"Nipple-sparing mastectomy in patients with a history of reduction mammaplasty or mastopexy: how safe is it?"Alperovich, Michael; Tanna, Neil; Samra, Fares; Blechman, Keith M; SHAPIRO, RICHARD L; Guth, Amber A; Axelrod, Deborah M; Choi, Mihye; Karp, Nolan S
BACKGROUND: : Nipple-sparing mastectomy has gained popularity, but the question remains of whether it can be offered safely to women with a history of reduction mammaplasty or mastopexy. The authors present their experience with nipple-sparing mastectomy in this patient population. METHODS: : Patients at the authors' institution who had reduction mammaplasty or mastopexy before nipple-sparing mastectomy were identified. Outcomes measured include nipple-areola complex viability, mastectomy flap necrosis, infection, presence of cancer in the nipple-areola complex, and breast cancer recurrence. RESULTS: : The records of the nipple-sparing mastectomy patients at the authors' institution from 2006 through 2012 were reviewed. The authors identified 13 breasts in eight patients that had nipple-sparing mastectomy following reduction mammaplasty or mastopexy. Within this subset of patients, the mean age was 46.6 years and the mean body mass index was 25.1. Nine of 13 breasts had therapeutic resections, whereas the remaining four were for prophylactic indications. Average time elapsed between reduction mammaplasty or mastopexy and nipple-sparing mastectomy was 51.8 months (range, 33 days to 11 years). In all cases, prior reduction mammaplasty/mastopexy incisions were used for nipple-sparing mastectomy. Ten breasts underwent reconstruction immediately with tissue expanders, one with a latissimus dorsi flap with immediate implant and two with immediate abdominally based free flaps. Complications included one hematoma requiring evacuation and one displaced implant requiring revision. There were no positive subareolar biopsy results, and the nipple viability was 100 percent. Mean follow-up time was 10.5 months. CONCLUSIONS: : The authors' experience demonstrates that nipple-sparing mastectomy can be offered to patients with a history of reduction mammaplasty or mastopexy with reconstructive outcomes comparable to those of nipple-sparing mastectomy alone. CLINICAL QUESTION/LEVEL OF EVIDENCE: : Therapeutic, IV..
"The lateral inframammary fold incision for nipple-sparing mastectomy: outcomes from over 50 immediate implant-based breast reconstructions"Blechman, Keith M; Karp, Nolan S; Levovitz, Chaya; Guth, Amber A; Axelrod, Deborah M; SHAPIRO, RICHARD L; Choi, Mihye
Nipple-sparing mastectomy (NSM) as a therapeutic or prophylactic procedure for breast cancer is rapidly gaining popularity as the literature continues to support it safety. The lateral inframammary fold (IMF) approach provides adequate exposure and eliminates visible scars on the anterior surface of the breast, making this incision cosmetically superior to radial or periareolar approaches. We reviewed 55 consecutive NSMs performed through a lateral IMF incision with immediate implant-based reconstruction, with or without tissue expansion, between June 2008 and June 2011. Prior to incision, breasts were lightly infiltrated with dilute anesthetic solution with epinephrine. Sharp dissection, rather than electrocautery, was used as much as possible to minimize thermal injury to the mastectomy flap. When indicated, acellular dermal matrix was placed as an inferolateral sling. Subsequent fat grafting to correct contour deformities was performed in select patients. Three-dimensional (3D) photographs assessed changes in volume, antero-posterior projection, and ptosis. Mean patient age was 46 years, and mean follow-up time was 12 months. Twelve mastectomies (22%) were therapeutic, and the remaining 43 (78%) were prophylactic. Seven of the nine sentinel lymph node biopsies (including one axillary dissection) (78%) were performed through the lateral IMF incision without the need for a counter-incision. Acellular dermal matrix was used in 34 (62%) breasts. Average permanent implant volume was 416 cc (range 176-750 cc), and average fat grafting volume was 86 cc (range 10-177 cc). In one patient a positive intraoperative subareolar biopsy necessitated resection of the nipple-areola complex (NAC), and in two other patients NAC resection was performed at a subsequent procedure based on the final pathology report. Mastectomy flap necrosis, requiring operative debridement, occurred in two breasts (4%), both in the same patient. One of these breasts required a salvage latissimus dorsi myocutaneous flap to complete the reconstruction. Three nipples (6%) required office debridement for partial necrosis and operative reconstruction later. No patient had complete nipple necrosis. No statistically significant differences existed between therapeutic and prophylactic mastectomies for developing partial skin and/or nipple necrosis (p = 0.35). Three episodes (5%) of cellulitis occurred, which responded to antibiotics without the need for explantation. Morphological outcomes using 3D scan measurements showed reconstructed breasts were larger, more projected, and less ptotic than the preoperative breasts (196 versus 248 cc, 80 versus 90 mm, 146 versus 134 mm, p < 0.01 for each parameter). Excellent results can be achieved with immediate implant-based reconstruction of NSM through a lateral IMF incision. NAC survival is reliable, and complication rates are low..
