Low Cancer Occurrence Rate following Prophylactic Nipple-Sparing Mastectomy.

BACKGROUND: Nipple-sparing mastectomy (NSM) has become widely available for breast cancer prophylaxis. There are limited data on its long-term oncologic safety. The objective of this study was to determine the incidence of breast cancer in patients who underwent prophylactic NSM. METHODS: All patients undergoing prophylactic NSM at a single institution from 2006 through 2019 were retrospectively reviewed. Patient demographic factors, genetic predispositions, mastectomy specimen pathology, and oncologic occurrences at follow-up were recorded. Descriptive statistics were performed where necessary to classify demographic factors and oncologic characteristics. RESULTS: A total of 871 prophylactic NSMs were performed on 641 patients, with median follow-up of 82.0 months (standard error 1.24). A total of 94.4% of patients ( n = 605) underwent bilateral NSMs, although only the prophylactic mastectomy was considered. The majority of mastectomy specimens (69.6%) had no identifiable pathology. A total of 38 specimens (4.4%) had cancer identified in mastectomy specimens, with ductal carcinoma in situ being the most common (92.1%; n = 35). Multifocal or multicentric disease was observed in seven cases (18.4%) and lymphovascular invasion was identified in two (5.3%). One patient (0.16%), who was a BRCA2 variant carrier, was found to have breast cancer 6.5 years after prophylactic mastectomy. CONCLUSIONS: Overall primary oncologic occurrence rates are very low in high-risk patients undergoing prophylactic NSM. In addition to reducing the risk of oncologic occurrence, prophylactic surgery itself may be therapeutic in a small proportion of patients. Continued surveillance for these patients remains important to assess at longer follow-up intervals. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, IV.

No Cancer Occurrences in 10-year Follow-up after Prophylactic Nipple-sparing Mastectomy.

Prophylactic nipple-sparing mastectomies (NSM) have become increasingly common, although there is little long-term data on its efficacy in prevention of breast cancer. The objective of this study was to assess the incidence of breast cancer in a cohort of patients undergoing prophylactic NSM with a median follow-up of 10 years. Methods: Patients receiving prophylactic NSM at a single institution from 2006 to 2019 were included in a retrospective nature. Patient demographics, genetic mutations, operative details, and specimen pathology were recorded, and all postoperative patient visits and documentation were screened for cancer occurrence. Descriptive statics were performed where appropriate. Results: Two hundred eighty-four prophylactic NSMs were performed on 228 patients with a median follow-up of 120.5 ± 15.7 months. Roughly, a third of patients had a known genetic mutation, with 21% BRCA1 and 12% BRCA2. The majority (73%) of prophylactic specimens had no abnormal pathology. The most commonly observed pathologies were atypical lobular hyperplasia (10%) and ductal carcinoma in situ (7%). Cancer was identified in 10% of specimens, with only one case of lymphovascular invasion. Thus far, there have been no incidences of locoregional breast cancer occurrence in this cohort. Conclusions: The long-term breast cancer occurrence rate in this cohort of prophylactic NSM patients at the time of this study is negligible. Despite this, continued surveillance of these patients is necessary until lifetime risk of occurrence following NSM has been established.

Long-Term Cancer Recurrence Rates following Nipple-Sparing Mastectomy: A 10-Year Follow-Up Study.

