John M. Malone

Ovarian cancer: changes in patterns at diagnosis and relative survival over the last three decades

OBJECTIVE The purpose of this study was to examine patterns of diagnosis and relative survival in women who had a diagnosis of primary invasive epithelial ovarian cancer (EOC) from 1973 to 1997, with follow-up through the end of 1999. STUDY DESIGN From the population-based Surveillance, Epidemiology and End Results (SEER) Program, 32,845 women diagnosed between 1973 and 1997 were used for analysis. The study population was divided in three cohorts based on year of diagnosis and the cohorts were compared with respect to variables of interest by using chi(2) tests and relative survival analysis by the life table method. RESULTS There was an increase in the proportions of minorities diagnosed with EOC, of women 60 years or older at diagnosis, and of women undergoing surgery over time. Survival continuously improved over time, although older patients (60 years or older) and African Americans continued to have the poorest survival. CONCLUSION Over time, relative survival of women who had primary invasive EOC diagnosed improved.

Lymphadenectomy and ovarian preservation in low-grade endometrial stromal sarcoma.

OBJECTIVE: To report the impact on overall survival of lymphadenectomy and ovarian preservation in patients with endometrial stromal sarcoma. METHODS: Data were extracted from the Surveillance, Epidemiology, and End Results Program from 1988 to 2005. Kaplan-Meier and Cox proportional hazards analyses were used to identify possible predictors for survival. RESULTS: Nine hundred seventy women were reported with endometrial stromal sarcoma. The 384 women with low-grade endometrial stromal sarcoma had a younger age, earlier stage, and longer survival than the 320 women with high-grade lesions. Among the low-grade endometrial stromal sarcoma patients, the incidence of extrauterine disease was 25%, and lymph node metastasis was 7%. Univariable and multivariable analysis demonstrated lymph node metastasis and ovarian preservation were not significant prognostic factors for survival. CONCLUSION: In low-grade endometrial stromal sarcoma, the risk of extrauterine spread and lymph node metastasis merit consideration for surgical staging. Neither lymph node metastasis nor ovarian preservation seems to affect the excellent overall survival of these patients. LEVEL OF EVIDENCE: II

Effects of Prostaglandin E2 on proliferation and apoptosis of epithelial ovarian cancer cells

OBJECTIVE There is strong evidence indicating that prostaglandins (PG) and their synthesizing enzyme cyclooxygenase-2 (COX-2) play an important role in tumorigenesis. The purposes of the present study were to determine the pattern of expression of COX-2 and the effect of PG treatment on proliferation and apoptosis in epithelial ovarian cancer cells. METHODS Two epithelial ovarian cancer cell lines, MDAH-2774 and SKOV3, were grown in flasks to confluence. Cells were then treated with exogenous dimethyl prostaglandin E(2) (dmPGE(2)) at increasing concentrations of 0-10 microg/mL. Total RNA was extracted from cells at different treatment doses and subjected to reverse transcriptase-polymerase chain reaction for the semiquantitative analysis of COX-2, Bcl-2, and bax expression. Flow cytometry was performed to assess effect of treatment on the cell cycle. The TUNEL assay was used to assess apoptosis. RESULTS We found that COX-2 was constitutively expressed in the MDAH-2774 and SKOV3 epithelial ovarian cancer cells as determined by detection of a 304-bp amplified fragment using specific primers for the COX-2 gene. Treatment of both cell lines with dmPGE(2) resulted in dose-dependently higher expression of COX-2, Bcl-2, and bax mRNA compared with untreated cells. These changes were associated with an increase in the proliferative fraction and with a simultaneous reduction in apoptosis. CONCLUSIONS Prostaglandin E(2) stimulated proliferation and reduced apoptosis in epithelial ovarian cancer cells. These effects were associated with overexpression of COX-2 and an increase in the ratio of Bcl-2:bax mRNA.

Inhibition of c-myc in breast and ovarian carcinoma cells by 1,25-dihydroxyvitamin D3, retinoic acid and dexamethasone.

