BackgroundIdentification of melanoma patients at high risk for recurrence and monitoring for recurrence are critical for informed management decisions. We hypothesized that serum microRNAs (miRNAs) could provide prognostic information at the time of diagnosis unaccounted for by the current staging system and could be useful in detecting recurrence after resection.MethodsWe screened 355 miRNAs in sera from 80 melanoma patients at primary diagnosis (discovery cohort) using a unique quantitative reverse transcription-PCR (qRT-PCR) panel. Cox proportional hazard models and Kaplan-Meier recurrence-free survival (RFS) curves were used to identify a miRNA signature with prognostic potential adjusting for stage. We then tested the miRNA signature in an independent cohort of 50 primary melanoma patients (validation cohort). Logistic regression analysis was performed to determine if the miRNA signature can determine risk of recurrence in both cohorts. Selected miRNAs were measured longitudinally in subsets of patients pre-/post-operatively and pre-/post-recurrence.ResultsA signature of 5 miRNAs successfully classified melanoma patients into high and low recurrence risk groups with significant separation of RFS in both discovery and validation cohorts (p = 0.0036, p = 0.0093, respectively). Significant separation of RFS was maintained when a logistic model containing the same signature set was used to predict recurrence risk in both discovery and validation cohorts (p < 0.0001, p = 0.033, respectively). Longitudinal expression of 4 miRNAs in a subset of patients was dynamic, suggesting miRNAs can be associated with tumor burden.ConclusionOur data demonstrate that serum miRNAs can improve accuracy in identifying primary melanoma patients with high recurrence risk and in monitoring melanoma tumor burden over time.

The sentinel lymph node is the initial site of metastasis. Down-regulation of anti-tumor immunity plays a role in nodal progression. Our objective was to investigate the relationship between immune modulation and sentinel lymph node positivity, correlating it with outcome in melanoma patients. Lymph node/primary tissues from melanoma patients prospectively accrued and followed at New York University Medical Center were evaluated for the presence of regulatory T-cells (Foxp3+) and dendritic cells (conventional: CD11c+, mature: CD86+) using immunohistochemistry. Primary melanoma immune cell profiles from sentinel lymph node-positive/-negative patients were compared. Logistic regression models inclusive of standard-of-care/immunologic primary tumor characteristics were constructed to predict the risk of sentinel lymph node positivity. Immunological responses in the positive sentinel lymph node were also compared to those in the negative non-sentinel node from the same nodal basin and matched negative sentinel lymph node. Decreased immune response was defined as increased regulatory T-cells or decreased dendritic cells. Associations between the expression of these immune modulators, clinicopathologic variables, and clinical outcome were evaluated using univariate/multivariate analyses. Primary tumor conventional dendritic cells and regression were protective against sentinel lymph node metastasis (odds ratio=0.714, 0.067; P=0.0099, 0.0816, respectively). Anti-tumor immunity was down-regulated in the positive sentinel lymph node with an increase in regulatory T-cells compared to the negative non-sentinel node from the same nodal basin (P=0.0005) and matched negative sentinel lymph node (P=0.0002). The positive sentinel lymph node also had decreased numbers of conventional dendritic cells compared to the negative sentinel lymph node (P<0.0001). Adding sentinel lymph node regulatory T-cell expression improved the discriminative power of a recurrence risk assessment model using clinical stage. Primary tumor regression was associated with prolonged disease-free (P=0.025) and melanoma-specific (P=0.014) survival. Our results support an assessment of local immune profiles in both the primary tumor and sentinel lymph node to help guide therapeutic decisions.

The classification of melanoma subtypes into prognostically relevant and therapeutically insightful categories has been a challenge since the first descriptions of melanoma in the 1800s. One limitation has been the assumption that the two most common histological subtypes of melanoma, superficial spreading and nodular, evolve according to a linear model of progression, as malignant melanocytes spread radially and then invade vertically. However, recent clinical, pathological, and molecular data indicate that these two histological subtypes might evolve as distinct entities. We here review the published data that support distinct molecular characterization of superficial spreading and nodular melanoma, the clinical significance of this distinction including prognostic relevance, and the therapeutic implications.

Previous reports have demonstrated a role for hedgehog signaling in melanoma progression, prompting us to explore the therapeutic benefit of targeting this pathway in melanoma. We profiled a panel of human melanoma cell lines and control melanocytes for altered expression of hedgehog pathway members and determined the consequences of both genetic and pharmacological inhibition of the hedgehog pathway activator Smoothened (SMO) in melanoma, both in vitro and in vivo. We also examined the relationship between altered expression of hedgehog pathway mediators and survival in a well-characterized cohort of metastatic melanoma patients with prospectively collected follow up information. Studies revealed that over 40% of the melanoma cell lines examined harbored significantly elevated levels of the hedgehog pathway mediators SMO, GLI2, and PTCH1 compared to melanocytes (p < 0.05). SMO inhibition using siRNA and the small molecule inhibitor, NVP-LDE-225, suppressed melanoma growth in vitro, particularly in those cell lines with moderate SMO and GLI2 expression. NVP-LDE-225 also induced apoptosis in vitro and inhibited melanoma growth in a xenograft model. Gene expression data also revealed evidence of compensatory up-regulation of two other developmental pathways, Notch and WNT, in response to hedgehog pathway inhibition. Pharmacological and genetic SMO inhibition also downregulated genes involved in human embryonic stem cell pluripotency. Finally, increased SMO expression and decreased expression of the hedgehog pathway repressor GLI3 correlated with shorter post recurrence survival in metastatic melanoma patients. Our data demonstrate that hedgehog pathway inhibition might be a promising targeted therapy in appropriately selected metastatic melanoma patients.

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LAGB is tolerable in pregnancy with rare intrapartum band slips. Weight gain is less in those with higher pre-pregnancy BMI and those who had their bands filled or not adjusted. Babies born to these mothers are as healthy as the general population.

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Reconstruction of the abdominal wall to repair ventral hernias continues to pose a challenge to surgeons due to relatively high rates of recurrence and morbidity. In 1990, Ramirez pioneered a technique of components separation of the abdominal wall for ventral hernia repair. Although an effective hernia repair, the mobilization of skin and subcutaneous tissue endangers the blood supply and predisposes midline skin to necrosis. The goal of this study is to determine whether releasing incisions in the transversus abdominis fascia and posterior rectus sheath provide adequate mobilization of the abdominal wall necessary for ventral hernia repair, thus paving the way for a laparoscopic component separation technique. Ten fresh cadavers were used and one side of the abdomen underwent the conventional Ramirez components separation: midline incision, dissection of skin and subcutaneous tissue off the anterior abdominal wall, and incisions in the external oblique aponeurosis and posterior rectus sheath, while the other side received incisions in the transversus abdominis fascia and the posterior rectus sheath with no undermining of the skin. The amount of fascial translation was measured after each incision. Incising only the external oblique aponeurosis produced greater mobilization of the abdominal wall at the level of the umbilicus (P = 0.02) and anterior superior iliac spine (ASIS, P = 0.029) than releasing only transversus abdominis fascia. More importantly, there was no statistically significant difference in the amount of release produced by the complete internal-release components separation versus the conventional technique. In order to test the feasibility of performing the procedure laparoscopically, one additional cadaver underwent a laparoscopic transversus abdominis fascia release. The procedure was successful and resulted in comparable amounts of fascial release as the other 10 cadavers. From this study, it appears technically feasible to perform a laparoscopic components separation to repair a ventral hernia and the procedure produces the same amount of release as the conventional open component separation technique.