BACKGROUND: Despite the increased use of nipple-sparing mastectomies, there are limited data examining long-term cancer recurrence rates in these patients. The objective of this study was to analyze breast cancer recurrence in patients who underwent therapeutic nipple-sparing mastectomy with a median of 10 years of follow-up. METHODS: All patients undergoing nipple-sparing mastectomy at a single institution were retrospectively reviewed temporally to obtain a median of 10 years of follow-up. Patient demographic factors, mastectomy specimen pathologic findings, and oncologic outcomes were analyzed. Univariate analysis was performed to identify independent risk factors for locoregional recurrence. RESULTS: One hundred twenty-six therapeutic nipple-sparing mastectomies were performed on 120 patients. The most frequently observed tumor histology included invasive ductal carcinoma (48.4 percent) and ductal carcinoma in situ (38.1 percent). Mean tumor size was 1.62 cm. Multifocal or multicentric disease and lymphovascular invasion were present in 31.0 percent and 10.3 percent of nipple-sparing mastectomy specimens, respectively. Sentinel lymph node biopsy was performed in 84.9 percent of nipple-sparing mastectomies, and 17.8 percent were positive. The rate of positive frozen subareolar biopsy was 7.3 percent ( n = 82) and that of permanent subareolar pathology was 9.5 percent ( n = 126). The most frequently observed pathologic tumor stages were stage I (44.6 percent) and stage 0 (33.9 percent). The incidence of recurrent disease was 3.17 percent per mastectomy and 3.33 percent per patient. On univariate analysis, no demographic, operative, or tumor-specific variables were independent risk factors for locoregional recurrence. CONCLUSIONS: Overall recurrence rates are low in patients undergoing nipple-sparing mastectomy at a median follow-up of 10-years. Close surveillance should remain a goal for patients and their providers to promptly identify potential recurrence. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Optimization of an automated tumor-infiltrating lymphocyte algorithm for improved prognostication in primary melanoma.

Tumor-infiltrating lymphocytes (TIL) have potential prognostic value in melanoma and have been considered for inclusion in the American Joint Committee on Cancer (AJCC) staging criteria. However, interobserver discordance continues to prevent the adoption of TIL into clinical practice. Computational image analysis offers a solution to this obstacle, representing a methodological approach for reproducibly counting TIL. We sought to evaluate the ability of a TIL-quantifying machine learning algorithm to predict survival in primary melanoma. Digitized hematoxylin and eosin (H&E) slides from prospectively enrolled patients in the NYU melanoma database were scored for % TIL using machine learning and manually graded by pathologists using Clark's model. We evaluated the association of % TIL with recurrence-free survival (RFS) and overall survival (OS) using Cox proportional hazards modeling and concordance indices. Discordance between algorithmic and manual TIL quantification was assessed with McNemar's test and visually by an attending dermatopathologist. In total, 453 primary melanoma patients were scored using machine learning. Automated % TIL scoring significantly differentiated survival using an estimated cutoff of 16.6% TIL (log-rank P < 0.001 for RFS; P = 0.002 for OS). % TIL was associated with significantly longer RFS (adjusted HR = 0.92 [0.84-1.00] per 10% increase in % TIL) and OS (adjusted HR = 0.90 [0.83-0.99] per 10% increase in % TIL). In comparison, a subset of the cohort (n = 240) was graded for TIL by melanoma pathologists. However, TIL did not associate with RFS between groups (P > 0.05) when categorized as brisk, nonbrisk, or absent. A standardized and automated % TIL scoring algorithm can improve the prognostic impact of TIL. Incorporation of quantitative TIL scoring into the AJCC staging criteria should be considered.

Preliminary analysis of distinct clinical and biologic features of bone metastases in melanoma.

