Frank D. Cirisano

The Role of the HER-2/neu Oncogene in Gynecologic Cancers

Objective: The HER-2/neu proto-oncogene (also known as c-erbB2, neu, and HER2) encodes a 185-kDa transmembrane glycoprotein with intrinsic tyrosine kinase activity that resembles the receptor for epidermal growth factor. Aberrant HER-2/neu protein overexpression occurs in human gynecologic adenocarcinomas, including those of the ovary, endometrium, breast, fallopian tube, and cervix, and is secondary to gene amplification and/or overexpression of the p185HER2 protein. Methods: A Medline literature search revealed numerous studies on HER-2/neu and tumor biology, cancer prognosis, and therapeutic targeting. We present a review of the literature pertinent to gynecologic malignancies. Results: Overexpression of HER-2/neu was found to be a poor prognostic factor for survival from advanced-stage ovarian cancer, node-positive breast cancer, and endometrial cancer. Although a specific ligand has not been definitvely identified, HER-2/neu may have unusually complex activation pathways because it can from both homodimeric and heterodimeric associations with other related receptor proteins. Preliminary findings usggest that serum HER-2/neu levels may be used as a tumor marker in a subset of patients with tumors that overexpress the HER-2/neu receptor. Receptor-targeted therapeutics currently being studied include the use of receptor antibodies, liposomally delivered antisense DNA, antigen-activated cytotoxic lymphocytes, and adenovirus-mediated E1A delivery to overexpressing tumor cells. Conclusion: HER-2/neu appears to play an important role in the biologic behavior of overian, endometrial, adn breast cancers and holds potential as a target for oncogene-directed therapies.

The Clinical Use of an Esophageal Doppler Monitor for Hemodynamic Monitoring in Sepsis

Esophageal Doppler monitoring has been available for over 25 years for the evaluation of cardiac performance. Nonetheless, its clinical use has been sparse in the management of critically ill and perioperative patients due to a paucity of data documenting its e¤cacy in individual patients.We present here the successful employment of an esophageal Doppler monitor or EDM (Deltex Medical, Inc., Irving, TX) for hemodynamic monitoring in a patient with a contraindication to a pulmonary artery catheter placement. This case also illustrates which cardiac parameters can be clinically followed in the utilization of this device.

BRCA2 monoclonal antibodies react with differentiating epithelium.

The BRCA2 gene has previously been suggested to play a role in proliferation and DNA repair. Germline mutations in the BRCA2 gene predispose individuals to early onset, hereditary breast cancer. To better understand the expression pattern and function of the BRCA2 gene product, we have developed immunological reagents specific for BRCA2. These reagents recognize full-length (384 kDa) recombinant human BRCA2 proteins in transfected cell lysates as well as multiple smaller recombinant BRCA2 polypeptides. Detection of native BRCA2 protein in most tissue types, including breast epithelium, requires sensitive techniques such as immunoprecipitation-Western blot analysis. However, we have demonstrated strong reactivity of our immunological reagents with differentiating epithelium, including epidermis, thymic epithelium, and squamous cell carcinoma. These data suggest that BRCA2 may play a role in processes associated with cellular differentiation, in addition to its previously suggested roles in proliferation and DNA repair.

Genetics of Ovarian Cancer

Epithelial ovarian cancer occurs primarily in postmenopausal women, and most cases are thought to be due to acquired alterations in oncogenes and tumor suppressor genes. In contrast, approximately 5–10% of ovarian cancers arise in women who carry inherited mutations in a cancer susceptibility gene. It is thought that more than 90% of hereditary ovarian cancer is due to inherited mutations in the BRCA1 breast/ovarian cancer susceptibility gene on chromosome 17q. BRCA1 mutational analysis is being performed in several academic medical centers on a research basis and also now is commercially available. With the ability to identify mutations in BRCA1, prophylactic oophorectomy and other interventions intended to decrease ovarian cancer mortality can be offered specifically to women who carry a mutation, but the optimal strategy for the clinical management of these families has not yet been determined.

PRACTICAL MANAGEMENT OF GESTATIONAL TROPHOBLASTIC DISEASE

Abstract Gestational trophoblastic disease (GTD) represents a spectrum of tumors that arise from the fetal chorion during pregnancy, including benign partial and complete hydatidiform moles, persistent invasive or metastatic moles, placental-site trophoblastic tumors, and gestational choriocarcinomas. Gestational trophoblastic diseases all exhibit proliferation of both cytotrophoblast and syncytiotrophoblast cells, with the exception of placental-site tumor, which is derived from the intermediate trophoblast cells. Practical management of these tumors begins with preoperative evaluation and screening for metastatic disease followed by uterine evacuation or hysterectomy. Postmolar GTD includes local noninvasive proliferation of molar tissue, invasive mole, or gestational choriocarcinoma. The management of malignant GTD may be directed from three classification systems developed to predict patient prognosis and guide the decision for either single or multiagent chemotherapy. These systems assess clinical risk factors in addition to sites of metastatic disease. Treatment with aggressive multiagent chemotherapy and individualized multimodality therapy is warranted in these extremely high-risk patients. After remission, patients should be followed closely for 1 year and periodically thereafter. Pregnancy is deferred and contraception instituted for 1 year to prevent disruption of serum human chorionic gonadotropin surveillance.