"Mitotic Rate in Melanoma: Prognostic Value of Immunostaining and Computer-assisted Image Analysis"Hale, Christopher S; Qian, Meng; Ma, Michelle W; Scanlon, Patrick; Berman, Russell S; SHAPIRO, RICHARD L; Pavlick, Anna C; Shao, Yongzhao; Polsky, David; Osman, Iman; Darvishian, Farbod
GRANTS:P30 CA016087/CA/NCI NIH HHS/United States;UL1 TR000038/TR/NCATS NIH HHS/United States
The prognostic value of mitotic rate in melanoma is increasingly recognized, particularly in thin melanoma in which the presence or absence of a single mitosis/mm can change staging from T1a to T1b. Still, accurate mitotic rate calculation (mitoses/mm) on hematoxylin and eosin (H&E)-stained sections can be challenging. Antimonoclonal mitotic protein-2 (MPM-2) and antiphosphohistone-H3 (PHH3) are 2 antibodies reported to be more mitosis-specific than other markers of proliferation such as Ki-67. We used light microscopy and computer-assisted image analysis software to quantify MPM-2 and PHH3 staining in melanoma. We then compared mitotic rates by each method with conventional H&E-based mitotic rate for correlation with clinical outcomes. Our study included primary tissues from 190 nonconsecutive cutaneous melanoma patients who were prospectively enrolled at New York University Langone Medical Center with information on age, gender, and primary tumor characteristics. The mitotic rate was quantified manually by light microscopy of corresponding H&E-stained, MPM-2-stained, and PHH3-stained sections. Computer-assisted image analysis was then used to quantify immunolabeled mitoses on the previously examined PHH3 and MPM-2 slides. We then analyzed the association between mitotic rate and both progression-free and melanoma-specific survival. Univariate analysis of PHH3 found significant correlation between increased PHH3 mitotic rate and decreased progression-free survival (P=0.04). Computer-assisted image analysis enhanced the correlation of PHH3 mitotic rate with progression-free survival (P=0.02). Regardless of the detection method, neither MPM-2 nor PHH3 offered significant advantage over conventional H&E determination of mitotic rate..
"TILs in metastatic melanoma tumors: A biomarker for immunotherapy?" [Meeting Abstract]Chandra, S; Ding, Y; Ma, M W; Bannan, M; Darvishian, F; Berman, R S; SHAPIRO, R; Krogsgaard, M; Osman, I; Pavlick, A C
Background: Increased tumor infiltrating lymphocytes (TILs) in primary (P) and locoregional melanoma tissue correlate with improved clinical outcome. Our recent data have suggested that matrix metalloproteinase 23 (MMP 23) expression (exp) in P result in lower prevalence of TILs and correlate with poor clinical outcome. On this basis, we examined P and metastatic (M) melanoma tissues to assess for concordance between the presence of TILs, MMP 23 protein levels and clinical response(resp) to anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) therapy (tx). Methods: 21 melanoma patients (pts) with M specimens were analyzed. 17 matched P specimens were also evaluated. Immunohistochemical (IHC) staining for TILs of the pre-anti-CTLA4 specimens were conducted and confirmed by 2 pathologists. IHC TILs were graded- 2+: >10% TILs present in multiple foci in both peri- and through the tumor; 1+: 1-10% TILs present in one or more foci in the tumor and predominantly peri-tumor; 0: no TILs were present or if the lymphocytes did not infiltrate the tumor. TILs in P and M were analyzed for concordance and potential for predictability of resp to anti-CTLA4 tx. Staining to identify lymphocyte subtypes and MMP 23 exp in M is being completed. Results: 20 pts received anti-CTLA4 tx. M analysis- 6 pts with 0 TILs in M (5 no response [NR], 1 partial response[PR]); 8 pts with 1-2+ TILs in M (1 complete response [CR], 5 PR, 2 progressive disease [PD]); 6 pts with 2+ TILs in M ( 3 CR, 2 PR, 1PD). 1 pt with 2+ TILs in M resected, no tx and 4 years disease free. TILs present in 13 P, absent in 4 P and not evaluable in 4 pts with unknown P melanoma. MMP 23 protein scores in P (range 2-4) correlated with melanoma recurrence. MMP 23 exp in M will be reported. Conclusions: TILs in P do not appear to correlate with TILs in M or predict for resp to anti-CTLA4 tx. TILs in M may be an indicator of responsiveness to anti-CTLA4 tx. Identification of the type of M TIL subsets may further refine tx recommendations.