The role and regulation of the c-myc protooncogene in breast and ovarian neoplasms is receiving increased attention. The downregulation of the c-myc protooncogene by 1,25-dihydroxyvitamin D3 (calcitriol), retinoic acid (RA) and dexamethasone (Dex) is closely associated with growth inhibition in leukemic cells. Calcitriol, RA and Dex have anti-proliferative activity in breast and gynecologic carcinoma cells; however, the regulation of c-myc by these agents in breast and ovarian cancers is mostly unknown. We have addressed the regulation of c-myc in these cancers using an adaptation of a novel method which employs an immunohistochemical procedure to detect c-myc protein followed by quantification of c-myc staining with computerized image analysis. This system represents an alternative to protein product assay by Western blotting and is straightforward, rapid (1 day), can be carried out on a small scale and provides a sample size that readily facilitates statistical analysis of assay data. In MCF-7 human breast cancer cells, c-myc was suppressed 29% by 0.5 nM Dex, 45% by 0.01 nM RA and 54% by 100 nM calcitriol after 24 h of drug treatment. At the same hormone concentrations, growth was inhibited 18% by Dex, 18% by RA and 39% by calcitriol after 3 days of treatment (p < 0.05 for all hormones). Similar patterns of growth and c-myc inhibition were seen in T47D human breast cancer cells and NIH:OVCAR3 human ovarian cancer cells, with the exception of Dex in T47D cells, which caused no inhibition of c-myc or growth.(ABSTRACT TRUNCATED AT 250 WORDS)

Reliability of frozen section examination in identifying poor prognostic indicators in Stage I endometrial adenocarcinoma

Management of Stage I adenocarcinoma of the uterus includes hysterectomy, bilateral salpingo-oophorectomy, and selective paraaortic and pelvic lymphadenectomy. Postoperative radiation therapy (RT) is selectively employed in patients with histologically defined poor prognostic indicators. We attempted to identify these poor prognostic indicators by frozen section (FS) at primary surgery in 55 patients with Stage I endometrial adenocarcinoma; we found an excellent correlation between the results obtained on gross examination of the uterus with selected FS and the results after extensive sampling and microscopic examination of permanent section (PS). The depth of myometrial invasion was accurately predicted in 96.5%, and histologic grade in 94.5% of these patients. Sixty-six percent of patients with occult invasion of the cervix on PS were identified on FS. Using the above criteria, we identified by FS all patients (15/55) who required adjuvant RT obviating the need for pelvic lymph node dissection. On the basis of our preliminary data, we recommend the use of careful gross examination and selective FS to identify patients requiring selective pelvic and paraaortic lymphadenectomy and adjuvant therapy, thereby eliminating the need for staging lymph node dissection with its associated morbidity and complications.

Ritonavir blocks AKT signaling, activates apoptosis and inhibits migration and invasion in ovarian cancer cells

BackgroundOvarian cancer is the leading cause of mortality from gynecological malignancies, often undetectable in early stages. The difficulty of detecting the disease in its early stages and the propensity of ovarian cancer cells to develop resistance to known chemotherapeutic treatments dramatically decreases the 5-year survival rate. Chemotherapy with paclitaxel after surgery increases median survival only by 2 to 3 years in stage IV disease highlights the need for more effective drugs. The human immunodeficiency virus (HIV) infection is characterized by increased risk of several solid tumors due to its inherent nature of weakening of immune system. Recent observations point to a lower incidence of some cancers in patients treated with protease inhibitor (PI) cocktail treatment known as HAART (Highly Active Anti-Retroviral Therapy).ResultsHere we show that ritonavir, a HIV protease inhibitor effectively induced cell cycle arrest and apoptosis in ovarian cell lines MDH-2774 and SKOV-3 in a dose dependent manner. Over a 3 day period with 20 μM ritonavir resulted in the cell death of over 60% for MDAH-2774 compared with 55% in case of SKOV-3 cell line. Ritonavir caused G1 cell cycle arrest of the ovarian cancer cells, mediated by down modulating levels of RB phosphorylation and depleting the G1 cyclins, cyclin-dependent kinase and increasing their inhibitors as determined by gene profile analysis. Interestingly, the treatment of ritonavir decreased the amount of phosphorylated AKT in a dose-dependent manner. Furthermore, inhibition of AKT by specific siRNA synergistically increased the efficacy of the ritonavir-induced apoptosis. These results indicate that the addition of the AKT inhibitor may increase the therapeutic efficacy of ritonavir.ConclusionOur results demonstrate a potential use of ritonavir for ovarian cancer with additive effects in conjunction with conventional chemotherapeutic regimens. Since ritonavir is clinically approved for human use for HIV, drug repositioning for ovarian cancer could accelerate the process of traditional drug development. This would reduce risks, limit the costs and decrease the time needed to bring the drug from bench to bedside.

