Farbod Darvishian, M.D.

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
2012 Jan 13;:?-?, Cancer
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
— id: 150011, year: 2012, vol: , page: ?, stat: Journal Article,

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
2012 ;7(1):e29336-e29336, PLoS ONE
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
— id: 149812, year: 2012, vol: 7, page: e29336, stat: Journal Article,

Impact of decalcification on receptor status in breast cancer
Darvishian, Farbod; Singh, Baljit; Krauter, Stephanie; Chiriboga, Luis; Gangi, Maryann D; Melamed, Jonathan
2011 Nov;17(6):689-691, Breast journal
— id: 141074, year: 2011, vol: 17, page: 689, stat: Journal Article,

miR-30b/30d Regulation of GalNAc Transferases Enhances Invasion and Immunosuppression during Metastasis
Gaziel-Sovran, Avital; Segura, Miguel F; Di Micco, Raffaella; Collins, Mary K; Hanniford, Douglas; Vega-Saenz de Miera, Eleazar; Rakus, John F; Dankert, John F; Shang, Shulian; Kerbel, Robert S; Bhardwaj, Nina; Shao, Yongzhao; Darvishian, Farbod; Zavadil, Jiri; Erlebacher, Adrian; Mahal, Lara K; Osman, Iman; Hernando, Eva
2011 Jul 12;20(1):104-118, Cancer cell
To metastasize, a tumor cell must acquire abilities such as the capacity to colonize new tissue and evade immune surveillance. Recent evidence suggests that microRNAs can promote the evolution of malignant behaviors by regulating multiple targets. We performed a microRNA analysis of human melanoma, a highly invasive cancer, and found that miR-30b/30d upregulation correlates with stage, metastatic potential, shorter time to recurrence, and reduced overall survival. Ectopic expression of miR-30b/30d promoted the metastatic behavior of melanoma cells by directly targeting the GalNAc transferase GALNT7, resulted in increased synthesis of the immunosuppressive cytokine IL-10, and reduced immune cell activation and recruitment. These data support a key role of miR-30b/30d and GalNAc transferases in metastasis, by simultaneously promoting cellular invasion and immunosuppression
— id: 135264, year: 2011, vol: 20, page: 104, stat: Journal Article,

Efficient in vivo microRNA targeting of liver metastasis
Huynh, C; Segura, M F; Gaziel-Sovran, A; Menendez, S; Darvishian, F; Chiriboga, L; Levin, B; Meruelo, D; Osman, I; Zavadil, J; Marcusson, E G; Hernando, E
2011 Mar 24;30(12):1481-1488, Oncogene
Targeting oncogenic microRNAs (miRNAs) is emerging as a promising strategy for cancer therapy. In this study, we provide proof of principle for the safety and efficacy of miRNA targeting against metastatic tumors. We tested the impact of targeting miR-182, a pro-metastatic miRNA frequently overexpressed in melanoma, the in vitro silencing of which represses invasion and induces apoptosis. Specifically, we assessed the effect of anti-miR-182 oligonucleotides synthesized with 2' sugar modifications and a phosphorothioate backbone in a mouse model of melanoma liver metastasis. Luciferase imaging showed that mice treated with anti-miR-182 had a lower burden of liver metastases compared with control. We confirmed that miR-182 levels were effectively downregulated in the tumors of anti-miR-treated mice compared with tumors of control-treated mice, both in the liver and in the spleen. This effect was accompanied by an upregulation of multiple miR-182 direct targets. Transcriptional profiling of tumors treated with anti-miR-182 or with control oligonucleotides revealed an enrichment of genes controlling survival, adhesion and migration modulated in response to anti-miR-182 treatment. These data indicate that in vivo administration of anti-miRs allows for efficient miRNA targeting and concomitant upregulation of miRNA-controlled genes. Our results demonstrate that the use of anti-miR-182 is a promising therapeutic strategy for metastatic melanoma and provide a solid basis for testing similar strategies in human metastatic tumors
— id: 138159, year: 2011, vol: 30, page: 1481, stat: Journal Article,

Correction: The Novel Gamma Secretase Inhibitor RO4929097 Reduces the Tumor Initiating Potential of Melanoma
Huynh, Chanh; Poliseno, Laura; Segura, Miguel F; Medicherla, Ratna; Haimovic, Adele; Menendez, Silvia; Shang, Shulian; Pavlick, Anna; Shao, Yongzhao; Darvishian, Farbod; Boylan, John F; Osman, Iman; Hernando, Eva
2011 ;6(11):?-?, PLoS ONE
[This corrects the article on p. e25264 in vol. 6.]
— id: 141637, year: 2011, vol: 6, page: ?, stat: Journal Article,

The Novel Gamma Secretase Inhibitor RO4929097 Reduces the Tumor Initiating Potential of Melanoma
Huynh, Chanh; Poliseno, Laura; Segura, Miguel F; Medicherla, Ratna; Haimovic, Adele; Menendez, Silvia; Shang, Shulian; Pavlick, Anna; Shao, Yongzhao; Darvishian, Farbod; Boylan, John F; Osman, Iman; Hernando, Eva
2011 ;6(9):e25264-e25264, PLoS ONE
Several reports have demonstrated a role for aberrant NOTCH signaling in melanoma genesis and progression, prompting us to explore if targeting this pathway is a valid therapeutic approach against melanoma. We targeted NOTCH signaling using RO4929097, a novel inhibitor of gamma secretase, which is a key component of the enzymatic complex that cleaves and activates NOTCH. The effects of RO4929097 on the oncogenic and stem cell properties of a panel of melanoma cell lines were tested both in vitro and in vivo, using xenograft models. In human primary melanoma cell lines, RO4929097 decreased the levels of NOTCH transcriptional target HES1. This was accompanied by reduced proliferation and impaired ability to form colonies in soft agar and to organize in tridimensional spheres. Moreover, RO4929097 affected the growth of human primary melanoma xenograft in NOD/SCID/IL2gammaR-/- mice and inhibited subsequent tumor formation in a serial xenotransplantation model, suggesting that inhibition of NOTCH signaling suppresses the tumor initiating potential of melanoma cells. In addition, RO4929097 decreased tumor volume and blocked the invasive growth pattern of metastatic melanoma cell lines in vivo. Finally, increased gene expression of NOTCH signaling components correlated with shorter post recurrence survival in metastatic melanoma cases. Our data support NOTCH inhibition as a promising therapeutic strategy against melanoma
— id: 138712, year: 2011, vol: 6, page: e25264, stat: Journal Article,

Old and new concepts in histopathological characterization of familial breast cancer
Mangia, A; Malfettone, A; Simone, G; Darvishian, F
2011 Jan;22 Suppl 1:i24-i30, Annals of oncology
BRCA1- and BRCA2-deficient cells display genomic instability due to impaired DNA repair and may subsequently be predisposed to malignant transformation. Cancers arising in BRCA1 gene mutation carriers differ substantially from sporadic breast cancers of age-matched controls in their histopathological appearance. BRCA1-related breast cancers have been morphologically associated with poorly differentiated and medullary types, exhibiting triple negativity and 'basal phenotype'. There are different types of mutations listed in Breast Cancer Information Core professional databases and most of them are small insertions or deletions. Moreover, the search for more pathological alterations has led to identification of missense mutations, intronic variant sequences and unclassified variants, reporting an unclear role in breast cancer susceptibility. We review the latest evidence regarding analysis of various mutations in BRCA1/2 genes and low-risk breast cancer susceptibility genes. Preliminary data from our laboratories indicate that biomarkers for invasiveness may lead to better characterization of familial breast cancers. Multivariate regression analysis has allowed us to select the best combination of markers to predict familial or hereditary breast cancers. We found that a marker signature comprising human epidermal growth factor receptor 2 (HER2) negativity, Na(+)/H(+) exchanger regulatory factor 1 (NHERF1) negativity and BRCA1 positivity (designated 'triple-biomarker' signature) is frequently associated with familial breast cancer and promises to be a reliable test in its molecular characterization
— id: 134113, year: 2011, vol: 22 Suppl 1, page: i24, stat: Journal Article,

Deletion of PTENP1 Pseudogene in Human Melanoma
Poliseno, Laura; Haimovic, Adele; Christos, Paul J; Vega Y Saenz de Miera, Eleazar C; Shapiro, Richard; Pavlick, Anna; Berman, Russell S; Darvishian, Farbod; Osman, Iman
2011 Dec;131(12):2497-2500, Journal of investigative dermatology
— id: 141068, year: 2011, vol: 131, page: 2497, stat: Journal Article,