"Five Year Outcome of 145 Patients With Ductal Carcinoma In Situ (DCIS) After Accelerated Breast Radiotherapy"Ciervide, Raquel; Dhage, Shubhada; Guth, Amber; SHAPIRO, RICHARD L; Axelrod, Deborah M; Roses, Daniel F; Formenti, Silvia C
BACKGROUND: Accelerated whole-breast radiotherapy (RT) with tumor bed boost in the treatment of early invasive breast cancer has demonstrated equivalent local control and cosmesis when compared with standard RT. Its efficacy in the treatment of ductal carcinoma in situ (DCIS) remains unknown. METHODS AND MATERIALS: Patients treated for DCIS with lumpectomy and negative margins were eligible for 2 consecutive hypofractionated whole-breast RT clinical trials. The first trial (New York University [NYU] 01-51) prescribed to the whole breast 42 Gy (2.8 Gy in 15 fractions) and the second trial (NYU 05-181) 40.5 Gy (2.7 Gy in 15 fractions) with an additional daily boost of 0.5 Gy to the surgical cavity. RESULTS: Between 2002 and 2009, 145 DCIS patients accrued, 59 to the first protocol and 86 to the second trial. Median age was 56 years and 65% were postmenopausal at the time of treatment. Based on optimal sparing of normal tissue, 79% of the patients were planned and treated prone and 21% supine. At 5 years' median follow-up (60 months; range 2.6-105.5 months), 6 patients (4.1%) experienced an ipsilateral breast recurrence in all cases of DCIS histology. In 3/6 patients, recurrence occurred at the original site of DCIS and in the remaining 3 cases outside the original tumor bed. New contralateral breast cancers arose in 3 cases (1 DCIS and 2 invasive carcinomas). Cosmetic self-assessment at least 2 years after treatment is available in 125 patients: 91% reported good-to-excellent and 9% reported fair-to-poor outcomes. CONCLUSIONS: With a median follow-up of 5 years, the ipsilateral local recurrence rate is 4.1%, comparable to that reported from the NSABP (National Surgical Adjuvant Breast and Bowel Project) trials that employed 50 Gy in 25 fractions of radiotherapy for DCIS. There were no invasive recurrences. These results provide preliminary evidence that accelerated hypofractionated external beam radiotherapy is a viable option for DCIS..
"Serum microRNAs as biomarkers for recurrence in melanoma"Friedman, Erica B; Shang, Shulian; de Miera, Eleazar Vega-Saenz; Fog, Jacob Ulrik; Teilum, Maria Wrang; Ma, Michelle W; Berman, Russell S; SHAPIRO, RICHARD L; Pavlick, Anna C; Hernando, Eva; Baker, Adam; Shao, Yongzhao; Osman, Iman
GRANTS:1UL1RR029893/RR/NCRR NIH HHS/United States;5P30CA16087/CA/NCI NIH HHS/United States
ABSTRACT: BACKGROUND: Identification 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. METHODS: We 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. RESULTS: A 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. CONCLUSION: Our 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..
