
Myungshin Oh,
Daniel E Furst,
Grace S Park, David A Elashoff,
John T Sharp,
Richard H Gold,
James B Peter,
Harold E Paulus
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ABSTRACT: To evaluate responses by time to initiation of nonbiologic disease-modifying antirheumatic drugs (DMARD) in a DMARD-naive cohort of patients with early seropositive rheumatoid arthritis (RA).
Subjects were categorized by the time from symptom onset to the first DMARD use (median 5.7 months, range 0.6-15.9). Subjects who started their first DMARD within 5 months of symptom onset were compared to subjects who started after 5 months. Disease Activity Scores (DAS-44) and total Sharp Score (TSS) progression rates were analyzed using Wilcoxon rank-sum and chi-square tests; multiple linear regression analysis adjusted for potential covariates. The slope of the least-squares regression line was calculated to estimate the annualized TSS progression rates.
Of 233 RA patients, 76% were female and mean age was 50 (SD 13) years. At DMARD start, DAS-44 was similar in all subsets within the 0.6 to 15 months' duration between symptom onset and DMARD initiation. Erosion scores tended to be higher in those who started DMARD later, but Health Assessment Questionnaire-Disability Index (HAQ-DI) scores were higher in those who started DMARD earlier. During the 2 years after DMARD initiation, improvements in HAQ-DI and DAS-44 were similar in the various duration subsets, with about 25% ever achieving DAS remission (DAS < 1.6). Radiographic progression tended to be numerically but not statistically more rapid in the earlier subsets.
Following initiation of nonbiologic DMARD therapy at various times within 15 months of symptom onset, improvements of DAS-44, HAQ-DI, remission rate, and radiographic progression rate were similar, although higher baseline erosion scores were present in those with later initiation of DMARD.
The Journal of Rheumatology 03/2010; 37(3):550-7. · 3.69 Impact Factor
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Jane Yanagawa,
Tonya C Walser,
Li X Zhu,
Longsheng Hong,
Michael C Fishbein,
Vei Mah,
David Chia,
Lee Goodglick, David A Elashoff,
Jie Luo,
Clara E Magyar,
Mariam Dohadwala,
Jay M Lee,
Maie A St John,
Robert M Strieter,
Sherven Sharma,
Steven M Dubinett
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ABSTRACT: As a transcriptional repressor of E-cadherin, Snail has predominantly been associated with epithelial-mesenchymal transition, invasion, and metastasis. However, other important Snail-dependent malignant phenotypes have not been fully explored. Here, we investigate the contributions of Snail to the progression of non-small cell lung cancer (NSCLC).
Immunohistochemistry was done to quantify and localize Snail in human lung cancer tissues, and tissue microarray analysis was used to correlate these findings with survival. NSCLC cell lines gene-modified to stably overexpress Snail were evaluated in vivo in two severe combined immunodeficiency murine tumor models. Differential gene expression between Snail-overexpressing and control cell lines was evaluated using gene expression microarray analysis.
Snail is upregulated in human NSCLC tissue, and high levels of Snail expression correlate with decreased survival (P < 0.026). In a heterotopic model, mice bearing Snail-overexpressing tumors developed increased primary tumor burden (P = 0.008). In an orthotopic model, mice bearing Snail-overexpressing tumors also showed a trend toward increased metastases. In addition, Snail overexpression led to increased angiogenesis in primary tumors as measured by MECA-32 (P < 0.05) positivity and CXCL8 (P = 0.002) and CXCL5 (P = 0.0003) concentrations in tumor homogenates. Demonstrating the importance of these proangiogenic chemokines, the Snail-mediated increase in tumor burden was abrogated with CXCR2 blockade. Gene expression analysis also revealed Snail-associated differential gene expression with the potential to affect angiogenesis and diverse aspects of lung cancer progression.
Snail upregulation plays a role in human NSCLC by promoting tumor progression mediated by CXCR2 ligands.
Clinical Cancer Research 11/2009; 15(22):6820-9. · 7.74 Impact Factor
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Maie A St John,
Mariam Dohadwala,
Jie Luo,
Guanyu Wang,
Gina Lee,
Hubert Shih,
Eileen Heinrich,
Kostantyn Krysan,
Tonya Walser,
Saswati Hazra,
Li Zhu,
Chi Lai,
Elliot Abemayor,
Michael Fishbein, David A Elashoff,
Sherven Sharma,
Steven M Dubinett
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ABSTRACT: Inflammatory cytokines have been implicated in the progression of head and neck squamous cell carcinoma (HNSCC). Herein we investigate the mechanisms by which interleukin-1beta (IL-1beta) might contribute to Epithelial-Mesenchymal Transition (EMT) in HNSCC.
