Faculty Bibliography

Introduction: Surgery offers the only chance for cure in patients with pancreatic cancer. Currently, pancreaticoduodenectomy can be performed with a mortality of under 5% and a morbidity of 40-50%. Little, however, is known about outcomes of pancreaticoduodenectomy (PD) in octogenarians. This manuscript details outcomes after PD for adenocarcinoma in patients 80 years and older. Methods: From our comprehensive pancreatic adenocarcinoma database of 248 patients, we identified 200 patients who underwent PD (1990-2009). We categorized patients into two groups, according to age at time of surgery: Group I (>= 80 year-old) and Group II (< 80 year-old). The study end-points were length of post-operative stay (LOS), overall morbidity, 30-day mortality, overall survival (OS). Differences between groups were evaluated using t-test or chi-squared test. Survival was compared using Kaplan-Meier analysis and log-rank test. Results: There were 25 patients in group I (mean age 83.1) and 175 patients in Group II (mean age 64.4). Octogenarians had worse ECOG performance status (PS >= 1 in 90% vs. 50.8%, p < 0.01) and ASA score (ASA 3- 4 in 70.8% vs. 47.4%, p < 0.01). The two groups were similar in regard to underlying co-morbidities (including coronary artery disease, COPD, diabetes, chronic renal failure), operative time, rates of portal vein resection, intraoperative complications, blood loss, pathologic AJCC stage, status of resection margins. Octogenarians had longer LOS (20 vs. 13.7 days, p=0.01) and higher overall morbidity (68% vs. 44%, p=0.03). There was a single death in each group (p=0.23). At median follow-up of 13 months older patients had a median OS of 17.3 months compared to 13.1 months in younger patients (p=0.06). Conclusions: Surgical morbidity and LOS are significantly increased in octogenarians. However 30-day mortality was not significantly increased and OS was superior (but not statistically significant) when compared to younger patients. The decision for PD should be individualized and offered to carefully selected octogenarians

Background: The AJCC staging for pancreatic cancer is relatively non-discriminatory for prediction of survival after resection. At the Moffitt Cancer Center a prognostic score for patients with localized pancreatic cancer (AJCC <= IIb) has been developed. In the Moffitt Prognostic Index (MPI) patients are grouped in 5 risk categories on the basis of extra-pancreatic tumor extension, degree of differentiation and lymphatic invasion. The aim of this study is to assess the MPI's predictive value in an independent cohort of patients who underwent pancreaticoduodenectomy (PD) at the New York University. Methods From our retrospective pancreatic adenocarcinoma database of 248 patients, we identified and grouped by MPI category patients with AJCC stage <= IIb who underwent PD (1990-2009). Differences between groups were evaluated using ANOVA and chi-squared test. Overall survival (OS) for each group was estimated using the Kaplan-Meier method and compared using the log-rank statistic. Results Among 131 patients with stage Ia-IIb cancer, MPI could be calculated for 126 (96%). Only few patients fell in MPI lower-risk groups 1- 4 (respectively 1, 4, 3, 22), while the majority (96, 76.1%) fell in MPI group 5 (poor prognosis). The 5 groups were similar in demographics, underlying comorbidities, laboratory data, ASA score and ECOG performance status. There were no differences in operative time, blood loss, intra- and post-operative complications, length of stay, 30-day mortality. Pathology revealed more advanced stage in groups 3 to 5 (p=0.001). At mean follow-up of 18 months, there was no difference in median OS across MPI groups (respectively 19, 6, 16, 17, 12 months, p=0.91). Of note, AJCC staging did correlate with median OS (respectively 43, 12, 16, 11 months in stages Ia to IIb, p = 0.004). Conclusions In our experience the MPI performed worse than AJCC staging as a prognostic tool. The clustering of patients in the worst-prognosis group defied the very purpose of prognosis discrimination. Furthermore, in our experience MPI did not correlate with overall survival in patients undergoing DP for earlystage (<= IIb) pancreatic cancer

