Nicholas Theodosakis

Tumor recurrence after complete resection for non-small cell lung cancer.

BACKGROUND Long-term survival after R0 resection for non-small cell lung cancer (NSCLC) is less than 50%. The majority of mortality after resection is related to tumor recurrence. The purpose of this study was to identify independent perioperative and pathologic variables that are associated with NSCLC recurrence after complete surgical resection. METHODS A retrospective examination was performed of a prospectively maintained database of patients who underwent resection for NSCLC from July 1999 to August 2008 at a single institution. Clinicopathologic variables were evaluated for their influence on time to recurrence. Coxs proportional regression hazard model examined the association of recurrence in NSCLC. RESULTS A total of 1,143 patients met inclusion criteria and had complete follow-up information. Of these patients, 378 (33.1%) had recurrence of the primary cancer. Median follow-up was 24 months (range, 3-134 months). Preoperative tumor maximum standardized uptake value (SUVmax) greater than 5 was associated with increased risk of recurrence (hazard ratio [HR], 1.81; p=0.01). Preoperative radiation was independently associated with recurrence (HR, 1.98; p=0.05) as well as the presence of pathologic stage II and stage III disease (stage II: HR, 2.53; p=0.05; stage III: HR, 6.49; p=0.006). Subgroup analysis found that sublobar resection was also associated with locoregional recurrence after resection (HR, 4.17; p=0.02) and lymphovascular invasion of distant recurrence (HR, 4.21; p=0.002). CONCLUSIONS In the largest series reported to date on postresectional recurrence of NSCLC, SUVmax greater than 5, increasing pathologic stage, and the administration of preoperative radiation were independently associated with NSCLC recurrence after resection. Sublobar resection was independently associated with locoregional recurrence, and lymphovascular invasion was associated with distant recurrence.

Melanoma metastasis: new concepts and evolving paradigms.

Melanoma progression is typically depicted as a linear and stepwise process in which metastasis occurs relatively late in disease progression. Significant evidence suggests that in a subset of melanomas, progression is much more complex and less linear in nature. Epidemiologic and experimental observations in melanoma metastasis are reviewed here and are incorporated into a comprehensive model for melanoma metastasis, which takes into account the varied natural history of melanoma formation and progression.

mTORC1 Activation Blocks BrafV600E-Induced Growth Arrest but Is Insufficient for Melanoma Formation

Braf(V600E) induces benign, growth-arrested melanocytic nevus development, but also drives melanoma formation. Cdkn2a loss in Braf(V600E) melanocytes in mice results in rare progression to melanoma, but only after stable growth arrest as nevi. Immediate progression to melanoma is prevented by upregulation of miR-99/100, which downregulates mTOR and IGF1R signaling. mTORC1 activation through Stk11 (Lkb1) loss abrogates growth arrest of Braf(V600E) melanocytic nevi, but is insufficient for complete progression to melanoma. Cdkn2a loss is associated with mTORC2 and Akt activation in human and murine melanocytic neoplasms. Simultaneous Cdkn2a and Lkb1 inactivation in Braf(V600E) melanocytes results in activation of both mTORC1 and mTORC2/Akt, inducing rapid melanoma formation in mice. In this model, activation of both mTORC1/2 is required for Braf-induced melanomagenesis.

Fluorodeoxyglucose positron emission tomography and tumor marker expression in non–small cell lung cancer