Integrative genomics identifies molecular alterations that challenge the linear model of melanoma progression
Rose AE; Poliseno L; Wang J; Clark M; Pearlman A; Wang G; Vega Y Saenz de Miera EC; Medicherla R; Christos PJ; Shapiro RL; Pavlick AC; Darvishian F; Zavadil J; Polsky D; Hernando E; Ostrer H; Osman I
2011 Apr 1;71(7):2561-2571, Cancer research
Superficial spreading melanoma (SSM) and nodular melanoma (NM) are believed to represent sequential phases of linear progression from radial to vertical growth. Several lines of clinical, pathological and epidemiologic evidence suggest, however, that SSM and NM might be the result of independent pathways of tumor development. We utilized an integrative genomic approach that combines single nucleotide polymorphism array (SNP 6.0, Affymetrix) with gene expression array (U133A 2.0, Affymetrix) to examine molecular differences between SSM and NM. Pathway analysis of the most differentially expressed genes between SSM and NM (N=114) revealed significant differences related to metabolic processes. We identified 8 genes (DIS3, FGFR1OP, G3BP2, GALNT7, MTAP, SEC23IP, USO1, ZNF668) in which NM/SSM-specific copy number alterations correlated with differential gene expression (P<0.05, Spearman's rank). SSM-specific genomic deletions in G3BP2, MTAP, and SEC23IP were independently verified in two external data sets. Forced overexpression of metabolism-related gene methylthioadenosine phosphorylase (MTAP) in SSM resulted in reduced cell growth. The differential expression of another metabolic related gene, aldehyde dehydrogenase 7A1 (ALDH7A1), was validated at the protein level using tissue microarrays of human melanoma. In addition, we show that the decreased ALDH7A1 expression in SSM may be the result of epigenetic modifications. Our data reveal recurrent genomic deletions in SSM not present in NM, which challenge the linear model of melanoma progression. Furthermore, our data suggest a role for altered regulation of metabolism-related genes as a possible cause of the different clinical behavior of SSM and NM
— id: 124135, year: 2011, vol: 71, page: 2561, stat: Journal Article,

Clinical Relevance of Detection of Lymphovascular Invasion in Primary Melanoma Using Endothelial Markers D2-40 and CD34
Rose, Amy E; Christos, Paul J; Lackaye, Dan; Shapiro, Richard L; Berman, Russell; Mazumdar, Madhu; Kamino, Hideko; Osman, Iman; Darvishian, Farbod
2011 Oct;35(10):1441-1449, American journal of surgical pathology
Immunohistochemistry (IHC) using endothelial markers may facilitate the detection of lymphovascular invasion (LVI) in primary melanoma; however, the clinical implications of enhanced detection are unknown. We evaluated whether the use of lymphatic endothelial marker D2-40 and panvascular marker CD34 increases LVI positivity relative to routine histology alone and then evaluated the prognostic relevance of LVI detected using these markers in terms of disease-free (DFS) and overall survival (OS). A total of 246 primary melanomas were assessed for LVI using D2-40, CD34, and routine histology. Associations between LVI positivity and clinicopathologic variables, DFS, and OS were compared using univariate and multivariate analyses. The use of endothelial markers increased the rate of LVI positivity (18% using D2-40 and/or CD34 vs. 3% by routine histology, P<0.0001). On univariate analysis, IHC-detected LVI was significantly associated with more adverse clinicopathologic variables (thickness, ulceration, mitoses, and nodular subtype) compared with LVI detected by routine histology (thickness and ulceration only). In a multivariate model controlling for stage, LVI detected using IHC markers remained a significant marker of both reduced DFS [hazard ratio (HR), 2.01; 95% confidence interval (CI): 1.27-3.18; P=0.003] and OS (HR, 2.08; 95% CI: 1.25-3.46; P=0.005). Results show that D2-40 and CD34 increase the detection of LVI in primary melanoma and that cases missed by routine histology have prognostic relevance
— id: 137842, year: 2011, vol: 35, page: 1441, stat: Journal Article,

Clinical relevance of SKP2 alterations in metastatic melanoma
Rose, Amy E; Wang, Guimin; Hanniford, Douglas; Monni, Stefano; Tu, Ting; Shapiro, Richard L; Berman, Russell S; Pavlick, Anna C; Pagano, Michele; Darvishian, Farbod; Mazumdar, Madhu; Hernando, Eva; Osman, Iman
2011 Feb;24(1):197-206, Pigment cell & melanoma research
In this study, we investigated the mechanism(s) of altered expression of protooncogene SKP2 in metastatic melanoma and its clinical relevance in patients with metastatic melanoma. The genomic status of SKP2 was assessed in cell lines by sequencing, single nucleotide polymorphism array, and genomic PCR. Copy number status was then evaluated for concordance with SKP2 mRNA and protein expression. SKP2 protein was further evaluated by immunohistochemistry in 93 human metastatic tissues. No mutations were identified in SKP2. Increased copy number at the SKP2 locus was observed in 6/14 (43%) metastatic cell lines and in 9/22 (41%) human metastatic tissues which was associated with overexpression of SKP2 protein. Overexpression of SKP2 protein in human tissues was associated with worse survival in a multivariate model controlling for the site of metastasis. Copy number gain is a major contributing mechanism of SKP2 overexpression in metastatic melanoma. Results may have implications for the development of therapeutics that target SKP2
— id: 138133, year: 2011, vol: 24, page: 197, stat: Journal Article,

A high proliferative index of recurrent melanoma is associated with worse survival
Tu, Ting J; Ma, Michelle W; Monni, Stefano; Rose, Amy E; Yee, Herman; Darvishian, Farbod; Polsky, David; Berman, Russell S; Shapiro, Richard L; Pavlick, Anna C; Mazumdar, Madhu; Osman, Iman
2011 ;80(3-4):181-187, Oncology (New York)
Objective: Previous melanoma studies evaluating prognostic factors of survival at recurrence have focused on primary tumor characteristics and clinical variables at first recurrence. We examined the prognostic relevance of recurrent tumor proliferation. Methods: 114 melanoma patients with available recurrent tissues who were prospectively enrolled at New York University Medical Center were studied. Standard of care prognostic variables (e.g. stage at initial diagnosis and lactate dehydrogenase level) and recurrent tissue expression of proliferative marker Ki-67 were evaluated for their association with overall survival. Results: High Ki-67 expression was observed in 57 (50%) of the 114 recurrent melanomas. On univariate analysis, the median overall survival of patients whose recurrent tumors overexpressed Ki-67 was significantly shorter than that of patients whose recurrent tumors had low Ki-67 expression (3.6 vs. 9.5 years, p = 0.03). On multivariate analysis, a high proliferative index of the recurrent melanoma remained an independent predictor of worse overall survival, controlling for stage at initial diagnosis, disease-free survival, and stage at first recurrence [HR = 2.09 (95% CI 1.24-3.54), p = 0.006]. Conclusions: Our results demonstrate the prognostic relevance of tumor proliferation in recurrent melanoma patients. Data also support restratification of risk assessment upon recurrence that considers tumor biology in addition to clinical variables evaluated as part of the standard of care
— id: 135575, year: 2011, vol: 80, page: 181, stat: Journal Article,

Clinical variables and primary tumor characteristics predictive of the development of melanoma brain metastases and post-brain metastases survival
Zakrzewski, Jan; Geraghty, Laurel N; Rose, Amy E; Christos, Paul J; Mazumdar, Madhu; Polsky, David; Shapiro, Richard; Berman, Russell; Darvishian, Farbod; Hernando, Eva; Pavlick, Anna; Osman, Iman
2011 Apr 15;117(8):1711-1720, Cancer
BACKGROUND: Melanoma patients who develop brain metastases (B-Met) have limited survival and are excluded from most clinical trials. In the current study, the authors attempted to identify primary tumor characteristics and clinical features predictive of B-Met development and post-B-Met survival. METHODS: A prospectively accrued cohort of 900 melanoma patients was studied to identify clinicopathologic features of primary melanoma (eg, thickness, ulceration, mitotic index, and lymphovascular invasion) that are predictive of B-Met development and survival after a diagnosis of B-Met. Associations between clinical variables present at the time of B-Met diagnosis (eg, extracranial metastases, B-Met location, and the presence of neurological symptoms) and post-B-Met survival were also assessed. Univariate associations were analyzed using Kaplan-Meier survival analysis, and the effect of independent predictors was assessed using multivariate Cox proportional hazards regression analysis. RESULTS: Of the 900 melanoma patients studied, 89 (10%) developed B-Met. Ulceration and site of the primary tumor on the head and neck were found to be independent predictors of B-Met development on multivariate analysis (P = .001 and P = .003, respectively). Clinical variables found to be predictive of post-B-Met survival on multivariate analysis included the presence of neurological symptoms (P = .008) and extracranial metastases (P = .04). Ulceration was the only primary tumor characteristic that remained a significant predictor of post-B-Met survival on multivariate analysis (P = .04). CONCLUSIONS: Primary tumor ulceration was found to be the strongest predictor of B-Met development and remained an independent predictor of decreased post-B-Met survival in a multivariate analysis inclusive of primary tumor characteristics and clinical variables. The results of the current study suggest that patients with ulcerated primary tumors should be prospectively studied to determine whether heightened surveillance for B-Met can improve clinical outcome. Cancer 2011. (c) 2010 American Cancer Society
— id: 130314, year: 2011, vol: 117, page: 1711, stat: Journal Article,