We evaluated the effect of IL-1beta on the molecular events of EMT in surgical specimens and HNSCC cell lines. We examined the correlation with tumor histologic features, and a SCID xenograft model was used to assess the effects of Snail overexpression.
Cyclooxygenase-2 (COX-2)-dependent pathways contribute to the modulation of E-cadherin expression in HNSCC. An inverse relationship between COX-2 and E-cadherin was shown in situ by double immunohistochemical staining of human HNSCC tissue sections. Treatment of HNSCC cells with IL-1beta caused the downregulation of E-cadherin expression and upregulation of COX-2 expression. This effect was blocked in the presence of COX-2 small hairpin RNA. IL-1beta-treated HNSCC cell lines showed a significant decrease in E-cadherin mRNA and an increase in the mRNA expression of the transcriptional repressor Snail. IL-1beta exposure led to enhanced Snail binding at the chromatin level. Small hairpin RNA-mediated knockdown of Snail interrupted the capacity of IL-1beta to downregulate E-cadherin. In a SCID xenograft model, HNSCC Snail-overexpressing cells showed significantly increased primary and metastatic tumor burdens.
IL-1beta modulates Snail and thereby regulates COX-2-dependent E-cadherin expression in HNSCC. This is the first report indicating the role of Snail in the inflammation-induced promotion of EMT in HNSCC. This newly defined pathway for transcriptional regulation of E-cadherin in HNSCC has important implications for targeted chemoprevention and therapy.
Clinical Cancer Research 10/2009; 15(19):6018-27. · 7.74 Impact Factor
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ABSTRACT: Although considerable attention has been given to zero-inflated count data, research on zero-inflated lognormal data is limited. In this article, we consider a study to examine human sperm cell DNA damage obtained from single-cell electrophoresis (COMET assay) experiment in which the outcome measures present a typical example of log-normal data with excess zeros. The problem is further complicated by the fact that each study subject has multiple outcomes at each of up to three visits separated by six-week intervals. Previous methods for zero-inflated log-normal data are based on either simple experimental designs, where comparison of means of zero-inflated log-normal data across different experiment groups is of primary interest, or longitudinal measurements, where only one observation is available for each subject at each visit. Their methods cannot be applied when multiple observations per visit are possible and both inter- and intra-subject variations are present. Our zero-inflated model extends the previous methods by incorporating a hierarchical structure using latent random variables to take into account both inter- and intra-subject variations in zero-inflated log-normal data. An EM algorithm has been developed to obtain the Maximum likelihood estimates of the parameters and their standard errors can be estimated by parametric bootstrap. The model is illustrated using the COMET assay data.
Statistical Methods in Medical Research 10/2008; 20(3):175-89. · 2.44 Impact Factor
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Veena K Ranganath,
Jeonglim Yoon,
Dinesh Khanna,
Grace S Park,
Daniel E Furst, David A Elashoff,
Damini Jawaheer,
John T Sharp,
Richard H Gold,
Edward C Keystone,
Harold E Paulus
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ABSTRACT: To evaluate concordance and agreement of the original DAS44/ESR-4 item composite disease activity status measure with nine simpler derivatives when classifying patient responses by European League of Associations for Rheumatology (EULAR) criteria, using an early rheumatoid factor positive (RF+) rheumatoid arthritis (RA) patient cohort.
Disease-modifying anti-rheumatic drug-naïve RF+ patients (n = 223; mean duration of symptoms, 6 months) were categorised as ACR none/20/50/70 responders. One-way analysis of variance and two-sample t tests were used to investigate the relationship between the ACR response groups and each composite measure. EULAR reached/change cut-point scores were calculated for each composite measure. EULAR (good/moderate/none) responses for each composite measure and the degree of agreement with the DAS44/ESR-4 item were calculated for 203 patients.
Patients were mostly female (78%) with moderate to high disease activity. A centile-based nomogram compared equivalent composite measure scores. Changes from baseline in the composite measures in patients with ACRnone were significantly less than those of ACR20/50/70 responders, and those for ACR50 were significantly different from those for ACR70. EULAR reached/change cut-point scores for our cohort were similar to published cut-points. When compared with the DAS44/ESR-4 item, EULAR (good/moderate/none) percentage agreements were 92 with the DAS44/ESR-3 item, 74 with the Clinical Disease Activity Index, and 80 with the DAS28/ESR-4 item, the DAS28/CRP-4 item and the Simplified Disease Activity Index.
The relationships of nine different RA composite measures against the DAS44/ESR-4 item when applied to a cohort of seropositive patients with early RA are described. Each of these simplified status and response measures could be useful in assessing patients with RA, but the specific measure selected should be pre-specified and described for each study.