Melanoma disseminates to the skeletal system where it is then difficult to treat. Yet, there remains limited research investigating metastatic bone disease (MBD) in melanoma. Here, we evaluate whether there are distinct clinicopathologic variables at the time of primary melanoma diagnosis that predispose metastases to engraft bone, and we test the hypothesis that patients with MBD have different responses to treatment. Cutaneous melanoma patients enrolled in a prospective database were studied. Individuals with metastatic melanoma and bone metastases (M-Bone) were compared to those with metastatic disease but no M-Bone. Of the 463 (42.7%) patients, 198 with unresectable metastatic melanoma had M-Bone and 98 developed bone metastasis (bone mets) as first site. Progression-free survival and overall survival were significantly worse in patients with M-Bone compared to those without M-Bone (P < 0.001) independent of treatment modalities, and in patients whose melanoma spread to bone first, compared to those who developed first mets elsewhere (P < 0.001). Interestingly, patients with bone mets presented with primary tumors that had more tumor infiltrating lymphocytes (P < 0.001) and less often a nodular histologic subtype compared to patients without M-Bone (P < 0.001). Our data suggest that melanoma bone metastasis is a distinct clinical and biological entity that cannot be explained by generalized metastatic phenotype in all patients. The observed dichotomy between more favorable primary histopathologic characteristics and a grave overall prognosis requires more studies to elucidate the molecular processes by which melanomas infiltrate bone and to build a mechanistic understanding of how melanoma bone metastases yield such detrimental outcomes.

Metastasectomy for melanoma is associated with improved overall survival in responders to targeted molecular or immunotherapy.

BACKGROUND AND OBJECTIVES: Metastasectomy for melanoma provides durable disease control in carefully selected patients. Similarly, BRAF-targeted and immune checkpoint inhibition has improved median overall survival (OS) in metastatic patients. We hypothesized that there is an increasing role for metastasectomy in melanoma patients responding to these therapies. METHODS: Retrospective analysis of a prospectively maintained database identified 128 patients with stage IV melanoma who received targeted molecular and/or checkpoint inhibitors at an academic institution from 2006 to 2017. Records were reviewed to characterize clinicopathologic characteristics, response to treatment, and intent of surgery for those who underwent metastasectomy. OS was analyzed by the Kaplan-Meier method. RESULTS: Median OS from stage IV diagnosis was 31.3 months. A total of 81 patients received checkpoint inhibitors, 11 received targeted inhibitors, and 36 received both. A total of 73 patients underwent metastasectomy. Indications for surgery included the intent to render disease-free (54%), palliation (34%), and diagnostic confirmation (11%). Responders to systemic therapy who underwent metastasectomy had improved OS compared to responders who did not (84.3 vs. 42.9 months, P = .018). CONCLUSIONS: Metastasectomy for melanoma is associated with improved OS in patients that respond to targeted molecular or immunotherapy. Resection should be strongly considered in this cohort as multimodality treatment results in excellent OS.

Impact of initial stage on metastatic melanoma survival.

Patients diagnosed with metastatic melanoma have varied clinical courses, even in patients with similar disease characteristics. We examine the impact of initial stage of melanoma diagnosis, BRAF status of primary melanoma, and receiving adjuvant therapy on postmetastatic overall survival (pmOS). We studied melanoma patients presenting to Perlmutter Cancer Center at New York University and prospectively enrolled in New York University melanoma biospecimen database and followed up on protocol-driven schedule. Patients were stratified by stage at initial melanoma diagnosis as per AJCC 7th ed. guidelines. pmOS was determined using the Kaplan-Meier method and Cox's proportional hazards models were used to assess hazard ratios (HRs). Three hundred and four out of 3204 patients developed metastatic disease over the time of follow-up (median follow-up 2.2 years, range: 0.08-35.2 years). Patients diagnosed with stage I (n=96) melanoma had longer pmOS (29.5 months) than those diagnosed with stage II (n=99, pmOS 14.9 months) or stage III (n=109, pmOS 15.1 months) melanoma (P=0.036). Initial stage of diagnosis remained significant in multivariate analysis when controlling for lactate dehydrogenase and site of metastases [primary diagnosis stage II (HR 1.44, P=0.046), stage III (HR 1.5, P=0.019)]. Adjuvant treatment was associated with better survival but BRAF mutation status did not show an association. Our data challenge the general assumption that primary melanomas converge upon diagnosis of metastatic disease and behave uniformly. Primary stage of melanoma at the time of diagnosis may be prognostic of outcome, similar to lactate dehydrogenase and metastatic disease sites.