The prevalence and prognostic impact of lymph node metastasis in malignant germ cell tumors of the ovary

BACKGROUND The purpose of this study is to report the prevalence and prognostic importance of lymph node metastasis in malignant germ cell tumors of the ovary (OGCT). METHODS Demographic and clinicopathologic information were abstracted from the Surveillance, Epidemiology, and End Results Program (SEER) from 1988 to 2004. Patients with a histologic diagnosis of OGCT after surgical resection were included. The study population was divided into Cohort A (lymph node metastasis absent) and Cohort B (lymph node metastasis present). Statistical analysis using Fishers Exact Test, Kaplan-Meier survival methods, and Cox regression proportional hazards were performed. RESULTS In 613 patients with lymphadenectomy, the prevalence of lymphnode metastasis was 18.1% (111/613). In dysgerminoma, malignant teratoma and mixed germ cell tumors including pure non-dysgerminoma histology, the lymphnode metastasis was present in 28%, 8% and 16% patients respectively (p<0.05). Age, race, grade and extent of lymph node dissection influenced lymph node involvement but this was statistically not significant. Five year survival in Cohort A was 95.7% compared to 82.8% in Cohort B (p<0.001). After controlling for age, race, stage, grade and histology, multivariate analysis revealed the presence of lymph node involvement as an independent predictor of poor survival with a hazards ratio of 2.87 (95% CI 1.439-5.725; p<0.05). CONCLUSIONS Prevalence of lymph node metastasis varies according to histology in OGCT and is an independent predictor of poor survival in these patients. These findings highlight the value of lymphadenectomy and may be helpful in creating risk stratification models for individualization of adjuvant therapies.

Receptors for 1,25-dihydroxyvitamin D3 in gynecologic neoplasms

To determine if gynecologic malignancies are candidates for 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) therapy we measured vitamin D receptor (VDR) levels in 11 tumor specimens using a radiolabeled ligand-binding assay. VDR was demonstrated in 3 of 6 ovarian tumors and 1 of 1 uterine sarcomas, but not in endometrial tumors (2), cervical tumors (1), or Krukenberg tumors (1). Scatchard plots revealed that [3H]1,25(OH)2D3 was bound to a single class of high-affinity (Kd = 0.3 to 0.6 nM), saturable sites characteristic of authentic 1,25(OH)2D3 receptors. Specificity of binding activity for 1,25(OH)2D3, the active vitamin D3 metabolite, was demonstrated by failure of 25-hydroxy- and 24,25-dihydroxyvitamin D3 to compete effectively against 1,25(OH)2D3 binding in total cellular tumor extracts. The ovarian carcinoma cell line NIH:OVCAR3 was shown to possess VDR (binding capacity = 137 fmol/mg protein, Kd = 0.48 nM). A 3-day incubation of NIH:OVCAR3 cells with 100 nM 1,25(OH)2D3 resulted in 49% inhibition of cell growth. The growth inhibition of an ovarian carcinoma line and the observation that 36% of gynecologic tumors assayed were shown to be VDR-positive suggest that further study is warranted to delineate the mechanism and possible therapeutic aspects of 1,25(OH)2D3 action in gynecologic tumors.

Inhibition of breast and ovarian carcinoma cell growth by 1,25-dihydroxyvitamin D3 combined with retinoic acid or dexamethasone

This study examined the growth inhibitory effects of combining 1,25-dihydroxyvitamin D3 (calcitriol) with retinoic acid or dexamethasone against cultured breast and ovarian carcinoma cells. Retinoic acid (12.5-50 nM) increased the effectiveness of calcitriol (12.5-50 nM) against MCF-7 and NIH:OVCAR3 cells, with synergistic interactions at two of the three ratios tested. Dexamethasone augmented calcitriol effects, with synergism at 0.05 and 0.1 nM dexamethasone in MCF-7 cells and 5 nM in Caov-4 ovarian cells. This study showed favorable interactions for calcitriol-retinoic acid and calcitriol-dexamethasone combinations in breast and ovarian cancer cell lines.

Debulking surgery for ovarian cancer with the Cavitron Ultrasonic Surgical Aspirator (CUSA)—A preliminary report

The Cavitron Ultrasonic Surgical Aspirator (CUSA) can be used to fragment and aspirate tissue precisely. The CUSA was utilized as an adjunctive procedure to standard operative techniques to optimally debulk 11 women with advanced epithelial carcinoma of the ovary. No significant intraoperative or postoperative complications were encountered. It is suggested that this technique may be safely attempted in combination with the standard surgical techniques for debulking nonfibrous ovarian tumors or may allow removal of nonfibrous tumor masses which cannot be resected safely utilizing the standard surgical techniques. The authors found the CUSAs efficiency was limited in dense and fibrotic tissue. On the basis of our experience with this small number of patients, we believe this technique deserves further study.