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A Randomized, Phase 3, Trial of Interferon-α versus Hydroxyurea in Polycythemia Vera and Essential Thrombocythemia

Mascarenhas, John; Kosiorek, Heidi E; Prchal, Josef T; Rambaldi, Alessandro; Berenzon, Dmitriy; Yacoub, Abdulraheem; Harrison, Claire N; McMullin, Mary Frances Frances; Vannucchi, Alessandro Maria; Ewing, Joanne; O'Connell, Casey L; Kiladjian, Jean-Jacques; Mead, Adam J; Winton, Elliott F; Leibowitz, David S; De Stefano, Valerio; Arcasoy, Murat O; Kessler, Craig M; Catchatourian, Rosalind; Rondelli, Damiano; Silver, Richard T; Bacigalupo, Andrea; Nagler, Arnon; Kremyanskaya, Marina; Levine, Max Fine; Arango Ossa, Juan Esteban; McGovern, Erin M; Sandy, Lonette; Salama, Mohamed E; Najfeld, Vesna; Tripodi, Joseph; Farnoud, Noushin; Penson, Alex Vincent; Weinberg, Rona Singer; Price, Leah; Goldberg, Judith D; Barbui, Tiziano; Marchioli, Roberto; Tognoni, Gianni; Rampal, Raajit K; Mesa, Ruben A; Dueck, Amylou C; Hoffman, Ronald
The goal of therapy for essential thrombocythemia (ET) and polycythemia vera (PV) patients is to reduce thrombotic events by normalizing blood counts. Hydroxyurea (HU) and interferon-α (IFN-α) are the most frequently used cytoreductive options for ET and PV patients at high-risk for vascular complications. Myeloproliferative Disorders Research Consortium 112 was an investigator-initiated, phase 3 trial comparing HU to pegylated IFN-α (PEG) in treatment naïve, high-risk ET/PV patients. The primary endpoint was complete response (CR) rate at 12 months. A total of 168 patients were treated for a median of 81.0 weeks. CR for HU was 37% and 35% for PEG (p=0.80) at 12 months. At 24/36 months, CR was 20%/17% for HU and 29%/33% for PEG. PEG led to a greater reduction in JAK2V617F at 24 months, but histopathologic responses were more frequent with HU. Thrombotic events and disease progression were infrequent in both arms, while grade 3/4 adverse events were more frequent with PEG (46% vs. 28%). At 12 months of treatment there was no significant difference in CR rates between HU and PEG. This study indicates that PEG and HU are both effective treatments for PV and ET. With longer treatment PEG was more effective in normalizing blood counts and reducing driver mutation burden, while HU produced more histopathologic responses. Despite these differences, both agents did not differ in limiting thrombotic events and disease progression in high-risk ET/PV patients. (Funded by the National Cancer Institute, 5P01CA108671-09; number (NCT01259856).
PMID: 35007321
ISSN: 1528-0020
CID: 5118452

A prospective evaluation of pegylated interferon alfa-2a therapy in patients with polycythemia vera and essential thrombocythemia with a prior splanchnic vein thrombosis [Letter]

Mascarenhas, J; Kosiorek, H; Prchal, J; Yacoub, A; Berenzon, D; Baer, M R; Ritchie, E; Silver, R T; Kessler, C; Winton, E; Finazzi, M C; Rambaldi, A; Vannucchi, A M; Leibowitz, D; Rondelli, D; Arcasoy, M O; Catchatourian, R; Vadakara, J; Rosti, V; Hexner, E; Kremyanskaya, M; Sandy, L; Tripodi, J; Najfeld, V; Farnoud, N; Salama, M E; Weinberg, R S; Rampal, R; Goldberg, J D; Mesa, R; Dueck, A C; Hoffman, R
PMID: 31363161
ISSN: 1476-5551
CID: 4015282

