Operative expectations for Mohs surgery in patients with chronic lymphocytic leukemia: A multicenter retrospective cohort study.

Background: Patients with chronic lymphocytic leukemia (CLL) are immunocompromised and have both a higher incidence of and more aggressive skin cancers, often requiring treatment with Mohs micrographic surgery. Objective: Characterize operative expectations for Mohs surgery in patients with CLL. Methods: Multicenter retrospective cohort study. Results: One hundred fifty-nine tumors from 99 patients with CLL were matched 1:4 with controls. Cases had higher odds for requiring at least 3 stages during Mohs surgery compared to controls (odds ratio = 1.91; 95% CI [1.21-3.02]; P = .01). The mean number of Mohs stages in cases was 1.97 (±0.92) compared with 1.67 (±0.87) in controls (P = .0001). A regression analysis showed that cases had larger postoperative tumor areas (cm2) versus controls (mean = 5.57 vs 4.47; estimate difference Δß = 1.10 cm2; 95% CI [0.18-2.03]; P = .02). In logistic regression, cases were twice as likely to receive a flap repair compared to controls (odds ratio = 2.45; 95% CI [1.58-3.8]). Limitations: Retrospective cohort study and lack of histologic subtyping of tumors. Conclusion: Patients with CLL require more Mohs stages to attain clear surgical margins, have larger postoperative defect areas, and require more advanced repair techniques compared to a control population without CLL. These findings are essential for preoperative planning and patient counseling and further support the use of Mohs surgery in patients with CLL.

Normalization of electroretinogram and symptom resolution of melanoma-associated retinopathy with negative autoantibodies after treatment with programmed death-1 (PD-1) inhibitors for metastatic melanoma.

Melanoma-associated retinopathy (MAR) is a paraneoplastic syndrome that involves the production of autoantibodies which can cross-react with retinal epitopes leading to visual symptoms. Autoantibodies can target intracellular proteins, and only a few are directed against membrane proteins. This discrepancy in autoantibody-protein target can translate into different immune responses (T-cell mediated vs B-cell mediated). Historically, treatment of MAR has focused on surgical reduction or immunosuppressive medication, mainly glucocorticoids. However, tumor resection is not relevant in metastatic melanoma in which MAR is mostly encountered. Moreover, the use of glucocorticoids can reduce the efficacy of immunotherapy. We report the first case to our knowledge with subjective resolution of visual symptoms and objective evidence of normalization of electroretinogram of MAR with undetectable autoantibodies after administration of programmed death-1 (PD-1) inhibitor (pembrolizumab) without the use of surgical reduction or systemic immunosuppression. This case highlights the potential improvement and resolution of negative autoantibody MAR with the use of PD-1 inhibitors and emphasizes the importance of multidisciplinary approach and team discussion to avoid interventions that can decrease immunotherapy-mediated anti-tumor effect.

Ras-associated protein-1 regulates extracellular signal-regulated kinase activation and migration in melanoma cells: two processes important to melanoma tumorigenesis and metastasis.

Melanoma is one of the most devastating malignancies with a rising incidence and lack of effective treatments for advanced disease. Constitutive activation of the mitogen-activated protein kinase (MAPK) pathway and altered expression of alpha(v)beta(3) integrin are critical for melanoma development and progression. Ras-associated protein-1 (Rap1), a Ras family member of the small GTPases, has emerged as a key mediator in these two important processes. In this study, we have shown Rap1 activation in cells derived from two human metastatic melanomas and also in three of seven cutaneous metastatic melanoma tissues. We found increased extracellular signal-regulated kinase (ERK) activity in the tumors with detected Rap1 activity that interestingly harbored neither BRAF nor N-Ras mutation, suggesting a role for Rap1 in ERK activation in vivo. We also showed Rap1 and ERK activation by both hepatocyte growth factor (HGF) and 8CPT-2Me-cAMP (an activator of Epac, a Rap1 guanine nucleotide exchange factor) in two human melanoma cell lines. In addition, the activation of ERK by HGF was reduced, at least in part, by small interfering RNAs against Rap1 and a dominant-negative Rap1. Finally, a functional role for Rap1 activation was shown by Rap1-induced alpha(v)beta(3) integrin activation and consequent increased melanoma cell migration in vitro. Taken together, these results show that Rap1 is involved in the activation of MAPK pathway and integrin activation in human melanoma and suggest a potential role for Rap1 in melanoma tumorigenesis and metastasis.