Catherine Dang

Breast cancer following ovarian cancer in BRCA mutation carriers.

IMPORTANCE BRCA mutation carriers are at increased risk of developing breast cancer. However, the incidence of breast cancer after a diagnosis of epithelial ovarian cancer (EOC), one of the tubal/peritoneal cancers collectively referred to as pelvic serous carcinomas, is not well known. Optimal breast cancer surveillance and detection for these patients have also not been well characterized. OBJECTIVES To determine the incidence of breast cancer after a diagnosis of EOC and to evaluate the need for breast cancer surveillance for these patients. DESIGN, SETTING, AND PARTICIPANTS A retrospective database review of 364 patients who underwent BRCA mutation testing for EOC (stages I-IV) between 1998 and 2012 at an academic medical center with gynecologic and breast cancer centers. MAIN OUTCOMES AND MEASURES Incidence of breast cancer and methods of surveillance. RESULTS Of 364 patients, 135 (37.1%) were found to carry a germline BRCA1 or BRCA2 mutation. The mean age of patients at diagnosis of EOC was 49.5 years (range, 28-89 years). Of the 135 patients, 12 (8.9%) developed breast cancer. The median time from diagnosis of EOC to diagnosis of breast cancer was 50.5 months. Annual mammography was performed for 80 patients (59.3%), with annual magnetic resonance imaging of the breasts performed for 60 patients (44.4%). Thirteen patients (9.6%) underwent a bilateral prophylactic mastectomy at a median of 23 months following EOC diagnosis. Breast cancer was most commonly diagnosed by mammography for 7 of the 12 patients (58.3%), 3 (25.0%) of whom had a palpable mass and 2 (16.7%) of whom had incidental breast cancer detected during a prophylactic mastectomy. Seven patients with breast cancer (58.3%) underwent a bilateral mastectomy. All patients had early-stage breast cancer (stages 0-II). Four patients (33.3%) received adjuvant chemotherapy. At a median follow-up of 6.3 years, 4 of the 12 patients (33.3%) died of recurrent EOC after a diagnosis of breast cancer. The overall 10-year survival rate for the entire cohort of 135 patients was 17.0%. CONCLUSIONS AND RELEVANCE The risk of metachronous breast cancer is low in patients with known BRCA mutations and EOC. A majority of these cases of breast cancer at an early stage are detected by use of mammography. Despite the small number of patients in our study, these results suggest that optimal breast cancer surveillance for patients with BRCA-associated EOC needs to be reevaluated given the low incidence of breast cancer among these high-risk patients. Confirmation of our findings from larger studies seems to be indicated.

A 2-minute pre-extubation protocol for ventilated intensive care unit patients

BACKGROUND Clinicians often are challenged with safely predicting the optimal time of extubation for ventilated patients. Commonly used weaning parameters have poor positive predictive value for successful extubation. METHODS A total of 213 intubated patients in our 20-bed surgical intensive care unit were enrolled in a trial to test a prospective, observational, 2-minute extubation protocol (TMEP). Daily measurements were obtained on all intubated patients who met criteria, which included adequate oxygenation, systolic blood pressure, heart rate, hemoglobin, Glasgow Coma Score greater than 10t, absence of significant metabolic/respiratory acidosis, and absence of therapeutic or neurologic paralysis. During TMEP, endotracheally intubated patients were physically disconnected from the ventilator for a 2-minute period of observation while spontaneously breathing room air. Patients were extubated if they tolerated the trial without clinically significant desaturation or alteration of vital signs or mental status. RESULTS The TMEP reliably predicted successful extubations in 203 of 213 patients (95.3%). Patients who required reintubation had a longer intensive care unit stay and a longer hospital stay. CONCLUSIONS TMEP is a simple and reliable method of predicting successful extubation.

A novel clinical trial recruitment strategy for women's cancer

OBJECTIVE To address a deficiency in clinical trial and research enrollment in gynecologic cancer studies, we launched a paper based patient research registry. To improve registry enrollment, we transitioned to an online registry and trial matching mechanism to aid women in accessing open studies. METHODS Utilizing a validated verification platform, we designed a web-based registry and trial matching mechanism for women over age 18. Participants completed a questionnaire to provide information for trial matching. A focus group of registry participants was held 9 months after the start of the study to evaluate barriers to participation. RESULTS A total of 322 women were enrolled in the online registry over a 14 month period which was a 4.3 fold increase over the paper-based registry (p<0.0001). Two hundred and sixty three (82%) women were matched to at least one study. Fifteen percent (39/263) of those eligible for studies went on to enroll. The online enrollment rate to studies was not different from that observed in the paper-based registry (26/172, p=0.934), however, the web-based registry linked participants to subsequent studies 27% more rapidly (68 (+/-98) days vs. 93 (+/-81) days for the paper-based registry, p=0.017). Focus group participants identified areas for improvement. CONCLUSION Web-based patient driven registry provides dramatic improvement in the number of participants enrolled and the time to trial linkage compared to a paper based registry at a single institution. Further studies of barriers to research participation are necessary to improve on this model.