Multipotent fetal-derived Cdx2 cells from placenta regenerate the heart

Vadakke-Madathil, Sangeetha; LaRocca, Gina; Raedschelders, Koen; Yoon, Jesse; Parker, Sarah J; Tripodi, Joseph; Najfeld, Vesna; Van Eyk, Jennifer E; Chaudhry, Hina W
The extremely limited regenerative potential of adult mammalian hearts has prompted the need for novel cell-based therapies that can restore contractile function in heart disease. We have previously shown the regenerative potential of mixed fetal cells that were naturally found migrating to the injured maternal heart. Exploiting this intrinsic mechanism led to the current hypothesis that Caudal-type homeobox-2 (Cdx2) cells in placenta may represent a novel cell type for cardiac regeneration. Using a lineage-tracing strategy, we specifically labeled fetal-derived Cdx2 cells with enhanced green fluorescent protein (eGFP). Cdx2-eGFP cells from end-gestation placenta were assayed for cardiac differentiation in vitro and in vivo using a mouse model of myocardial infarction. We observed that these cells differentiated into spontaneously beating cardiomyocytes (CMs) and vascular cells in vitro, indicating multipotentiality. When administered via tail vein to infarcted wild-type male mice, they selectively and robustly homed to the heart and differentiated to CMs and blood vessels, resulting in significant improvement in contractility as noted by MRI. Proteomics and immune transcriptomics studies of Cdx2-eGFP cells compared with embryonic stem (ES) cells reveal that they appear to retain "stem"-related functions of ES cells but exhibit unique signatures supporting roles in homing and survival, with an ability to evade immune surveillance, which is critical for cell-based therapy. Cdx2-eGFP cells may potentially represent a therapeutic advance in allogeneic cell therapy for cardiac repair.
PMID: 31109997
ISSN: 1091-6490
CID: 3920352

A Novel t(1;9)(p36;p24.1) JAK2 Translocation and Review of the Literature [Case Report]

Levavi, Hannah; Tripodi, Joseph; Marcellino, Bridget; Mascarenhas, John; Jones, Amy V; Cross, Nicholas C P; Gruenstein, Diana; Najfeld, Vesna
The JAK2V617F point mutation has been implicated in the pathogenesis of the vast majority of myeloproliferative neoplasms (MPNs), but translocations involving JAK2 have increasingly been identified in patients with JAK2V617F-negativeMPNs. Here, we present a case of a patient diagnosed with JAK2V617F-negativepolycythemia vera (PV) that transformed to the MPN-blast phase. Cytogenetic and FISH analysis revealed a novel translocation of t(1;9)(p36;p24.1), causing a PEX14-JAK2 gene fusion product. The t(1;9)(p36;p24.1) represents a new addition to the list of known translocations involving JAK2that have been identified in hematologic malignancies. Although the prognostic and treatment implications of JAK2 translocations in MPNs have not been elucidated, positive outcomes have been described in case reports describing the use of JAK inhibitors in these patients. Further research into the role of JAK2 translocations in the pathogenesis and outcomes of hematologic malignancies is warranted.
PMID: 31063994
ISSN: 1421-9662
CID: 3918952

Advanced forms of MPNs are accompanied by chromosomal abnormalities that lead to dysregulation of TP53

Marcellino, Bridget K; Hoffman, Ronald; Tripodi, Joseph; Lu, Min; Kosiorek, Heidi; Mascarenhas, John; Rampal, Raajit K; Dueck, Amylou; Najfeld, Vesna
The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and the prefibrotic form of primary myelofibrosis (PMF), frequently progress to more overt forms of MF and a type of acute leukemia termed MPN-accelerated phase/blast phase (MPN-AP/BP). Recent evidence indicates that dysregulation of the tumor suppressor tumor protein p53 (TP53) commonly occurs in the MPNs. The proteins MDM2 and MDM4 alter the cellular levels of TP53. We investigated in 1,294 patients whether abnormalities involving chromosomes 1 and 12, which harbor the genes for MDM4 and MDM2, respectively, and chromosome 17, where the gene for TP53 is located, are associated with MPN disease progression. Gain of 1q occurred not only in individuals with MPN-BP but also in patients with PV and ET, who, with further follow-up, eventually evolve to either MF and/or MPN-BP. These gains of 1q were most prevalent in patients with a history of PV and those who possessed the JAK2V617F driver mutation. The gains of 1q were accompanied by increased transcript levels of MDM4 In contrast, 12q chromosomal abnormalities were exclusively detected in patients who presented with MF or MPN-BP, but were not accompanied by further increases in MDM2/MDM4 transcript levels. Furthermore, all patients with a loss of 17p13, which leads to a deletion of TP53, had either MF or MPN-AP/BP. These findings suggest that gain of 1q, as well as deletions of 17p, are associated with perturbations of the TP53 pathway, which contribute to MPN disease progression.
PMID: 30563882
ISSN: 2473-9537
CID: 3679732

