Anthony J. Guidi

Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer

Solid tumors must induce a vascular stroma to grow beyond a minimal size, and the intensity of the angiogenic response has been correlated with prognosis in breast cancer patients. Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), is a secreted protein that has been implicated in tumor-associated angiogenesis. Vascular permeability factor directly stimulates endothelial cell growth and also increases microvascular permeability, leading to the extravasation of plasma proteins, which alter the extracellular matrix in a manner that promotes angiogenesis. To determine whether VPF has a role in breast cancer, we used in situ hybridization to study VPF mRNA expression in normal breast tissue (13 specimens), comedo-type ductal carcinoma in situ (DCIS) (four specimens), infiltrating ductal carcinoma (12 specimens), infiltrating lobular carcinoma (two specimens), metastatic ductal carcinoma (three specimens) and metastatic lobular carcinoma (one specimen). Vascular permeability factor mRNA was expressed at a low level by normal duct epithelium but was expressed at high levels in tumor cells in all cases of comedo-type DCIS, infiltrating ductal carcinoma, and metastatic ductal carcinoma. In contrast, VPF mRNA was not expressed at high levels in infiltrating lobular carcinoma. We also used in situ hybridization to study the expression of two recently described endothelial cell surface VPF receptors, flt-1 and kdr. Vascular permeability factor receptor mRNA was strongly expressed in endothelial cells of small vessels adjacent to malignant tumor cells in DCIS, infiltrating ductal carcinoma, and metastatic ductal carcinoma. In contrast, no definite labeling for receptor mRNA was detected in infiltrating lobular carcinoma or nonmalignant breast tissue. The intense expression of VPF mRNA by breast carcinoma cells and of VPF receptor mRNA by endothelial cells of adjacent small blood vessels provides strong evidence linking VPF expression to the angiogenesis associated with comedo-type DCIS, infiltrating ductal, and metastatic ductal breast carcinoma.

Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in endometrial carcinoma

Solid tumors, including endometrial carcinomas, must induce a vascular stroma to grow beyond a minimal size. The mechanisms responsible for angiogenesis in endometrial carcinoma, however, are not well defined. Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), is a multifunctional cytokine that is an important regulator of tumor angiogenesis. We evaluated VPF/VEGF mRNA and protein expression, as well as VPF/VEGF receptor mRNA expression, in endometrial carcinoma.

Vascular Permeability Factor/Vascular Endothelial Growth Factor and Vascular Stroma Formation in Neoplasia: Insights from In Situ Hybridization Studies

The formation of vascular stroma plays an important role in the pathophysiology of malignancy. We describe the use of in situ hybridization in our laboratory as a tool to study the role of vascular permeability factor/vascular endothelial growth factor in the angiogenesis associated with malignancy.

Using machine learning to parse breast pathology reports

Purpose Extracting information from electronic medical record is a time-consuming and expensive process when done manually. Rule-based and machine learning techniques are two approaches to solving this problem. In this study, we trained a machine learning model on pathology reports to extract pertinent tumor characteristics, which enabled us to create a large database of attribute searchable pathology reports. This database can be used to identify cohorts of patients with characteristics of interest.Methods We collected a total of 91,505 breast pathology reports from three Partners hospitals: Massachusetts General Hospital, Brigham and Women’s Hospital, and Newton-Wellesley Hospital, covering the period from 1978 to 2016. We trained our system with annotations from two datasets, consisting of 6295 and 10,841 manually annotated reports. The system extracts 20 separate categories of information, including atypia types and various tumor characteristics such as receptors. We also report a learning curve analysis to show how much annotation our model needs to perform reasonably.Results The model accuracy was tested on 500 reports that did not overlap with the training set. The model achieved accuracy of 90% for correctly parsing all carcinoma and atypia categories for a given patient. The average accuracy for individual categories was 97%. Using this classifier, we created a database of 91,505 parsed pathology reports.ConclusionsOur learning curve analysis shows that the model can achieve reasonable results even when trained on a few annotations. We developed a user-friendly interface to the database that allows physicians to easily identify patients with target characteristics and export the matching cohort. This model has the potential to reduce the effort required for analyzing large amounts of data from medical records, and to minimize the cost and time required to glean scientific insight from these data.

Breast Cancer Risk and Follow-up Recommendations for Young Women Diagnosed with Atypical Hyperplasia and Lobular Carcinoma In Situ (LCIS).