Oncologic Trends, Outcomes, and Risk Factors for Locoregional Recurrence: An Analysis of Tumor-to-Nipple Distance and Critical Factors in Therapeutic Nipple-Sparing Mastectomy.

BACKGROUND: Oncologic outcomes with nipple-sparing mastectomy continue to be established. The authors examine oncologic trends, outcomes, and risk factors, including tumor-to-nipple distance, in therapeutic nipple-sparing mastectomies. METHODS: Demographics, outcomes, and overall trends for all nipple-sparing mastectomies performed for a therapeutic indication from 2006 to 2017 were analyzed. Oncologic outcomes were investigated with specific focus on recurrence and associated factors, including tumor-to-nipple distance. RESULTS: A total of 496 therapeutic nipple-sparing mastectomies were performed, with an average follow-up time of 48.25 months. The most common tumor types were invasive carcinoma (52.4 percent) and ductal carcinoma in situ (50.4 percent). Sentinel lymph node sampling was performed in 79.8 percent of nipple-sparing mastectomies; 4.1 percent had positive frozen sentinel lymph node biopsy results, whereas 15.7 percent had positive nodal status on permanent pathologic examination. The most common pathologic cancer stage was stage IA (42.5 percent) followed by stage 0 (31.3 percent). The rate of local recurrence was 1.6 percent (n = 8), and the rate of regional recurrence was 0.6 percent (n = 3). In all, 171 nipple-sparing mastectomies had magnetic resonance imaging available with which to assess tumor-to-nipple distance. Tumor-to-nipple distance of 1 cm or less (25.0 percent versus 2.4 percent; p = 0.0031/p = 0.1129) and of 2 cm or less (8.7 percent versus 2.0 percent; p = 0.0218/p = 0.1345) trended to higher rates of locoregional recurrence. In univariate analysis, tumor-to-nipple distance of 1 cm or less was the only significant risk factor for recurrence (OR, 13.5833; p = 0.0385). No factors were significant in regression analysis. CONCLUSIONS: In early stage and in situ breast carcinoma, therapeutic nipple-sparing mastectomy appears oncologically safe, with a locoregional recurrence rate of 2.0 percent. Tumor-to-nipple distances of 1 cm or less and 2 cm or less trended to higher recurrence rates. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Association between Ki-67 expression and clinical outcomes among patients with clinically node-negative, thick primary melanoma who underwent nodal staging.

BACKGROUND: Patients with thick primary melanomas (≥4 mm) have highly variable survival outcomes. Cell proliferation marker Ki-67 has been identified as promising biomarker in thick melanoma but has not been evaluated since the wide spread adoption of sentinel lymph node biopsy. We revisit its prognostic relevance in the sentinel node era. METHODS: We studied patients with thick (≥4 mm) primary melanoma prospectively enrolled in a clinicopathological biospecimen database from 2002 to 2015, and evaluated the prognostic value of Ki-67 expression while controlling for features included in the existing staging criteria. RESULTS: We analyzed 68 patients who underwent lymph node sampling and who had an available tumor for Ki-67 immunohistochemical (IHC) staining. The median tumor thickness was 6.0 mm; the median follow-up was 2.6 years. In multivariable analysis including nodal status and primary tumor ulceration, Ki-67 expression was an independent predictor of worse recurrence-free survival (HR 2.19, P = 0.024) and overall survival (HR 2.49, P = 0.028). Natural log-transformed tumor thickness (ln [thickness]) was also significantly associated with worse OS (HR 2.39, P = 0.010). CONCLUSION: We identify Ki-67 and ln (thickness) as potential biomarkers for patients with thick melanoma who have undergone nodal staging. If validated in additional studies, these biomarkers could be integrated into the staging criteria to improve risk-stratification.

Treatment Outcomes for Metastatic Melanoma of Unknown Primary in the New Era: A Single-Institution Study and Review of the Literature.

