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1.  Prognostic Relevance of Carbonic Anhydrase-IX in High-Risk, Early-Stage Cervical Cancer: A Gynecologic Oncology Group Study 
Gynecologic oncology  2009;116(3):452.
To determine whether carbonic anhydrase-IX (CA-IX) was associated with progression-free survival (PFS) and overall survival (OS) in women with high-risk, early-stage cervical cancer treated with adjuvant pelvic radiotherapy with or without radiosensitizing chemotherapy.
CA-IX expression was detected using an immunohistochemistry assay and categorized as low when ≤80% of tumor cells exhibited CA-IX staining and high when >80% tumor cells display CA-IX staining. Associations between CA-IX expression and clinical characteristics, angiogenesis marker expression and clinical outcome were evaluated.
High CA-IX expression was observed in 35/166 (21.1%) of cases. CA-IX expression was not associated with age, race, stage, cell type, grade, positive margins, parametrial extensions, positive lymph nodes or lymphovascular space invasion but was associated with tumor size categorized as <2 cm, 2-2.9 cm, or ≥3 cm (high expression: 4.7% vs. 23.2% vs. 32.5%, p=0.003) and cervical invasion confined to the inner two thirds compared with the outer third of the cervix (high expression: 6.1% vs. 23.7%, p=0.028). CA-IX expression was not associated with immunohistochemical expression of p53, CD31, CD105, thrombospondin-1 or vascular endothelial growth factor-A. Women with high versus low CA-IX expression had similar PFS (p=0.053) and significantly worse OS (p=0.044). After adjusting for prognostic clinical covariates, high CA-IX expression was an independent prognostic factor for PFS (hazard ratio [HR]=2.12; 95% confidence interval [CI]=1.13 -3.95; p=0.019) and OS (HR=2.41; 95% CI=1.24-4.68; p=0.009).
Tumor hypoxia measured by immunohistochemical expression of CA-IX is an independent prognostic factor for both PFS and OS in high-risk, early-stage cervical cancer.
PMCID: PMC2822024  PMID: 19913895
2.  Carbonic anhydrase IX (CA-IX) and human papillomavirus (HPV) as diagnostic biomarkers of cervical dysplasia/neoplasia in women with a cytologic diagnosis of atypical glandular cells (AGC): a Gynecologic Oncology Group (GOG) Study 
High-risk human papillomavirus (H-HPV) infection is strongly linked to cervical neoplasia but its role in detecting glandular lesions is unclear. In the cervix, carbonic anhydrase IX (CA-IX) is expressed in cervical neoplasia, but rarely in the benign cervix. The diagnostic utility of these biomarkers was evaluated in women with a cytologic diagnosis of atypical glandular cells (AGC). H-HPV was detected using Hybrid Capture 2 (HC2) in liquid based cytology and CA-IX immunoreactivity was studied on conventional Pap smears. Of 403 patients, 111 (28%) were positive for significant cervical lesions (SCLs) including CIN2, CIN3, adenocarcinoma in situ or invasive carcinoma. CA-IX testing alone (n=403) had a sensitivity of 75%, 95%, or 65% for SCLs, significant glandular lesions (GLs) or squamous lesions (SLs), respectively, with a specificity of 88%, and a false negative rate (FNR defined as one minus negative predictive value) of 10%. Testing for H-HPV (n=122) had a sensitivity of 97%, 100%, or 96% for SCLs, GLs or SLs, respectively, with a specificity of 87%, and a FNRof 1%. The combination of CA-IX and H-HPV testing (n=122), collectively, had the same sensitivity, specificity and FNR for SCLs, GLs or SLs as H-HPV testing alone. The conclusions of this study are that both H-HPV and CA-IX testing are useful diagnostic markers for GLs. However, H-HPV testing is a better diagnostic marker for SLs. The combination of CA-IX with H-HPV testing does not improve the diagnostic accuracy for cervical neoplasia in women with AGC diagnosis over that of H-HPV testing alone.
PMCID: PMC2779726  PMID: 19670419
CA-IX; HPV; AGC diagnosis; cervix
3.  A fast Monte Carlo EM algorithm for estimation in latent class model analysis with an application to assess diagnostic accuracy for cervical neoplasia in women with AGC 
Journal of applied statistics  2013;40(12):2699-2719.
