John R. Davis

CHARACTERIZATION OF A NEW HUMAN ENDOMETRIAL CARCINOMA (RL95-2) ESTABLISHED IN TISSUE CULTURE

SummaryA new human endometrial cell line, RL95-2, derived from a Grade 2 moderately differentiated adenosquamous carcinoma of the endometrium has been passaged successfully in cell culture for more than 2 yr. The cells are characteristically epithelioid with well-defined junctional complexes, tonofilaments, filopodialike extensions, and surface microvilli. Nuclei are large, irregular, and invaginated frequently with multiple, prominent, lamellar nucleoli. The cells have a log phase doubling time of 22 to 34 h followed by continued growth at a reduced rate with no apparent plateau phase. They exhibit a strong tendency for piling up as well as for the formation of glandlike dome structures. Karyotypically the line is trisomic 8 (47,XX,+8) and has an 8% frequency of polyploidization. Both cytoplasmic and nuclear estrogen receptors are present. Antihuman α-keratin characterizes the cell line as epithelial, nonstromal. The RL95-2 cell line may provide a useful in vitro system for the investigation of the endocrine regulation of endometrial neoplasia.

Chromosome abnormalities in ovarian adenocarcinoma: I. Nonrandom chromosome abnormalities from 244 cases.

Cytogenetics provides important insights into the molecular pathogenesis of human cancers. Although extensive data exist on recurring cytogenetic abnormalities in hematologic cancers, data on individual solid tumor types remain limited. Previous studies of ovarian carcinoma indicated the presence of multiple, complex clonal chromosome abnormalities. Cytogenetics remains one of a few techniques capable of detecting these multiple, simultaneously occurring genetic abnormalities. We describe cytogenetic abnormalities from a series of 244 primary ovarian cancer specimens referred to a single institution. A total of 201/244 cases had fully characterized clonal chromosome abnormalities, of which 134 showed clonal chromosome breakpoints. We used a novel statistical technique to detect nonrandom chromosome breakpoints at the level of chromosome regions. Nonrandom occurrence of chromosome breakpoints was detected at regions 1p1*, 1q1*, 1p2*, 1q2*, 1p3*, 1q3, 3p1*, 1q4*, 6q1*, 6p2, 6q2, 7p1*, 7q1, 7p2*, 11p1*, 11q1, 11q2*, 12p1, 12q2*, 13p1, and 19q1. Simultaneous occurrence of multiple abnormalities was common. However, 120/134 cases had breakpoints at one or more of 13 commonly involved regions (*), suggesting a hierarchy of genetic abnormalities. Among clinical and tumor variables that predict patient survival, tumor grade was significantly associated with the presence of chromosome breakpoints. In additional studies, we show that nonrandom chromosome abnormalities are associated with impaired survival in ovarian cancer and that specific, nonrandomly involved chromosome regions retain significant effects on survival when analyses are controlled for important clinical variables. Additional specific chromosome abnormalities in this series are described, including chromosome gains and losses in near‐diploid cases and homogeneously staining regions. These results suggest that recurring, nonrandom chromosome abnormalities are important in the pathogenesis and/or progression of ovarian cancers, and target areas of the genome for molecular genetic studies. Genes Chromosomes Cancer 25:290–300, 1999.

Relation of Cytogenetic Abnormalities and Clinical Outcome in Metastatic Melanoma

The value of chromosomal analysis is well established in human hematologic neoplasms. In contrast, the relation between chromosomal abnormalities and clinical outcome in solid tumors in humans has received little study. We undertook this study to determine whether chromosomal abnormalities could provide information on the survival of patients with malignant melanoma. Chromosome-banding analysis was performed on tumor-biopsy samples from 62 patients with metastatic melanoma, and recurring cytogenetic abnormalities were correlated with survival. Patients with structural abnormalities of chromosome 7 or 11 had significantly shorter survival than patients without these abnormalities. We conclude that cytogenetic analysis may provide useful prognostic information about patients with metastatic melanoma.

Cross-sectional study of patient- and physician-collected cervical cytology and human papillomavirus.

