Robert E. Emerson

Reclassification of serous ovarian carcinoma by a 2-tier system: a Gynecologic Oncology Group Study.

A study was undertaken to use the 2‐tier system to reclassify the grade of serous ovarian tumors previously classified using the International Federation of Gynecology and Obstetrics (FIGO) 3‐tier system and determine the progression‐free survival (PFS) and overall survival (OS) of patients treated on Gynecologic Oncology Group (GOG) Protocol 158.

Enhanced peritoneal ovarian tumor dissemination by tissue transglutaminase

Tissue transglutaminase (TG2) is involved in Ca(2+)-dependent aggregation and polymerization of proteins. We previously reported that TG2 mRNA is up-regulated in epithelial ovarian cancer (EOC) cells compared with normal ovarian epithelium. Here, we show overexpression of the TG2 protein in ovarian cancer cells and tumors and its secretion in ascites fluid and define its role in EOC. By stable knockdown and overexpression, we show that TG2 enhances EOC cell adhesion to fibronectin and directional cell migration. This phenotype is preserved in vivo, where the pattern of tumor dissemination in the peritoneal space is dependent on TG2 expression levels. TG2 knockdown diminishes dissemination of tumors on the peritoneal surface and mesentery in an i.p. ovarian xenograft model. This phenotype is associated with deficient beta(1) integrin-fibronectin interaction, leading to weaker anchorage of cancer cells to the peritoneal matrix. Highly expressed in ovarian tumors, TG2 facilitates i.p. tumor dissemination by enhancing cell adhesion to the extracellular matrix and modulating beta(1) integrin subunit expression.

Chromosome 12p abnormalities in dysgerminoma of the ovary: a FISH analysis.

Dysgerminoma is the most common malignant ovarian germ cell tumor and shares histological and immunophenotypical features with its testicular counterpart, seminoma. Chromosome 12p abnormalities are genetic hallmarks of testicular seminomas. Little is known about these genetic changes in dysgerminoma. We performed dual color fluorescence in situ hybridization (FISH) analyses with a centromeric α-satellite probe for chromosome 12 and a subtelomeric probe for 12p on paraffin-embedded tissue sections from 21 dysgerminomas and two gonadoblastomas. Chromosome 12p abnormalities were detected in 81% of dysgerminomas. In all, 57% of cases had only isochromosome 12p and 5% had only 12p overrepresentation. In all, 19% had both isochrome 12p and 12p overrepresentation. Gonadoblastomas were negative for isochromosome 12p or 12p overrepresentation. Chromosome 12p abnormalities are common in dysgerminoma of the ovary. FISH analyses for chromosome 12p abnormalities may be a useful diagnostic adjunct for confirming the diagnosis of dysgerminoma and for distinguishing it from nongerm cell malignancies that enter into the differential diagnosis.

Imatinib mesylate in combination with docetaxel for the treatment of patients with advanced, platinum-resistant ovarian cancer and primary peritoneal carcinomatosis : a Hoosier Oncology Group trial.

Ovarian tumors frequently express c‐Kit and/or platelet‐derived growth factor receptors (PDGFRs). Imatinib mesylate blocks the growth of ovarian cancer cells in vitro and may enhance the activity of chemotherapy. This study was conducted to determine the activity of imatinib in combination with docetaxel in patients with recurrent, platinum‐resistant epithelial ovarian cancer (EOC).

Closest distance between tumor and resection margin in radical prostatectomy specimens: Lack of prognostic significance

Complete removal of the tumor by surgery offers the best chance for cancer cure; however, many prostate cancer patients who have negative surgical margins at radical prostatectomy will still experience local and distant tumor recurrence. In other organs, the closest distance between tumor and resection margin has prognostic significance. This has not been adequately studied in prostatectomy specimens. We undertook a prospective study of 278 consecutive margin-negative whole-mount prostatectomy cases. The anatomic location and closest distance between tumor and resection margin, measured with an ocular micrometer, were analyzed. All the slides were reviewed by a single pathologist, and data were collected prospectively. The closest distance between tumor and resection margin ranged from 0.02 to 5.0 mm (mean, 0.7 mm; median, 0.5 mm) and correlated with patient age (P = 0.03), prostate weight (P = 0.002), Gleason score (P = 0.001), pathologic stage (P = 0.01), tumor volume (P < 0.001), and perineural invasion (P < 0.001). The closest distance between tumor and resection margin was not a significant predictor of PSA recurrence in univariate or multivariate logistic regression; and we do not, therefore, advocate reporting the closest distance between tumor and resection margin as a standard part of the surgical pathology report on prostatectomy specimens.