The Association Between Lobular Involution and Histology in Older Women With Nonpalpable Lesions
Checka, Cristina; Chun, Jennifer; Schnabel, Freya; Darvishian, Farbod; Axelrod, Deborah; Siegel, Beth; Roses, Daniel
2010 APR ;17(2):S166-S166, Annals of surgical oncology
— id: 132518, year: 2010, vol: 17, page: S166, stat: Journal Article,

Lobular Carcinoma Progression Model: Immunohistochemical Analysis on Tissue Microarray
Chen, F; Cangiarella, J; Chiriboga, L; Darvishian, F
2010 FEB ;23(3):39A-39A, Modern pathology
— id: 109929, year: 2010, vol: 23, page: 39A, stat: Journal Article,

Lobular Carcinoma Progression Model: Immunohistochemical Analysis on Tissue Microarray
Chen, F; Cangiarella, J; Chiriboga, L; Darvishian, F
2010 FEB ;90(11):39A-39A, Laboratory investigation
— id: 109948, year: 2010, vol: 90, page: 39A, stat: Journal Article,

Impact of Decalcification on Receptor Status in Breast Cancer
Darvishian, F; Singh, B; Krauter, S; Chiriboga, L; Melamed, J
2010 FEB ;23(3):43A-43A, Modern pathology
— id: 109930, year: 2010, vol: 23, page: 43A, stat: Journal Article,

Impact of Decalcification on Receptor Status in Breast Cancer
Darvishian, F; Singh, B; Krauter, S; Chiriboga, L; Melamed, J
2010 FEB ;90(11):43A-43A, Laboratory investigation
— id: 109949, year: 2010, vol: 90, page: 43A, stat: Journal Article,

A Note from History: Diagnosis and Treatment of Tumors by Physicians in Antiquity
Hajdu, Steven I.; Darvishian, Farbod
2010 ;40(4):386-390 FAL, Annals of clinical & laboratory science
— id: 114028, year: 2010, vol: 40, page: 386, stat: Journal Article,

Radiology quiz case 2
Jiang, Nancy; Pramanik, Bidyut; Darvishian, Farbod; Jethanamest, Daniel; Myssiorek, David
2010 Jan;136(1):96-96, Archives of otolaryngology, head & neck surgery
— id: 106283, year: 2010, vol: 136, page: 96, stat: Journal Article,

Video-assisted thoracoscopic lobectomy for pulmonary aspergilloma after life-threatening hemoptysis in a patient with lupus
Parker, Kathryn L; Zervos, Michael D; Darvishian, Farbod; Bizekis, Costas S
2010 Jan;89(1):291-292, Annals of thoracic surgery
Open thoracotomy procedures serve as the mainstay for surgical resection of pulmonary aspergilloma. These procedures are considered among the most challenging for thoracic surgeons, and postoperative morbidity and mortality rates are high. Here, we present patient who underwent video-assisted thoracoscopic lobectomy for aspergilloma. Based on the success of the operation, we suggest that video-assisted thoracoscopic surgical resection be considered as an option for pulmonary aspergilloma
— id: 106375, year: 2010, vol: 89, page: 291, stat: Journal Article,

Melanoma MicroRNA Signature Predicts Post-Recurrence Survival
Segura, Miguel F; Belitskaya-Levy, Ilana; Rose, Amy E; Zakrzewski, Jan; Gaziel, Avital; Hanniford, Douglas; Darvishian, Farbod; Berman, Russell S; Shapiro, Richard L; Pavlick, Anna C; Osman, Iman; Hernando, Eva
2010 Mar 1;16(5):1577-1586, Clinical cancer research
PURPOSE: To identify a melanoma microRNA (miRNA) expression signature that is predictive of outcome and then evaluate its potential to improve risk stratification when added to the standard-of-care staging criteria. EXPERIMENTAL DESIGN: Total RNA was extracted from 59 formalin-fixed paraffin-embedded melanoma metastases and hybridized to miRNA arrays containing 911 probes. We then correlated miRNA expression with post-recurrence survival and other clinicopathologic criteria. RESULTS: We identified a signature of 18 miRNAs whose overexpression was significantly correlated with longer survival, defined as more than 18 months post-recurrence survival. Subsequent cross-validation showed that a small subset of these miRNAs can predict post-recurrence survival in metastatic melanoma with an estimated accuracy of 80.2% (95% confidence interval, 79.8-80.6%). In contrast to standard-of-care staging criteria, a six-miRNA signature significantly stratified stage III patients into 'better' and 'worse' prognostic categories, and a multivariate Cox regression analysis revealed the signature to be an independent predictor of survival. Furthermore, we showed that most miRNAs from the signature also showed differential expression between patients with better and worse prognoses in the corresponding paired primary melanoma. CONCLUSIONS: MiRNA signatures have potential as clinically relevant biomarkers of prognosis in metastatic melanoma. Our data suggest that molecularly based models of risk assessment can improve the standard staging criteria and support the incorporation of miRNAs into such models. Clin Cancer Res; 16(5); 1577-86
— id: 107357, year: 2010, vol: 16, page: 1577, stat: Journal Article,

Clinical variables and primary tumor characteristics predictive of the development of melanoma brain metastases and post-brain metastases survival
Zakrzewski J; Geraghty LN; Rose AE; Christos PJ; Mazumdar M; Polsky D; Shapiro R; Berman R; Darvishian F; Hernando E; Pavlick A; Osman I
2010 Nov 8;:?-?, Cancer
BACKGROUND:: Melanoma patients who develop brain metastases (B-Met) have limited survival and are excluded from most clinical trials. In the current study, the authors attempted to identify primary tumor characteristics and clinical features predictive of B-Met development and post-B-Met survival. METHODS:: A prospectively accrued cohort of 900 melanoma patients was studied to identify clinicopathologic features of primary melanoma (eg, thickness, ulceration, mitotic index, and lymphovascular invasion) that are predictive of B-Met development and survival after a diagnosis of B-Met. Associations between clinical variables present at the time of B-Met diagnosis (eg, extracranial metastases, B-Met location, and the presence of neurological symptoms) and post-B-Met survival were also assessed. Univariate associations were analyzed using Kaplan-Meier survival analysis, and the effect of independent predictors was assessed using multivariate Cox proportional hazards regression analysis. RESULTS:: Of the 900 melanoma patients studied, 89 (10%) developed B-Met. Ulceration and site of the primary tumor on the head and neck were found to be independent predictors of B-Met development on multivariate analysis (P = .001 and P = .003, respectively). Clinical variables found to be predictive of post-B-Met survival on multivariate analysis included the presence of neurological symptoms (P = .008) and extracranial metastases (P = .04). Ulceration was the only primary tumor characteristic that remained a significant predictor of post-B-Met survival on multivariate analysis (P = .04). CONCLUSIONS:: Primary tumor ulceration was found to be the strongest predictor of B-Met development and remained an independent predictor of decreased post-B-Met survival in a multivariate analysis inclusive of primary tumor characteristics and clinical variables. The results of the current study suggest that patients with ulcerated primary tumors should be prospectively studied to determine whether heightened surveillance for B-Met can improve clinical outcome. Cancer 2010. (c) 2010 American Cancer Society
— id: 141464, year: 2010, vol: , page: ?, stat: Journal Article,

Immune profile and mitotic index of metastatic melanoma lesions enhance clinical staging in predicting patient survival
Bogunovic, Dusan; O'Neill, David W; Belitskaya-Levy, Ilana; Vacic, Vladimir; Yu, Yi-Lo; Adams, Sylvia; Darvishian, Farbod; Berman, Russell; Shapiro, Richard; Pavlick, Anna C; Lonardi, Stefano; Zavadil, Jiri; Osman, Iman; Bhardwaj, Nina
2009 Dec 1;106(48):20429-20434, Proceedings of the National Academy of Sciences of the United States of America
Although remission rates for metastatic melanoma are generally very poor, some patients can survive for prolonged periods following metastasis. We used gene expression profiling, mitotic index (MI), and quantification of tumor infiltrating leukocytes (TILs) and CD3+ cells in metastatic lesions to search for a molecular basis for this observation and to develop improved methods for predicting patient survival. We identified a group of 266 genes associated with postrecurrence survival. Genes positively associated with survival were predominantly immune response related (e.g., ICOS, CD3d, ZAP70, TRAT1, TARP, GZMK, LCK, CD2, CXCL13, CCL19, CCR7, VCAM1) while genes negatively associated with survival were cell proliferation related (e.g., PDE4D, CDK2, GREF1, NUSAP1, SPC24). Furthermore, any of the 4 parameters (prevalidated gene expression signature, TILs, CD3, and in particular MI) improved the ability of Tumor, Node, Metastasis (TNM) staging to predict postrecurrence survival; MI was the most significant contributor (HR = 2.13, P = 0.0008). An immune response gene expression signature and presence of TILs and CD3+ cells signify immune surveillance as a mechanism for prolonged survival in these patients and indicate improved patient subcategorization beyond current TNM staging
— id: 105312, year: 2009, vol: 106, page: 20429, stat: Journal Article,

