John Hoff

Frequency and Disposition of Ovarian Abnormalities Followed With Serial Transvaginal Ultrasonography

OBJECTIVE: To examine the prevalence, incidence, persistence, and resolution of ovarian abnormalities using serial transvaginal ultrasonography. METHODS: A group of 39,337 women in the University of Kentucky Ovarian Cancer Screening Program were monitored with 221,576 baseline and interval transvaginal ultrasonography. RESULTS: The transvaginal ultrasonogram was normal for first and all subsequent visits for 31,834 participants (80.9%), whereas 6,807 women (17.3%) had transvaginal ultrasonograms interpreted as abnormal and were monitored over 21,588 ultrasonograms. Ovarian cysts were more common in premenopausal (prevalence 34.9%, incidence 15.3%) than in postmenopausal women (prevalence 17.0%, incidence 8.2%). For the group with abnormalities, the initial transvaginal ultrasonogram was abnormal in 46.7% of the cases, of which 63.2% resolved to normal on subsequent ultrasonograms. Of 35,314 cases classified as normal on the first examination, 9.9% were abnormal on subsequent annual examinations. The abnormal findings were classified as follows: unilocular cysts (11.5%), cysts with septations (9.8%), cysts with solid areas (7.1%), and solid masses (1.8%). Many transvaginal ultrasonographic abnormalities were followed to resolution. Surgery was performed on 557 participants for 85 ovarian malignancies and 472 nonmalignancies. Over the duration of the study, the positive predictive value (PPV) increased from 8.1% to 24.7%. CONCLUSION: Serial ultrasonography has shown that many ovarian abnormalities resolve, even if the initial appearance is complex, solid, or bilateral. Thus, it is advantageous to avoid a single transvaginal ultrasonographic abnormality as the sole trigger for surgery and to take a measured serial approach to reduce false-positive results and increase the PPV. LEVEL OF EVIDENCE: II

Transvaginal Ultrasonography in Ovarian Cancer Screening: Current Perspectives

Transvaginal ultrasonography (TVS) is an integral part of all major ovarian cancer screening trials. TVS is accurate in detecting abnormalities in ovarian volume and morphology, but is less reliable in differentiating benign from malignant ovarian tumors. When used as the only screening test, TVS is sensitive, but has a low positive predictive value. Therefore, serum biomarkers and tumor morphology indexing are used together with TVS to identify ovarian tumors at high risk for malignancy. This allows preoperative triage of high-risk cases to major cancer centers for therapy while decreasing unnecessary surgery for benign disease. Ovarian cancer screening has been associated with a decrease in stage at detection in most trials, thereby allowing treatment to be initiated when the disease is most curable.

Serial ultrasonographic evaluation of ovarian abnormalities with a morphology index.

OBJECTIVE Transvaginal ultrasonography with tumor morphology index (MI) has been used to predict the risk of ovarian malignancy. Our objective was to analyze changes in serial MI scores for malignant and non-malignant ovarian tumors in a large and asymptomatic population. METHODS Eligible subjects participated in the University of Kentucky Ovarian Cancer Screening Program and had abnormalities that included cysts, cysts with septations, complex cysts with solid areas, and solid masses. Analysis included: MI, change in MI (delta MI), delta MI per scan and per month, number and duration of scans. RESULTS From 1987 to 2012, 38,983 women received 218,445 scans. Of the 7104 eligible subjects, 6758 tumors were observed without surgery and 472 were surgically removed. Eighty-six percent (5811) of observed tumors were resolved. There were 74 malignant and 272 non-malignant tumors. Eighty-five percent of malignancies had MI ≥5 at decision for surgery. The risk of malignancy based on MI was: MI=5 (3%), MI=6 (3.7%), MI=7 (12.6%), MI=8 (26.7%), MI=9 (27.8%), MI=10 (33.3%). The mean delta MI per month decreased for tumors that resolved (delta MI -1.0, p<0.001) or persisted without surgery (delta MI -0.7, p<0.001). For abnormalities surgically removed, the mean delta MI per month increased significantly more for malignancies than for benign tumors (delta MI +1.6 vs. +0.3, p<0.001). CONCLUSIONS The mean MI for malignant ovarian tumors increases over time, while non-malignant tumors have a decreasing or stable MI. Serial MI analysis can improve the prediction of ovarian malignancy by reducing false-positive results, thereby decreasing the number of operations performed for benign abnormalities.