OBJECTIVE The best current noninvasive surrogate for tumor biology is fluorodeoxyglucose positron emission tomography (FDG-PET). Both FDG-PET maximal standardized uptake values and selected tumor markers have been shown to correlate with stage, nodal disease, and survival in non-small cell lung cancer (NSCLC). However, there are limited data correlating FDG-PET with tumor markers. The purpose of this study was to determine the correlation of tumor marker expression with FDG-PET maximal standardized uptake values in NSCLC. METHODS FDG-PET maximal standardized uptake values were calculated in patients with NSCLC (n = 149). No patient had induction chemoradiotherapy. Intraoperative NSCLC tissue was obtained and tissue microarrays were created. Immunohistochemical analysis was performed for 5 known NSCLC tumor markers (glucose transporter 1, p53, cyclin D1, epidermal growth factor receptor, and vascular endothelial growth factor). Each tumor marker was assessed independently by two pathologists using common grading criteria. Subgroup analysis based on histologic characteristics and regional nodal status was performed. RESULTS FDG-PET correlated with T classification (P < .0001), N stage (P = .002), and greatest tumor dimension (P < .0001). In addition, increasing maximal standardized uptake values correlated with increased expression of glucose transporter 1 (P < .0001) and p53 (P = .04) in adenocarcinoma. Epidermal growth factor receptor expression correlated with maximal standardized uptake values without predilection for histologic subtype (P = .004). CONCLUSION FDG-PET maximal standardized uptake values correlate with an increased expression of glucose transporter 1 and p53 in lung adenocarcinoma, but not squamous cell cancer. Future studies attempting to correlate FDG-PET with tumor biology will need to consider the effect of different tumor histologic types.

Melanoma Treatments: Advances and Mechanisms

Advances in the understanding of the molecular pathogenesis of melanoma and in cancer immunology have led to the rational design and recent clinical implementation of a variety of novel therapies for metastatic melanoma. BRAF and MEK inhibitors that target the MAPK pathway have high rates of clinical response in BRAF‐mutant melanoma. Therapies that modulate the immune response to melanoma, including monoclonal antibodies that interfere with pathways that inhibit T‐cell function, have been shown to be effective in melanoma. Lessons learned from these encouraging results are driving the development of new treatments for melanoma and other cancers. This review will focus on the science and clinical findings related to targeted therapies that inhibit BRAF or MEK as well as the immunotherapies that block the CTLA‐4 or PD‐1 pathways. Other experimental and combinatorial therapeutic approaches will also be discussed. J. Cell. Physiol. 9999: 2626–2633, 2015.

Correlations between selected tumor markers and fluorodeoxyglucose maximal standardized uptake values in esophageal cancer

OBJECTIVE Esophageal cancer tumor biology is best assessed clinically by 2-[18F]fluoro-2-deoxy-d-glucose (FDG)-PET. Both FDG-PET maximal positron emission tomography (PET) standardized uptake values (SUVmax) and selected tumor markers have been shown to correlate with stage, nodal disease, and survival in esophageal cancer. Interestingly, there is limited data examining the relationship between FDG-PET SUVmax and expression of these tumor markers in esophageal cancer. The purpose of this study was to determine the correlation of tumor markers with FDG-PET SUVmax in esophageal cancer. METHODS FDG-PET SUVmax was calculated in 67 patients with esophageal cancer of which 59 (88%) had adenocarcinoma. Neoadjuvant radiotherapy and/or chemotherapy were administered to 42% (28/67) of patients. Esophageal tumor tissue and surrounding normal tissue was obtained and tissue microarrays were created. Immunohistochemical analysis was performed for five known esophageal cancer tumor markers (GLUT-1, p53, cyclin D1, epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF)). Assessment of each tumor marker was made by two independent, blinded pathologists using common grading criteria of intensity and percentage of cells stained. A p value <0.05 was considered significant. RESULTS There were 55 men (82%) and 12 women (18%) with a median age of 63 years (range 40-83). Pathologic staging included stage I (n=29, 43%), stage II (n=19, 28%), stage III disease (n=18, 27%), and stage IV disease (n=1, 2%). PET SUVmax correlated with T stage (p=0.001). In patients undergoing surgery without induction therapy, increasing SUVmax values correlated with increased expression of GLUT-1 transporter (p=0.01). There was no correlation between SUVmax and EGFR, cyclin D1, VEGF, or p53 expression in primary tumor. CONCLUSIONS FDG-PET SUVmax correlates with an increased expression of GLUT-1 transporter in esophageal cancer specimens not subjected to induction therapy. No significant difference in tumor marker expression was noted between patients undergoing induction therapy or surgery alone except p53 expression decreased in primary tumors following induction therapy. Failure of SUVmax values to correlate with known prognostic esophageal cancer tumor markers suggests that FDG-PET may have limited clinical utility in assessing response to therapies targeting these markers.