Mammographic Density and Lobular Involution in Older Women with Abnormal Breast Imaging
Checka, CM; Chun, J; Schnabel, FR; Darvishian, F; Lee, J; Bergknoff, Y; Axelrod, DM; Siegel, BM; Roses, DF
2009 DEC 15 ;69(24):847S-847S, Cancer research
— id: 106458, year: 2009, vol: 69, page: 847S, stat: Journal Article,

Atypia on breast core needle biopsies: reproducibility and significance
Darvishian, Farbod; Singh, Baljit; Simsir, Aylin; Ye, Weimin; Cangiarella, Joan F
2009 Summer;39(3):270-276, Annals of clinical & laboratory science
This study analyzes the interobserver variability in interpreting atypia on breast core needle biopsies and in each category of atypia calculates the upgrade risk of carcinoma in the subsequent surgical excision. We identified 51 cases of atypia on breast core needle biopsies performed at our institution from January 2003 to August 2006. The atypia was classified into 4 categories: atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), flat epithelial atypia (FEA), and atypia of undetermined significance (AUS). After a tutorial session, these cases were independently reviewed by four pathologists, whose overall multi-rater kappa value for agreement on different categories of atypia was 0.79 (95% CI, 0.69-0.89), which is within the substantial agreement range. The upgrade risk in each category of atypia was as follows: ADH 20% (p = 0.04); ALH 10% (p = 0.6); FEA 16.6% (p = 0.23), and AUS 100% (p = 0.96). Based on our findings, we conclude that follow-up excision should be performed after a diagnosis of ADH. The upgrade risk did not reach statistical significance in ALH or FEA. Although follow-up excision cannot be strongly recommended in ALH and FEA, it should be considered since the upgrade risk is not negligible. Strict adherence to the diagnostic criteria and tutorial sessions can help pathologists to achieve substantial agreement in interpreting atypia on breast core needle biopsies
— id: 101451, year: 2009, vol: 39, page: 270, stat: Journal Article,

Association of MDM2 SNP309, age of onset, and gender in cutaneous melanoma
Firoz, Elnaz F; Warycha, Melanie; Zakrzewski, Jan; Pollens, Danuta; Wang, Guimin; Shapiro, Richard; Berman, Russell; Pavlick, Anna; Manga, Prashiela; Ostrer, Harry; Celebi, Julide Tok; Kamino, Hideko; Darvishian, Farbod; Rolnitzky, Linda; Goldberg, Judith D; Osman, Iman; Polsky, David
2009 Apr 1;15(7):2573-2580, Clinical cancer research
PURPOSE: In certain cancers, MDM2 SNP309 has been associated with early tumor onset in women. In melanoma, incidence rates are higher in women than in men among individuals less than 40 years of age, but among those older than 50 years of age, melanoma is more frequent in men than in women. To investigate this difference, we examined the association among MDM2 SNP309, age at diagnosis, and gender among melanoma patients. EXPERIMENTAL DESIGN: Prospectively enrolled melanoma patients (N = 227) were evaluated for MDM2 SNP309 and the related polymorphism, p53 Arg72Pro. DNA was isolated from patient blood samples, and genotypes were analyzed by PCR-restriction fragment length polymorphism. Associations among MDM2 SNP309, p53 Arg72Pro, age at diagnosis, and clinicopathologic features of melanoma were analyzed. RESULTS: The median age at diagnosis was 13 years earlier among women with a SNP309 GG genotype (46 years) compared with women with TG+TT genotypes (59 years; P = 0.19). Analyses using age dichotomized at each decade indicated that women with a GG genotype had significantly higher risks of being diagnosed with melanoma at ages <50 years compared with women >or=50 years, but not when the comparison was made between women <60 and >or=60 years. At ages <50 years, women with a GG genotype had a 3.89 times greater chance of being diagnosed compared with women with TG+TT genotypes (P = 0.01). Similar observations were not seen among men. CONCLUSIONS: Our data suggest that MDM2 may play an important role in the development of melanoma in women. The MDM2 SNP309 genotype may help identify women at risk of developing melanoma at a young age
— id: 104875, year: 2009, vol: 15, page: 2573, stat: Journal Article,

Essential role for eIF4GI overexpression in the pathogenesis of inflammatory breast cancer
Silvera, Deborah; Arju, Rezina; Darvishian, Farbod; Levine, Paul H; Zolfaghari, Ladan; Goldberg, Judith; Hochman, Tsivia; Formenti, Silvia C; Schneider, Robert J
2009 Jul;11(7):903-908, Nature cell biology
Inflammatory breast cancer (IBC) is the most lethal form of primary breast cancer. IBC lethality derives from generation of tumour emboli, which are non-adherent cell clusters that rapidly spread by a form of continuous invasion known as passive metastasis. In most cancers, expression of E-cadherin, an epithelial marker, is indicative of low metastatic potential. In IBC, E-cadherin is overexpressed and supports formation of tumour emboli by promoting tumour cell interactions rather than adherence to stroma. E-cadherin, a surface component of adherens junctions, is anchored by interaction with p120 catenin (p120). We show that the unique pathogenic properties of IBC result in part from overexpression of the translation initiation factor eIF4GI in most IBCs. eIF4GI reprograms the protein synthetic machinery for increased translation of mRNAs with internal ribosome entry sites (IRESs) that promote IBC tumour cell survival and formation of tumour emboli. Overexpression of eIF4GI promotes formation of IBC tumour emboli by enhancing translation of IRES-containing p120 mRNAs. These findings provide a new understanding of translational control in the development of advanced breast cancer
— id: 100610, year: 2009, vol: 11, page: 903, stat: Journal Article,

Developing a multidisciplinary prospective melanoma biospecimen repository to advance translational research
Wich, Lindsay G; Hamilton, Heather K; Shapiro, Richard L; Pavlick, Anna; Berman, Russell S; Polsky, David; Goldberg, Judith D; Hernando, Eva; Manga, Prashiela; Krogsgaard, Michelle; Kamino, Hideko; Darvishian, Farbod; Lee, Peng; Orlow, Seth J; Ostrer, Harry; Bhardwaj, Nina; Osman, Iman
2009 ;1(1):35-43, American Journal of Translational Research
Several challenges face the development and operation of a biospecimen bank linked to clinical information, a critical component of any effective translational research program. Melanoma adds particular complexity and difficulty to such an endeavor considering the unique characteristics of this malignancy. We describe here a review of biospecimen bank and our experience in establishing a multi-disciplinary, prospective, integrated clinicopathological-biospecimen database in melanoma. The Interdisciplinary Melanoma Cooperative Group (IMCG), a prospective clinicopathological and biospecimen database, was established at the New York University (NYU) Langone Medical Center. With patients' informed consent, biospecimens from within and outside NYU, clinicopathological data, and follow-up information are collected using developed protocols. Information pertaining to biospecimens is recorded in 35 fields, and clinicopathological information is recorded in 371 fields within 5 modules in a virtual network system. Investigators conducting research utilizing the IMCG biospecimen resource are blind to clinicopathological information, and molecular data generated using biospecimens are linked independently with clinicopathological data by biostatistics investigators. This translational research enterprise acts as a valuable resource to efficiently translate laboratory discoveries to the clinic
— id: 105566, year: 2009, vol: 1, page: 35, stat: Journal Article,

Gene expression profile for metastatic melanoma and patient survival
Bogunovic D; O'Neill D; Adams S; Wang J; Darvishian F; Pavlick AC; Shapiro RL; Zavadil J; Osman I; Bhardwaj N
2008 May 20;26(Suppl):?-? #9049, Proceedings (American Society of Clinical Oncology)
Background: Although remission rates for metastatic melanoma are generally very poor, some patients can survive for prolonged periods following metastasis. Here we use gene expression profiling of metastatic melanoma samples to search for a molecular basis for this observation. Methods: We analyzed gene expression profiles of 44 metastatic melanoma specimens collected from 38 patients who were followed clinically for a median of 20 months after surgery. RNA was processed using standard methods and hybridized to Affymetrix Human Genome HU133 Plus 2.0 arrays. Data were analyzed using GeneSpring and PathwayAssist software, normalizing using a PLIER algorithm and utilizing ANOVA statistical tests. Results: Unsupervised clustering yielded 4 distinct groups of subjects, 2 of which had large differences in overall survival. We then used supervised clustering to compare patients whose post-surgery survival was less then 1.5 years (11 subjects, 9.5 month median survival) to those who survived greater than 1.5 years (23 subjects, 26 month median survival, 17 alive at last follow-up). Only genes with changes in expression of > 2 with a p value of < 0.05 were accepted, resulting in a group of approximately 200 genes. Genes associated with immune response (TNFa, IRF1, Granzyme B, CD8a, CXCL11, IL27AR, GBP1, CXCL10, CCBP2, GBP2, CCR9 and IFIT4) or with cell proliferation (FGFR1, MET, MDM2, CDC25A, RFC2, SOS1, HOXA3, MCM4, MCM7, ORC5L, KIF23 and VAV3) were highly represented. Prolonged survival was associated with elevated expression of immune response genes and decreased expression of genes associated with cell proliferation. Conclusions: Gene expression profiling of metastatic melanoma samples identified a set of genes associated with patient survival, and suggests that immune surveillance is a mechanism for prolonged survival in these patients
— id: 106301, year: 2008, vol: 26, page: ?, stat: Journal Article,