"Prognostic value of mitosis-specific antibodies and computer image analysis in calculating mitotic rate in melanoma" [Meeting Abstract]Hale, C; Qian, M; Ma, M W; Shao, Y; Polsky, D; SHAPIRO, R L; Berman, R S; Pavlick, A C; Osman, I; Darvishian, F
Background: Mitotic rate (MR) is an important part of staging for thin melanomas (1 mm) but its value in thick melanomas (>1 mm) has not been determined. Additionally, accurate calculation of MR on hematoxylin and eosin (H&E) stained sections can be challenging. Several mitosis-specific antibodies are commercially available but their role in predicting clinical outcome in melanoma has not been adequately assessed compared to H&E. Methods: Primary tissues from 190 cutaneous melanoma patients [1 mm (n = 22); >1 mm (n=168)] prospectively enrolled at New York University Medical Center were stained with MPM-2 and PHH3, two mitosis-specific antibodies. Using light microscopy, MR was quantified manually from corresponding H&E, MPM-2, and PHH3-stained sections. Computer-assisted image analysis was then applied to detect immunolabeled mitoses on the previously examined PHH3 and MPM-2 slides. We then analyzed the association between MR and progression-free survival (PFS) and melanoma-specific survival (MSS). Results: Manual quantification of PHH3-derived MR was associated with shorter PFS in thick melanomas (P=0.042). Computer-assisted quantification of PHH3 showed a significant association with shorter PFS and MSS in thick melanomas (P=0.021, P=0.04, respectively). Relative to manual analysis of corresponding H&E-stained sections, manual analysis of PHH3 and MPM-2 stains increased mean MR (86% and 159% increases, respectively). MPM-2 did not have value as mitosis-specific marker in melanoma of any thickness. Conclusions: PHH3-derived MR might be useful in predicting worse clinical outcome in primary melanoma patients with thicker melanoma.
"Early alterations of microRNA expression to predict and modulate melanoma metastasis" [Meeting Abstract]Hernando, E; Hanniford, D; Shang, S; Segura, M F; Pavlick, A C; Berman, R S; SHAPIRO, R L; Darvishian, F; Osman, I; Shao, Y
Background: Melanoma is curable for most patients whose tumors are surgically removed early in disease progression; however, many primary melanomas recur and progress to metastasis. Clinical staging is insufficient to robustly classify patients at highest risk of recurrence, and prognostic molecular biomarkers have not yet been identified. Methods: We performed miRNA profiling of 92 FFPE primary melanomas to discover metastasis relevant miRNAs and develop predictive models of recurrence, which were then validated in an independent cohort. We identified miRNAs differentially expressed between primary tumors that did and did not recur (3-year minimum follow-up) and between thick and thin lesions. We selected candidate miRs for screening in a fluorescence-based in vitro invasion assay, and prioritized a subset for in vivo testing. Potential downstream mediators of these miRNAs were selected by mRNA array analysis and tested in a secondary invasion screen. mRNA candidates that mimicked the miR's invasion-suppressive effect were tested in 3'UTR reporter assays to confirm them as direct targets. Results: Using the discovery cohort we identified a 20 miRNA signature that can distinguish Stage I/II primary tumors (n=70) that did from those did not recur with 3-year minimum follow-up with an AUC=94%, 95% CI: (0.88, 0.99). Applying this model to predict risk for recurrence in the independent validation cohort yielded an AUC = 96%, 95% CI: (0.90, 1) in discriminating recurrent versus non-recurrent stages I/ II patients (n=45). From the discovery cohort, 40 candidates were selected for invasion assay screening, of which 5 miRNAs robustly inhibit in vitro invasion in 5 melanoma cell lines. Three miRs (miR-382, miR-516b, and miR-7) strongly suppressed metastasis in a mouse model. Moreover, multiple mRNAs tested as potential mediators mimicked the invasion-suppressive effects of candidate miRs. Of those, NCAPG2 and CDC42 were identified as miR-516b targets, CTTN as a miR-382 target, and PIK3CD as a miR-7 targ!.
"Single versus multiple primary melanomas: Old questions and new answers"Hwa C; Price LS; Belitskaya-Levy I; Ma MW; SHAPIRO RL; Berman RS; Kamino H; Darvishian F; Osman I; Stein JA
BACKGROUND: In patients with multiple primary melanomas (MPM), mean tumor thickness tends to decrease from the first melanoma to the second melanoma, and prognosis may be improved compared with the prognosis for patients who have a single primary melanoma (SPM). In this study, the authors compared the clinicopathologic features of patients with MPM and SPM to better characterize the differences between these 2 groups and to determine whether or not there is an inherent difference in tumor aggression. METHODS: In total, 788 patients with melanoma who were enrolled prospectively in the Interdisciplinary Melanoma Cooperative Group database from 2002 to 2008 were studied. Patients with SPM and with MPM were compared with regard to clinical and primary melanoma characteristics. RESULTS: Of 788 patients with melanoma, 61 patients (7.7%) had 2 or more primary melanomas. The incidence of developing a second primary melanoma 1 year and 5 years after initial melanoma diagnosis was 4.1% and 8.7%, respectively, and most of the risk accumulated within the first year. The incidence of MPM was greater in patients aged >/=60 years than in those aged </=60 years. The absence or presence of mitosis and other tumor characteristics did not differ significantly between patients with SPM and patients with MPM (P = .61). CONCLUSIONS: No difference was observed in the presence or absence of mitoses, a marker of tumor proliferation, in SPM and MPM. Because it has been demonstrated that the presence of mitosis is a powerful prognostic marker, the current findings suggested that the tumors behave similarly in patients with SPM and patients with MPM. The authors concluded that differences in tumor thickness and prognosis between SPM and MPM more likely are caused by factors other than tumor biology, such as increased surveillance. Cancer 2012;. (c) 2012 American Cancer Society.
