Rewired ERK-JNK signaling pathways in melanoma.

Constitutive activation of MEK-ERK signaling is often found in melanomas. Here, we identify a mechanism that links ERK with JNK signaling in human melanoma. Constitutively active ERK increases c-Jun transcription and stability, which are mediated by CREB and GSK3, respectively. Subsequently, c-Jun increases transcription of target genes, including RACK1, an adaptor protein that enables PKC to phosphorylate and enhance JNK activity, enforcing a feed-forward mechanism of the JNK-Jun pathway. Activated c-Jun is also responsible for elevated cyclin D1 expression, which is frequently overexpressed in human melanoma. Our data reveal that, in human melanoma, the rewired ERK signaling pathway upregulates JNK and activates the c-Jun oncogene and its downstream targets, including RACK1 and cyclin D1.

Papillary thyroid cancer presenting as Horner syndrome.

Thyroid carcinomas are an uncommon entity in childhood. We report a case of papillary thyroid cancer presenting as Horner syndrome in a 14 year-old child, which is the only reported such case in the pediatric population.

A phase 0 trial of riluzole in patients with resectable stage III and IV melanoma.

PURPOSE: Ectopic expression of GRM1 in murine melanocytes results in transformation into a form of melanoma, and more than 60% of human melanoma samples tested ectopically express GRM1. Stimulation of this receptor in vitro results in up-regulation of activated extracellular signal-regulated kinase (ERK). Furthermore, a xenograft model of melanoma treated with riluzole, an oral GRM1 blocking agent, showed decreased tumor growth compared with the untreated controls. We have now completed a phase 0 trial of riluzole in patients with melanoma. EXPERIMENTAL DESIGN: Patients enrolled on this trial underwent a pretreatment biopsy, took 200 mg of oral riluzole per day for 14 days, and then underwent resection of their remaining tumor. We compared the levels of pERK and pAKT in the pretreatment and post-treatment samples and assessed the metabolic activity of pretreatment and post-treatment tumors using fluorodeoxyglucose positron emission tomography (FDG-PET) scanning. RESULTS: We accrued 12 patients and all expressed GRM1. We found a significant decrease in pAKT and/or pERK in post-treatment tumor samples as compared with pretreatment samples in 4 (34%) patients. These four patients had a significant decrease in FDG-PET intensity post-treatment as well. Two other patients had a clinical response with no corresponding metabolic response; five patients had similar pretreatment and post-treatment FDG-PET scan findings; and one patient had progressive disease. CONCLUSIONS: Our data show that glutamate blockade with riluzole can inhibit signaling through the mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT pathways and suppress the metabolic activity of melanoma. The ectopic expression of metabotropic glutamate receptors may be important in the pathogenesis of human melanoma, and targeting this pathway may be an effective therapy.

The effect of positive and negative verbal feedback on surgical skills performance and motivation.

There is considerable effort and time invested in providing feedback to medical students and residents during their time in training. However, little effort has been made to measure the effects of positive and negative verbal feedback on skills performance and motivation to learn and practice. To probe these questions, first-year medical students (n = 25) were recruited to perform a peg transfer task on Fundamentals of Laparoscopic Surgery box trainers. Time to completion and number of errors were recorded. The students were then randomized to receive either positive or negative verbal feedback from an expert in the field of laparoscopic surgery. After this delivery of feedback, the students repeated the peg transfer task. Differences in performance pre- and post-feedback and also between the groups who received positive feedback (PF) vs negative feedback (NF) were analyzed. A survey was then completed by all the participants. Baseline task times were similar between groups (PF 209.3 seconds; NF 203 seconds, p = 0.58). The PF group averaged 1.83 first-time errors while the NF group 1 (p = 0.84). Post-feedback task times were significantly decreased for both groups (PF 159.75 seconds, p = 0.05; NF 132.08 seconds, p = 0.002). While the NF group demonstrated a greater improvement in mean time than the PF group, this was not statistically significant. Both groups also made fewer errors (PF 0.33 errors, p = 0.04; NF 0.38 errors, p = 0.23). When surveyed about their responses to standardized feedback scenarios, the students stated that both positive and negative verbal feedback could be potent stimulants for improved performance and motivation. Further research is required to better understand the effects of feedback on learner motivation and the interpersonal dynamic between mentors and their trainees.

MDM4 is a key therapeutic target in cutaneous melanoma.