Predicting cancer progression in patients with penile squamous cell carcinoma: the importance of depth of invasion and vascular invasion.

The ability to predict cancer progression may help the clinical management of patients with penile squamous cell carcinoma. We studied 22 cases of squamous cell carcinoma of the penis diagnosed between 1989 and 1998. The depth of invasion was measured from the basement membrane of the squamous epithelium to the deepest invasive cancer cells. Cancer progression was defined as the development of lymph node metastasis or distant metastasis. The mean patient age was 63 years and the mean follow-up was 28 months. Ten patients developed cancer progression. The mean depth of invasion among patients with cancer progression was 9.8 mm, as compared to the mean depth of invasion of 4.0 mm among those patients without cancer progression (P = .02). Vascular invasion was also predictive of cancer progression (P = .02). Metastases developed in the majority (6 out of 7) of cases invading more than 6 mm, but developed only in a minority (4 out of 15) of cases invading 6 mm or less. We conclude that depth of invasion and vascular invasion are significant predictors of cancer progression for penile squamous cell carcinoma.

Tissue Transglutaminase Regulates Matrix Metalloproteinase-2 in Ovarian Cancer by Modulating cAMP-response Element-binding Protein Activity

Tissue transglutaminase 2 (TG2) is overexpressed in epithelial ovarian cancer (EOC) and promotes intraperitoneal metastasis. How TG2 facilitates the spread of EOC is unknown. Here, we show that TG2 regulates the expression and function of matrix metalloproteinase-2 (MMP-2), a critical mediator of tissue invasiveness. TG2 knockdown down-regulates MMP-2 protein and mRNA expression in SKOV3, IGROV-1, MDA-MB-436, and PC-3 cancer cells. TG2 knockdown or inhibition of TG2 activity using KCC009 decreases MMP-2 gelatinase activity in cancer cells. MMP-2 expression and function are regulated by TG2 at transcriptional level, as demonstrated by quantitative PCR and reporter assays. We used bioinformatics and chromatin immunoprecipitation to identify a CREB binding site in the MMP-2 promoter. Binding of CREB to the MMP-2 promoter was diminished in cells that expressed decreased TG2 levels. TG2 knockdown decreased CREB phosphorylation, and CREB knockdown decreased MMP-2 expression. The effect of TG2 on CREB activity and MMP-2 transcription is mediated by TG2-dependent degradation of protein phosphatase 2 (PP2A-α). We show that PP2A-α complexes with and is targeted for degradation by TG2. In addition to their related in vitro expression levels, TG2 and MMP-2 expression were significantly correlated in vivo, as shown by concordant immunostaining in peritoneal xenografts and in human ovarian tumors. The capacity of TG2 to regulate MMP-2 expression in vitro and in vivo identifies a mechanism that may facilitate tissue invasion and the spread of EOC. The demonstration that TG2 induced degradation of PP2A-α activates CREB, and thereby increases MMP-2 transcription, provides novel mechanistic insight into the pro- metastatic function of TG2.