"Surgical treatment of malignant melanoma: practical guidelines"Levine, Steven M; SHAPIRO, RICHARD L
Melanoma is currently the fifth and sixth most common solid malignancy diagnosed in men and women, respectively. Although accounting for only 4% of cases of all cutaneous malignancies, melanoma accounts for more than 75% of all deaths from skin cancer. This article discusses epidemiology and risk factors, proper biopsy technique, advanced histologic evaluation of biopsy material, assessment of tumor thickness and staging, preoperative metastatic evaluation, excision margin, treatment of regional lymph nodes, treatment of recurrence, and some special clinical situations..
"MicroRNA alterations associated with BRAF status in melanoma" [Meeting Abstract]Ma, M W; Farhadian, J A; Friedman, E B; De, Miera E V -S; Hanniford, D; Segura, M F; Berman, R S; SHAPIRO, R L; Pavlick, A C; Zavadil, J; Hernando, E; Osman, I
Background: We hypothesize that BRAF mutations result in microRNA (miRNA) alterations which contribute to orchestrating the mutant BRAF's oncogenic effects in melanoma. Our study is the first to examine the association between the BRAF mutation status in primary melanomas and the expression of miRNAs that target known tumor suppressors. Methods: 84 prospectively accrued melanoma patients at New York University Langone Medical Center were studied. DNA and total RNA were extracted from consecutive sections of formalin-fixed paraffin-embedded primary tissues. BRAF mutation status was determined by DNA sequencing. RNA was hybridized to miRCURY miRNA microarrays containing 1314 probes. Normalized miRNA data were analyzed using the t-test (p<0.05) to identify differentially expressed miRNAs between BRAFmut vs. BRAFwt cases. Those with an average fold change (FC) > 2 were selected for predicted (TargetScan, PicTar) and validated (miRWalk) gene target analysis, and overlapping genes targeted by 2 miRNAs were analyzed using pathway-mapping algorithms (KEGG, BioCarta, PANTHER). Results: 48 (57%) primaries were BRAFwt and 36 (43%) were BRAFmut (26 V600E, 4 V600K, 1 V600R, 1 V600D, 4 other). 30 miRNAs met the criteria for statistically significant differential expression and FC thresholding: let-7i, miR-23c, -26a/b, -27b, -34a, -98, -126*, -141, -148a, -181b, -195, -199a-3p, -199a/b-5p, -200a/b/c, -203, -205, -455-3p, -491-3p, -606, -641, -646, -1297, -4301; miRPlus-C1070, -C1110, -G1246-3p (average FC: 2.3-3.5, all increased in BRAFmut vs. BRAFwt). Predicted and validated target gene analysis revealed 317 genes, of which 110 (35%) were convergent targets of 2 miRNAs. Pathway analyses of the predicted, validated, and convergent target genes pointed to the potential impact of BRAFmut-associated miRNAs on known tumor suppressors FAS, PTEN, and TNF and the p53 pathway. Conclusions: Differentially expressed miRNAs in BRAFmut vs. BRAFwt primaries target genes with known roles in melanoma biology and/or treatmen!.
"Immune response in melanoma: an in-depth analysis of the primary tumor and corresponding sentinel lymph node"Ma, Michelle W; Medicherla, Ratna C; Qian, Meng; Vega-Saenz de Miera, Eleazar; Friedman, Erica B; Berman, Russell S; SHAPIRO, RICHARD L; Pavlick, Anna C; Ott, Patrick A; Bhardwaj, Nina; Shao, Yongzhao; Osman, Iman; Darvishian, Farbod
GRANTS:5 P30 CA016087-27/CA/NCI NIH HHS/United States
The sentinel lymph node is the initial site of metastasis. Downregulation of antitumor immunity has 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/immunological 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 with 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, clinicopathological 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). Antitumor immunity was downregulated in the positive sentinel lymph node with an increase in regulatory T cells compared with 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 with 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..
