Edward E. Partridge

Effect of Screening on Ovarian Cancer Mortality: The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial

CONTEXT Screening for ovarian cancer with cancer antigen 125 (CA-125) and transvaginal ultrasound has an unknown effect on mortality. OBJECTIVE To evaluate the effect of screening for ovarian cancer on mortality in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. DESIGN, SETTING, AND PARTICIPANTS Randomized controlled trial of 78,216 women aged 55 to 74 years assigned to undergo either annual screening (n = 39,105) or usual care (n = 39,111) at 10 screening centers across the United States between November 1993 and July 2001. Intervention The intervention group was offered annual screening with CA-125 for 6 years and transvaginal ultrasound for 4 years. Participants and their health care practitioners received the screening test results and managed evaluation of abnormal results. The usual care group was not offered annual screening with CA-125 for 6 years or transvaginal ultrasound but received their usual medical care. Participants were followed up for a maximum of 13 years (median [range], 12.4 years [10.9-13.0 years]) for cancer diagnoses and death until February 28, 2010. MAIN OUTCOME MEASURES Mortality from ovarian cancer, including primary peritoneal and fallopian tube cancers. Secondary outcomes included ovarian cancer incidence and complications associated with screening examinations and diagnostic procedures. RESULTS Ovarian cancer was diagnosed in 212 women (5.7 per 10,000 person-years) in the intervention group and 176 (4.7 per 10,000 person-years) in the usual care group (rate ratio [RR], 1.21; 95% confidence interval [CI], 0.99-1.48). There were 118 deaths caused by ovarian cancer (3.1 per 10,000 person-years) in the intervention group and 100 deaths (2.6 per 10,000 person-years) in the usual care group (mortality RR, 1.18; 95% CI, 0.82-1.71). Of 3285 women with false-positive results, 1080 underwent surgical follow-up; of whom, 163 women experienced at least 1 serious complication (15%). There were 2924 deaths due to other causes (excluding ovarian, colorectal, and lung cancer) (76.6 per 10,000 person-years) in the intervention group and 2914 deaths (76.2 per 10,000 person-years) in the usual care group (RR, 1.01; 95% CI, 0.96-1.06). CONCLUSIONS Among women in the general US population, simultaneous screening with CA-125 and transvaginal ultrasound compared with usual care did not reduce ovarian cancer mortality. Diagnostic evaluation following a false-positive screening test result was associated with complications. Trial Registration clinicaltrials.gov Identifier: NCT00002540.

Results From Four Rounds of Ovarian Cancer Screening in a Randomized Trial

OBJECTIVE: To test whether annual screening with transvaginal ultrasonography and CA 125 reduces ovarian cancer mortality. METHODS: Data from the first four annual screens, denoted T0–T3, are reported. A CA 125 value at or above 35 units/mL or an abnormality on transvaginal ultrasonography was considered a positive screen. Diagnostic follow-up of positive screens was performed at the discretion of participants’ physicians. Diagnostic procedures and cancers were tracked and verified through medical records. RESULTS: Among 34,261 screening arm women without prior oophorectomy, compliance with screening ranged from 83.1% (T0) to 77.6% (T3). Screen positivity rates declined slightly with transvaginal ultrasonography, from 4.6 at T0 to 2.9–3.4 at T1–T3; CA 125 positivity rates (range 1.4–1.8%) showed no time trend. Eighty-nine invasive ovarian or peritoneal cancers were diagnosed; 60 were screen detected. The positive predictive value (PPV) and cancer yield per 10,000 women screened on the combination of tests were similar across screening rounds (range 1.0–1.3% for PPV and 4.7–6.2 for yield); however, the biopsy (surgery) rate among screen positives decreased from 34% at T0 to 15–20% at T1–T3. The overall ratio of surgeries to screen-detected cancers was 19.5:1. Seventy-two percent of screen-detected cases were late stage (III/IV). CONCLUSION: Through four screening rounds, the ratio of surgeries to screen-detected cancers was high, and most cases were late stage. However, the effect of screening on mortality is as yet unknown. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00002540 LEVEL OF EVIDENCE: II

Surgical treatment of women found to have invasive cervix cancer at the time of total hysterectomy

&NA; Twenty‐three patients were referred after the unexpected finding of invasive cervix cancer at the time of total hysterectomy. Each was deemed a candidate for additional therapy and was treated surgically with a radical reoperation consisting of a lymphadenectomy, radical parametrectomy, and upper vaginectomy. When compared with patients undergoing radical hysterectomy at this institution, this reoperation was not technically more difficult as judged by the objective measures of operative time and blood loss. The risk of perioperative morbidity was not greater than radical hysterectomy. The surgical findings obviated the need for additional radiation therapy in more than 73% of patients. While therapy for all patients must be individualized, a radical reoperation should be considered a safe and efficacious alternative to pelvic radiation for patients who are deemed to require additional therapy in this clinical situation. (Obstet Gynecol 68:353, 1986)