BACKGROUND: Metastatic melanoma of unknown primary (MUP) is uncommon, biologically ill defined, and clinically understudied. MUP outcomes are seldom reported in clinical trials. In this study, we analyze responses of MUP patients treated with systemic therapy in an attempt to inform treatment guidelines for this unique population. METHODS: New York University (NYU)'s prospective melanoma database was searched for MUP patients treated with systemic therapy. PubMed and Google Scholar were searched for MUP patients treated with immunotherapy or targeted therapy reported in the literature, and their response and survival data were compared to the MUP patient data from NYU. Both groups' response data were compared to those reported for melanoma of known primary (MKP). RESULTS: The MUP patients treated at NYU had better outcomes on immunotherapy but worse on targeted therapy than the MUP patients in the literature. The NYU MUP patients and those in the literature had worse outcomes than the majority-MKP populations in 10 clinical trial reports. CONCLUSIONS: Our study suggests that MUP patients might have poorer outcomes on systemic therapy as compared to MKP patients. Our cohort was small and limited data were available, highlighting the need for increased reporting of MUP outcomes and multi-institutional efforts to understand the mechanism behind the observed differences.

Outcomes in Melanoma Patients Treated with BRAF/MEK-Directed Therapy or Immune Checkpoint Inhibition Stratified by Clinical Trial versus Standard of Care.

OBJECTIVES: Since 2011, metastatic melanoma treatment has evolved with commercial approval of BRAF- and MEK-targeted therapy and CTLA-4- and PD-1-blocking antibodies (immune checkpoint inhibitors, ICI). While novel therapies have demonstrated improved prognosis in clinical trials, few studies have examined the evolution of prognosis and toxicity of these drugs among an unselected population. We assess whether survival and toxicity reported in trials, which typically exclude most patients with brain metastases and poor performance status, are recapitulated within a commercial access population. METHODS: 182 patients diagnosed with stage IV melanoma from July 2006 to December 2013 and treated with BRAF- and/or MEK-targeted therapy or ICI were prospectively studied. Outcomes and clinicopathologic differences between trial and commercial cohorts were assessed. RESULTS: Patients receiving commercial therapy (vs. on trial) had poorer prognostic features (i.e., brain metastases) and lower median overall survival (mOS) when assessed across all treatments (9.2 vs. 17.5 months, p = 0.0027). While toxicity within trial and commercial cohorts did not differ, patients who experienced toxicity had increased mOS (p < 0.001), irrespective of stratification by trial status or therapy. CONCLUSION: Metastatic melanoma patients receiving commercial treatment may represent a different clinical population with poor prognostic features compared to trial patients. Toxicity may prognosticate treatment benefit.

The Expression Quantitative Trait Loci in Immune Pathways and their Effect on Cutaneous Melanoma Prognosis.

PURPOSE: The identification of personalized germline markers with biologic relevance for the prediction of cutaneous melanoma prognosis is highly demanded but to date, it has been largely unsuccessful. As melanoma progression is controlled by host immunity, here we present a novel approach interrogating immunoregulatory pathways using the genome-wide maps of expression quantitative trait loci (eQTL) to reveal biologically relevant germline variants modulating cutaneous melanoma outcomes. EXPERIMENTAL DESIGN: Using whole genome eQTL data from a healthy population, we identified 385 variants significantly impacting the expression of 268 immune-relevant genes. The 40 most significant eQTLs were tested in a prospective cohort of 1,221 patients with cutaneous melanoma for their association with overall (OS) and recurrence-free survival using Cox regression models. RESULTS: We identified highly significant associations with better melanoma OS for rs6673928, impacting IL19 expression (HR, 0.56; 95% CI, 0.41-0.77; P = 0.0002) and rs6695772, controlling the expression of BATF3 (HR, 1.64; 95% CI, 1.19-2.24; P = 0.0019). Both associations map in the previously suspected melanoma prognostic locus at 1q32. Furthermore, we show that their combined effect on melanoma OS is substantially enhanced reaching the level of clinical applicability (HR, 1.92; 95% CI, 1.43-2.60; P = 2.38e-5). CONCLUSIONS: Our unique approach of interrogating lymphocyte-specific eQTLs reveals novel and biologically relevant immunomodulatory eQTL predictors of cutaneous melanoma prognosis that are independent of current histopathologic markers. The significantly enhanced combined effect of identified eQTLs suggests the personalized utilization of both SNPs in a clinical setting, strongly indicating the promise of the proposed design for the discovery of prognostic or risk germline markers in other cancers. Clin Cancer Res; 22(13); 3268-80. ©2016 AACR.