"Challenging the current paradigm of melanoma progression: brain metastasis as isolated first visceral site"Ma, Michelle W; Qian, Meng; Lackaye, Daniel J; Berman, Russell S; SHAPIRO, RICHARD L; Pavlick, Anna C; Golfinos, John G; Parker, Erik C; Darvishian, Farbod; Hernando, Eva; Shao, Yongzhao; Osman, Iman
GRANTS:5P30CA016087/CA/NCI NIH HHS/United States
Melanoma brain metastasis that develops as the isolated first visceral site challenges the current paradigm of tumor progression in which brain metastasis is regarded as the final stage. Here we test the hypothesis that melanoma patients who develop brain metastasis as the isolated first visceral site have distinct clinicopathological features at the time of primary melanoma diagnosis. Cutaneous melanoma patients enrolled in 2 prospectively collected databases were studied (Cohort 1: 1972-1982, Cohort 2: 2002-2009). Patients who developed brain metastasis as isolated first visceral site were compared with (1) all other patients, (2) patients who developed visceral metastasis: extracranial only or extracranial and brain, and (3) patients who progressed to other isolated visceral sites first. Two hundred seven of 2280 (9.1%) patients developed brain metastasis (median follow-up, 5.2 y). Seventy-four of 207 (35.7%) brain metastasis patients progressed to brain metastasis as the isolated first visceral site. These patients presented with primaries that were thinner and had no mitosis compared with all other visceral metastasis patients (Fisher's combined P = .02, .05, respectively), and there was a significant difference in American Joint Committee on Cancer stage distribution at initial melanoma diagnosis (combined P = .02). Post-visceral metastasis survival, however, was shorter in patients with brain metastasis as isolated first visceral site than in patients with visceral metastasis: extracranial and brain (combined P = .03). Brain metastasis as isolated first visceral site is a distinct clinicopathological entity. Studies are needed to better understand the biological factors driving this phenotype at the time of primary melanoma diagnosis and to determine its clinical implications..
"Histology-Specific MicroRNA Alterations in Melanoma"Poliseno, Laura; Haimovic, Adele; Segura, Miguel F; Hanniford, Douglas; Christos, Paul J; Darvishian, Farbod; Wang, Jinhua; SHAPIRO, RICHARD L; Pavlick, Anna C; Berman, Russell S; Hernando, Eva; Zavadil, Jiri; Osman, Iman
GRANTS:5 P30 CA 016087-27/CA/NCI NIH HHS/United States;UL1-RR024996/RR/NCRR NIH HHS/United States
We examined the microRNA signature that distinguishes the most common melanoma histological subtypes, superficial spreading melanoma (SSM) and nodular melanoma (NM). We also investigated the mechanisms underlying the differential expression of histology-specific microRNAs. MicroRNA array performed on a training cohort of 82 primary melanoma tumors (26 SSM, 56 NM), and nine congenital nevi (CN) revealed 134 microRNAs differentially expressed between SSM and NM (P<0.05). Out of 134 microRNAs, 126 remained significant after controlling for thickness and 31 were expressed at a lower level in SSM compared with both NM and CN. For seven microRNAs (let-7g, miR-15a, miR-16, miR-138, miR-181a, miR-191, and miR-933), the downregulation was associated with selective genomic loss in SSM cell lines and primary tumors, but not in NM cell lines and primary tumors. The lower expression level of six out of seven microRNAs in SSM compared with NM was confirmed by real-time PCR on a subset of cases in the training cohort and validated in an independent cohort of 97 melanoma cases (38 SSM, 59 NM). Our data support a molecular classification in which SSM and NM are two molecularly distinct phenotypes. Therapeutic strategies that take into account subtype-specific alterations might improve the outcome of melanoma patients..
