A phase 1/2 clinical trial of the nitric oxide synthase inhibitor L-NMMA and taxane for treating chemoresistant triple-negative breast cancer.

The inducible nitric oxide signaling (iNOS) pathway is associated with poor prognosis in triple-negative breast cancer (TNBC). Prior studies using in vivo models showed that inhibition of the iNOS signaling pathway using the pan-NOS inhibitor NG-monomethyl-l-arginine (L-NMMA) reduced tumor growth and enhanced survival in patients with TNBC. Here, we report a first-in-class phase 1/2 trial of L-NMMA combined with taxane for treating patients with chemorefractory, locally advanced breast cancer (LABC) or metastatic TNBC. We also examined immune cell correlates of chemotherapy response. 35 patients with metastatic TNBC were recruited: 15 in the phase 1 trial and 24 in the phase 2 trial (including 4 recommended phase 2 dose patients from the phase 1 trial). The overall response rate was 45.8% (11 of 24): 81.8% (9 of 11) for patients with LABC and 15.4% (2 of 13) for patients with metastatic TNBC. Among the patients with LABC, three patients had a pathological complete response at surgery (27.3%). Grade ≥3 toxicity was noted in 21% of patients; however, no adverse events were attributed to L-NMMA. Immune cells analyzed by CyTOF indicated that chemotherapy nonresponders showed greater expression of markers associated with M2 macrophage polarization and increased concentrations of circulating IL-6 and IL-10 cytokines. In contrast, chemotherapy responders showed an increase in CD15+ neutrophils in blood, as well as a decrease in arginase (a marker of protumor N2 neutrophils) in tumor biopsies obtained at the end of treatment. L-NMMA combined with taxane warrants further investigation in larger clinical studies of patients with breast cancer.

Osseous Metaplasia in Hemangiomas of the Breast: Case Reports and Literature Review.

Unusual or prominent calcifications found on screening mammography may prompt additional radiologic and clinical work-up given the possible association with pre-malignant lesions, other high-risk lesions, or malignancies. Osseous metaplasia (OM) of the breast, also referred to as metaplastic ossification or heterotopic bone formation, is an uncommon finding that may present as radiographic calcification. There are isolated case reports of OM associated with benign or malignant tumors of the breast, as well as with a variety of non-neoplastic conditions. We report 2 cases of OM in the breast associated with a hemangioma and review the relevant literature. To the best of our knowledge, these are the first reported cases of this association in the breast.

Flat epithelial atypia in directional vacuum-assisted biopsy of breast microcalcifications: surgical excision may not be necessary.

The aim of this study was to analyze the clinicopathological features of patients with flat epithelial atypia, diagnosed in directional vacuum-assisted biopsy targeting microcalcifications, to identify upgrade rate to in situ ductal or invasive breast carcinoma, and determine factors predicting carcinoma in the subsequent excision. We retrospectively evaluated the histological, clinical, and mammographic features of 69 cases from 65 women, with directional vacuum-assisted biopsy-diagnosed flat epithelial atypia with or without atypical ductal hyperplasia or atypical lobular hyperplasia, which underwent subsequent surgical excision. The extent and percentage of microcalcifications sampled by directional vacuum-assisted biopsy were evaluated by mammography. All biopsy and surgical excision slides were reviewed. The age of the women ranged from 40 to 85 years (mean 57 years). All patients presented with mammographically detected microcalcifications only, except in one case that had associated architectural distortion. Extent of calcifications ranged from <1 cm (n = 47), 1-3 cm (n = 15) to > 3 cm (n = 6), and no measurement (n = 1). A mean of 11 cores (range 6-25) was obtained from each lesion. Post-biopsy mammogram revealed >90% removal of calcifications in 81% of cases. Pure flat epithelial atypia represented nearly two-thirds of directional vacuum-assisted biopsy specimens (n = 43, 62%), while flat epithelial atypia coexisted with atypical ductal hyperplasia (18 cases, 26%), or atypical lobular hyperplasia (8 cases, 12%). Upon excision, none of the cases were upgraded to in situ ductal or invasive breast cancer. In one case, however, an incidental, tubular carcinoma (4 mm) was found away from biopsy site. Excluding this case, the upgrade rate was 0%. Our study adds to the growing evidence that diagnosis of flat epithelial atypia on directional vacuum-assisted biopsy for microcalcifications as the only imaging finding is not associated with a significant upgrade to carcinoma on excision, and therefore, excision may not be necessary. Additionally, excision may not be necessary for flat epithelial atypia with atypical ductal hyperplasia limited to ≤2 terminal duct-lobular units, if at least 90% of calcifications have been removed on biopsy.

