Faculty Bibliography

BACKGROUND: Increasing evidence suggests that the ratio of number of nodes harboring metastatic cancer to the total number of lymph nodes examined (lymph node ratio, LNR) may affect survival after esophagogastric resection for cancer. We analyzed the impact of LNR in overall survival in patients undergoing esophagogastric resection for cancer. METHODS: Patients who underwent gastroesophageal resection for cancer (1998 to 2008) were categorized into 4 groups according to their LNR: 113 patients had negative nodes (N0), 86 LNR less than .3, 40 LNR .31 to .6, and 47 LNR greater than .6. Study endpoint was overall median survival. RESULTS: Higher LNR was associated (P < .001) with more advanced stage and adverse pathologic features (eg, grading, venous/perineural invasion). Multivariate analysis demonstrated that LNR is an independent predictor of survival. CONCLUSION: In our experience, LNR correlates with adverse pathologic features and is a negative prognostic factor in patients undergoing radical resection for gastroesophageal cancer.

BACKGROUND: Due to high melanoma immunogenicity, germline genetic variants in immune pathways have been studied for association with melanoma prognosis. However, limited candidate selection, inadequate power, or lack of independent validation have hampered the reproducibility of these prior findings, preventing personalised clinical applicability in melanoma prognostication. Our objective was to assess the prognostic utility of genetic variants in immunomodulatory pathways for prediction of melanoma clinical outcomes. METHODS: We genotyped 72 tag single nucleotide polymorphisms (SNPs) in 44 immunomodulatory genes in a population sample of 1022 melanoma patients and performed Cox regression analysis to test the association between SNPs and melanoma recurrence-free (RFS) and overall survival (OS). We have further investigated the most significant associations using a fine mapping strategy and followed with functional analyses in CD4+ T cells in a subset of 75 melanoma patients. RESULTS: The most significant associations were found with melanoma OS for rs3024493 in IL10 at chromosome 1q32.1 (heterozygous HR 0.58, 95% CI 0.39 to 0.86; p=0.0006), a variant previously shown to be linked with autoimmune conditions. Multiple additional SNPs at 1q32.1 were also nominally associated with OS confirming at least two independent association signals in this locus. In addition, we found rs3024493 associated with the downregulation of interleukin 10 (IL10) secretion in CD4+ T cells. CONCLUSIONS: We discovered novel associations of IL10 with melanoma survival at 1q32.1, suggesting this locus should be considered as a novel melanoma prognostic biomarker with potential for aiding melanoma patient management. Our findings also provide further support for an alternative role of IL10 in stimulation of anti-tumour immune response.

BACKGROUND: Surgical management of primary melanoma is curative for most patients with clinically localized disease at diagnosis; however, a substantial number of patients recur and progress to advanced disease. Understanding molecular alterations that influence differential tumor progression of histopathologically similar lesions may lead to improved prognosis and therapies to slow or prevent metastasis. METHODS: We examined microRNA dysregulation by expression profiling of primary melanoma tumors from 92 patients. We screened candidate microRNAs selected by differential expression between recurrent and nonrecurrent tumors or associated with primary tumor thickness (Student's t test, Benjamini-Hochberg False Discovery Rate [FDR] < 0.05), in in vitro invasion assays. We performed in vivo metastasis assays, matrix remodeling experiments, and molecular studies to identify metastasis-regulating microRNAs and their cellular and molecular mechanisms. All statistical tests were two-sided. RESULTS: We identified two microRNAs (hsa-miR-382, hsa-miR-516b) whose expression was lower in aggressive vs nonaggressive primary tumors, which suppressed invasion in vitro and metastasis in vivo (mean metastatic foci: control: 37.9, 95% confidence interval [CI] = 25.6 to 50.2; miR-382: 19.5, 95% CI = 12.2 to 26.9, P = .009; miR-516b: 12.5, 95% CI = 7.7 to 17.4, P < .001, Student's t test). Mechanistically, miR-382 overexpression inhibits extracellular matrix degradation by melanoma cells. Moreover, we identified actin regulators CTTN, RAC1, and ARPC2 as direct targets of miR-382. Depletion of CTTN partially recapitulates miR-382 effects on matrix remodeling, invasion, and metastasis. Inhibition of miR-382 in a weakly tumorigenic melanoma cell line increased tumor progression and metastasis in vivo. CONCLUSIONS: Aberrant expression of specific microRNAs that can functionally impact progression of primary melanoma occurs as an early event of melanomagenesis.

The incidence of cutaneous melanoma is rising faster than that of almost any other cancer in the United States. Acral lentiginous melanoma is a subtype of melanoma that involves the palms, soles, and nail beds. Although it is one of the rarer types of melanoma, it has a poorer prognosis than other more common subtypes. We describe a case of plantar acral melanoma in a 66-year-old woman that was initially misdiagnosed as a traumatic foot ulcer. We highlight this case to emphasize the importance of close observation and biopsy of ulcerative lesions of the foot that have atypical features or are refractory to standard treatment.