"The melanoma risk loci as determinants of melanoma prognosis" [Meeting Abstract]Rendleman, J; Shang, S; Brocia, C; Ma, M W; SHAPIRO, R L; Berman, R S; Pavlick, A C; Shao, Y; Osman, I; Kirchhoff, T
Background: Genetic risk factors of human cancer emerge as promising markers of clinical outcome. The recent melanoma genome-wide scans (GWAS) have identified loci associated with the disease risk, nevi or UV/pigmentation, but the prognostic potential of these variants is yet to be determined. In this study, we performed the first-to-date systematic evaluation of the association between established melanoma risk loci and melanoma progression. Methods: 891 melanoma patients prospectively accrued and followed up at NYU Medical Center were studied. We examined the association of 108 melanoma susceptibility single nucleotide polymorphisms (SNPs), selected or imputed from recent GWASs on melanoma, nevi or pigmentation, with recurrence-free survival (RFS) and overall survival (OS). The genotyping was performed using Sequenom I-plex. Cox PH model was used to test the association between each SNP and RFS and OS adjusted by age at diagnosis, gender, tumor stage and histological subtype. ROC curves were used to measure predictive utility of SNPs in predicting 3-year recurrence. Results: The strong association was observed for rs7538876 (RCC2) with RFS (HR=2.445, 95% CI 1.57 - 3.8, p=0.0006) and rs9960018 (DLGAP1) with both RFS and OS (HR=4.7, 95% CI=2.11-10.43, p=0.0061, HR=1.55, 95% CI=1.11-2.17, p=0.0094, respectively) using adjusted multivariate analysis. In addition, we identified the classifier with rs7538876 and rs9960018, stage and histological type at primary tumor diagnosis, achieving a higher area under the ROC curve (AUC=84%) compared to the baseline (AUC=78%) in predicting 3-year recurrence. Univariate survival analyses have identified associations of several SNPs with ulceration and/or tumor thickness. Conclusions: Our data revealed an association between specific melanoma susceptibility variants and worse clinicopathological variables at the time of diagnosis as well as worse disease outcome. The strength of associations observed for rs7538876 and rs9960018 suggest biological implication of!.
"Nipple-sparing mastectomy and immediate free-flap reconstruction in the large ptotic breast"Schneider, Lisa F; Chen, Constance M; Stolier, Alan J; SHAPIRO, RICHARD L; Ahn, Christina Y; Allen, Robert J
ABSTRACT: Because of increased risk for nipple necrosis, many surgeons believe large ptotic breasts to be a relative contraindication to nipple-sparing mastectomy (NSM). A retrospective review was performed on 85 consecutive patients who underwent NSM with 141 immediate perforator free-flap breast reconstructions. We analyzed the subset of patients with large ptotic breasts, defined as cup size C or greater, sternal notch to nipple distance greater than 24 cm and grade 2 or 3 breast ptosis. Of the 85 patients, 19 fit the inclusion criteria. Breast cup size ranged from 34C to 38DDD. There was 1 case of nipple necrosis in the patient with previous breast radiation (5%), 1 hematoma (5%), and no flap losses. Five (26%) patients underwent subsequent mastopexy or breast reduction, a mean of 6.6 months after the primary procedure. We demonstrate that NSM and free-flap breast reconstruction can be safely and reliably performed in selected patients..
"Intra- and Inter-Tumor Heterogeneity of BRAFMutations in Primary and Metastatic Melanoma"Yancovitz, Molly; Litterman, Adam; Yoon, Joanne; Ng, Elise; SHAPIRO, RICHARD L; Berman, Russell S; Pavlick, Anna C; Darvishian, Farbod; Christos, Paul; Mazumdar, Madhu; Osman, Iman; Polsky, David
GRANTS:5P30CA16087-31/CA/NCI NIH HHS/United States;R21 CA109388/CA/NCI NIH HHS/United States;T32 AR07190 - 31/AR/NIAMS NIH HHS/United States
The rationale for using small molecule inhibitors of oncogenic proteins as cancer therapies depends, at least in part, on the assumption that metastatic tumors are primarily clonal with respect to mutant oncogene. With the emergence of BRAF(V600E) as a therapeutic target, we investigated intra- and inter-tumor heterogeneity in melanoma using detection of the BRAF(V600E) mutation as a marker of clonality. BRAF mutant-specific PCR (MS-PCR) and conventional sequencing were performed on 112 tumors from 73 patients, including patients with matched primary and metastatic specimens (n = 18). Nineteen patients had tissues available from multiple metastatic sites. Mutations were detected in 36/112 (32%) melanomas using conventional sequencing, and 85/112 (76%) using MS-PCR. The better sensitivity of the MS-PCR to detect the mutant BRAF(V600E) allele was not due to the presence of contaminating normal tissue, suggesting that the tumor was comprised of subclones of differing BRAF genotypes. To determine if tumor subclones were present in individual primary melanomas, we performed laser microdissection and mutation detection via sequencing and BRAF(V600E)-specific SNaPshot analysis in 9 cases. Six of these cases demonstrated differing proportions of BRAF(V600E)and BRAF(wild-type) cells in distinct microdissected regions within individual tumors. Additional analyses of multiple metastatic samples from individual patients using the highly sensitive MS-PCR without microdissection revealed that 5/19 (26%) patients had metastases that were discordant for the BRAF(V600E) mutation. In conclusion, we used highly sensitive BRAF mutation detection methods and observed substantial evidence for heterogeneity of the BRAF(V600E) mutation within individual melanoma tumor specimens, and among multiple specimens from individual patients. Given the varied clinical responses of patients to BRAF inhibitor therapy, these data suggest that additional studies to determine possible associations between clinical outcomes and intra- and inter-tumor heterogeneity could prove fruitful.