Is pleomorphic lobular carcinoma really a distinct clinical entity?
Buchanan, Claire L; Flynn, Laurie W; Murray, Melissa P; Darvishian, Farbod; Cranor, Milicent L; Fey, Jane V; King, Tari A; Tan, Lee K; Sclafani, Lisa M
2008 Oct 1;98(5):314-317, Journal of surgical oncology
BACKGROUND: Attempts to define the clinical behavior of pleomorphic lobular carcinoma (PLC) have been limited to small series, and clinical management strategies have yet to be established. We describe our experience with PLC as compared to classic ILC and invasive ductal carcinoma (IDC). METHODS: From 9/1996 to 5/2003, clinical and histopathologic data for 5,635 patients undergoing primary surgical treatment and sentinel lymph node biopsy for breast cancer were collected. Four hundred eighty one (8.5%) patients were diagnosed with ILC; 3,978 (70.6%) with IDC. Of those with ILC, 356 (74%) patients had material available for pathologic re-review and comprise our study population: 52 were classified as PLC; 298 were classified as classic ILC; and 6 cases were reclassified as IDC. We compared clinical, pathologic, and treatment factors for patients with PLC, ILC, and IDC using the Wilcoxon rank sum and Fisher's exact tests. RESULTS: PLC were larger than ILC and IDC (20 vs. 15 vs. 13, P < 0.001), had more positive nodes (median 1 vs. 0 vs. 0, P < 0.05) and more frequently required mastectomy (63.5% vs. 38.7% vs. 28.8%, P < 0.001). In addition, more patients with PLC had developed metastatic disease compared to patients with ILC (11.5% vs. 3.7%, P < 0.05). CONCLUSIONS: These findings suggest that PLC is a distinct clinical entity that presents at a more advanced stage and may require more aggressive surgical and adjuvant treatment. J. Surg. Oncol. (c) 2008 Wiley-Liss, Inc
— id: 81351, year: 2008, vol: 98, page: 314, stat: Journal Article,

Is surgical excision necessary for the management of atypical lobular hyperplasia and lobular carcinoma in situ diagnosed on core needle biopsy?: a report of 38 cases and review of the literature
Cangiarella, Joan; Guth, Amber; Axelrod, Deborah; Darvishian, Farbod; Singh, Baljit; Simsir, Aylin; Roses, Daniel; Mercado, Cecilia
2008 Jun;132(6):979-983, Archives of pathology & laboratory medicine
CONTEXT: Both atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS) have traditionally been considered to be risk factors for the development of invasive carcinoma and are followed by close observation. Recent studies have suggested that these lesions may represent true precursors with progression to invasive carcinoma. Due to the debate over the significance of these lesions and the small number of cases reported in the literature, the treatment for lobular neoplasia diagnosed by percutaneous core biopsy (PCB) remains controversial. OBJECTIVE: To review our experience with pure LCIS or ALH diagnosed by PCB and correlate the radiologic findings and surgical excision diagnoses to develop management guidelines for lobular neoplasia diagnosed by PCB. DESIGN: We searched the pathology database for patients who underwent PCB with a diagnosis of either pure LCIS or ALH and had subsequent surgical excision. We compared the core diagnoses with the surgical excision diagnoses and the radiologic findings. RESULTS: Thirty-eight PCBs with a diagnosis of ALH (18 cases) or LCIS (20 cases) were identified. Carcinoma was present at excision in 1 (6%) of the ALH cases and in 2 (10%) of the LCIS cases. In summary, 8% (3/38) of PCBs diagnosed as lobular neoplasia (ALH or LCIS) were upgraded to carcinoma (invasive carcinoma or ductal carcinoma in situ) at excision. CONCLUSIONS: Surgical excision is indicated for all PCBs diagnosed as ALH or LCIS, as a significant percentage will show carcinoma at excision
— id: 79288, year: 2008, vol: 132, page: 979, stat: Journal Article,

Interobserver variability in differentiation of nodal nevus from melanoma micrometastasis in sentinel lymph adenectomy specimens
Celin, N; Bannan, M; Darvishian, F; Hajdu, C; Nonaka, D; Ye, W; Pei, Z; Melamed, J
2008 ;21(2):409-409, Modern pathology
— id: 100682, year: 2008, vol: 21, page: 409, stat: Journal Article,

Isolated tumor cells on sentinel lymph node biopsy: Our experience over a decade
Darvishian, F; Guth, A; Dhage, S; Singh, B; Roses, D; Axelrod, D; Mercado, C; Cangiarella, J
2008 JAN ;21(2):27A-28A, Modern pathology
— id: 75903, year: 2008, vol: 21, page: 27A, stat: Journal Article,

Polymorphisms of p53 and its negative regulator MDM2 in human melanoma
Firoz, EF; Warycha, M; Shapiro, R; Berman, R; Kamino, H; Darvishian, F; Rolnitzky, L; Goldberg, J; Osman, I; Polsky, D
2008 APR ;128(5):S226-S226, Journal of investigative dermatology
— id: 78655, year: 2008, vol: 128, page: S226, stat: Journal Article,

Can axillary dissection be avoided in patients with sentinel node micrometastasis? The role of pathologic assessment of breast tumors in predicting non-sentinel node metastasis
Gupta, R; Cangiarella, J; Singh, B; Gath, A; Axelrod, D; Roses, D; Darvishian, F
2008 JAN ;21(2):35A-35A, Modern pathology
— id: 75905, year: 2008, vol: 21, page: 35A, stat: Journal Article,

Can axillary dissection be avoided in patients with sentinel node micrometastasis? The role of pathologic assessment of breast tumors in predicting non-sentinel node metastasis
Gupta, R; Cangiarella, J; Singh, B; Guth, A; Axelrod, D; Roses, D; Darvishian, F
2008 JAN ;88(2):35A-35A, Laboratory investigation
— id: 75927, year: 2008, vol: 88, page: 35A, stat: Journal Article,

Microinvasive breast cancer and the role of sentinel node biopsy: an institutional experience and review of the literature
Guth, Amber A; Mercado, Cecilia; Roses, Daniel F; Darvishian, Farbod; Singh, Baljit; Cangiarella, Joan F
2008 Jul-Aug;14(4):335-339, Breast journal
Ductal carcinoma in situ with microinvasion (DCISM) is a distinct clinicopathologic entity. Its true metastatic potential has been unclear, due in part to historical differences in the definition of microinvasion. The role of routine axillary staging for DCISM is controversial, given the reportedly low incidence of axillary metastases. We describe our institutional experience with DCISM, and define the role of axillary staging. A retrospective analysis was made of patients with DCISM. Forty-four patients underwent axillary staging (24 axillary lymph node dissection [ALND], 22 sentinel node biopsy [SNB]). Macrometastatic disease was present in three patients (7%), and two patients had isolated tumor cells (itc) in the sentinel node. Patients with axillary metastases tended to be younger. Comedonecrosis, nuclear grade, multifocal microinvasion or presentation as a clinical mass was not associated with a higher rate of axillary metastases. In this series, 7% of patients had macrometastatic disease, and two patients (5%) had itc only. Axillary staging is indicated, and SNB is appropriate for the identification of axillary metastatic disease
— id: 81349, year: 2008, vol: 14, page: 335, stat: Journal Article,