Chondroid syringoma of the axilla: An unusual tumor diagnosed by fine needle aspiration.

Chondroid syringoma (CS) is a rare benign adnexal tumor of the skin with a resemblance to pleomorphic adenoma of salivary gland, most commonly involving the head and neck region. In the present literature, reports of the cytologic appearance of CS are scarce as it is rarely encountered by fine needle aspiration (FNA). A 67-year-old woman presented with a 1 year history of a 1 cm subcutaneous nodule in the right axilla. FNA biopsy was performed revealing an epithelial-mesenchymal biphasic neoplasm suggesting CS. Surgical excision confirmed the diagnosis and demonstrated extensive ossification, an extremely rare feature, with only seven reported cases, all located on the head. CS is a rare benign adnexal tumor of the skin, often overlooked due to its unremarkable clinical presentation. FNA is a reliable tool for the diagnosis of CS and helps guide optimal surgical management.

Nipple-sparing Mastectomy and Sub-areolar Biopsy: To Freeze or not to Freeze? Evaluating the Role of Sub-areolar Intraoperative Frozen Section.

Use of nipple-sparing mastectomy (NSM) for risk-reduction and therapeutic breast cancer resection is growing. The role for intraoperative frozen section of the nipple-areolar complex remains controversial. Records of patients undergoing NSM at our institution from 2006 to 2013 were reviewed. Records from 501 nipple-sparing mastectomies were reviewed (216 therapeutic, 285 prophylactic). Of the 480 breasts with sub-areolar biopsies, 307 had intraoperative frozen sections and 173 were evaluated with permanent paraffin section only. Among the 307 intraoperative frozen sections, 12 biopsies were positive on permanent paraffin section (3.9% or 12/307). Of the 12 positive permanent biopsies, five were false negative and the remaining seven concordant intraoperatively. Sensitivity and specificity of sub-areolar frozen section were 0.58 and 1, respectively. Positive sub-areolar biopsies consisted primarily of ductal carcinoma in situ (62% or 13/21). The nipples or nipple-areolar complex were resected in a separate procedure following mastectomy (10/21), intraoperatively following frozen section results (7/21) or during second-stage breast reconstruction (3/21; 1 additional scheduled). Only 30% (6/20) of resected specimens had abnormal residual pathology. Intraoperative frozen section is highly specific and moderately sensitive for the detection of positive sub-areolar biopsies in NSM. Its use can help guide intraoperative reconstructive planning. The presence of positive sub-areolar biopsies in both contralateral and high-risk prophylactic mastectomy specimens emphasizes the need to perform sub-areolar biopsies in all nipple-sparing mastectomies.

Identification of a Novel Pathogenic Germline KDR Variant in Melanoma.