"Impact of population genetic substructure on association studies and risk assessment for melanoma" [Meeting Abstract]Lobach I; Belitskaya-Levy I; Goldberg JD; Ostrer H; Berman RS; Pavlick AC; SHAPIRO RL; Osman I; Manga P
Background: Genetic substructure due to varying allele frequencies between populations can confound association studies. Ancestry informative genetic marker (AIMs) data combined with statistical adjustment can reveal spurious associations and identify population specific risk markers. In melanoma, AIMs may also be risk markers, e.g. pigment genes contribute to melanoma susceptibility and segregate with ancestry. We have thus developed a strategy to adjust for population genetic substructure (PGS) using AIMs, while identifying potentially novel genes associated with melanoma. Methods: 326 melanoma patients and 400 controls of European ancestry from the New York area were studied. Tag SNPs spanning 14 candidate genes and 75 AIMs were genotyped and odds ratios (OR), unadjusted and adjusted for PGS, computed. Results: A PGS model based on all AIMs separated cases and controls, suggesting that some AIMs were associated with melanoma. An algorithm was developed to select AIMs least capable of separating cases and controls to infer PGS and validated using simulations. The resulting model, which was reproduced using 49 additional AIMs, separated Northern (NE) and Southern Europeans (SE) and was used to adjust ORs. Three classes of SNPs were identified 1. Associated before and after PGS correction in both groups (10 SNPs localized to MATP, TYR and ERCC5). 2. Not associated in unadjusted analysis, but significantly associated with melanoma in NEs (6 SNPs localized to XPC, ERCC4, OCA2, ASIP and TYR). 3. Associated with melanoma before but not after adjustment. To determine if AIMs that separate cases and controls can identify novel melanoma genes, we genotyped 16 SNPs localized to 4 genes that house candidate AIMs. Four SNPs at 2 different loci were associated with melanoma (e.g. AIM1: OR=0.35, p=0.01; AIM2: OR=1.77, p=0.03). Conclusions: Our approach demonstrated that ancestry is a significant confounding factor in identifying melanoma susceptibility genes. Melanoma risk markers vary significantly between groups and a DNA based risk assessment model will require adjustment for ancestry. We have also identified potentially novel susceptibility melanoma genes for futher study.
"Donor-Transmitted Malignancies in Organ Transplantation: Assessment of Clinical Risk"Nalesnik, M. A.; Woodle, E. S.; DiMaio, J. M.; Vasudev, B.; Teperman, L. W.; Covington, S.; Taranto, S.; Gockerman, J. P.; SHAPIRO, R.; Sharma, V.; Swinnen, L. J.; Yoshida, A.; Ison, M. G.
The continuing organ shortage requires evaluation of all potential donors, including those with malignant disease. In the United States, no organized approach to assessment of risk of donor tumor transmission exists, and organs from such donors are often discarded. The ad hoc Disease Transmission Advisory Committee (DTAC) of the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) formed an ad hoc Malignancy Subcommittee to advise on this subject. The Subcommittee reviewed the largely anecdotal literature and held discussions to generate a framework to approach risk evaluation in this circumstance. Six levels of risk developed by consensus. Suggested approach to donor utilization is given for each category, recognizing the primacy of individual clinical judgment and often emergent clinical circumstances. Categories are populated with specific tumors based on available data, including active or historical cancer. Benign tumors are considered in relation to risk of malignant transformation. Specific attention is paid to potential use of kidneys harboring small solitary renal cell carcinomas, and to patients with central nervous system tumors. This resource document is tailored to clinical practice in the United States and should aid clinical decision making in the difficult circumstance of an organ donor with potential or proven neoplasia.