Aberrant DNA methylation in melanoma: biomarker and therapeutic opportunities

Aberrant DNA methylation is an epigenetic hallmark of melanoma, known to play important roles in melanoma formation and progression. Recent advances in genome-wide methylation methods have provided the means to identify differentially methylated genes, methylation signatures, and potential biomarkers. However, despite considerable effort and advances in cataloging methylation changes in melanoma, many questions remain unanswered.The aim of this review is to summarize recent developments, emerging trends, and important unresolved questions in the field of aberrant DNA methylation in melanoma. In addition to reviewing recent developments, we carefully synthesize the findings in an effort to provide a framework for understanding the current state and direction of the field. To facilitate clarity, we divided the review into DNA methylation changes in melanoma, biomarker opportunities, and therapeutic developments. We hope this review contributes to accelerating the utilization of the diagnostic, prognostic, and therapeutic potential of DNA methylation for the benefit of melanoma patients.

DNMT3b Modulates Melanoma Growth by Controlling Levels of mTORC2 Component RICTOR.

DNA methyltransferase DNMT3B is frequently overexpressed in tumor cells and plays important roles during the formation and progression of several cancer types. However, the specific signaling pathways controlled by DNMT3B in cancers, including melanoma, are poorly understood. Here, we report that DNMT3B plays a pro-tumorigenic role in human melanoma and that DNMT3B loss dramatically suppresses melanoma formation in the Braf/Pten mouse melanoma model. Loss of DNMT3B results in hypomethylation of the miR-196b promoter and increased miR-196b expression, which directly targets the mTORC2 component Rictor. Loss of RICTOR in turn prevents mTORC2 activation, which is critical for melanoma formation and growth. These findings establish Dnmt3b as a regulator of melanoma formation through its effect on mTORC2 signaling. Based on these results, DNMT3B is a potential therapeutic target in melanoma.

Combined proteasome and histone deacetylase inhibition attenuates epithelial–mesenchymal transition through E-cadherin in esophageal cancer cells

OBJECTIVE Metastasis is thought to be governed partially by induction of epithelial-mesenchymal transition. Combination of proteasome and histone deacetylase inhibitors has shown significant promise, but no studies have investigated this in esophageal cancer. This study investigated effects of vorinostat (histone deacetylase inhibitor) and bortezomib (proteasome inhibitor) on esophageal cancer epithelial-mesenchymal transition. METHODS Three-dimensional tumor spheroids mimicking tumor architecture were created with esophageal squamous and adenocarcinoma cancer cells. Cells were treated with tumor necrosis factor alpha (to simulate proinflammatory tumor milieu) and transforming growth factor beta (cytokine critical for induction of epithelial-mesenchymal transition). Tumor models were then treated with vorinostat, bortezomib, or both. Cytotoxic assays assessed cell death. Messenger RNA and protein expressions of metastasis suppressor genes were assessed. After treatment, Boyden chamber invasion assays were performed. RESULTS Combined therapy resulted in 3.7-fold decrease in adenocarcinoma cell invasion (P = .002) and 2.8-fold decrease in squamous cell invasion (P = .003). Three-dimensional invasion assays demonstrated significant decrease in epithelial-mesenchymal transition after combined therapy. Quantitative reverse transcriptase polymerase chain reaction and Western blot analyses revealed robust rescue of E-cadherin transcription and protein expression after combined therapy. Importantly, inhibition of the E-cadherin gene resulted in abolition of the salutary benefits of combined therapy, highlighting the importance of this metastasis suppressor gene in the epithelial-mesenchymal transition process. CONCLUSIONS Combined vorinostat and bortezomib therapy significantly decreased esophageal cancer epithelial-mesenchymal transition. This combined therapeutic effect on esophageal cancer epithelial-mesenchymal transition was associated with upregulation of E-cadherin protein expression.

Mitochondrial function in melanoma

Melanoma is the most lethal form of skin cancer and its incidence is rapidly rising. Breakthroughs in the understanding of the basic biology of melanoma in the past decade have yielded several new treatments, and advances continue to be made on a variety of fronts. One such area involves the delineation of changes in mitochondria that occur during melanoma formation, and how these changes affect responses to therapy. In this review, we summarize recent developments on the multiple functions that mitochondria play in melanoma, and how these roles are currently being evaluated as new targets for clinical intervention.