Here, we determined the possible association of stromal caveolin-1 (Cav-1) levels with DCIS recurrence and/or progression to invasive breast cancer. An initial cohort of 78 DCIS patients with follow-up data was examined. As ER-positivity was associated with recurrence, we focused our analysis on this subset of 56 patients. In this group, we observed that DCIS progressed to invasive breast cancer in ~14% of the patient population (8/56), in accordance with an expected progression rate of 12-15%. Nearly ninety percent of DCIS patients (7/8) that underwent recurrence to invasive breast cancer had reduced or absent levels of stromal Cav-1. Remarkably, an absence of stromal Cav-1 (score = 0) was specifically associated with early disease progression to invasive breast cancer, with reduced time to recurrence and higher recurrence rate. All DCIS patients with an absence of stromal Cav-1 underwent some form of recurrence (5/5) and the majority (4/5) underwent progression to invasive breast cancer. This represents an overall cumulative incidence rate of 100% for recurrence and 80% for progression. An absence of stromal Cav-1 in DCIS lesions was also specifically associated with the presence of inflammatory cells. Conversely, ninety-seven percent of ER(+) DCIS patients (35/36) with high levels of stromal Cav-1 (score = 2) did not show any invasive recurrence over the duration of follow-up (4-208 mo), and 89% of such patients are estimated to remain free of invasive recurrence, even after 15 y. Thus, determination of stromal Cav-1 levels may be a useful new biomarker for guiding the treatment of ER(+) DCIS patients.

LOXL2 catalyzes the oxidative deamination of ε-amines of lysine and hydroxylysine residues within collagen and elastin, generating reactive aldehydes (allysine). Condensation with other allysines or lysines drives the formation of inter- and intramolecular cross-linkages, a process critical for the remodeling of the ECM. Dysregulation of this process can lead to fibrosis, and LOXL2 is known to be upregulated in fibrotic tissue. Small-molecules that directly inhibit LOXL2 catalytic activity represent a useful option for the treatment of fibrosis. Herein, we describe optimization of an initial hit 2, resulting in identification of racemic-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone 28, a potent irreversible inhibitor of LOXL2 that is highly selective over LOX and other amine oxidases. Oral administration of 28 significantly reduced fibrosis in a 14-day mouse lung bleomycin model. The (R,R)-enantiomer 43 (PAT-1251) was selected as the clinical compound which has progressed into healthy volunteer Phase 1 trials, making it the "first-in-class" small-molecule LOXL2 inhibitor to enter clinical development.

Pancreatic cancer is a devastating disease that afflicts over 35,000 Americans every year. Since therapeutic options are limited, understanding the molecular aspects of this disease is critical for moving towards targeted treatment of this aggressive form of cancer. Caveolin-1 (Cav-1) and fatty acid synthase (FASN) are two proteins that have been shown to be dysregulated in a number of cancers. Functionally these proteins have been shown to be involved in the process of tumorigenesis. We thus surveyed the expression of both these critical proteins in a series of pancreatic precancerous lesions (pancreatic intraepithelial neoplasia, PanIN) and pancreatic cancers. Cav-1 and FASN expression correlated predominantly with clinical characteristics, such as histologic grade and advanced tumor stage (e.g., high Cav-1 and FASN expression correlated with poor differentiation status) and a significant survival advantage was found in patients with low co-expressing FASN and Cav-1 tumors. Cav-1 and FASN expression was absent in PanIN lesions and the normal ducts and acini. Of note, Cav-1 expression was detected in the fibroblasts of the desmoplastic pancreatic cancer stroma, but not in stromal cells of the normal pancreas. Mechanistically, these data support the notion that these proteins are co-regulated either directly or indirectly by another factor. Importantly, the co-expression of these proteins significantly correlates with clinical features and survival status of pancreatic cancer patients. Thus, Cav-1 and FASN may functionally cooperate in the process of pancreatic tumorigenesis, and as such, may be good candidate prognostic markers and targets for therapeutic intervention.

Objective.To examine the possible association between augmentation mammoplasty and systemic sclerosis (SSc; scleroderma).Methods. Eight hundred thirty-seven women with a clinical diagnosis of SSc, recruited as a volunteer sample from 3 university-based, tertiary care scleroderma clinical research centers, and 2,507 race-matched local control women, recruited by the technique of random-digit-dialing and frequency-matched on age, completed a questionnaire providing data on history of augmentation mammoplasty, including possible complications of the procedure. The odds ratio (OR) and 95 percent confidence interval (95% CI) for the association of augmentation mammoplasty with SSc were estimated Presented in part at the 56th National Meeting of the American College of Rheumatology, .4tlanta, GA, October 1 9 2 , the 57th National Meeting of the American College of Rheumatology, San Antonio, TX, November 1993 by multivariate logistic regression analysis with adjustment for age, race and center, and by conditional logistic regression analysis with adjustment for age.Results. Eleven (131%) of the 837 cases reported a history of augmentation mammoplasty prior to diagnosis of SSc, compared with 31 (1.24%) of the 2,507 controls. The adjusted OR from the unmatched analysis was 1.07 (95% CI 0.53-2.13), while that from the matched analysis was 1.11 (95% CI 0.55-2.24). Conclusion.These results fail to demonstrate a significant association between augmentation mammoplasty and SSc, and are consistent with those reported from other epidemiologic studies.Thirty years ago, Miyoshi and colleagues published the first report of patients with a presumed connective tissue disease following cosmetic breast augmentation by direct injection of liquid paraffin and silicone (1). In 1984, Kumagai and colleagues described 11 patients with definite connective tissue disease and 7 with possible connective tissue disease and reviewed 28 additional cases from the Japanese literature (2). All of these patients had breast augmentation by injection of a foreign substance, most commonly paraffin or silicone, and 8 had a diagnosis of systemic sclerosis (SSc; scleroderma). The first report of patients developing definite connective tissue disease following augmentation mammoplasty with silicone gel-filled breast implants was presented by van Nunen and colleagues in 1982 (3). Numerous case reports and case series describing patients with rheumatic disease symptoms and connective tissue diseases following augmentation mammoplasty with silicone gel-filled breast implants were published during the ensuing decade (4-20). In a review of the English-language literature published from 1979 through June 1993, Sanchez-Guerrero and colleagues identified reports of 293 patients with rheumatic disease symptoms following augmentation mammoplasty with silicone gel-filled breast implants; of 57 patients with a 1126 HOCHBERG ET AL definite connective tissue disease, 38 (66.7%) had a diagnosis of SSc (21). Subsequent to that review, data on 376 patients with rheumatic sy...

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