OBJECTIVE To compare the performance of patient- and physician-obtained cytology and human papillomavirus (HPV) testing for the detection of high-grade cervical intraepithelial neoplasia. METHODS A cross-sectional study was performed involving 334 women seen at three colposcopy clinics (Tucson, Arizona; Hermosillo, Mexico; and Lima, Peru). All women used a cytobrush to self-collect specimens for cervical cytology and HPV testing. Subjects subsequently underwent physician collection for cytology and HPV, followed by a complete colposcopic evaluation with directed biopsy. Cytology was processed using thin-layer technology, and HPV was determined using the polymerase chain reaction technique. Test performance characteristics were determined using the histopathologic diagnosis as the reference standard and designating high-grade cervical intraepithelial neoplasia as clinically significant disease for the purpose of the analysis. RESULTS The sensitivity of patient-collected cytology was significantly lower (55.0%) and specificity was significantly better (84.1%) than those of physician-directed sampling (85.2% and 73.4%, respectively). Patient-collected HPV had significantly lower sensitivity (49.0%) than physician sampling (82.2%), although specificity did not significantly differ. CONCLUSION Patient collection is a feasible although inferior alternative to physician-collected cervical cytology and HPV testing.

Second-look laparotomy in epithelial ovarian carcinoma. Prognostic factors associated with survival duration

This article that reports on 70 consecutive patients is one of only a few studies of advanced ovarian cancer that have attempted to define predictive factors associated with survival duration after second‐look laparotomy. As in many other investigations, several factors have been analyzed for predicting second‐look outcome. The prognostic variables analyzed in this study included age, stage, histologic grade, residual disease status after initial surgery, and type (cisplatin versus no cisplatin) and number of cycles of chemotherapy. Only stage (P = 0.002) and optimal disease (less than 2 cm residual tumor size) after initial surgery (P < 0.001) were significantly associated with the absence of disease at second‐look laparotomy, and both were significant predictors of second‐look outcome in a multivariate logistic regression model. Their impact on actuarial survival after second‐look laparotomy diminished, however. Actuarial survival after second‐look laparotomy was associated with residual tumor size at second‐look surgery (P = 0.02). According to second‐look findings, the 3‐year actuarial survival rates and standard errors were as follows: no pathologic evidence of disease, 80.7% ± 13.4% 3‐year survival; microscopic disease plus less than or equal to 2 cm residual disease, 49.1% ± 13.1% survival; and gross residual disease (i.e., greater than 2 cm maximum tumor diameter), 29.5% ± 11.4% survival. We also examined the effect of extensive tumor resection at second‐look laparotomy on survival for patients with greater than 2 cm gross residual disease. Optimum resection (less than 2 cm residual tumor mass) resulted in significantly greater survival than suboptimum resection (P < 0.001). This strongly suggests that there is a survival advantage associated with optimum resection at second‐look laparotomy.

Laparoscopic optical coherence tomography imaging of human ovarian cancer

OBJECTIVES Ovarian cancer is the fourth leading cause of cancer-related death among women in the US largely due to late detection secondary to unreliable symptomology and screening tools without adequate resolution. Optical coherence tomography (OCT) is a recently emerging imaging modality with promise in ovarian cancer diagnostics, providing non-destructive subsurface imaging at imaging depths up to 2 mm with near-histological grade resolution (10-20 microm). In this study, we developed the first ever laparoscopic OCT (LOCT) device, evaluated the safety and feasibility of LOCT, and characterized the microstructural features of human ovaries in vivo. METHODS A custom LOCT device was fabricated specifically for laparoscopic imaging of the ovaries in patients undergoing oophorectomy. OCT images were compared with histopathology to identify preliminary architectural imaging features of normal and pathologic ovarian tissue. RESULTS Thirty ovaries in 17 primarily peri- or post-menopausal women were successfully imaged with LOCT: 16 normal, 5 endometriosis, 3 serous cystadenoma, and 4 adenocarcinoma. Preliminary imaging features developed for each category reveal qualitative differences in the homogeneous character of normal post-menopausal ovary, the ability to image small subsurface inclusion cysts, and distinguishable features for endometriosis, cystadenoma, and adenocarcinoma. CONCLUSIONS We present the development and successful implementation of the first laparoscopic OCT probe. Comparison of OCT images and corresponding histopathology allowed for the description of preliminary microstructural features for normal ovary, endometriosis, and benign and malignant surface epithelial neoplasms. These results support the potential of OCT both as a diagnostic tool and an imaging modality for further evaluation of ovarian cancer pathogenesis.