Invasive lobular carcinoma of the breast: role of endothelial lymphatic marker D2-40
Laser, Jordan; Cangiarella, Joan; Singh, Baljit; Melamed, Jonathan; Chiriboga, Luis; Yee, Herman; Darvishian, Farbod
2008 Spring;38(2):99-104, Annals of clinical & laboratory science
Lymphovascular invasion (LVI) of breast cancer is an independent adverse prognosticator that is associated with increased regional and distant tumor recurrence. LVI is infrequently encountered in invasive lobular carcinoma when compared to invasive ductal carcinoma. We employed D2-40 antibody, a novel marker for lymphatic endothelial cells, in an attempt to enhance the detection of LVI in invasive lobular carcinomas. We identified 78 patients with invasive lobular carcinoma with known axillary status, who were studied between 2003 and 2006. D2-40 antibody was applied to one representative paraffin block from each case and the results were compared to LVI on routine histology. LVI was identified in 12 (15%) and 19 (24%) cases by routine histology and D2-40 antibody, respectively. Eleven of 12 patients (92%) with LVI identified by routine histology had axillary nodal metastasis compared to 14 of 19 patients (74%) with LVI identified by D2-40 antibody. LVI was missed by routine histology in 8 cases (10%). D2-40 antibody enhanced the identification of LVI by 9% in node negative patients. D2-40 antibody increased the identification of LVI by 12% in classic invasive lobular carcinoma. In conclusion, D2-40 antibody staining may be useful as an adjunct in detecting LVI in invasive lobular carcinoma, especially in node-negative patients with the classic variant of invasive lobular carcinoma
— id: 78828, year: 2008, vol: 38, page: 99, stat: Journal Article,

Changes in the presentation of nodular and superficial spreading melanomas over 35 years
Warycha, Melanie A; Christos, Paul J; Mazumdar, Madhu; Darvishian, Farbod; Shapiro, Richard L; Berman, Russell S; Pavlick, Anna C; Kopf, Alfred W; Polsky, David; Osman, Iman
2008 Dec 15;113(12):3341-3348, Cancer
BACKGROUND: Nodular melanoma (NM) may be biologically aggressive compared with the more common superficial spreading melanoma (SSM), with recent data suggesting underlying genetic differences between these 2 subtypes. To better define the clinical behavior of NMs, the authors compared their clinical and histopathologic features to those of SSMs at their institution, a tertiary referral center, over 3 decades. METHODS: A total of 1,684 patients diagnosed with 1,734 melanomas were prospectively enrolled. Of these, 1,143 patients (69% SSM, 11% NM, 20% other) were diagnosed between 1972 and 1982; 541 patients (54% SSM, 23% NM, 23% other) were diagnosed between 2002 and the present. Differences between the features of NM and SSM within each time period as well as changes over time were analyzed. RESULTS: The authors found that SSMs are now diagnosed as thinner lesions (P < .0001) with a low incidence of histologic ulceration (P < .0001), whereas there was no significant change in the median tumor thickness or ulceration status of NMs over time (P = .10, P = .30, respectively). The median age at diagnosis of NM, however, did significantly increase over time (51 years to 63 years, P < .01). The median duration of NMs was reported to be only 5 months compared with 9 months in SSM patients. CONCLUSIONS: The authors' data suggest that improvements have been made in the early detection of SSM but not NM. Modifications of current screening practices, including increased surveillance of high-risk patients with an emphasis on the 'E' for 'evolution' criterion of the ABCDE acronym used for early detection of melanoma, are thus warranted
— id: 91976, year: 2008, vol: 113, page: 3341, stat: Journal Article,

Assessing the clinical utility of measuring Insulin-like Growth Factor Binding Proteins in tissues and sera of melanoma patients
Yu, Jessie Z; Warycha, Melanie A; Christos, Paul J; Darvishian, Farbod; Yee, Herman; Kaminio, Hideko; Berman, Russell S; Shapiro, Richard L; Buckley, Michael T; Liebes, Leonard F; Pavlick, Anna C; Polsky, David; Brooks, Peter C; Osman, Iman
2008 ;6:70-70, Journal of translational medicine
BACKGROUND: Different Insulin-like Growth Factor Binding Proteins (IGFBPs) have been investigated as potential biomarkers in several types of tumors. In this study, we examined both IGFBP-3 and -4 levels in tissues and sera of melanoma patients representing different stages of melanoma progression. METHODS: The study cohort consisted of 132 melanoma patients (primary, n = 72; metastatic, n = 60; 64 Male, 68 Female; Median Age = 56) prospectively enrolled in the New York University School of Medicine Interdisciplinary Melanoma Cooperative Group (NYU IMCG) between August 2002 and December 2006. We assessed tumor-expression and circulating sera levels of IGFBP-3 and -4 using immunohistochemistry and ELISA assays. Correlations with clinicopathologic parameters were examined using Wilcoxon rank-sum tests and Spearman-rank correlation coefficients. RESULTS: Median IGFBP-4 tumor expression was significantly greater in primary versus metastatic patients (70% versus 10%, p = 0.01) A trend for greater median IGFBP-3 sera concentration was observed in metastatic versus primary patients (4.9 microg/ml vs. 3.4 microg/ml, respectively, p = 0.09). However, sera levels fell within a normal range for IGFBP-3. Neither IGFBP-3 nor -4 correlated with survival in this subset of patients. CONCLUSION: Decreased IGFBP-4 tumor expression might be a step in the progression from primary to metastatic melanoma. Our data lend support to a recently-described novel tumor suppressor role of secreting IGFBPs in melanoma. However, data do not support the clinical utility of measuring levels of IGFBP-3 and -4 in sera of melanoma patients
— id: 92159, year: 2008, vol: 6, page: 70, stat: Journal Article,

Intraparenchymal leiomyoma of the breast: a case report and review of the literature
Ende, Lauren; Mercado, Cecilia; Axelrod, Deborah; Darvishian, Farbod; Levine, Pascale; Cangiarella, Joan
2007 Summer;37(3):268-273, Annals of clinical & laboratory science
We report a case of an intraparenchymal leiomyoma of the breast with description of the radiologic, histopathologic, and immunohistochemical findings. To the best of our knowledge, this is the first case of an intraparenchymal leiomyoma of the breast diagnosed by core needle biopsy and the 22nd case described in the literature. In addition, we review the literature on this uncommon breast neoplasm
— id: 73878, year: 2007, vol: 37, page: 268, stat: Journal Article,

Microinvasive breast cancer: The role of sentinel node biopsy
Guth, AA; Mercado, C; Roses, DF; Darvishian, F; Singh, B; Cangiarella, JF
2007 FEB ;14(2):43-43, Annals of surgical oncology
— id: 71054, year: 2007, vol: 14, page: 43, stat: Journal Article,

The road to discovery of an uncommon tracheobronchial tumor
Hajdu, Steven I; Darvishian, Farbod
2007 Autumn;37(4):375-377, Annals of clinical & laboratory science
— id: 76084, year: 2007, vol: 37, page: 375, stat: Journal Article,

Accuracy of intraoperative sentinel lymph node evaluation for breast
Richards, V; Roses, DF; Axelrod, DM; Guth, AA; Shapiro, RL; Cangiarella, J; Ziguridis, N; Darvishian, F
2007 ;20(3):195-273, Modern pathology
— id: 93501, year: 2007, vol: 20, page: 195, stat: Journal Article,

Accuracy of intraoperative sentinel lymph node evaluation for breast cancer
Richards, V; Roses, DF; Axelrod, DM; Guth, AA; Shapiro, RL; Cangiarella, J; Ziguridis, N; Darvishian, F; Singh, B
2007 ;87(3):195-273, Laboratory investigation
— id: 93502, year: 2007, vol: 87, page: 195, stat: Journal Article,

Inflammatory breast cancer pathogenesis is mediated in significant part by translation initiation factor eIF4G amplification and unorthodox protein synthesis
Silvera, D; Arju, R; Darvishian, F; Levine, PH; Formenli, SC; Schneider, RJ
2007 DEC ;106(1):S18-S18, Breast cancer research & treatment
— id: 75798, year: 2007, vol: 106, page: S18, stat: Journal Article,

Impact of complete removal of breast carcinoma by aggressive biopsy techniques
Wen, YH; Roses, DF; Axelrod, DM; Guth, AA; Shapiro, RL; Cangiarella, J; Ziguridis, N; Darvishian, F; Mercado, C; Singh, B
2007 ;20(2):226-50, Modern pathology
— id: 93504, year: 2007, vol: 20, page: 226, stat: Journal Article,

Impact of complete removal of breast carcinoma by aggressive biopsy techniques
Wen, YH; Roses, DF; Axelrod, DM; Guth, AA; Shapiro, RL; Cangiarella, J; Ziguridis, N; Darvishian, F; Mercado, C; Singh, B
2007 ;87(2):226-50, Laboratory investigation
— id: 93505, year: 2007, vol: 87, page: 226, stat: Journal Article,

Prophylactic mastectomy - trends in pathology findings
Wen, YH; Roses, DF; Axelrod, DM; Guth, AA; Shapiro, RL; Cangiarella, J; Ziguridis, N; Darvishian, F; Singh, B
2007 DEC ;106(1):S136-S136, Breast cancer research & treatment
— id: 75803, year: 2007, vol: 106, page: S136, stat: Journal Article,

Breast carcinoma in women 30 years and younger
Wen, YH; Roses, DF; Axelrod, DM; Guth, AA; Shapiro, RL; Cangiarella, JF; Ziguridis, N; Darvishian, F; Singh, B
2007 ;14(2):50-50, Annals of surgical oncology
— id: 93503, year: 2007, vol: 14, page: 50, stat: Journal Article,