In this article we use a latent class model (LCM) with prevalence modeled as a function of covariates to assess diagnostic test accuracy in situations where the true disease status is not observed, but observations on three or more conditionally independent diagnostic tests are available. A fast Monte Carlo EM (MCEM) algorithm with binary (disease) diagnostic data is implemented to estimate parameters of interest; namely, sensitivity, specificity, and prevalence of the disease as a function of covariates. To obtain standard errors for confidence interval construction of estimated parameters, the missing information principle is applied to adjust information matrix estimates. We compare the adjusted information matrix based standard error estimates with the bootstrap standard error estimates both obtained using the fast MCEM algorithm through an extensive Monte Carlo study. Simulation demonstrates that the adjusted information matrix approach estimates the standard error similarly with the bootstrap methods under certain scenarios. The bootstrap percentile intervals have satisfactory coverage probabilities. We then apply the LCM analysis to a real data set of 122 subjects from a Gynecologic Oncology Group (GOG) study of significant cervical lesion (S-CL) diagnosis in women with atypical glandular cells of undetermined significance (AGC) to compare the diagnostic accuracy of a histology-based evaluation, a CA-IX biomarker-based test and a human papillomavirus (HPV) DNA test.
PMCID: PMC3806648  PMID: 24163493
adjusted information matrix; bootstrap standard errors; diagnostic accuracy; imperfect gold standard; latent class model; MCEM estimation
4.  A modified Latent Class Model assessment of human papillomavirus-based screening tests for cervical lesions in women with atypical glandular cells: a Gynecologic Oncology Group study 
Cancer causes & control : CCC  2012;23(12):2013-2021.
Absent gold standard diagnoses, we estimate age-specific false-positive and false-negative prediction rates of HPV-, cytology- and histology-based tests for significant cervical lesions (SCL) in U.S. women with AGC-NOS Pap smear diagnoses.
Modified Latent Class Model (LCM) analyses, with prevalence of SCL modeled as a function of age, were applied to GOG-0171 study data (n=122). The accuracies of several HPV-based tests, including Hybrid Capture II high-risk HPV (HC2 H-HPV); carbonic anhydrase IX (CA-IX) and invasive histological diagnosis were compared. 1-PPV and 1-NPV were written as functions of sensitivity, specificity and prevalence to obtain age-specific false-positive and false-negative rates.
The histology-based test was nearly perfect (sensitivity=1.00, CI=0.98-1.00; specificity=0.99, CI=0.96-1.00). Otherwise, HC2 H-HPV performed best (sensitivity=1.00, CI=1.00-1.00; specificity=0.87, CI=0.79-0.94). The false-positive detection rates (1-PPV) for HC2 H-HPV were high (>17%) at each age, while those of the histological diagnoses were low (<5% at ages≤60 and <17% overall ages). False negative prediction rates (1-NPV) for HC2 H-HPV were < 0.11% at each age and were uniformly lower than those of other tests, including the histology-based test (<0.25%). CA-IX together with HC2 H-HPV did not improve performance.
Women with negative HC2 H-HPV can safely forego invasive treatment (i.e., cone or LEEP biopsy, hysterectomy) in favor of observational follow-up. Additional biomarkers must be found for use in combination with HC2 H-HPV to reduce false-positive rates. This novel application of a modified Latent Class Model (LCM) exemplifies methods for potential use in future cancer screening studies when gold standard diagnoses are not available.
PMCID: PMC3499682  PMID: 23073789
5.  Multifocal Breast Cancer in Young Women with Prolonged Contact between Their Breasts and Their Cellular Phones 
Case Reports in Medicine  2013;2013:354682.
Breast cancer occurring in women under the age of 40 is uncommon in the absence of family history or genetic predisposition, and prompts the exploration of other possible exposures or environmental risks. We report a case series of four young women—ages from 21 to 39—with multifocal invasive breast cancer that raises the concern of a possible association with nonionizing radiation of electromagnetic field exposures from cellular phones. All patients regularly carried their smartphones directly against their breasts in their brassieres for up to 10 hours a day, for several years, and developed tumors in areas of their breasts immediately underlying the phones. All patients had no family history of breast cancer, tested negative for BRCA1 and BRCA2, and had no other known breast cancer risks. Their breast imaging is reviewed, showing clustering of multiple tumor foci in the breast directly under the area of phone contact. Pathology of all four cases shows striking similarity; all tumors are hormone-positive, low-intermediate grade, having an extensive intraductal component, and all tumors have near identical morphology. These cases raise awareness to the lack of safety data of prolonged direct contact with cellular phones.
PMCID: PMC3789302  PMID: 24151509
6.  Surveillance on secular trends of incidence and mortality for device–associated infection in the intensive care unit setting at a tertiary medical center in Taiwan, 2000–2008: A retrospective observational study 
BMC Infectious Diseases  2012;12:209.