Gastrointestinal complications associated with pelvic exenteration

Between October, 1969, and August, 1981, 125 pelvic exenterations were performed by gynecologic oncologists at the University of Alabama in Birmingham. One hundred twenty patients underwent an exenterative procedure that required urinary diversion and a gastrointestinal anastomosis. Gastrointestinal complications accounted for 60% of all nonmalignant indications for reoperation after exenteration. The common factor in the majority of gastrointestinal complications was the presence of an anastomosis in previously irradiated small bowel. Other preoperative factors, such as significant medical disease, previous laparotomy, or malnutrition, had little apparent effect on the rate of gastrointestinal complications. Avoidance of a small bowel anastomosis by means of a colon conduit, use of an omental pedicle to bring new blood supply into the pelvis, and hyperalimentation have reduced the risk of small bowel obstruction and fistula to 2.2%, while alteration in surgical technique has decreased the rectovaginal fistula rate to 5.3%.

Urinary diversion in patients undergoing pelvic exenteration

Between October, 1969, and April, 1981, gynecologic oncologists at the University of Alabama Medical Center in Birmingham have performed 119 pelvic exenterations. One hundred fifteen of these patients had a concurrent supravesical urinary diversion. Fifty-six patients (48.7%) had an anterior exenteration and 59 patients (51.3%) had a total exenteration. An ileal segment was used as a conduit in 97 patients while the segment of transverse colon was used in 16 patients. Two patients had sigmoid conduits. Eighty-five patients (73.9%) had the intestinal anastomosis and conduit constructed with gastrointestinal staplers. Stapler use shortened the mean operating time for the exenterative procedure by approximately 30%. No increase in postoperative gastrointestinal complications was noted. Urinary diversion preformed as part of a pelvic exenteration has been associated with short- and long-term complications. The use of ureteral stents and the gastrointestinal staplers shortens the procedure without predisposing the patient to major urologic complications. The use of a segment of unirradiated bowel (transverse colon) in conjunction with these techniques constitutes the preferred method of supravesical urinary diversion in patients undergoing a pelvic exenteration.

Mitochondrial DNA sequence variants in epithelial ovarian tumor subtypes and stages

Background A majority of primary ovarian neoplasms arise from cell surface epithelium of the ovaries. Although old age and a positive family history are associated risk factors, the etiology of the epithelial ovarian tumors is not completely understood. Additionally, knowledge of factors involved in the histogenesis of the various subtypes of this tumor as well as those factors that promote progression to advanced stages of ovarian malignancy are largely unknown. Current evidence suggests that mitochondrial alterations involved in cellular signaling pathways may be associated with tumorigenesis. Methods In this study, we determined the presence of polymorphisms and other sequence variants of mitochondrial DNA (mtDNA) in 102 epithelial ovarian tumors including 10 matched normal tissues that paired with some of the tumors. High-resolution restriction endonucleases and PCR-based sequencing were used to assess the mtDNA variants spanning 3.3 kb fragment that comprised the D-Loop and 12S rRNA-tRNAphe, tRNAval, tRNAser, tRNAasp, tRNAlys, ATPase 6, ATPase 8, cytochrome oxidase I and II genes. Results Three hundred and fifty-two (352) mtDNA sequence variants were identified, of which 238 of 352 (68%) have not been previously reported. There were relatively high frequencies of three mutations in the 12S rRNA gene at np 772, 773, and 780 in stage IIIC endometrioid tumors, two of which are novel (773delT and 780delC), and occurred with a frequency of 100% (7/7). Furthermore, two mutations were observed in serous tumors only at np 1657 in stage IV (10/10), and at np 8221delA in benign cystadenomas (3/3) and borderline tumors (4/4). A high frequency, 81% (13/16) of TC insertion at np 310 was found only in early stages of serous subtype (benign cystadenomas, 3/3; borderline tumors, 4/4; stage I tumors, 2/5 and matched normal tissues 4/4). Conclusion Our findings indicate that certain mtDNA mutations can reliably distinguish the different histologic subtypes of epithelial ovarian tumors. In addition, these data raise the possibility that certain mtDNA mutations may be useful biomarkers for predicting tumor aggressiveness and may play a potential role in tumorigenesis.

The effects of the PDQ patient information file (PIF) on patients' knowledge, enrollment in clinical trials, and satisfaction.

BACKGROUND This study examined the outcomes of providing a copy of the PDQ Patient Information File (PIF) to cancer patients. METHODS Patients with cervical, endometrial, and ovarian cancers were randomized to two groups: 1) verbal communication only and 2) verbal communication plus PIF. Cancer knowledge and satisfaction with the PIF and the information received were assessed with telephone interviews. Clinical trial registries were reviewed to determine enrollment in clinical trials. RESULTS The overall reaction to the PIF was good or excellent for 92% of the patients surveyed, but there was no significant difference between the two groups in their cancer knowledge, enrollment in clinical trials, or satisfaction with the information they received from their physicians. The majority of patients from both groups lacked basic knowledge about their disease, did not use any source of information other than their physicians and/or nurses, and were satisfied with the information they received. CONCLUSIONS Patients appreciate receiving written cancer information, although it may not increase their cancer knowledge.