BackgroundThe risk of breast cancer in young women diagnosed with atypical hyperplasia and (LCIS) is not well defined. The objectives were to evaluate outcomes and to help determine guidelines for follow-up in this population.MethodsA retrospective review of women under age 35 diagnosed with ADH, ALH, LCIS, and severe ADH from 1987 to 2010 was performed. Patient characteristics, pathology and follow-up were determined from chart review.ResultsWe identified 58 young women with atypical breast lesions. Median age at diagnosis was 31 years (range 19–34). 34 patients had ADH, 11 had ALH, 8 had LCIS, and 5 had severe ADH.7 (12%) patients developed breast cancer. The median follow-up was 86 months (range 1–298). Median time to cancer diagnosis was 90 months (range 37–231). 4 cancers were on the same side, 3 were contralateral. 4 were IDC, 1 was ILC, and 2 were DCIS.Cancer was detected by screening mammogram in 4 patients, 2 by clinical exam, and 1 unknown. In the entire cohort, 26 (45%) patients had screening mammograms as part of their follow up, 12 patients had only clinical follow up, and 20 had no additional follow up. 13 patients required subsequent biopsies.ConclusionYoung women with atypical breast lesions are at a markedly increased risk for developing breast cancer and should be followed closely. Based on our findings, we recommend close clinical follow-up, MRI starting at age 25 through age 29, and screening mammograms for those over 30 in this high-risk group of patients.

Lumpectomy margins and much more—reply

Dr. Edwin Fisher has provided a detailed commentary on National Surgical Adjuvant Breast Project (NSABP) protocols B-06 and B17, with particular emphasis on the role of microscopic margin evaluation. It is not feasible to address all of the important points raised in his counterpoint. However, we were pleased to see that Dr. Fisher is in agreement with us about the use of radial (or breadloafed) microscopic margin evaluation for patients being considered for treatment with conservative surgery and radiation therapy. Despite the obvious limitations of this approach, clinical outcome studies have consistently demonstrated its value. Hence, we agree that efforts to assess margin status more precisely–such as ours, using shaved margins– should not be adopted into routine clinical practice until and unless clinical outcome studies demonstrate superiority over the current method of margin evaluation. We do, however, have a somewhat different view of the importance of a local recurrence than that of Dr. Fisher. Regardless of the relationship between local recurrence and survival, a recurrence in the treated breast is psychologically devastating for patients, and this provides a strong incentive to determine reasonable methods for reducing the risk of local recurrence. In addition, we feel that the relationship between local recurrence and survival is not completely resolved. The results of five randomized clinical trials, including the NSABP B-06 trial, have unequivocally shown that radiation therapy in addition to breast-conserving surgery results in a large reduction in the rate of local recurrence. For four of these five trials, survival results were provided, and in all four of these studies there was a small survival advantage for patients who received radiation therapy, See editorial counterpoint on pages 1453–8 with crude reductions in mortality ranging from 2% to 12.5% with the and referenced original article on pages 1568– addition of irradiation. Although the survival advantage for patients 73, this issue. receiving radiation therapy was not statistically significant in any of Address for reprints: Stuart J. Schnitt, M.D., these studies, none of these trials had the statistical power to rule Department of Pathology, Beth Israel Deaconout a small but clinically important difference in survival. Given the ess Medical Center, 330 Brookline Avenue, Bosavailable information, we believe that it is sound medical practice to ton, MA 02215. attempt to identify factors associated with local recurrence so that the likelihood of this event can be reduced to the lowest possible level Received December 27, 1996; accepted January 3, 1997. for patients treated with breast-conserving therapy.

Pathologic findings in reduction mammoplasty specimens: a surrogate for the population prevalence of breast cancer and high-risk lesions

PurposeMammoplasty removes random samples of breast tissue from asymptomatic women providing a unique method for evaluating background prevalence of breast pathology in normal population. Our goal was to identify the rate of atypical breast lesions and cancers in women of various ages in the largest mammoplasty cohort reported to date.MethodsWe analyzed pathologic reports from patients undergoing bilateral mammoplasty, using natural language processing algorithm, verified by human review. Patients with a prior history of breast cancer or atypia were excluded.ResultsA total of 4775 patients were deemed eligible. Median age was 40 (range 13–86) and was higher in patients with any incidental finding compared to patients with normal reports (52 vs. 39 years, p = 0.0001). Pathological findings were detected in 7.06% (337) of procedures. Benign high-risk lesions were found in 299 patients (6.26%). Invasive carcinoma and ductal carcinoma in situ were detected in 15 (0.31%) and 23 (0.48%) patients, respectively. The rate of atypias and cancers increased with age.ConclusionThe overall rate of abnormal findings in asymptomatic patients undergoing mammoplasty was 7.06%, increasing with age. As these results are based on random sample of breast tissue, they likely underestimate the prevalence of abnormal findings in asymptomatic women.