Michael E. Egger

Prognostic implications of anatomic location of primary cutaneous melanoma of 1 mm or thicker

BACKGROUND Breslow thickness, ulceration, and sentinel lymph node (SLN) status are well established as the most important prognostic factors for patients with cutaneous melanoma. Anatomic location of the primary tumor is generally considered to play a minor role in determining prognosis compared with these other factors. This analysis was performed to better define the influence of anatomic location of the primary melanoma on prognosis. METHODS In this post hoc analysis of a prospective randomized trial that included patients ages 18 to 70 years with melanomas 1 mm or greater in Breslow thickness, all patients underwent SLN biopsy and completion lymphadenectomy if tumor-positive SLN were found. Kaplan-Meier survival analysis and univariate and multivariate analyses were performed to evaluate factors predictive of disease-free survival (DFS), local and in-transit recurrence-free survival (LITRFS), and overall survival (OS). RESULTS A total of 2,500 patients were included in this analysis with a median follow-up period of 68 months. Anatomic locations included head, neck, trunk, upper extremity, and lower extremity. Age, Breslow thickness, and percentage of patients with a positive SLN were significantly different by anatomic location on univariate analysis, as were positive SLN status, presence of regression, sex, and histologic subtype (P < .0001). On multivariate analysis, anatomic location was an independent predictor of SLN status (P < .0001), DFS (P = .045), LITRFS (P = .023), and OS (P < .0001). By Kaplan-Meier analysis, anatomic location was associated significantly with DFS, LITRFS, and OS. CONCLUSIONS Anatomic location of the primary melanoma is an important independent predictor of SLN status and prognosis. Patients with primary melanomas of the head/neck and trunk have a worse prognosis than primary melanomas of other anatomic locations.

Assessment of Chemotherapy Response in Colorectal Liver Metastases in Patients Undergoing Hepatic Resection and the Correlation to Pathologic Residual Viable Tumor

BACKGROUND The Response Evaluation Criteria in Solid Tumors (RECIST), which evaluates maximum tumor diameter only, is commonly used to determine response to chemotherapy in patients with colorectal liver metastases. Limitations of RECIST include its inability to assess the changes in tumor enhancement. The aim of this study was to assess the correlation of these criteria as well as the modified RECIST (mRECIST) with pathologic tumor response. A novel semi-automated volumetric assessment of tumor size was also investigated. STUDY DESIGN A review of a 1,948-patient prospective hepatic database to assess response and pathologic criteria was performed. Patients undergoing preoperative chemotherapy before hepatic resection for colorectal liver metastases were reviewed. Radiographic responses according to RECIST and mRECIST were determined. The percentage of viable tumor cells compared with the total tumor area was determined from the pathologic specimens. RESULTS We identified 38 patients with adequate imaging who had undergone anatomic hepatic resection and full pathologic evaluation. The percentages of residual viable tumor in the resected specimens were significantly different across RECIST categories (p = 0.045), but not mRECIST (p = 0.305). For mRECIST, there were improved and significant linear trends for residual viable tumor, necrosis, and necrosis + fibrosis when compared with RECIST (p = 0.056). Neither RECIST nor mRECIST responses were predictive of residual viable tumor burden in regression analyses. A novel semi-automated volumetric assessment of tumor size correlated well with pathologic tumor size. CONCLUSIONS Neither RECIST nor mRECIST were predictive of residual viable burden, although the linear trend for mRECIST and residual necrosis + fibrosis compared favorably with RECIST. Continued evaluation for tumor enhancement and standardization of tumor size remain a critical unmet need in patients with solid organ disease.

Melanoma cell-derived exosomes promote epithelial-mesenchymal transition in primary melanocytes through paracrine/autocrine signaling in the tumor microenvironment.

The tumor microenvironment is abundant with exosomes that are secreted by the cancer cells themselves. Exosomes are nanosized, organelle-like membranous structures that are increasingly being recognized as major contributors in the progression of malignant neoplasms. A critical element in melanoma progression is its propensity to metastasize, but little is known about how melanoma cell-derived exosomes modulate the microenvironment to optimize conditions for tumor progression and metastasis. Here, we provide evidence that melanoma cell-derived exosomes promote phenotype switching in primary melanocytes through paracrine/autocrine signaling. We found that the mitogen-activated protein kinase (MAPK) signaling pathway was activated during the exosome-mediated epithelial-to-mesenchymal transition (EMT)-resembling process, which promotes metastasis. Let-7i, an miRNA modulator of EMT, was also involved in this process. We further defined two other miRNA modulators of EMT (miR-191 and let-7a) in serum exosomes for differentiating stage I melanoma patients from non-melanoma subjects. These results provide the first strong molecular evidence that melanoma cell-derived exosomes promote the EMT-resembling process in the tumor microenvironment. Thus, novel strategies targeting EMT and modulating the tumor microenvironment may emerge as important approaches for the treatment of metastatic melanoma.