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

ABSTRACT: BACKGROUND: Increased levels of cryptic collagen epitope HU177 in the sera of melanoma patients have been shown to be associated with thicker primary melanomas and with the nodular histologic subtype. In this study, we investigate the association between HU177 shedding in the sera and clinical outcome in terms of disease-free survival (DFS) and overall survival (OS). METHODS: Serum samples from 209 patients with primary melanoma prospectively enrolled in the Interdisciplinary Melanoma Cooperative Group at the New York University Langone Medical Center (mean age=58, mean thickness=2.09 mm, stage I=136, stage II=41, stage III=32, median follow-up=54.9 months) were analyzed for HU177 concentration using a validated ELISA assay. HU177 serum levels at the time of diagnosis were used to divide the study cohort into two groups: low and high HU177. DFS and OS were estimated by Kaplan-Meier survival analysis, and the log-rank test was used to compare DFS and OS between the two HU177 groups. Multivariate Cox proportional hazards regression models were employed to examine the independent effect of HU177 category on DFS and OS. RESULTS: HU177 sera concentrations ranged from 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 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: Teaching and assessing the Accreditation Council for Graduate Medical Education (ACGME) competencies of Professionalism and Communication have proven to be a challenge for surgical residency training programs. This study used innovative pedagogic approaches and tools in teaching these two competencies. The purpose of this study was to determine whether the learners actually are assimilating and using the concepts and values communicated through this curriculum. METHODS: A six-station Objective Structured Clinical Examination (OSCE) was designed using standardized patients to create varying Professionalism and Communication scenarios. The surgical resident learners were evaluated using these OSCEs as a baseline. The faculty then facilitated a specially designed curriculum consisting of six interactive sessions focusing on information gathering, rapport building, patient education, delivering bad news, responding to emotion, and interdisciplinary respect. At the conclusion of this curriculum, the surgical resident learners took the same six-station OSCE to determine if their professionalism and communication skills had improved. RESULTS: The surgical resident learners were rated by the standardized patients according to a strict task checklist of criteria at both the precurricular and postcurricular OSCEs. Improvement in the competencies of Professionalism and Communication did achieve statistical significance (P = .029 and P = .011, respectively). CONCLUSIONS: This study suggests that the Communication and Professionalism ACGME competencies can be taught to surgical resident learners through a carefully crafted curriculum. Furthermore, these newly learned competencies can affect surgical resident interactions with their patients positively

Background: Most skin cancer-related deaths are due to malignant melanoma. Risk assessment criteria for melanoma currently include skin phenotype, family and sun exposure history, factors that are subject to observer and recall bias. Genetic markers of susceptibility have been identified in association studies; however little progress has been made in developing them to improve screening and identification of individuals at risk of melanoma. Tyrosinase (TYR), a known susceptibility gene and a determinant of skin pigmentation, was thus investigated further to characterize its association with melanoma susceptibility and to identify markers which can be used in a risk assessment model. Methods: The cohort consisted of 326 individuals diagnosed with melanoma and 400 control subjects. TYR was interrogated using fifteen tag single nucleotide polymorphisms (SNPs) spanning the gene and statistical association tests performed. Additionally, ancestry informative markers were utilized to correct for population genetic sub-structure. Haplotype analysis was performed to determine if specific regions of the gene contributed more significantly to susceptibility. Coding regions of the gene are currently being sequenced and identified variants will be tested for impact on enzymatic function. Results: Of the 15 SNPs, 8 were associated with melanoma; 4 with decreased risk (Odds ratios 0.41-0.71) and 4 with increased risk (Odds ratios 1.43-1.96). SNPs localized to 2 regions of the gene (spanning exon 1 to intron 2 and intron 3 to 4) with markers of increased as well as decreased susceptibility present in both areas. With the exception of one coding region variant, SNPs were localized to introns. Conclusions: SNPs localized to TYR may serve as useful biomarkers for determining susceptibility to melanoma. We are currently sequencing the gene in our population in order to identify additional and potentially more potent markers of melanoma susceptibility. Coding region variants are being characterized for their effect on protein stability and enzyme activity such that functional active variants (most likely to affect susceptibility to melanoma) can be identified and assessed for their utility in melanoma risk assessment

Although remission rates for metastatic melanoma are generally very poor, some patients can survive for prolonged periods following metastasis. We used gene expression profiling, mitotic index (MI), and quantification of tumor infiltrating leukocytes (TILs) and CD3+ cells in metastatic lesions to search for a molecular basis for this observation and to develop improved methods for predicting patient survival. We identified a group of 266 genes associated with postrecurrence survival. Genes positively associated with survival were predominantly immune response related (e.g., ICOS, CD3d, ZAP70, TRAT1, TARP, GZMK, LCK, CD2, CXCL13, CCL19, CCR7, VCAM1) while genes negatively associated with survival were cell proliferation related (e.g., PDE4D, CDK2, GREF1, NUSAP1, SPC24). Furthermore, any of the 4 parameters (prevalidated gene expression signature, TILs, CD3, and in particular MI) improved the ability of Tumor, Node, Metastasis (TNM) staging to predict postrecurrence survival; MI was the most significant contributor (HR = 2.13, P = 0.0008). An immune response gene expression signature and presence of TILs and CD3+ cells signify immune surveillance as a mechanism for prolonged survival in these patients and indicate improved patient subcategorization beyond current TNM staging