Susan M. Love

Breast-duct endoscopy to study stages of cancerous breast disease

BACKGROUND In breast-cancer research, we lack reproducible non-invasive access to breast tissue. Breast cancer is thought to start in the lining of the milk duct or lobule. We have had no direct access to this area other than in tissue removed surgically or by fine-needle aspiration. Our objective was to explore an intraductal approach to studying breast cancer and precancerous changes by duct cannulation and endoscopy. METHODS In this pilot study, women in a university hospital were asked to participate. Nine patients with previously diagnosed ductal carcinoma-in-situ (DCIS) or invasive breast cancer who were about to undergo mastectomy under general anaesthesia agreed. After the patient was asleep but before the operation, we spent 15 minutes cannulating their ducts, obtaining washings, and attempting endoscopy. The ducts that had been cannulated were marked by instillation of dye or other materials, the nipple was sutured shut, and the mastectomy proceeded as planned. The mastectomy specimen underwent extensive histopathological examination. FINDINGS We were successful in intraductal cannulation and endoscopy in seven of the nine patients. In five of the nine, we obtained epithelial cells in the washings. In one the cells were consistent with proliferative disease, in three there was atypical epithelium, and in one there was frank DCIS. With several different contrast materials injected into separate duct orifices, DCIS was confined to a single duct system. INTERPRETATION We found that the intraductal approach is feasible for the study of the early changes of breast cancer Technical difficulties include identification of the breast duct orifices, determining the distensibility of the duct, and developing a reliable technique to obtain washings.

‘Revertant’ DCIS in human axillary breast carcinoma metastases

Recent experimental evidence obtained in Scid mice has suggested that the metastatic process is in large part epigenetically regulated and undergoes partial reversion once the metastatic process is completed: the metastatic colonies become more engaged in the process of growing in situ than actively metastasizing. Based on this experimental evidence, examples were sought of metastatic human cancers where similar reversion to an in situ growth state was occurring. Review of 200 cases of metastatic human breast cancer revealed a 21 per cent incidence of reversion to a ductal carcinoma in situ (DCIS) growth pattern within axillary nodal metastases. The revertant DCIS areas were characterized by an intact and circumferential basement membrane, as demonstrated by extracellular laminin and type IV collagen immunoreactivity. These revertant DCIS areas could be distinguished from primary DCIS, however, by the absence of surrounding myoepithelial cells in the former, identified in the latter by their positive maspin, S‐100, and smooth muscle actin immunoreactivity. The pattern of revertant DCIS, poorly differentiated (comedo) (13 per cent), intermediate (non‐comedo) (6 per cent), or well‐differentiated (non‐comedo) (2%), exhibited complete 100 per cent concordance with the primary DCIS pattern. The concordance of histological patterns held true for even the subtypes of DCIS determined by architectural pattern, such as the micropapillary or cribriform subtypes. Nuclear size by digital image analysis and Her‐2/neu, p53, and Ki‐67 status in the revertant DCIS also exhibited complete concordance with the primary DCIS counterparts. Cases exhibiting a revertant DCIS pattern tended to be ER‐negative/EGFR‐positive and exhibited significant nodal involvement (mean number, 9; mean area, 90 per cent) compared with cases lacking a revertant pattern (mean number, 4; mean area, 15 per cent) (P<0·01) These findings suggest that reversion of the metastatic phenotype may also be occurring within autochthonous human metastasis.

The intraductal approach to the breast: raison d'être

Opportunities for the detection, prediction, and treatment of breast cancer exist at three biological levels: systemically via the blood, at the whole organ level, and within the individual ductal lobular structures of the breast. This review covers the evaluation of approaches targeted to the ductal lobular units, where breast cancer begins. Studies to date suggest the presence of 5 to 12 independent ductal lobular systems per breast, each harboring complex cellular fluids contributed by local and systemic processes. New techniques for accessing and interrogating these systems offer the potential to gauge the microenvironment of the breast and distill biological risk profiles.

Vitamin E and memantine in Alzheimer's disease: Clinical trial methods and baseline data

Alzheimers disease (AD) has been associated with both oxidative stress and excessive glutamate activity. A clinical trial was designed to compare the effectiveness of (i) alpha‐tocopherol, a vitamin E antioxidant; (ii) memantine (Namenda), an N‐methyl‐D‐aspartate antagonist; (iii) their combination; and (iv) placebo in delaying clinical progression in AD.

Status of Intraductal Therapy for Ductal Carcinoma in Situ.