Carcinoid tumorlets simulate pulmonary metastases in women with breast cancer
Darvishian, Farbod; Ginsberg, Michelle S; Klimstra, David S; Brogi, Edi
2006 Jul;37(7):839-844, Human pathology
A pulmonary carcinoid tumorlet (PCT) is a nodular proliferation of neuroendocrine cells smaller than 0.5 cm. On computed tomographic (CT) imaging, these nodules are nonspecific in appearance and can mimic metastatic disease. Cases of multiple PCTs diagnosed between 1992 and 2003 in patients with history of breast cancer were identified through a search of the pathology files. The clinical information was abstracted from the medical records. We identified 12 women with a history of breast cancer and biopsy-proven PCTs, who were treated at our institution in a period of 12 years. Only 3 women were smokers. The mean age at diagnosis of the breast cancer was 62.8 years. The breast cancer was invasive carcinoma in 10 cases (9 ductal and 1 lobular) and ductal carcinoma in situ and malignant phyllodes tumor in 1 case each. Six women received radiotherapy; 5, chemotherapy; and 4, hormonal treatment, alone or in combination. Pulmonary carcinoid tumorlets were identified within 5 months from diagnosis of the breast malignancy in 7 patients and at follow-up (range, 57-162 months) in the remaining 5. In all cases, the PCTs consisted of multiple pulmonary nodules that were radiologically interpreted as suspicious for pulmonary metastases. Misdiagnosis of metastatic carcinoma was rendered intraoperatively by frozen section analysis in 3 cases. None of the patients had known metastatic disease at the time of diagnosis of PCTs. Three patients subsequently developed recurrent disease, including 2 with extramammary spread. Pulmonary carcinoid tumorlets are radiologic and histologic mimickers of pulmonary metastases in patients with a history of breast cancer. Consideration should be given to the possibility of PCTs in patients with breast cancer with pulmonary nodules, even if multiple
— id: 81346, year: 2006, vol: 37, page: 839, stat: Journal Article,

Immunoreactivity of p16 in anal cytology specimens: histologic correlation
Darvishian, Farbod; Stier, Elizabeth A; Soslow, Robert A; Lin, Oscar
2006 Feb 25;108(1):66-71, Cancer
BACKGROUND: Cytology has been proposed as a potential screening tool in the evaluation of squamous anorectal disease in view of the morphologic similarities between anal and cervical squamous lesions. Previous studies have demonstrated that p16 overexpression correlates with the degree of dysplasia in the uterine cervix with promising results. Due to potential diagnostic pitfalls in anal cytology, p16 overexpression in these specimens was studied. METHODS: Patients with anorectal cytology who underwent follow-up biopsy within 1 year were selected. Forty-three anorectal cytologic specimens from 29 patients were selected. One slide of each case was destained. Avidin-biotin immunocytochemical studies with the monoclonal antibody CINtec p16(INK4a) were performed. The results of the p16 immunostaining were correlated with the histologic findings. RESULTS: Twenty-eight of the 43 cases demonstrated the presence of squamous cells immunoreactive for p16 in cytology specimens. The p16-positive cells were identified in cases of low-grade squamous intraepithelial lesion (LSIL) (n = 3 cases), high-grade squamous intraepithelial lesion (HSIL) (n = 22 cases), and invasive squamous carcinoma (n = 1 case), and in 2 cases with negative follow-up biopsies. No cell immunoreactive for p16 was found in 15 cases (5 benign cases and 10 cases with either LSIL or HSIL). The sensitivity and specificity of p16 immunoreactivity in the detection of anal intraepithelial neoplasia or carcinoma were 72% and 71%, respectively. The positive and negative predictive values were 93% and 33%, respectively. CONCLUSIONS: The presence of p16 immunoreactivity is a good predictor of dysplasia in anal specimens. However, the sensitivity and specificity of this marker are not high
— id: 81344, year: 2006, vol: 108, page: 66, stat: Journal Article,

Correlation of DNA mismatch repair genes, hormone receptor status and proliferation markers in male breast cancer
Giashuddin, S; Yee, H; Arju, R; Chiriboga, L; Silvera, D; Darvishian, F
2006 JAN ;19(4):28A-28A, Modern pathology
— id: 61432, year: 2006, vol: 19, page: 28A, stat: Journal Article,

Correlation of DNA mismatch repair genes, hormone receptor status and proliferation markers in male breast cancer
Giashuddin, S; Yee, H; Arju, R; Chiriboga, L; Silvera, D; Darvishian, F
2006 JAN ;86(4):28A-28A, Laboratory investigation
— id: 62613, year: 2006, vol: 86, page: 28A, stat: Journal Article,

Extramedullary hematopoiesis in breast after neoadjuvant chemotherapy for breast carcinoma
Wang, Jun; Darvishian, Farbod
2006 Autumn;36(4):475-478, Annals of clinical & laboratory science
We report incidental extramedullary hematopoiesis (EMH) in breasts of 2 patients following neoadjuvant chemotherapy for locally advanced breast cancer. Neither of the patients had a history of hematologic disorders. After chemotherapy, one of the patients had a complete pathologic response and the other had residual carcinoma. In both cases, EMH was mostly seen as myelopoiesis in a background of chemotherapy-induced changes. In the patient with residual carcinoma, EMH was observed in the contralateral prophylactic mastectomy specimen. EMH should be considered a diagnostic pitfall in the differential diagnosis of unusual cellular infiltrates in breast after neoadjuvant chemotherapy. To our knowledge, the association of EMH and neoadjuvant chemotherapy has not been previously reported
— id: 69703, year: 2006, vol: 36, page: 475, stat: Journal Article,

Clinical and pathologic features of proximal biliary strictures masquerading as hilar cholangiocarcinoma
Corvera, Carlos U; Blumgart, Leslie H; Darvishian, Farbod; Klimstra, David S; DeMatteo, Ronald; Fong, Yuman; D'Angelica, Michael; Jarnagin, William R
2005 Dec;201(6):862-869, Journal of the American College of Surgeons
BACKGROUND: Nontraumatic inflammatory hilar strictures are uncommon, but are known to mimic malignancy. This study examines the clinical and pathologic features of benign idiopathic strictures. STUDY DESIGN: Patients without a history of trauma or earlier biliary operation treated for benign strictures were identified. Clinical information was obtained from the medical record and all resected specimens were reexamined. RESULTS: From January 1992 to July 2003, 275 patients with proximal biliary strictures were referred. Among these, 22 patients had a final histologic diagnosis of benign stricture, despite a suspected preoperative diagnosis of malignancy. All 22 patients underwent resection of the extrahepatic biliary tree, which in 10 patients was combined with en bloc partial hepatectomy. Histologic reexamination identified five different benign processes: lymphoplasmacytic sclerosing pancreatitis and cholangitis, primary sclerosing cholangitis, granulomatous disease, nonspecific fibrosis/inflammation, and stone disease. Major postoperative morbidity occurred in 6 (26%) patients but none died. No preoperative clinical or radiographic features were identified that could reliably distinguish patients with benign strictures from those with cancer. CONCLUSIONS: 'Malignant masquerade' of the proximal bile duct results from several different underlying conditions, and differentiating benign strictures from cancer remains problematic. The treatment approach should continue to be resection for presumed malignancy
— id: 81343, year: 2005, vol: 201, page: 862, stat: Journal Article,

Serous endometrial cancers that mimic endometrioid adenocarcinomas: a clinicopathologic and immunohistochemical study of a group of problematic cases
Darvishian, Farbod; Hummer, Amanda J; Thaler, Howard T; Bhargava, Rohit; Linkov, Irina; Asher, Marina; Soslow, Robert A
2004 Dec;28(12):1568-1578, American journal of surgical pathology
BACKGROUND: Uterine serous carcinomas (USCs) can exhibit an architecturally well-differentiated tubuloglandular morphology with or without an accompanying papillary growth pattern. These features make it difficult to distinguish USCs from endometrial endometrioid carcinomas (EECs). Given the aggressive behavior of USC, compared with EEC, and differences in management, it is important to correctly classify endometrial carcinomas that exhibit a tubuloglandular architecture with high nuclear grade. We sought an immunohistochemical panel to minimize subjectivity in the distinction of USC from EEC. MATERIALS AND METHODS: We identified 8 problematic endometrial cancers, exhibiting a tubuloglandular growth pattern and high nuclear grade, whose classification as EEC or USC was debated or resulted in disagreement. We selected 13 cases of International Federation of Gynecology and Obstetrics (FIGO) grade 2 EEC and 16 cases of USC as controls. An immunohistochemical panel, including p53, beta-catenin, cyclin D1, estrogen receptor (ER), progesterone receptor (PR), and PTEN, was evaluated. RESULTS: As a group, the clinical features and immunoprofile of the study cases resembled those of the serous controls. The study cases expressed p53, beta-catenin, cyclin D1, and ER and PR, and showed loss of PTEN in 75%, 12.5%, 0%, 37.5%, 37.5%, and 12.5% of cases, respectively. p53, beta-catenin, cyclin D1, ER and PR expression, and PTEN loss were seen in 87.5%, 0%, 19%, 31%, 12%, and 0% of the serous controls and in 7%, 70%, 54%, 92%, 92%, and 61.5% of the endometrioid controls, respectively. The combination of lack of p53 expression, positive PR expression, and loss of PTEN best distinguished between EEC and USC using discriminant analysis (multivariate P = 0.008, <0.001, and 0.05, respectively). CONCLUSION: In endometrial carcinomas exhibiting high nuclear grade and low architectural grade, using a panel of immunohistochemical stains may facilitate the distinction of USC from EEC. Our clinical and immunohistochemical data also support the concept that there is a group of endometrial adenocarcinomas composed of tubular glands that are indeed serous carcinomas
— id: 81342, year: 2004, vol: 28, page: 1568, stat: Journal Article,