CD151 represses mammary gland development by maintaining the niches of progenitor cells

Tetraspanin CD151 interacts with laminin-binding integrins (i.e., α3β1, α6β1 and α6β4) and other cell surface molecules to control diverse cellular and physiological processes, ranging from cell adhesion, migration and survival to tissue architecture and homeostasis. Here, we report a novel role of CD151 in maintaining the branching morphogenesis and activity of progenitor cells during the pubertal development of mammary glands. In contrast to the disruption of laminin-binding integrins, CD151 removal in mice enhanced the tertiary branching in mammary glands by 2.4-fold and the number of terminal end buds (TEBs) by 30%, while having minimal influence on either primary or secondary ductal branching. Consistent with these morphological changes are the skewed distribution of basal/myoepithelial cells and a 3.2-fold increase in proliferating Ki67-positive cells. These novel observations suggest that CD151 impacts the branching morphogenesis of mammary glands by upregulating the activities of bipotent progenitor cells. Indeed, our subsequent analyses indicate that upon CD151 removal the proportion of CD24HiCD49fLow progenitor cells in the mammary gland increased by 34%, and their proliferating and differentiating activities were significantly upregulated. Importantly, fibronectin, a pro-branching extracellular matrix (ECM) protein deposited underlying mammary epithelial or progenitor cells, increased by >7.2-fold. Moreover, there was a concomitant increase in the expression and nuclear distribution of Slug, a transcription factor implicated in the maintenance of mammary progenitor cell activities. Taken together, our studies demonstrate that integrin-associated CD151 represses mammary branching morphogenesis by controlling progenitor cell activities, ECM integrity and transcription program.

Renal disease appears not to affect carcinogenesis in CD151-null mice.

As published in Oncogene,1 CD151 null mice were backcrossed four generations onto the FVB/N genetic background to increase chemical carcinogenesis sensitivity.2 Although CD151-null mice can have substantial kidney pathology in the FVB/N background,3, 4 we are confident that kidney pathology is not a major confounding issue in our studies of CD151 in a skin chemical carcinogenesis model,1 and in an ErbB2 transgene expression model.5

Survival Advantage Associated with Decrease in Stage at Detection from Stage IIIC to Stage IIIA Epithelial Ovarian Cancer

Objective. The aim of this study was to document the survival advantage of lowering stage at detection from Stage IIIC to Stage IIIA epithelial ovarian cancer. Methods. Treatment outcomes and survival were evaluated in patients with Stage IIIA and Stage IIIC epithelial ovarian cancer treated from 2000 to 2009 at the University of Kentucky Markey Cancer Center (UKMCC) and SEER institutions. Results. Cytoreduction to no visible disease (P < 0.0001) and complete response to platinum-based chemotherapy (P < 0.025) occurred more frequently in Stage IIIA than in Stage IIIC cases. Time to progression was shorter in patients with Stage IIIC ovarian cancer (17 ± 1 months) than in those with Stage II1A disease (36 ± 8 months). Five-year overall survival (OS) improved from 41% in Stage IIIC patients to 60% in Stage IIIA patients treated at UKMCC and from 37% to 56% in patients treated at SEER institutions for a survival advantage of 19% in both data sets. 53% of Stage IIIA and 14% of Stage IIIC patients had NED at last followup. Conclusions. Decreasing stage at detection from Stage IIIC to stage IIIA epithelial ovarian cancer is associated with a 5-year survival advantage of nearly 20% in patients treated by surgical tumor cytoreduction and platinum-based chemotherapy.

Metrics of the Gynecologic Oncology Literature Focused on Cited Utilization and Costs

OBJECTIVE The newest findings on literature utilization relevant to gynecologic oncology were published by Thomson Reuters during June 2013 as determinants of journal standing. Our objective was to assess the different metrics reported for relative impact and cost for journals relevant to gynecologic oncology. METHODS 55 journals were evaluated for Impact Factor (IF), 5 Year IF, Immediacy Index, Cited Half Life, Eigenfactor (EF) Score, Article Influence (AI) scores and subscription costs obtained from publisher information. RESULTS CA-A Cancer Journal for Clinicians had the highest IF (101.78) & AI (24.502). The top EF cancer-specific journals were the Journal of Clinical Oncology, Cancer Research, Clinical Cancer Research and Oncogene. Rankings for Gynecologic Oncology (409 articles, 18,243 citations) were IF = 3.929, 43/55, EF = 0.038, 28/55, and AI = 1.099, 44/55, all higher than the previous year. The IF improved from the 5 year IF in 31 journals, including Gynecologic Oncology, 29/31. Subscription costs for Gynecologic Oncology compared favorably to other journals. CONCLUSIONS The high utilization of review information in CA-A Cancer Journal for Clinicians and Nature Review Cancer illustrated by the IF coupled with a relatively low number of articles and short cited half life indicates that they serve as a leading source of quoted cancer statistics (CA-A Cancer Journal for Clinicians). Rankings for Gynecologic Oncology and the International Journal of Gynecologic Cancer have improved. Regardless of specialty size, the Impact Factor for Gynecologic Oncology is respectably strong. The decreased IF in 44% of the journals may reflect the international economys effect on cancer research.