Blood-based screening and light based imaging for the early detection and monitoring of ovarian cancer xenografts.

We report a novel technology for in vivo early detection, identification, and monitoring of ovarian cancer in live mice leading to better treatment outcome. A genetic dualistic reporter system that uses an adenoviral (Ad) vector to transfer the genetic reporters to the ovarian cancer is described. Infection of the cancer cells leads to expression of one reporter that is detected in blood, namely, secreted human placental alkaline phosphatase (SEAP). A second reporter, namely, enhanced green fluorescent protein (GFP) is also delivered by the Ad, leading to expression at the site of ovarian cancer. The SEAP gene under control of the cytomegalovirus (CMV) promoter element is linked to the GFP gene with an IRES element. A diagnostic adenoviral vector (Ad) encoding the SEAP and GFP (Ad5-SEAP-GFP) is produced. Efficacy of newly developed diagnostic vector is tested in cell culture and animal models. SKOV3ip.1 cells are infected with Ad5-SEAP-GFP. Over time the cells are monitored for fluorescence and SEAP is also measured in the growth media supernatant. For animal experiments, SKOV3ip.1 cells are implanted first in nude mice either subcutaneously (SC) or intraperitoneally (IP) separately. After 4–7 days, the Ad5-SEAP-GFP is administered. Control mice do not receive any Ad vector. All mice are imaged with a fluorescent stereomicroscope after 24 h, and blood is collected for SEAP analyses. Increasing green fluorescence is detected in all SKOV3ip.1 cells infected with Ad5-SEAP-GFP, while SEAP levels in growth media increase over monitoring period. Expression of GFP in both SC and IP tumors is detected by 24 h in the live mice. At this time, the SEAP blood levels are more than 2–3 fold greater than blood levels of control group. GFP fluorescence and SEAP levels continue to increase in all mice that are injected with Ad5-SEAP-GFP until termination. Control mice (both SC and IP) do not express GFP or SEAP throughout the experiment. GFP contrast is necessary to differentiate between micro-sized early stage non-palpable ovarian tumor nodules and surrounding normal tissue. While the studies are conducted in mice, it is envisioned that the dual-based approach will eventually be translated into human applications for routine diagnosis and monitoring of ovarian cancer when an ovarian cancer specific promoter will be available. Due to the thickness of the abdominal wall in human laparoscopy or laparotomy will be necessary. This system will provide gynecologic oncologists with a more effective tool for treating patients. The blood-based screening assay provides a quick test to determine the presence of the ovarian cancer at its earliest stage. The location of the ovarian cancer is afforded by the light-based imaging component, which represents a new and improving technology with tremendous advantages of sensitivity and spatial resolution to localize micro-sized tumor nodules. The novelty of the dualistic system is the linkage of blood-based reporter screening as a selection criteria for subsequent light-based imaging procedures. This combination will lead to an accurate and widely applicable method for the early detection and monitoring of ovarian cancer, especially in high-risk women.

Hemodynamic parameters following pelvic exenteration

Hemodynamic parameters were prospectively studied in 31 patients who underwent pelvic exenteration. With the use of a thermistor-tipped pulmonary artery catheter, hemodynamic parameters were calculated during the intraoperative and acute (less than 48 hours) postoperative interval. The mean operative time was 5.5 +/- 0.8 hours, and volume replacement (mean, 21.6 ml/kg/hr) consisted of crystalloid, colloid, and blood. Postoperative urine production (mean, 1.9 ml/kg/hr) was maintained with crystalloid (mean, 2.5 ml/kg/hr), colloid (0.2 ml/kg/hr), and blood (0.4 ml/kg/hr). Despite individual variations, the important parameters of cardiovascular function were maintained in the physiologic range. No patient developed cardiovascular or respiratory failure. We believe that the lack of perioperative morbidity and mortality was related, in substantial part, to this type of cardiovascular monitoring, which allows for the prompt diagnosis of potential problems and enables the physician to make appropriate interventions to correct these problems.

Treatment of cervical dysplasia with large loop excision of the transformation zone: Is endocervical curettage necessary?

Endocervical curettage (ECC) is done during most colposcopic examinations. To evaluate the need for routine ECC, we reviewed the records of all new patients seen in the colposcopy clinic at our institution from July 15, 1992, to April 15, 1993. During the study period, ECC was done in 341 patients with an adequate colposcopy. Only one case of mild dysplasia was discovered after ECC in the 123 patients referred for evaluation of cervical intraepithelial neoplasia (CIN) I or atypia seen on Pap smear. ECC specimens were positive for dysplastic cells in only 3 of 203 patients (1.4%) in whom biopsy revealed CIN I or atypia, and Pap smears for all 3 patients were suggestive of more severe lesions. Routine ECC during the initial colposcopic examination adds expense and may cause significant patient discomfort. ECC can be safely omitted in patients with CIN I on referral Pap smear and before large loop excision of the transformation zone for treatment of more severe lesions.