Device–associated infection (DAI) plays an important part in nosocomial infection. Active surveillance and infection control are needed to disclose the specific situation in each hospital and to cope with this problem effectively. We examined the rates of DAI by antimicrobial-resistant pathogens, and 30–day and in–hospital mortality in the intensive care unit (ICU).
Prospective surveillance was conducted in a mixed medical and surgical ICU at a major teaching hospital from 2000 through 2008. Trend analysis was performed and logistic regression was used to assess prognostic factors of mortality.
The overall rate of DAIs was 3.03 episodes per 1000 device–days. The most common DAI type was catheter–associated urinary tract infection (3.76 per 1000 urinary catheter–days). There was a decrease in DAI rates in 2005 and rates of ventilator–associated pneumonia (VAP, 3.18 per 1000 ventilator–days) have remained low since then (p < 0.001). The crude rates of 30–day (33.6%) and in–hospital (52.3%) mortality, as well as infection by antibiotic-resistant VAP pathogens also decreased. The most common antimicrobial-resistant pathogens were methicillin–resistant Staphylococcus aureus (94.9%) and imipenem–resistant Acinetobacter baumannii (p < 0.001), which also increased at the most rapid rate. The rate of antimicrobial resistance among Enterobacteriaceae also increased significantly (p < 0.05). After controlling for potentially confounding factors, the DAI was an independent prognostic factor for both 30–day mortality (OR 2.51, 95% confidence interval [CI] 1.99–3.17, p = 0.001) and in–hospital mortality (OR 3.61, 95% CI 2.10–3.25, p < 0.001).
The decrease in the rate of DAI and infection by resistant bacteria on the impact of severe acute respiratory syndrome can be attributed to active infection control and improved adherence after 2003.
PMCID: PMC3458996  PMID: 22963041
Surveillance; Secular trend; Device–associated infection; Intensive care unit; Infection control
7.  Markers of angiogenesis in high-risk, early-stage cervical cancer: A Gynecologic Oncology Group study☆ 
Gynecologic oncology  2008;112(3):583-589.
To determine whether markers of tumor angiogenesis were associated with progression-free survival (PFS) and overall survival (OS) in women with high-risk, early-stage cervical cancer treated on a phase III trial.
One hundred seventy-three tumor specimens were analyzed by semi-quantitative immunohistochemical (IHC) staining for vascular endothelial growth factor (VEGF, pro-angiogenesis factor), thrombospondin-1 (TSP-1, anti-angiogenesis factor), CD31 (non-specific endothelial marker), and CD105 (tumor-specific endothelial marker). Tumoral histoscores (HS) were calculated for VEGF using the formula: [% cells positive×(intensity+1)]. TSP-1 specimens were categorized as negative or positive. CD31 and CD105 microvessel density (MVD) “hotspots” were counted in three 20× high-power fields. Associations between angiogenesis markers and survival were evaluated.
TSP-1 expression was observed in 65% of cases while 66% expressed high VEGF (≥200), 34% exhibited high CD31 (CD31≥110) and 66% displayed high CD105 (CD105≥28). In univariate analyses CD31 MVD, but not tumor TSP-1, was associated with improved PFS (HR=0.37; 95% CI=0.18–0.76; p=0.007) and OS (HR=0.37; 95% CI=0.17–0.79; p=0.010). After adjusting for prognostic clinical covariates, high CD31 MVD, but not TSP-1, VEGF or CD105 MVD, was an independent prognostic factor for PFS (HR=0.36; 95% CI=0.17–0.75; p=0.006) and OS (HR=0.36; 95% CI=0.17–0.79; p=0.010).
Tumor angiogenesis measured by CD31 MVD is an independent prognostic factor for both PFS and OS in high-risk, early-stage cervical cancer. We hypothesize that this finding may be explained by improved treatment response in well-vascularized, well-oxygenated tumors.
PMCID: PMC2858218  PMID: 19110305
Angiogenesis; Cervical cancer; GOG; Angiogenic markers
8.  Transcriptional control of the tumor- and hypoxia-marker carbonic anhydrase 9: a one transcription factor (HIF-1) show? 
Biochimica et biophysica acta  2009;1795(2):162-172.