Diagnostic Management of Fibroepithelial Lesions: When Is Excision Indicated?

Fibroepithelial lesions represent a spectrum of breast lesions characterized by biphasic proliferation of the epithelial and stromal components of normal breast tissue. Their behavior may be benign (fibroadenomas and pseudoangiomatous stromal hyperplasia (PASH)) or malignant (some phyllodes tumors). The various types of fibroepithelial lesions share many characteristics on clinical exam and imaging, though subtle differences may guide clinical diagnosis. Therefore, pathologic evaluation by biopsy frequently is required to achieve a definitive diagnosis and direct management. Upon diagnosis, benign lesions such as fibroadenomas and PASH can be closely monitored, with surgical excision reserved for suspicious features, morphologic changes, ongoing growth, or other symptomatologies. Conversely, phyllodes tumors require wide local excision without need for axillary staging.

Characterization of primary human mammary epithelial cells isolated and propagated by conditional reprogrammed cell culture

Purpose Conditional reprogramming methods allow for the inexhaustible in vitro proliferation of primary epithelial cells from human tissue specimens. This methodology has the potential to enhance the utility of primary cell culture as a model for mammary gland research. However, few studies have systematically characterized this method in generating in vitro normal human mammary epithelial cell models. Results We show that cells derived from fresh normal breast tissues can be propagated and exhibit heterogeneous morphologic features. The cultures are composed of CK18, desmoglein 3, and CK19-positive luminal cells and vimentin, p63, and CK14-positive myoepithelial cells, suggesting the maintenance of in vivo heterogeneity. In addition, the cultures contain subpopulations with different CD49f and EpCAM expression profiles. When grown in 3D conditions, cells self-organize into distinct structures that express either luminal or basal cell markers. Among these structures, CK8-positive cells enclosing a lumen are capable of differentiation into milk-producing cells in the presence of lactogenic stimulus. Furthermore, our short-term cultures retain the expression of ERα, as well as its ability to respond to estrogen stimulation. Materials and Methods We have investigated conditionally reprogrammed normal epithelial cells in terms of cell type heterogeneity, cellular marker expression, and structural arrangement in two-dimensional (2D) and three-dimensional (3D) systems. Conclusions The conditional reprogramming methodology allows generation of a heterogeneous culture from normal human mammary tissue in vitro. We believe that this cell culture model will provide a valuable tool to study mammary cell function and malignant transformation.

Surgical Management of the Axilla

In patients with breast cancer, the pathologic status of the axillary lymph nodes remains one of the most important factors predictive of long-term survival. The management of the axilla has changed dramatically since the results of several large randomized trials have shown that sentinel lymph node biopsy and selective use of axillary nodal dissection is preferential to routine full axillary dissection. The concept of the sentinel lymph node biopsy for breast cancer was first introduced in 1991. Various identification techniques, including blue dye, radiocolloid, or a combination of both, have been successful in identifying sentinel nodes. The technique has replaced full axillary nodal dissection as a highly accurate and less morbid axillary staging procedure in patients with clinically node-negative early-stage breast cancer. Surgeons can now choose amongst various options for managing the axilla, including sentinel node biopsy, full axillary dissection, and axillary irradiation. The management of the axilla in the elderly, during pregnancy, in the setting of DCIS, prior axillary surgery, prophylactic mastectomy, inflammatory breast cancer, or after neoadjuvant chemotherapy require special consideration. With the widespread use of sentinel node biopsy, more intensive examination of the sentinel node has led to the detection of micrometastases and isolated tumor cells in the axilla. Recent large randomized trials have helped determine the management of these findings in patients. As newer data becomes available, axillary management will continue to evolve.

Individualizing Axillary Management in Breast Cancer Treatment

Management of the axilla in patients with breast cancer has evolved significantly in the last century. The status of the axillary lymph nodes continues to provide important prognostic information. However, in contrast to the beliefs of Halsted, we now understand that surgical clearance of the axilla is not critical to long-term survival. Indeed, tumor biology and occult systemic metastases determine long-term survival after breast cancer treatment. Randomized controlled trials have demonstrated the safety and efficacy of sentinel lymph node biopsy in patients with early breast cancer and without clinical evidence of axillary involvement. Management of the axilla should be tailored to the individual patient’s clinical stage, patient and tumor characteristics, and treatment preferences. Special consideration should be given to the following situations: elderly patients, pregnancy, treatment of DCIS, prior axillary surgery, prophylactic mastectomy, inflammatory breast cancer, and neoadjuvant chemotherapy. Management of the axilla will continue to change as additional evidence from randomized controlled trials becomes available.