Tamoxifen therapy in recurrent epithelial ovarian carcinoma

Thirty-seven patients with recurrent epithelial ovarian carcinoma were entered into a trial of tamoxifen therapy (10 mg BID) to determine the effect on long-term survival. Thirty-one patients were evaluable with follow-up ranging from 6 to 42 months since initiation of hormonal therapy. All patients were heavily pretreated with multiple chemotherapeutic regimens (median 3). There was 1 complete responder (3.2%), 2/31 (6.4%) had a partial response, 6/31 (19.3%) had stable disease, and 22/31 (71%) had progressive disease. Twenty-four patients are dead (23 from advanced carcinoma, 1 from cardiac causes); 5 patients are alive with disease; 2 patients are lost to follow-up. Median survival of nonresponders was 7 months versus 16 months for responders (CR + PR + stable disease) (P = 0.001 life table analysis). Of the 9 responders, 7 had poorly differentiated tumors (grades 3 or 4), and 2 had moderately differentiated tumors (grade 2). Eleven patients had estrogen and progesterone receptor studies (ER, PR). No correlation between response rate and receptor status was evident. We conclude that although significant disease regression is unlikely to result from tamoxifen therapy, there may be a subset of patients who can benefit from the cytostatic properties of hormonal manipulation.

Imaging of the Ovary

Epithelial ovarian cancer has the highest mortality rate among the gynecologic cancers and spreads beyond the ovary in 90% of the women diagnosed with ovarian cancer. Detection before the disease has spread beyond the ovary would significantly improve the survival from ovarian cancer, which is currently only 30% over 5 years, despite extensive efforts to improve the survival. This study describes initial investigation of the use of optical technologies to improve the outcome for this disease by detecting cancers at an earlier and more treatable stage. Women undergoing oophorectomy were recruited for this study. Ovaries were harvested for fluorescence spectroscopy, confocal microscopy, and optical coherence tomography. Fluorescence spectroscopy showed large diagnostic differences between normal and abnormal tissue at 270 and 340 nm excitation. Optical coherence tomography was able to image up to 2mm deep into the ovary with particular patterns of backscattered intensity observed in normal versus abnormal tissue. Fluorescence confocal microscopy was able to visualize sub-cellular structures of the surface epithelium and underlying cell layers. Optical imaging and/or spectroscopy has the potential to improve the diagnostic capability in the ovary, but extended systematic investigations are needed to identify the unique signatures of disease. The combination of optical technologies supported by modern molecular biology may lead to an instrument that can accurately detect early carcinogenesis.

Bilateral primary germ cell testicular tumors: report of four cases and review of the literature.

Bilateral primary germ cell tumors of the testicle are rare. The last comprehensive review of the literature (1955) revealed a 1.6% incidence. However, during the past twenty years, cases have been reported more often, raising the questions of increased frequency due to prolonged survival following surgery and/or roentgen therapy for unilateral tumors. A search of the medical journals during the past two decades fails to show any increased frequency of bilaterality (1.56%). All general combinations of cell types may occur and the tumors may appear simultaneously or sequentially. Successive seminomas are seen more often followed in frequency by concurrent seminomas. Although 50% of the second primaries were diagnosed within five years, 3% of the patients developed the second tumor after 20 years, stressing the need for extended follow‐up. Factors affecting the diagnosis, management and prognosis of bilateral testicular tumors are discussed. Four additional cases of bilateral germ cell tumors are described.

Complete resolution of Paget disease of the vulva with imiquimod cream.

Extra mammary Paget disease (EMPD) is a neoplastic disease of apocrine gland bearing skin. Surgical excision is the standard of care for EMPD; however, it is accompanied by recurrence in more than 60% of the patients. Recently, imiquimod cream has been reported to induce complete responses in primary or recurrent EMPD. We report on 2 women with vulva EMPD who achieved biopsy-confirmed resolution of their disease after topical application of imiquimod 5% cream.