Reappraising hyalinizing clear cell carcinoma: A population-based study with molecular confirmation

Hernandez-Prera, Juan C; Kwan, Ricky; Tripodi, Joseph; Chiosea, Simion; Cordon-Cardo, Carlos; Najfeld, Vesna; Demicco, Elizabeth G
BACKGROUND:Hyalinizing clear cell carcinoma (HCCC) is a rare malignancy, characterized by EWSR1-ATF1 gene fusion, whose behavior is poorly understood, as it was for many years considered a diagnosis of exclusion. METHODS:All available salivary gland carcinomas (n = 594) from our institution were reviewed. Diagnosis of HCCC was confirmed by fluorescence in situ hybridization (FISH) for EWSR1. Literature review was performed. RESULTS:We found 15 patients with HCCCs (10 women, 5 men), 13 with EWSR1 rearrangement. Median age at diagnosis was 57 years (range, 31-87 years). Oral cavity (n = 9) and base of tongue (n = 4) were the most frequent primary sites. Combining our cases with those identified in literature review, the 10-year risk of local recurrence and locoregional nodal metastasis were 49% and 15%, respectively. CONCLUSION:Molecularly confirmed HCCC accounted for 2.5% of salivary gland malignancies at our institution. HCCCs are indolent tumors with a propensity for locoregional recurrence. © 2016 Wiley Periodicals, Inc. Head Neck 39: 503-511, 2017.
PMID: 27898192
ISSN: 1097-0347
CID: 3672902

Double minute amplification of mutant PDGF receptor α in a mouse glioma model

Zou, Hongyan; Feng, Rui; Huang, Yong; Tripodi, Joseph; Najfeld, Vesna; Tsankova, Nadejda M; Jahanshahi, Maryam; Olson, Lorin E; Soriano, Philippe; Friedel, Roland H
In primary brain tumors, oncogenes are frequently amplified and maintained on extrachromosomal DNA as double minutes (DM), but the underlying mechanisms remain poorly understood. We have generated a mouse model of malignant glioma based on knock-in of a mutant PDGF receptor α (PDGFRα) that is expressed in oligodendrocyte precursor cells (OPCs) after activation by a Cre recombinase. In the tumor suppressor INK4/Arf(-/-) background, mutant animals frequently developed brain tumors resembling anaplastic human gliomas (WHO grade III). Besides brain tumors, most animals also developed aggressive fibrosarcomas, likely triggered by Cre activation of mutant PDGFRα in fibroblastic cell lineages. Importantly, in the brain tumors and cell lines derived from brain tumor tissues, we identified a high prevalence of DM Pdgfra gene amplification, suggesting its occurrence as an early mutational event contributing to the malignant transformation of OPCs. Amplicons extended beyond the Pdgfra locus and included in some cases neighboring genes Kit and Kdr. Our genetically defined mouse brain tumor model therefore supports OPC as a cell of origin for malignant glioma and offers an example of a defined temporal sequence of mutational events, thus providing an entry point for a mechanistic understanding of DM gene amplification and its functionality in gliomagenesis.
PMID: 25683249
ISSN: 2045-2322
CID: 3670582

Analysis of ALK gene in 133 patients with breast cancer revealed polysomy of chromosome 2 and no ALK amplification