Annals of the rheumatic diseases 01/2008; 66(12):1633-40. · 8.11 Impact Factor
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ABSTRACT: This article describes the lifestyle patterns of boron mining and processing workers (N=936) and a comparison group (N=251) in northeast China, and explores relationships between boron exposure and reproductive health. An English version of an interview guide addressing areas of work and lifestyle relevant to boron exposure and metabolism was developed by an occupational health research team, translated to Chinese, and translated back, for clarity. Modifications incorporated suggestions from a local community advisory board and boron industry workers; the translation-back translation process was reapplied, and cultural and semantic equivalence was attained. Results from the interviews showed more than 64% of workers and comparison group participants smoked tobacco and more than 92% reported exposure to environmental tobacco smoke. Boron workers and the comparison group varied in their food intake and alcohol consumption, but not in their smoking habits. Thirty-four percent of boron workers reported eating in the contaminated work area. Nearly all boron workers (99%) showered or bathed after work, although approximately 10% redressed in their contaminated clothes. Reproductive health outcomes were explored, including delayed pregnancy, multiple births, spontaneous miscarriages, induced abortions, stillbirths, and an unusual ratio of male to female offspring. Implications for occupational health nurses and recommendations for future research are provided.
AAOHN Journal 11/2006; 54(10):435-43. · 0.51 Impact Factor
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ABSTRACT: To evaluate the effect of age adjustment on baseline erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in patients with late-onset rheumatoid arthritis (LORA, age > or = 55 yrs) and younger-onset RA (YORA, age < 55 yrs) in a cohort with early, rheumatoid factor (RF) positive RA that has not received disease modifying antirheumatic drugs (DMARD).
In an ongoing prospective cohort study of 263 patients with seropositive RA who were enrolled within 14 months of symptom onset, baseline assessments included ESR, CRP, tender and swollen joint counts, and functional status. Westergren ESR determinations were performed in the rheumatologist's office or in a local laboratory using appropriate methods. CRP were performed at the Specialty Laboratories in Santa Monica, CA, using Behring nephelometry. Percentages of patients with greater than the upper limit of normal (ULN) laboratory values using both age-unadjusted and age-adjusted ESR and CRP values were determined. The late-onset and younger-onset RA patients were compared using Wilcoxon rank-sum and chi-square tests.
At study entry, both the YORA and LORA patients had comparable symptom duration, disease activity scores, tender and swollen joint counts, and Health Assessment Questionnaire values. RF, CRP, and ESR were significantly higher (p < 0.05) in LORA patients. Although the percentages of patients with age-unadjusted ESR and CRP above ULN were higher in LORA patients, the percentages exceeding the age-adjusted ULN did not differ significantly between the YORA and LORA groups.
In patients with late-onset and younger-onset RA with similar disease duration and severity, the apparent discrepancy in elevation of both the baseline ESR and CRP disappears after age-adjustment.
The Journal of Rheumatology 07/2005; 32(6):1040-2. · 3.69 Impact Factor
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ABSTRACT: It is unclear why men who undergo radical prostatectomy (RP) and are found to have pathologically organ-confined disease develop prostate-specific antigen (PSA) recurrences. We previously found that patients with less than 45% of cells in the prostate needle biopsy specimen (PNBx) staining positive for the cell cycle regulator p27 had a significantly increased risk of biochemical recurrence after RP. We sought to determine whether p27 staining in the PNBx specimen might serve as a molecular marker for PSA failure in the subset of patients who develop PSA recurrence despite organ-confined disease at RP.
The PNBx specimens of 161 men treated with RP between 1991 and 2000 were examined for p27 expression using immunohistochemistry. The p27 cutpoint of less than 45% expression was used to define the high and low-risk categories. Patients were separated into two groups for analysis: organ-confined (pT2 and negative surgical margins) and non-organ-confined (pT2 with positive surgical margins, pT3, pT4, or lymph node involvement). The mean and median follow-up for patients with organ-confined and non-organ-confined disease was 47 and 43 months and 42 and 38 months, respectively. Multivariate Cox proportional hazards analysis was used to examine the preoperative clinical variables that were the strongest predictors of biochemical recurrence after RP among each group.
Among organ-confined patients, p27 expression was the only significant independent predictor of the time to biochemical recurrence after RP (hazard ratio 5.15, 95% confidence interval 1.41 to 18.83, P = 0.013). Among patients with non-organ-confined disease, the percentage of biopsy tissue with cancer, biopsy Gleason score, and PSA level were independent predictors of PSA recurrence. p27 expression was not a significant independent predictor of PSA recurrence among men with non-organ-confined disease.
p27 expression in the PNBx was a significant independent predictor of PSA failure for patients with pathologically organ-confined disease, but not for those with non-organ-confined disease. Patients with organ-confined disease but low p27 expression had a greater than fivefold risk of developing PSA recurrence than were men with high p27 expression, suggesting that p27 may be a molecular marker associated with micrometastatic disease at the time of RP.
Urology 07/2003; 61(6):1187-92. · 2.43 Impact Factor
