Thus, while current efforts to target VEGF and other pro-angiogenic factors whose expression is regulated by the melanoma cell have thus far been unsuccessful, our approach focused on non-cellular epitopes as new targets for biomarkers and treatment is novel and highly selective. 0-139.8 ng/ml (mean and median of 6.2 ng/ml and 3.7 ng/ml, respectively). Thirty-eight of the 209 (18%) patients developed recurrences, and 34 of the 209 (16%) patients died during follow-up. Higher HU177 serum level was associated with an increased rate of melanoma recurrence (p = 0.04) and with increasing mortality (p = 0.01). The association with overall survival remained statistically significant after controlling for thickness MUT056399 and histologic subtype in a multivariate model (p = 0.035). == Conclusions == Increased shedding of HU177 in the serum of primary melanoma patients is associated with poor prognosis. Further studies are warranted to determine the clinical utility of HU177 in risk stratification compared to the current standard of care. == Background == Limitations of the current melanoma staging paradigm beget limitations in our ability to determine the most appropriate treatment for primary melanoma patients with regard to maximizing therapeutic benefit and minimizing morbidity. Well-characterized clinical prognostic markers such as tumor thickness and ulceration only partly explain the variability in the clinical course of melanoma. Patients with thin melanoma <1 mm, characterized as having a favorable prognosis, have reported rates of metastasis ranging from 3-22% [1]. Conversely, patients with thicker lesions not uncommonly have extended periods of disease-free survival. Although sentinel lymph node biopsy has improved our ability to predict prognosis for patients Rabbit Polyclonal to SLC27A5 with intermediate thickness lesions, further markers are needed to determine which of these patients are most likely to develop metastases and thus are most likely to benefit from post-surgical adjuvant therapy. There is a need for development of new biomarkers that reflect the underlying melanoma biology. Mitotic rate has recently become part of the American Joint Committee on Cancer staging criteria based on studies demonstrating that its addition to a morphologically-based classification system improved risk stratification for patients with thin primary melanoma [2]. Advances in the understanding of melanoma biology have resulted in the discovery of other promising protein biomarkers that are predictive of melanoma-specific mortality and reflective of varying aspects of tumorigenesis including resistance to antigrowth signals (p16/INK4a), limitless replicative potential (Ki-67), tissue invasion (matrix metalloproteinase-2), and sustained angiogenesis (iNOS) [3]. None of these biomarkers, however, have been adopted into clinical practice which may be attributable to several reasons including lack of multivariate analyses with subsequent overestimation of prognostic utility [3]. Recent efforts in genomics research have focused on the development of tumor specific and patient specific gene expression signatures that are predictive of clinical outcome or response to treatment. Even in large scale studies, however, the prognostic accuracy of gene classifiers has not yet proven to be superior to thickness and ulceration in predicting metastasis [4]. Furthermore, gene expression profiling typically MUT056399 requires fresh frozen tissue from the surgical resection, and studies of the effect of sampling melanocytic lesions for research have raised concerns about the possibility of compromising the MUT056399 accuracy of the pathologic diagnosis and subsequent staging [5]. At present, the emerging technology is labor-intensive and likely prohibitively expensive for integration into the common clinical practice for melanoma patients. Immunohistochemistry-based biomarkers are also limited by experimental variability, lack of reproducibility, and inter-observer variation in the classification of staining intensities [6]. By contrast, serum-based biomarkers are non-invasive, relatively low cost, and can easily be incorporated into clinical practice as a way to monitor disease progression over time. It is known that cellular interactions with the extracellular matrix (ECM) can regulate a wide range of biologic functions including adhesion, migration, proliferation, and angiogenesis [7]. Previous studies have identified cryptic regulatory epitopes that, under normal physiologic conditions, are hidden within the 3-dimensional structure of the ECM protein collagen [8,9]. Following proteolytic redesigning of the collagenous ECM during tumor growth and invasion, however, these unique cryptic epitopes are revealed and shed into the serum. Cryptic collagen epitope HU177 has been specifically associated with improved angiogenesis and tumor growthin vivo[9]. We have successfully developed an ELISA assay to detect and quantify levels of cryptic epitope HU177 in the serum of melanoma individuals and shown that the level of HU177 correlated with tumor thickness and with the nodular histologic subtype [10]. In the current study, we wanted to determine the.