Hanna, Matthew G; Najfeld, Vesna; Irie, Hanna Y; Tripodi, Joseph; Nayak, Anupma
ALK has emerged as a novel tumorigenic factor in several epithelial human cancers. Crizotinib, an ALK tyrosine kinase inhibitor, is currently approved to treat lung cancer patients exhibiting ALK gene rearrangements. Our goal was to determine the incidence of ALK aberrations in relation to different breast cancer types. Tissue micro-arrays were constructed of ER+/PR±/HER2- (n = 37), ER-/PR-/HER2+ (n = 15), ER-/PR-/HER2- (n = 61) and ER+/PR+/HER2+ (n = 20) breast cancers; including 13 inflammatory breast carcinomas. FISH was performed using ALK break-apart and chromosome 2 centromere enumeration probes (CEP2). Neither ALK rearrangements nor amplification were identified in the 133 breast cancer cases evaluated. However, copy number gains (CNG) of ALK were identified in 82 of 133 patients (62 %). The CEP2 analysis revealed polysomy of chromosome 2 in all HCNG and LCNG cases, indicating the CNG of ALK are due to polysomy of chromosome 2, rather than true amplification of ALK. To conclude, we observed CNG of ALK secondary to chromosome 2 polysomy in a significant percentage of breast cancer cases, a phenomenon similar to polysomy 17. This study is one of the largest studies to have investigated ALK aberrations in breast cancer and the only study to include all subtypes.
PMID: 26312204
ISSN: 2193-1801
CID: 3671222

Oncogene-mediated alterations in chromatin conformation

Rickman, David S; Soong, T David; Moss, Benjamin; Mosquera, Juan Miguel; Dlabal, Jan; Terry, Stéphane; MacDonald, Theresa Y; Tripodi, Joseph; Bunting, Karen; Najfeld, Vesna; Demichelis, Francesca; Melnick, Ari M; Elemento, Olivier; Rubin, Mark A
Emerging evidence suggests that chromatin adopts a nonrandom 3D topology and that the organization of genes into structural hubs and domains affects their transcriptional status. How chromatin conformation changes in diseases such as cancer is poorly understood. Moreover, how oncogenic transcription factors, which bind to thousands of sites across the genome, influence gene regulation by globally altering the topology of chromatin requires further investigation. To address these questions, we performed unbiased high-resolution mapping of intra- and interchromosome interactions upon overexpression of ERG, an oncogenic transcription factor frequently overexpressed in prostate cancer as a result of a gene fusion. By integrating data from genome-wide chromosome conformation capture (Hi-C), ERG binding, and gene expression, we demonstrate that oncogenic transcription factor overexpression is associated with global, reproducible, and functionally coherent changes in chromatin organization. The results presented here have broader implications, as genomic alterations in other cancer types frequently give rise to aberrant transcription factor expression, e.g., EWS-FLI1, c-Myc, n-Myc, and PML-RARα.
PMID: 22615383
ISSN: 1091-6490
CID: 3668172

Contemplations on preclinical validation of fluorescence in situ hybridization probe assay for paraffin-embedded tissues in hematologic disorders

Reddy, Kavita S; Tripodi, Joseph
A validation of fluorescence in situ hybridization (FISH) assays for paraffin-embedded tissues (PET) is required before clinical use. Although the FISH probe validation process for hematologic disorders has been described during recent years, none of these descriptions, to our knowledge, address the validation process for paraffin-embedded tissues in detail. We describe an applicable preclinical validation process. The following five-step validation is outlined: (1) pathologist's review of slide; (2) probe validation on metaphases to assess sensitivity and specificity; (3) a pilot study using FISH probes on PET; (4) analytical validation using normal and abnormal PET samples to establish a normal reference range or cutoff; and (5) application of the cutoffs to test samples. Although the procedure focuses on dual-color, dual-fusion FISH assays, the same steps could be used for any type of probe. We have described a preclinical validation for probes on paraffin-embedded tissue.
PMID: 18474289
ISSN: 1873-4456
CID: 3666902