The influence of extent of surgical margin positivity on prostate specific antigen recurrence

Background: Positive surgical margins are an adverse prognostic factor in patients undergoing prostatectomy for prostate cancer. The extent of margin positivity varies and its influence on clinical outcome is uncertain. Aims: To evaluate the linear extent of margin positivity and the number and location of positive sites as prognostic indicators in a series of prostatectomy specimens evaluated with the whole mount technique. Methods: Eighty six consecutive margin positive prostatectomy specimens were evaluated, and all pathology data were collected prospectively. The linear extent of margin positivity was measured with an ocular micrometer and the total extent of all positive sites was summed. The total number of sites with positive margins and anatomical sites of the positive margins were analysed. Results: The linear extent of margin positivity ranged from 0.01 to 68 mm (mean, 6.8; median, 3.0) and was associated with prostate specific antigen (PSA) recurrence in univariate logistic regression (p = 0.031). In addition, the extent of margin positivity weakly correlated with preoperative PSA (p = 0.017) and tumour volume (p = 0.013), but not with age, prostate weight, Gleason score, pathological stage, or perineural invasion. The total number of positive sites was significantly higher in patients with PSA recurrence (p = 0.037). The location of the positive margin site was not associated with PSA recurrence. The extent of margin positivity correlated with PSA recurrence in univariate analysis, although it had only marginal predictive value when adjusted for Gleason score (p = 0.076). Conclusions: The extent of margin positivity correlates with PSA recurrence in univariate analysis, although it has no predictive value independent of Gleason score.

Nephroblastoma Arising in a Germ Cell Tumor of Testicular Origin

We report a nephroblastoma arising in a germ cell tumor of testicular origin occurring in a 22-year-old man. Orchiectomy demonstrated a malignant mixed germ cell tumor composed of mature and immature teratoma with nephroblastoma and rhabdomyosarcoma. Following chemotherapy, the patient developed supraclavicular and retroperitoneal lymphadenopathy. Excision demonstrated metastatic teratoma at both sites. No recurrence was noted with 21 months of additional follow-up. Using tissue microdissection and loss of heterozygosity analysis, we investigated the clonality of the mature teratoma, immature teratoma, nephroblastoma, and rhabdomyosarcoma components of the primary tumor and of the metastatic mature teratoma at the two separate distant sites. Nine microsatellite polymorphic makers were used to examine the pattern of allelic loss in both primary and metastatic tumors. Loss of heterozygosity was found in 4 DNA loci, and the same pattern of allelic loss was demonstrated at all 4 loci in all of the different components of the primary tumor and the metastatic mature teratomas, supporting the germ cell tumor origin of the nephroblastoma component. Loss of heterozygosity on chromosome 17p13 (TP53) was detected in metastatic mature teratoma, but not in the primary tumor. Loss of heterozygosity was observed at 11p13, the locus of WT1 inactivation in patients genetically predisposed to nephroblastoma, and this loss may be an important genetic mechanism in nephroblastomatous differentiation of germ cell tumors. These data support a common clonal origin for nephroblastoma and the other germ cell tumor components.

PDGF BB induces VEGF secretion in ovarian cancer

We identified the platelet derived growth factor receptor (PDGFR) as a potential target in epithelial ovarian carcinoma (EOC). This led us to test whether inhibition of the PDGFR affects ovarian cancer cell proliferation and survival and regulates other processes critical to tumor growth and metastasis. We postulated that there is a correlation between the PDGF-PDGFR axis and the secretion of VEGF in EOC. VEGF secretion in ovarian tumors, cancer cells, serum and ascites fluid was measured by IHC, Western Blot and ELISA. We found increased VEGF expression and secretion in most ovarian tumors (by IHC), in EOC malignant ascites and in the conditioned media of primary ovarian cancer cells (quantified by ELISA). In malignant ascites, the levels of secreted PDGF BB and VEGF were strongly correlated (Pearson coefficient of correlation R=0.728), suggesting that the two pathways interconnect. In PDGFR expressing immortalized ovarian cancer cells, PDGF potently induced VEGF secretion, while imatinib mesylate (Gleevec), a partially selective PDGFR inhibitor, reduced PDGF stimulated VEGF production to basal state. In ovarian cancer cells overexpressing constitutively active Akt, imatinib inhibited partially VEGF secretion, suggesting that the PI3K/Akt pathway is implicated in PDGF-stimulated VEGF secretion. In summary, these results suggest a correlation between the PDGF and VEGF networks in ovarian cancer cells and tumors. The effects of imatinib on VEGF secretion in tumor cells may affect the tumor microenvironment in a manner detrimental to tumor progression.