Performance of computer-aided diagnosis in the interpretation of lesions on breast sonography.

RATIONALE AND OBJECTIVES: To investigate the potential usefulness of computer-aided diagnosis as a tool for radiologists in the characterization and classification of mass lesions on ultrasound. MATERIALS AND METHODS: Previously, a computerized method for the automatic classification of breast lesions on ultrasound was developed. The computerized method includes automatic segmentation of the lesion from the ultrasound image background and automatic extraction of four features related to lesion shape, margin, texture, and posterior acoustic behavior. In this study, the effectiveness of the computer output as an aid to radiologists in their ability to distinguish between malignant and benign lesions, and in their patient management decisions in terms of biopsy recommendation are evaluated. Six expert mammographers and six radiologists in private practice at an institution accredited by the American Ultrasound Institute of Medicine participated in the study. Each observer first interpreted 25 training cases with feedback of biopsy results, and then interpreted 110 additional ultrasound cases without feedback. Simulating an actual clinical setting, the 110 cases were unknown to both the observers and the computer. During interpretation, observers gave their confidence that the lesion was malignant and also their patient management recommendation (biopsy or follow-up). The computer output was then displayed, and observers again gave their confidence that the lesion was malignant and theirpatient management recommendation. Statistical analyses included receiver operator characteristic analysis and Student t-test. RESULTS: For the expert mammographers and for the community radiologists, the Az (area under the receiver operator characteristic curve) increased from 0.83 to 0.87 (P = .02) and from 0.80 to 0.84 (P = .04), respectively, when the computer aid was used in the interpretation of the ultrasound images. Also, the Az values for the community radiologists with aid and for the expert mammographers without aid are similar to the Az value for the computer alone (Az = 0.83). CONCLUSION: Computer analysis of ultrasound images of breast lesions has been shown to improve the diagnostic accuracy of radiologists in the task of distinguishing between malignant and benign breast lesions and in recommending cases for biopsy.

Computerized diagnosis of breast lesions on ultrasound.

We present a computer-aided diagnosis (CAD) method for breast lesions on ultrasound that is based on the automatic segmentation of lesions and the automatic extraction of four features related to the lesion shape, margin, texture, and posterior acoustic behavior. Using a database of 400 cases (94 malignant lesions, 124 complex cysts, and 182 benign solid lesions), we investigate the marginal benefit of each feature in our CAD method and the performance of our CAD method in distinguishing malignant lesions from various classes of benign lesions. Finally, independent validation is performed on our CAD method. Eleven independent trials yielded an average Az value of 0.87 in the task of distinguishing malignant from benign lesions.

Patient satisfaction with the communication of mammographic results before and after the Mammography Quality Standards Reauthorization Act of 1998.

OBJECTIVE: The goal of this study was to evaluate the difference in patient satisfaction, timeliness of reporting, patient recollection of recommendations, and patient anxiety before and after passage of the Mammography Quality Standards Reauthorization Act of 1998, which requires written notification of all mammographic results. MATERIALS AND METHODS: We used a telephone survey with sampling that was stratified to reflect patients with normal and abnormal findings who had screening and diagnostic mammograms. Patients with visits before the mandate became effective (April 1999, n = 298) and after (January 2000, n = 316) were interviewed about the average time to receive results, satisfaction with communication about results, anxiety, and perceived follow-up recommendations. Multiple logistic regression was used to test the association of time period with patient dissatisfaction, controlling for age, anxiety level (considerable or extreme vs none or moderate), examination type (screening vs diagnostic), and examination result (normal vs abnormal findings). RESULTS: No significant difference was found between periods in anxiety about results or agreement with documented radiology recommendations, but we found a substantial increase in the number of screening patients who reported timely receipt of results. Significantly fewer patients were dissatisfied with mammographic results communication after the mandate (multivariable odds ratio = 0.46, p = 0.006). Screening examination patients and patients who reported considerable or extreme anxiety about test results were more likely to be dissatisfied in both periods. CONCLUSION: By standardizing results notification, the Mammography Quality Standards Reauthorization Act improved patient satisfaction and reporting timeliness among screening examination patients, but did little to improve anxiety or recollection of recommendations. Future quality improvement efforts should focus on improving patients' understanding of follow-up recommendations.