PURPOSE: The application of pan-cancer next-generation sequencing panels in the clinical setting has facilitated the identification of low frequency somatic mutations and the testing of new therapies in solid tumors using the "basket trial" scheme. However, little consideration has been given to the relevance of nonsynonymous germline variants, which are likely to be uncovered in tumors and germline and which may be relevant to prognostication and prediction of treatment response. EXPERIMENTAL DESIGN: We analyzed matched tumor and normal DNA from 34 melanoma patients using an Ion Torrent cancer-associated gene panel. We elected to study the germline variant Q472H in the kinase insert domain receptor (KDR), which was identified in 35% of melanoma patients in both a pilot and an independent 1,223 patient cohort. Using patient-derived melanoma cell lines and human samples, we assessed proliferation, invasion, VEGF levels, and angiogenesis by analyzing tumor microvessel density (MVD) using anti-CD34 antibody. RESULTS: Serum VEGF levels and tumor MVD were significantly higher in Q472H versus KDR wild-type (WD) patients. Primary cultures derived from melanomas harboring the KDR variant were more proliferative and invasive than KDR wild type. Finally, using a VEGFR2 antibody, we showed that KDR Q472H cells were sensitive to targeted inhibition of VEGFR2, an effect that was not observed in KDR WT cells. CONCLUSIONS: Our data support the integration of germline analysis into personalized treatment decision-making and suggest that patients with germline KDR variant might benefit from antiangiogenesis treatment. Clin Cancer Res; 22(10); 2377-85. ©2015 AACR.

Oncologic outcomes after nipple-sparing mastectomy: A single-institution experience.

INTRODUCTION: Long-term oncologic outcomes in nipple-sparing mastectomy (NSM) continue to be defined. Rates of locoregional recurrence for skin-sparing mastectomy (SSM) and NSM in the literature range from 0% to 14.3%. We investigated the outcomes of NSM at our institution. METHODS: Patients undergoing NSM at our institution from 2006 to 2014 were identified and outcomes were analyzed. RESULTS: From 2006 to 2014, 319 patients (555 breasts) underwent NSM. One-hundered and fourty-one patients (237 breasts) had long-term follow-up available. Average patient age and BMI were 47.78 and 24.63. Eighty-four percent of patients underwent mastectomy primarily for a therapeutic indication. Average tumor size was 1.50 cm with the most common histologic type being invasive ductal carcinoma (62.7%) followed by DCIS (23.7%). Average patient follow-up was 30.73 months. There was one (0.8%) incidence of ipsilateral chest-wall recurrence. There were 0.37 complications per patient. CONCLUSIONS: We examined our institutional outcomes with NSM and found a locoregional recurrence rate of 0.8% with no nipple-areolar complex recurrence. This rate is lower than published rates for both NSM and SSM.

Cost Analysis of Intraoperative Subareolar Frozen Section During Nipple-Sparing Mastectomy.

BACKGROUND: Permanent paraffin subareolar biopsy during nipple-sparing mastectomy (NSM) tests for occult cancer at the nipple-areolar complex. Intraoperative subareolar frozen section can provide earlier detection intraoperatively. Cost analysis for intraoperative subareolar frozen section has never been performed. METHODS: NSM cases from 2006-2013 were reviewed. Patient records including financial charges were analyzed. RESULTS: Of 480 subareolar biopsies for NSM from 2006-2013, 21 were abnormal (4.4 %). A total of 307 of the subareolar biopsies included intraoperative frozen section. Of the 307, 12 (3.9 %) were abnormal with 7 of 12 detected on intraoperative frozen section. The median baseline charge for an intraoperative subareolar frozen section was $309 for an estimated total cost of $94,863 in 307 breasts. The median baseline charge for interval operative resection of a nipple-areolar complex following an abnormal subareolar pathology result was $11,021. Intraoperative subareolar biopsy avoided an estimated six return trips to the operating room for savings of $66,126. At our institution, routine use of intraoperative frozen section resulted in an additional $28,737 in healthcare charges or $95 per breast. CONCLUSIONS: We present the first cost analysis to evaluate intraoperative subareolar frozen section in NSM. This practice obviated an estimated six return trips to the operating room. With our institutional frequency of abnormal subareolar pathology, intraoperative frozen sections resulted in a marginal increased charge per mastectomy.

Identification of metastasis-suppressive microRNAs in primary melanoma.

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.