Final Results of the Sunbelt Melanoma Trial: A Multi-Institutional Prospective Randomized Phase III Study Evaluating the Role of Adjuvant High-Dose Interferon Alfa-2b and Completion Lymph Node Dissection for Patients Staged by Sentinel Lymph Node Biopsy.

PURPOSE The Sunbelt Melanoma Trial is a prospective randomized trial evaluating the role of high-dose interferon alfa-2b therapy (HDI) or completion lymph node dissection (CLND) for patients with melanoma staged by sentinel lymph node (SLN) biopsy. PATIENTS AND METHODS Patients were eligible if they were age 18 to 70 years with primary cutaneous melanoma ≥ 1.0 mm Breslow thickness and underwent SLN biopsy. In Protocol A, patients with a single tumor-positive lymph node after SLN biopsy underwent CLND and were randomly assigned to observation versus HDI. In Protocol B, patients with tumor-negative SLN by standard histopathology and immunohistochemistry underwent molecular staging by reverse transcriptase polymerase chain reaction (RT-PCR). Patients positive by RT-PCR were randomly assigned to observation versus CLND versus CLND+HDI. Primary end points were disease-free survival (DFS) and overall survival (OS). RESULTS In the Protocol A intention-to-treat analysis, there were no significant differences in DFS (hazard ratio, 0.82; P = .45) or OS (hazard ratio, 1.10; P = .68) for patients randomly assigned to HDI versus observation. In the Protocol B intention-to-treat analysis, there were no significant differences in overall DFS (P = .069) or OS (P = .77) across the three randomized treatment arms. Similarly, efficacy analysis (excluding patients who did not receive the assigned treatment) did not demonstrate significant differences in DFS or OS in Protocol A or Protocol B. Median follow-up time was 71 months. CONCLUSION No survival benefit for adjuvant HDI in patients with a single positive SLN was found. Among patients with tumor-negative SLN by conventional pathology but with melanoma detected in the SLN by RT-PCR, there was no OS benefit for CLND or CLND+HDI.

A novel and accurate computer model of melanoma prognosis for patients staged by sentinel lymph node biopsy: comparison with the American Joint Committee on Cancer model.

BACKGROUND We found that a computer model developed by the American Joint Committee on Cancer (AJCC) melanoma staging committee had limitations for predicting prognosis of patients staged by sentinel lymph node (SLN) biopsy. We sought to develop a model that more accurately predicts prognosis in this population. STUDY DESIGN Using a data set obtained from a prospective multi-institutional study of 2,507 patients with clinically node-negative melanomas ≥1.0 mm Breslow thickness, we developed a prognostic model using a Cox regression formula incorporating a number of significant clinicopathologic factors. The AJCC model and our model were used to predict 5-year survival from this test data set. The concordance correlation coefficient (CCC) was determined and chi-square tests were performed. Our new prognostic model was validated using an independent data set of 1,001 patients. RESULTS Using the test data set, the CCC for the AJCC model was 0.875; chi-square tests demonstrated statistically significant differences between observed and predicted survivals for numerous clinicopathologic factors. The CCC for our model was 0.976 and none of the chi-square tests was statistically significant. Our model performed similarly well in SLN-negative patients (CCC 0.929) and SLN-positive patients (CCC 0.889). The AJCC model performed well in SLN-negative patients (CCC 0.854), but not in SLN-positive patients (CCC 0.626). Using the validation data set, similar findings were obtained. CONCLUSIONS Our prognostic model provides superior survival estimates compared with the AJCC model for patients undergoing SLN biopsy. This online tool is available at www.melanomacalculator.com, and will provide important information that can be used to guide adjuvant therapy decisions and stratification in clinical trials.

Laparoscopic component separation reduces postoperative wound complications but does not alter recurrence rates in complex hernia repairs

BACKGROUND The purpose of this study was to evaluate and compare the incidence of wound complications after laparoscopic component separation (LCS) vs open component separation (OCS) in patients with complex abdominal wall hernias. METHODS A retrospective review was performed of all patients who underwent LCS or OCS for repair of a complex abdominal wall hernia at a single institution between 2009 and 2011. Charts were reviewed to identify postoperative wound complications. A computed tomographic scan or physical examination was used for the determination of hernia recurrence. Categoric variables were compared using the Fisher exact test. Univariate and multivariate analyses were performed using linear and Cox regression. Recurrence rates were compared using log-rank tests (Kaplan-Meier method). RESULTS A total of 44 patients underwent LCS (n = 18) or OCS (n = 26). There was no statistically significant difference between categoric variables. Multivariate analysis using wound complications as the dependent variable showed a statistically significantly lower rate of wound complications in the LCS group. CONCLUSIONS LCS is associated with a lower rate of wound complications when compared with OCS but yields comparable recurrence rates.