The inactivation of the p53 tumor suppressor pathway, which often occurs through mutations in TP53 (encoding tumor protein 53) is a common step in human cancer. However, in melanoma-a highly chemotherapy-resistant disease-TP53 mutations are rare, raising the possibility that this cancer uses alternative ways to overcome p53-mediated tumor suppression. Here we show that Mdm4 p53 binding protein homolog (MDM4), a negative regulator of p53, is upregulated in a substantial proportion (∼65%) of stage I-IV human melanomas and that melanocyte-specific Mdm4 overexpression enhanced tumorigenesis in a mouse model of melanoma induced by the oncogene Nras. MDM4 promotes the survival of human metastatic melanoma by antagonizing p53 proapoptotic function. Notably, inhibition of the MDM4-p53 interaction restored p53 function in melanoma cells, resulting in increased sensitivity to cytotoxic chemotherapy and to inhibitors of the BRAF (V600E) oncogene. Our results identify MDM4 as a key determinant of impaired p53 function in human melanoma and designate MDM4 as a promising target for antimelanoma combination therapy.

Preoperative basal calcitonin and tumor stage correlate with postoperative calcitonin normalization in patients undergoing initial surgical management of medullary thyroid carcinoma.

BACKGROUND: The optimal initial operative management of medullary thyroid cancer (MTC) and the use of biomarkers to guide the extent of operation remain controversial. We hypothesized that preoperative serum levels of calcitonin and carcinoembryonic antigen (CEA) correlate with extent of disease and postoperative levels reflect the extent of operation performed. METHODS: We assessed retrospectively clinical and pathologic factors among patients with MTC undergoing at least total thyroidectomy; these factors were correlated with biomarkers using regression analyses. RESULTS: Data were obtained from 104 patients, 28% with hereditary MTC. Preoperative calcitonin correlated with tumor size (P < .001) and postoperative serum calcitonin levels (P = .01) after multivariable adjustment for lymph node positivity, extent of operation, and hereditary MTC. No patient with a preoperative calcitonin level of <53 pg/mL (n = 20) had lymph node metastases. TNM stage (P = .001) and preoperative calcitonin levels (P = .04), but not extent of operation, independently correlated with the failure to normalize postoperative calcitonin. Postoperative CEA correlated with positive margins (adjusted P = 04). Neither preoperative nor postoperative CEA was correlated with lymph node positivity or extent of surgery. CONCLUSION: Preoperative serum calcitonin and TMN stage, but not extent of operation, were independent predictors of postoperative normalization of serum calcitonin levels. Future studies should evaluate preoperative serum calcitonin levels as a determinate of the extent of initial operation.

Routine second-opinion cytopathology review of thyroid fine needle aspiration biopsies reduces diagnostic thyroidectomy.

BACKGROUND: Follicular thyroid carcinoma cannot be distinguished reliably from benign follicular neoplasia by fine needle aspiration (FNA) biopsy. Given an estimated 20% risk of malignancy, many patients with indeterminate FNA biopsies require thyroidectomy for diagnosis. Some centers have shown significant discordance when a second pathologist evaluates the same FNA biopsy. We sought to determine whether routine second-opinion cytopathology reduces the need for diagnostic thyroidectomy, especially in patients with indeterminate FNA biopsies. METHODS: In all, 331 thyroid FNA biopsy specimens obtained from outside centers from 2004 to 2009 were reviewed at our institution. The FNA biopsy results were categorized into nondiagnostic (Bethesda I), benign (Bethesda II), indeterminate (follicular/Hurthle cell neoplasm, follicular/Hurthle cell lesion; Bethesda III & IV), and malignant (papillary or suspicious for papillary or other malignancy; Bethesda V and VI). Second-opinion cytology was compared with the initial opinion in 331 cases and with final operative pathology in the 250 patients who progressed to thyroidectomy. RESULTS: The average patient age was 51 with a predominant number of female (79%) participants. The overall cytology concordance for all 331 FNA biopsies was 66% (218/331). Concordance was highest at 86% (74/86) with malignant FNA biopsies. Concordance in the 129 patients with indeterminate FNA biopsies was only 37% (48/129). Indeterminate FNA biopsies were reread as nondiagnostic in 21% (27/129) of patients and as benign in 42% (54/129) of patients. Twenty-two patients with an indeterminate FNA biopsy reread as benign progressed to operative therapy for reasons other than cytology (eg, symptomatic nodule and radiation exposure/high risk) and were found to be benign in 95% (21/22) of patients on operative pathology for a 95% negative predictive value. An additional 11 patients with an indeterminate FNA reread as benign had follow-up FNA biopsies, each of which was benign. Indeterminate FNA biopsies on initial cytology had a malignancy rate of 13% (17/129) on operative pathology compared with 29% (14/48) for indeterminate FNA biopsies from second opinion. A second opinion improved FNA biopsy accuracy from 60% to 74%. Overall, second-opinion cytology of indeterminate FNA biopsies avoided diagnostic operation in 25% (32/129). CONCLUSION: Routine second opinion review of indeterminate thyroid FNA biopsies can potentially obviate the need for diagnostic thyroidectomy in 25% of patients without increases in false negatives.