Transcriptional activation by hypoxia is mediated by the hypoxia-inducible factor (HIF) via binding to the hypoxia-responsive element (HRE). Hypoxia in solid tumors associates with poorer outcome of the disease and reliable cellular markers of tumor hypoxia would represent a valuable diagnostic marker and a potential therapeutic target. In this category, carbonic anhydrase IX (CAIX) is one of the most promising candidates. Here, we summarize the knowledge about transcriptional regulation of CA9. The HRE is the central regulatory element in the CA9 promoter, whereas other elements are limited to lesser roles of amplification of signals received at the HRE. The analysis of known mechanisms of activation of CA9 reveals the prominent role of the HIF-1 pathway. Experimental paradigms with uncoupled HIF-1α stability and transcriptional activity (pericellular hypoxia, proteasomal inhibitor) provide evidence that CA9 expression monitors transcriptional activity of HIF-1, rather than the abundance of HIF-1α. Furthermore, these paradigms could provide a corollary to some of the apparently discordant cases (CAIX+, HIF-1α−) or (CAIX−, HIF-1α+) observed in vivo. In conclusion, the existing data support the notion that CA9, due to the unique structure of its promoter, is one of the most sensitive endogenous sensors of HIF-1 activity.
PMCID: PMC2670353  PMID: 19344680
Carbonic anhydrase IX; transcriptional regulation; hypoxia; hypoxia-inducible factor
9.  Expression of transmembrane carbonic anhydrases, CAIX and CAXII, in human development 
Transmembrane CAIX and CAXII are members of the alpha carbonic anhydrase (CA) family. They play a crucial role in differentiation, proliferation, and pH regulation. Expression of CAIX and CAXII proteins in tumor tissues is primarily induced by hypoxia and this is particularly true for CAIX, which is regulated by the transcription factor, hypoxia inducible factor-1 (HIF-1). Their distributions in normal adult human tissues are restricted to highly specialized cells that are not always hypoxic. The human fetus exists in a relatively hypoxic environment. We examined expression of CAIX, CAXII and HIF-1α in the developing human fetus and postnatal tissues to determine whether expression of CAIX and CAXII is exclusively regulated by HIF-1.
The co-localization of CAIX and HIF-1α was limited to certain cell types in embryonic and early fetal tissues. Those cells comprised the primitive mesenchyma or involved chondrogenesis and skin development. Transient CAIX expression was limited to immature tissues of mesodermal origin and the skin and ependymal cells. The only tissues that persistently expressed CAIX protein were coelomic epithelium (mesothelium) and its remnants, the epithelium of the stomach and biliary tree, glands and crypt cells of duodenum and small intestine, and the cells located at those sites previously identified as harboring adult stem cells in, for example, the skin and large intestine. In many instances co-localization of CAIX and HIF-1α was not evident. CAXII expression is restricted to cells involved in secretion and water absorption such as parietal cells of the stomach, acinar cells of the salivary glands and pancreas, epithelium of the large intestine, and renal tubules. Co-localization of CAXII with CAIX or HIF-1α was not observed.
The study has showed that: 1) HIF-1α and CAIX expression co- localized in many, but not all, of the embryonic and early fetal tissues; 2) There is no evidence of co-localization of CAIX and CAXII; 3) CAIX and CAXII expression is closely related to cell origin and secretory activity involving proton transport, respectively. The intriguing finding of rare CAIX-expressing cells in those sites corresponding to stem cell niches requires further investigation.
PMCID: PMC2666674  PMID: 19291313
10.  Expression of hypoxia-inducible carbonic anhydrases in brain tumors 
Neuro-Oncology  2005;7(4):465-475.
Malignant brain tumors exhibit distinct metabolic characteristics. Despite high levels of lactate, the intracellular pH of brain tumors is more alkaline than normal brain. Additionally, with increasing malignancy, brain tumors display intratumoral hypoxia. Carbonic anhydrase (CA) IX and XII are transmembrane isoenzymes that are induced by tissue hypoxia. They participate in regulation of pH homeostasis by catalyzing the reversible hydration of carbon dioxide. The aim of our study was to investigate whether brain tumors of different histology and grade of malignancy express elevated levels of CA IX and XII as compared to normal brain. We analyzed 120 tissue specimens from brain tumors (primary and metastatic) and normal brain for CA IX and XII expression by immunohistochemistry, Western blot, and in situ hybridization. Whereas normal brain tissue showed minimal levels of CA IX and XII expression, expression in tumors was found to be upregulated with increased level of malignancy. Hemangioblastomas, from patients with von Hippel–Lindau disease, also displayed high levels of CA IX and XII expression. Comparison of CA IX and XII staining with HIF-1α staining revealed a similar microanatomical distribution, indicating hypoxia as a major, but not the only, induction factor. The extent of CA IX and XII staining correlated with cell proliferation, as indicated by Ki67 labeling. The results demonstrate that CA IX and XII are upregulated in intrinsic and metastatic brain tumors as compared to normal brain tissue. This may contribute to the management of tumor-specific acid load and provide a therapeutic target.
PMCID: PMC1871734  PMID: 16212811
pH regulation; carbonic anhydrase; glioma; hypoxia

Results 1-10 (10)