Unique prognostic factors in acral lentiginous melanoma

BACKGROUND This study was performed to identify clinicopathologic factors associated with survival in acral lentiginous melanoma. METHODS A post hoc analysis of a prospective clinical trial and local database was performed in all patients with acral lentiginous melanomas. Multivariate analyses of factors associated with a tumor-positive sentinel lymph node (SLN) biopsy, disease-free survival (DFS), overall survival (OS), and local and in-transit recurrence-free survival (LITRFS) were performed. Kaplan-Meier survival analyses were performed. RESULTS Eighty-five patients were identified. Age younger than 59 years and Breslow thickness (BT) of 2.0 mm or greater were independent risk factors for a positive SLN. SLN status was the only independent risk factor for DFS and LITRFS on multivariate analysis. A BT of 2.0 mm or greater was the only independent risk factor for OS. SLN status distinguished differences in DFS, OS, and LITRFS on Kaplan-Meier analysis. CONCLUSIONS SLN status is the dominant factor for recurrence and survival in acral lentiginous melanoma. BT and ulceration are less important in this histologic subtype.

Chemoresistance in ovarian cancer linked to expression of microRNAs.

Abstract We evaluated the differential expression of several microRNAs (miRNAs) among malignant cells in ascites and matched omental metastasis in patients with epithelial ovarian cancer (EOC). Ascites and omental tumors were collected prospectively from five patients who were undergoing primary surgical cytoreduction. Patient samples were processed and treated with carboplatin, paclitaxel and combination chemotherapy. Cell viability was evaluated and miRNA profiling was performed on both tumor cells from ascites fluid and omental cake. Quantitative real-time PCR (RT-q-PCR) and western blots were used to evaluate expressions of miRNA-21 and miRNA -214 and associated proteins. Malignant cells in ascites showed greater cell viability when treated with carboplatin compared to omental metastasis. A significant up-regulation of miRNA-21 and miRNA-214 was observed in malignant cells of ascites compared to omental metastasis; this was confirmed by both cell viability assay and RT-q-PCR. Ours is the first report that demonstrates significant up-regulation of miRNA-21 and miRNA-214 in tumor cells from ascites of patients with EOC compared to omental metastasis. This finding has important implications for intrinsic carboplatin resistance in these patients.

Necrotizing peripheral vasculitis/vasculopathy following the use of cocaine laced with levamisole.

The objective of this study was to describe a novel presentation of peripheral vasculitis associated with levamisole-adulterated cocaine. Cocaine abuse is widespread in the United States with 5.3 million people using cocaine in 2008. Over the past decade, drug enforcement officials have noticed the presence of levamisole in confiscated cocaine samples as an adulterant. Known side effects of cocaine-related levamisole ingestion have included agranulocytosis and a cutaneous acral purpura that is histopathologically characterized by a mixture of inflammation (vasculitis) and occlusion (vasculopathy). A 54-year-old man who nasally ingested cocaine laced with levamisole developed widespread necrotic/purpuric skin lesions on approximately 20% of his body with an acral accentuation. These lesions were complicated by multiple areas of sloughing and necrosis. He was initially treated with topical silver sulfadiazine dressing changes but progressed to require debridement and split-thickness skin grafting. Peripheral vasculitis/vasculopathy with severe necrosis resembling Coumadin necrosis is a relatively recently recognized sequelae from levamisole-adulterated cocaine use.

MicroRNA-100 regulates IGF1-receptor expression in metastatic pancreatic cancer cells.

Abstract Patients with pancreatic adenocarcinoma have the lowest 5 year survival rate and yearly rates of incidence are nearly equal to the mortality rates. Long term cure rates by standard therapies are disappointing owing to disseminated disease at diagnosis and chemotherapeutic resistance. New therapeutic targets are necessary to decrease the progression of pancreatic cancer and the ability to identify targets specific to metastasis would improve patient care. We evaluated the levels of microRNA of metastatic and non-metastatic cell lines. The expression levels of microRNAs and mRNAs were determined using microarray analysis to examine and compare five pancreatic cancer cell lines, two that can metastasize in vivo (S2VP10 and S2CP9) and three that do not metastasize (MiaPaCa2, Panc-1 and ASPC-1). MicroRNA analysis indicated an increase in miR-100 and a decrease in miR-138 expression in metastatic cancer cells. Microarray analysis of different expressions of mRNAs in metastatic and non-metastatic pancreatic cell lines also indicated significantly increased insulin growth factor-1 receptor (IGF1-R) expression in metastatic pancreatic cancer cell lines compared to non-metastatic pancreatic cancer cell lines. To confirm microarray analysis results, western blot and immunocytochemistry were performed. Western blot revealed that IGF1-R expression exhibited in metastatic cancer cell lines a seven-fold increase compared to non-metastatic cell lines. In addition, downstream expressions of the proteins, GRB2 and phosphorylated PI3K, also were increased in aggressive cancer cell lines. Immunocytochemistry confirmed the linkage of IGF1-R to miR-100, because cells transfected with miR-100 inhibitor showed a decrease in IGF1-R. Cells transfected with a miR-138 mimic, however, did not affect IGF1-R expression.