Abstract 2704: Tetraspanin CD151 drives mammary tumor onset and metastasis by coordinating integrin-dependent cell adhesion, motility, survival and signaling

The ErbB2+ subtype of human breast tumors remains a significant threat to women9s health, as they are highly prone to recurrence or metastasis, and development of drug resistance. Here we report that CD151, a member of the tetraspanin family and a close partner of the laminin-binding (LB) integrins (≥3α1 and α6β4), contributes to the onset and malignancy of ErbB2-induced mammary tumors. By crossing gene-targeted mice onto a clinically-relevant MMTV-ErbB2 transgenic model, we demonstrated that deletion of CD151 significantly impaired the onset and metastasis of mammary tumors in mice. Our subsequent analyses of cell lines derived from mouse primary tumors showed that loss of CD151 decreased integrin-mediated cell-ECM adhesion and cell-cell contacts. Also, for ErbB2-overexpressing MCF-10A cells cultured in 2D or 3D, ablation of CD151 markedly reduced tumor cell motility, invasion and survival. However, only MAPK and FAK kinases among an array of signaling molecules downstream of integrins and ErbB receptors, exhibited a decreased activation in response to CD151 disruption. Importantly, there were corresponding changes in the activation and signaling of α6β4 integrin, as reflected by decreased phosphorylation of multiple serine residues at its cytoplasmic domain. Also, the cross-talk between integrins and ErbB receptors was strongly inhibited. Meanwhile, our analyses of clinical dataset revealed a strong correlation between CD151 gene expression and patients’ metastasis-free survival. Taken together, our results demonstrate that tetraspanin CD151 drives ErbB2-induced mammary tumorigenesis by coordinating the function and signaling of LB integrins. This newly-identified crucial role of CD151 offers a strong therapeutic potential for the treatment of breast cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2704. doi:1538-7445.AM2012-2704

Abstract 4613: A role of integrin-associated CD151 in human ovarian cancer

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Despite being implicated in multiple types of human epithelia-origin cancer, laminin-binding (LB) integrins (e.g., α3α1 and α6β4) have rarely been investigated for their roles in human ovarian tumors. More recently, we and others have shown that CD151, a member of the tetraspanin family, not only forms tight surface complexes with these adhesion receptors, but also mediates the malignancy of human carcinomas largely in a LB integrin-dependent manner. Here we report our studies on the role of CD151 in human ovarian cancer. Initially, we stained human ovarian tumor tissue microarrays with CD151-specific antibody. Our data showed that the majority of ovarian tumors exhibited a reduced expression of CD151 protein, compared to the fallopian tube, implying a putative suppressing role of this tetraspanin in ovarian cancer. With this hint we next evaluated the impact of CD151 ablation on the behaviors and proliferation of cultured human ovarian cancer cells. While CD151 removal had a minimal impact on cell motility or invasion, it markedly enhanced cell proliferation. Also, CD151-deficeint cells appeared to have reduced cell-cell contacts, suggestive of epithelial-mesenchymal transition (EMT)-like changes. However, there was no dramatic difference in the surface expression of E-cadherin protein, according to our FACS analyses. To substantiate these observations, we also injected ovarian cancer cells with or without CD151 knockdown into immuno-deficient nude mice subcutaneously or orthotopically (intra-peritoneal). Results from these ex vivo analyses showed that disruption of CD151 accelerated ovarian tumor growth and production of ascites fluid in mice, further supporting a role of CD151 in ovarian tumor progression. While tumors in the control group had homogenous epithelial-like appearance, those derived from CD151-ablated cells exhibited mucin-related vacuoles and diverse morphologies. Our subsequent DNA array and protein analyses indicated that there was indeed a marked increase in the expression of a mucin family member in CD151-deficient tumor cells. Collectively, these results provide strong evidence that CD151 suppresses human ovarian cancer progression by regulating tumor cell proliferation and extracellular microenvironment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4613. doi:1538-7445.AM2012-4613