The intraductal approach is particularly appealing in the setting of ductal carcinoma in situ (DCIS), a preinvasive breast neoplasm that is thought to be entirely intraductal in its extent. Based on an emerging understanding of the anatomy of the ductal system as well as novel techniques to leverage the access accorded by the intraductal approach, researchers are actively exploring how ductal lavage, ductoscopy, and intraductal infusion of therapeutic agents may enhance breast cancer treatment. Both cytologic and molecular diagnostics continue to improve, and work is ongoing to identify the most effective diagnostic biomarkers for DCIS and cancer, although optimal targeting of the diseased duct remains an important consideration. Ductoscopy holds potential in detection of occult intraductal lesions, and ductoscopically guided lumpectomy could increase the likelihood of a more comprehensive surgical excision. Exciting pilot studies are in progress to determine the safety and feasibility of intraductal chemotherapy infusion. These studies are an important starting point for future investigations of intraductal ablative therapy for DCIS, because as our knowledge and techniques evolve, it is likely that DCIS may be the target most amenable to treatment by intraductal therapy. If such studies are successful, these approaches will allow an important and meaningful transformation in treatment options for women diagnosed with DCIS.

Fiberoptic ductoscopy-guided intraductal biopsy improve the diagnosis of nipple discharge.

Abstract:  Fiberoptic ductoscopy (FDS)‐guided intraductal biopsy is a minimally invasive technique developed to obtain pathologic diagnoses for patients with spontaneous nipple discharge. We performed biopsies of 53 intraductal lesions from March 2006 to April 2007 followed by surgical microdochectomy. FDS‐guided intraductal biopsy was shown to be a minimally invasive, safe, and convenient technique with a high ability (90.6%) to get adequate samples. Twenty‐seven solitary papillomas, 12 multiple intraductal papilloma, five ductal hyperplasia, three ductal carcinoma in situ, and one invasive ductal carcinoma were diagnosed. Compared with conventional microdochectomy, FDS‐guided intraductal biopsy can significantly increase the detection rate of solitary papilloma (40.7% versus 92.6%, p < 0.05). It should be a routine procedure after intraductal lesion found by screening FDS. Since it would underestimate all multiple intraductal papilloma and some (50%) cancer, microdochectomy is inevitable if biopsies show atypical ductal hyperplasia.

Ondansetron in the treatment of cognitive decline in Alzheimer dementia.

The authors performed a multicenter, double-blind, placebo-controlled clinical trial to assess the efficacy and safety of ondansetron (20 microg/day and 100 microg/ day) in treating cognitive decline in 185 patients with Alzheimer disease. Although ondansetron was well tolerated without any serious drug-related side effects, the study failed to demonstrate any significant cognitive improvement.

The Fourth International Symposium on the Intraductal Approach to Breast Cancer, Santa Barbara, California, 10–13 March 2005

Intraductal approaches encompass procedures and technologies that are designed to access and interrogate the ductal–alveolar systems of the human breast, and include nipple aspiration, ductal lavage, random periareolar fine needle aspiration, and ductoscopy. These approaches are being used to collect and analyze fluids and cells to develop methods for breast cancer detection and risk assessment; to introduce imaging technologies to explore the mammary tree for abnormalities; to administer therapeutic and/or preventive agents directly to the breast tissue; and to explore the biology of the normal mammary gland. The latest research findings in these areas, presented at The 4th International Symposium on the Intraductal Approach to Breast Cancer in 2005, are summarized in this report.

Breast Cancer from a Public Health Perspective

Abstract:   By 2010, the majority of approximately 1.5 million annual new cases of breast cancer will be diagnosed in women in countries with limited resources. Public health approaches to medical problems emphasize the importance of practical, limited toxicity and very inexpensive interventions. While clinical trials in Western countries are testing the concept of breast cancer prevention, they are not defining useful public health approaches. Early detection of breast cancer using mammography, while effective, is a high‐technology, expensive approach. Adjuvant systemic and radiation therapies are increasingly expensive; careful consideration of efficacy and cost‐efficacy data appear warranted. Public health perspectives thus suggest that many current “standard” approaches to breast cancer in Western countries cannot help the majority of women in the world. 

Should We Schedule Breast Surgery Based on a Woman's Menstrual Cycle?

Abstract: The timing of surgery of breast cancer patients has been reported to impact recurrence and survival. It is well known that surgical manipulation of tumor induces micrometastasis. During the menstrual cycle, profound hormonal changes occur affecting the local environment of the breast and breast cancer. A significant amount of scientific research now suggests that estrogen may establish an environment more likely to produce micrometastasis, and an immune system less likely to manage micrometastasis. Progesterone may protect against the effects of estrogen, leading to improved disease‐free and overall survival during the luteal phase. The studies examining this association are conflicting, but claim a 30% advantage for those patients undergoing surgery during progesterone predominance. A solid prospective study examining this possible benefit has yet to be performed. Until then, no harm can come from scheduling patients for surgery during the early luteal phase, and these patients may actually have a significant improved survival over those whose tumors are excised during the follicular phase.