Faculty Bibliography

Immunohistochemistry (IHC) using endothelial markers may facilitate the detection of lymphovascular invasion (LVI) in primary melanoma; however, the clinical implications of enhanced detection are unknown. We evaluated whether the use of lymphatic endothelial marker D2-40 and panvascular marker CD34 increases LVI positivity relative to routine histology alone and then evaluated the prognostic relevance of LVI detected using these markers in terms of disease-free (DFS) and overall survival (OS). A total of 246 primary melanomas were assessed for LVI using D2-40, CD34, and routine histology. Associations between LVI positivity and clinicopathologic variables, DFS, and OS were compared using univariate and multivariate analyses. The use of endothelial markers increased the rate of LVI positivity (18% using D2-40 and/or CD34 vs. 3% by routine histology, P<0.0001). On univariate analysis, IHC-detected LVI was significantly associated with more adverse clinicopathologic variables (thickness, ulceration, mitoses, and nodular subtype) compared with LVI detected by routine histology (thickness and ulceration only). In a multivariate model controlling for stage, LVI detected using IHC markers remained a significant marker of both reduced DFS [hazard ratio (HR), 2.01; 95% confidence interval (CI): 1.27-3.18; P=0.003] and OS (HR, 2.08; 95% CI: 1.25-3.46; P=0.005). Results show that D2-40 and CD34 increase the detection of LVI in primary melanoma and that cases missed by routine histology have prognostic relevance

In this study, we investigated the mechanism(s) of altered expression of protooncogene SKP2 in metastatic melanoma and its clinical relevance in patients with metastatic melanoma. The genomic status of SKP2 was assessed in cell lines by sequencing, single nucleotide polymorphism array, and genomic PCR. Copy number status was then evaluated for concordance with SKP2 mRNA and protein expression. SKP2 protein was further evaluated by immunohistochemistry in 93 human metastatic tissues. No mutations were identified in SKP2. Increased copy number at the SKP2 locus was observed in 6/14 (43%) metastatic cell lines and in 9/22 (41%) human metastatic tissues which was associated with overexpression of SKP2 protein. Overexpression of SKP2 protein in human tissues was associated with worse survival in a multivariate model controlling for the site of metastasis. Copy number gain is a major contributing mechanism of SKP2 overexpression in metastatic melanoma. Results may have implications for the development of therapeutics that target SKP2

Several reports have demonstrated a role for aberrant NOTCH signaling in melanoma genesis and progression, prompting us to explore if targeting this pathway is a valid therapeutic approach against melanoma. We targeted NOTCH signaling using RO4929097, a novel inhibitor of gamma secretase, which is a key component of the enzymatic complex that cleaves and activates NOTCH. The effects of RO4929097 on the oncogenic and stem cell properties of a panel of melanoma cell lines were tested both in vitro and in vivo, using xenograft models. In human primary melanoma cell lines, RO4929097 decreased the levels of NOTCH transcriptional target HES1. This was accompanied by reduced proliferation and impaired ability to form colonies in soft agar and to organize in tridimensional spheres. Moreover, RO4929097 affected the growth of human primary melanoma xenograft in NOD/SCID/IL2gammaR-/- mice and inhibited subsequent tumor formation in a serial xenotransplantation model, suggesting that inhibition of NOTCH signaling suppresses the tumor initiating potential of melanoma cells. In addition, RO4929097 decreased tumor volume and blocked the invasive growth pattern of metastatic melanoma cell lines in vivo. Finally, increased gene expression of NOTCH signaling components correlated with shorter post recurrence survival in metastatic melanoma cases. Our data support NOTCH inhibition as a promising therapeutic strategy against melanoma

PURPOSE: To identify a melanoma microRNA (miRNA) expression signature that is predictive of outcome and then evaluate its potential to improve risk stratification when added to the standard-of-care staging criteria. EXPERIMENTAL DESIGN: Total RNA was extracted from 59 formalin-fixed paraffin-embedded melanoma metastases and hybridized to miRNA arrays containing 911 probes. We then correlated miRNA expression with post-recurrence survival and other clinicopathologic criteria. RESULTS: We identified a signature of 18 miRNAs whose overexpression was significantly correlated with longer survival, defined as more than 18 months post-recurrence survival. Subsequent cross-validation showed that a small subset of these miRNAs can predict post-recurrence survival in metastatic melanoma with an estimated accuracy of 80.2% (95% confidence interval, 79.8-80.6%). In contrast to standard-of-care staging criteria, a six-miRNA signature significantly stratified stage III patients into 'better' and 'worse' prognostic categories, and a multivariate Cox regression analysis revealed the signature to be an independent predictor of survival. Furthermore, we showed that most miRNAs from the signature also showed differential expression between patients with better and worse prognoses in the corresponding paired primary melanoma. CONCLUSIONS: MiRNA signatures have potential as clinically relevant biomarkers of prognosis in metastatic melanoma. Our data suggest that molecularly based models of risk assessment can improve the standard staging criteria and support the incorporation of miRNAs into such models. Clin Cancer Res; 16(5); 1577-86

Open thoracotomy procedures serve as the mainstay for surgical resection of pulmonary aspergilloma. These procedures are considered among the most challenging for thoracic surgeons, and postoperative morbidity and mortality rates are high. Here, we present patient who underwent video-assisted thoracoscopic lobectomy for aspergilloma. Based on the success of the operation, we suggest that video-assisted thoracoscopic surgical resection be considered as an option for pulmonary aspergilloma