Myoepithelial cell-rich neoplasms: cytologic features of benign and malignant lesions
Darvishian, Farbod; Lin, Oscar
2004 Dec 25;102(6):355-361, Cancer
BACKGROUND: Lesions that contain abundant myoepithelial cells may present as a diagnostic challenge in fine-needle aspiration (FNA) specimens. Potential diagnostic problems may arise due to morphologic heterogeneity of myoepithelial cell-rich lesions and difficulty in predicting malignancy in FNA specimens. An accurate diagnosis is important, because malignant myoepithelial cell-rich lesions require a wider local excision and lymph node dissection. The authors characterized the cytologic features of myoepithelial cell-rich lesions in an attempt to define the criteria that facilitate distinction between benign and malignant tumors. METHODS: FNA biopsies of myoepithelial cell-rich lesions with corresponding histologic specimens were selected. The cytology specimens were evaluated for the following criteria: cellularity, cell morphology, pleomorphism, chromatin pattern, presence of nucleoli, background material, necrotic debris, and presence of mitotic figures. A review of the histologic sections was performed for diagnostic confirmation. RESULTS: Seventeen specimens from 17 different patients were selected. The histologic diagnoses were myoepithelial carcinoma (n = 6 patients), malignant mixed tumor with predominant myoepithelial carcinoma (n = 2 patients), epithelial-myoepithelial carcinoma (n = 1 patient), and benign mixed tumor (n = 8 patients). The primary sites included the parotid gland (n = 10 patients), submandibular gland (n = 3 patients), minor salivary gland (n = 3 patients), and breast (n = 1 patient). Most specimens, whether they were benign or malignant, were very cellular. Pleomorphism, coarse chromatin, prominent nucleoli, mitotic figures, and necrosis were observed only in malignant specimens. Background material and ductal cells were seen in both benign and malignant specimens. CONCLUSIONS: The presence of pleomorphism, coarse chromatin, prominent nucleoli, mitotic figures, and/or necrosis should raise the possibility of myoepithelial carcinoma in FNA specimens from myoepithelial cell-rich lesions
— id: 81341, year: 2004, vol: 102, page: 355, stat: Journal Article,

Significance of linear extent of breast carcinoma at surgical margin
Darvishian, Farbod; Hajdu, Steven I; DeRisi, Dwight C
2003 Jan-Feb;10(1):48-51, Annals of surgical oncology
BACKGROUND: Our objective was to correlate the extent of margin positivity and the findings on re-excision specimens of infiltrating mammary carcinoma. METHODS: We selected 50 consecutive cases of infiltrating mammary carcinoma, including both infiltrating ductal carcinoma and infiltrating lobular carcinoma, with positive margins followed by re-excision. Margin positivity was defined as the presence of cancer at the inked margin. The extent of margin positivity was assessed by measuring the linear involvement of the inked margin by the carcinoma. RESULTS: Twenty-one of 50 cases (42%) showed positive findings on re-excision, including either infiltrating carcinoma or carcinoma in situ or both. Nine of 14 cases (64%) with ductal carcinoma in situ or infiltrating ductal carcinoma on re-excision and 4 of 7 cases (57%) with lobular carcinoma in situ or infiltrating lobular carcinoma on re-excision had initial linear margins >1.0 cm, whereas 28 of 29 cases (96%) with negative findings on re-excision had initial linear margins <1.0 cm. CONCLUSIONS: Linear measurement of the inked margin involved by infiltrating mammary carcinoma can be used as a predictor of findings on re-excisions
— id: 81340, year: 2003, vol: 10, page: 48, stat: Journal Article,

Familial visceral myopathy with carcinoma of unknown primary
Darvishian, Farbod; Basham, Kevin
2002 Winter;32(1):93-97, Annals of clinical & laboratory science
We report an autopsy case of a 35-yr-old man with familial visceral myopathy, a cause of primary intestinal pseudo-obstruction. The patient died from complications of familial visceral myopathy, sepsis, and generalized signet-ring cell carcinomatosis. The patient had massive distension of the large and small intestines, a dilated thickened esophagus, and fibroneoplastic adhesions between intra-abdominal and thoracic structures. This case provides an observation, not previously described in cases of familial visceral myopathy, which is fibrosis and atrophy of the outer longitudinal smooth muscle of the small bowel, alternating to involve only the inner smooth muscle layer of the large bowel. This case shows how a malignant neoplasm can compound the pathology of familial visceral myopathy
— id: 81338, year: 2002, vol: 32, page: 93, stat: Journal Article,

Langerhans' cell histiocytosis in the parotid gland
Darvishian, Farbod; Hirawat, Samit; Teichberg, Saul; Wolk, David; Allen, Steven L; Hajdu, Steven I
2002 Spring;32(2):201-206, Annals of clinical & laboratory science
Langerhans' cell histiocytosis presenting as a parotid gland mass is extremely rare. We report a case of Langerhans' cell histiocytosis in the parotid gland that occurred in a 34-year-old Korean male. The patient underwent parotidectomy followed by adjuvant chemotherapy. There has been no evidence of local recurrence or disease progression during 20 months after the lesion was first diagnosed. Differentiation of Langerhans' cell histiocytosis from Kimura's disease was crucial in this clinical setting
— id: 72072, year: 2002, vol: 32, page: 201, stat: Journal Article,

Ultrastructural comparison of "alveolar" and "solid" areas in bronchioloalveolar carcinoma
Darvishian, Farbod; Roberts, Beth; Teichberg, Saul; Steven, Hajdu I
2002 Summer;32(3):225-230, Annals of clinical & laboratory science
The purpose of this study was to compare the ultrastructural features of bronchioloalveolar carcinomas, contrasting the well-differentiated alveolar component and the poorly-differentiated solid component in the same tumor. We studied 7 cases of non-mucinous bronchioloalveolar carcinomas by electron microscopy. Two of these cases showed lamellar bodies in both the alveolar and solid components and the remaining 5 cases revealed Clara cell granules in both components. We conclude that the neoplastic cells in bronchioloalveolar carcinoma retain their ultrastructural phenotypes after becoming invasive carcinoma with loss of alveolar differentiation
— id: 72071, year: 2002, vol: 32, page: 225, stat: Journal Article,

Carcinosarcoma of the pancreas: a case report and review of the literature
Darvishian, Farbod; Sullivan, James; Teichberg, Saul; Basham, Kevin
2002 Sep;126(9):1114-1117, Archives of pathology & laboratory medicine
We report the case of a 74-year-old white man with a mass in the head of the pancreas, which was found incidentally on computerized tomographic scan during a workup for deep vein thrombosis. Endoscopy with pancreatic duct brushings yielded a diagnosis of adenocarcinoma. A pancreaticoduodenectomy followed, with complete resection of the tumor. Pathologic examination showed 2 distinct components. One component was a conventional infiltrating pancreatic ductal adenocarcinoma, and the other component was high-grade sarcoma with features of malignant fibrous histiocytoma. To our knowledge, this carcinosarcoma is the seventh reported case of a primary pancreatic neoplasm with mixed carcinomatous and sarcomatous elements
— id: 72070, year: 2002, vol: 126, page: 1114, stat: Journal Article,

Concurrent malakoplakia and papillary urothelial carcinoma of the urinary bladder
Darvishian F; Teichberg S; Meyersfield S; Urmacher CD
2001 Apr;31(2):147-150, Annals of clinical & laboratory science
A case of malakoplakia and papillary urothelial carcinoma of the urinary bladder is reported. In this case, malakoplakia was an incidental finding in a biopsy of the urinary bladder of a 74-yr old female, who presented with hematuria. The biopsy showed a low-grade papillary urothelial carcinoma in close association with malakoplakia. This is a rare association of these lesions
— id: 36471, year: 2001, vol: 31, page: 147, stat: Journal Article,