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Emerging targeted therapies for lymphoid malignancies.

The discovery that all-trans retinoic acid successfully relieves the block in myeloid differentiation caused by the fusion of the retinoic acid receptor [alpha] (RAR[alpha]) gene with the promyelocyte leukemia (PML) gene in cases of acute promyelocytic leukemia led to the first example of a molecularly targeted therapy for a hematologic malignancy. (1) All-trans retinoic acid is now used in conjunction with other chemotherapeutic agents as the standard treatment for this disease. (2) A more recent and celebrated example of molecularly targeted therapy is imatinib mesylate (Gleevec, Novartis International AG, Basel, Switzerland), a 2-phenylaminopyrimidine derivative, the first agent to inhibit ABL, a tyrosine kinase that is expressed and constitutively activated in myeloid progenitor cells as a result of the BCR/ABL translocation in chronic myelogenous leukemia. Imatinib mesylate acts as a competitive inhibitor of ATP binding to ABL, preventing kinase activity, and has become a safe and effective treatment of stable-phase chronic myelogenous leukemia; it results in hematologic and cytogenetic remission in most patients. (3-6) Given these successes, specific inhibitors have been developed for additional chronic myeloproliferative neoplasms with known dysregulated kinase activity, including inhibitors of JAK2 V617F for polycythemia vera and c-KIT D816V for systemic mastocytosis. These inhibitors are actively being evaluated in clinical trials with several other therapeutic agents either in initial trials or in preclinical studies.

In contrast to the dramatic successes achieved with novel targeted therapies for the treatment of select myeloid neoplasms, targeted therapeutics in lymphoid malignancies have been somewhat slower to evolve. However, recent investigations into the pathogenesis of lymphoid malignancies have identified many attractive molecular targets and have led to the development of a broad range of novel therapeutics, many of which are currently undergoing preclinical validation in animal models or in clinical trials. As an introduction to this rapidly developing field, we will focus on 4 distinct cellular pathways that are critical to the growth and survival of select lymphoid malignancies and highlight the most promising novel therapeutic agents that target these pathways. Specifically, we will discuss (1) the dependence of a subset of mature B-cell lymphomas on the B-cell receptor (BCR) signaling cascade and its blockade by an inhibitor of the SYK tyrosine kinase, namely, fostamatinib disodium (FosD, AstraZeneca Pharmaceuticals, LP, Wilmington, Delaware); (2) constitutive activation of NOTCH1 in T-lymphoblastic lymphoma, which is prevented by the [gamma]-secretase inhibitor MK-0752 (Merck & Co, Inc, Whitehouse Station, New Jersey); (3) the expression of the anti-apoptotic protein BCL2 by low-grade B-cell lymphomas and its blockade by the BCL2 inhibitor, ABT-263 (Navitoclax, F. Hoffmann-La Roche AG, Basel, Switzerland); and (4) the epigenetic modification of histones in cutaneous T-cell lymphoma, which can be targeted by the histone deacetylase inhibitor vorinostat (Zonlinza, Merck & Co).


Elegant genetic experiments in mice have shown that low-level, constitutive signaling through the B-cell receptor, termed "tonic" B-cell signaling, is necessary for B-cell survival in the absence of antigen stimulation. (7,8) More recently, it has become apparent that constitutive activation of the BCR signaling cascade is required for the survival of a subset of B-cell lymphoma cell lines and primary tumors. (9,10) Originally, it was proposed that this BCR signaling resulted from ligand-induced aggregation. (11) However, more recent studies (7,8,12-15) have revealed a critical role for "tonic" BCR survival signals in the absence of receptor engagement, with spleen tyrosine kinase (SYK) playing a central role in amplifying and propagating this critical survival signal. Under basal conditions, SYK kinase activity is suppressed by protein tyrosine phosphatases (PTPs), the activity of which is inhibited by BCR signaling. (16,17) Studies by Chen et al (12) and Aguiar et al (18) revealed that SYK is a major substrate of a tissue-specific, developmentally regulated lymphoid PTP, PTP receptortype O truncated (PTPTROt), which is decreased in normal germinal centers and a subset of B-cell lymphomas. In vitro overexpression of PTPTROt leads to inhibition of BCR triggered SYK tyrosyl phosphorylation and downstream signaling events and, more importantly, it leads to cell cycle arrest and the apoptosis of diffuse large B-cell lymphoma in the absence of BCR crosslinking. (12,18) Together these data support the hypothesis that SYK and PTPTROt regulate BCR signaling and the survival of some diffuse large B-cell lymphomas (DLBCLs) and first suggested that SYK could be a promising target in B-cell lymphoma.


As a proof of this hypothesis, Chen et al (9) went on to show that DLBCL cell lines with an active BCR signaling pathway undergo cell cycle arrest and apoptosis when treated with R406, a potent and selective inhibitor of SYK. In this study, the status of the BCR signaling cascade was monitored by using antibodies specific for select phosphoepitopes of active signaling molecules, including epitopes in SYK itself. Thus, the investigators were able to show, in DLBCL cell lines, a tight correlation between sensitivity to R406 and the presence of baseline active BCR signaling in these cells.

These encouraging data provided the rationale for the first phase 1/2 clinical trials with R406, using fostamatinib disodium (R788; FosD), a prodrug of R406 available in an oral formulation, in patients with relapsed or refractory Bcell non-Hodgkin lymphomas (Figure). This multi-institutional trial included patients with DLBCL (phase 1, 4 patients; phase 2, 23 patients), follicular lymphoma (FL; phase 1, 4 patients; phase 2, 21 patients), mantle cell lymphoma (phase 1, 3 patients; phase 2, 9 patients), marginal zone lymphoma (phase 2, 2 patients), lymphoplasmacytic lymphoma (phase 2, 1 patient), and chronic lymphocytic leukemia (CLL; phase 1, 2 patients; phase 2, 11 patients). (10) The results of the phase 2 trial showed that the best overall response rate (complete response plus partial response) was seen in patients with CLL (54.5%), with a progression-free survival of 6.4 months (2.2-7.1 months). (10) Patients with de novo DLBCL had an overall response rate of 23.5% and patients with transformed DLBCL had a 16.7% response rate, with a combined progression-free survival of 2.7 months (1.3-4.5 months). Interestingly, this response rate is in keeping with the predicted percentage of DLBCL tumors showing BCR dependence, based on expression profiling studies (19); however, functional validation of BCR activity has not been carried out in the tumors of this treated cohort to date. Although the overall response rates were lower in mantle cell lymphoma and FL (11.1% and 9.5%, respectively), several patients with FL demonstrated prolonged stable disease (61.9%). (10) Overall, this study showed that the treatment of non-Hodgkin lymphomas with FosD resulted in clinical responses in a significant proportion of patients with relapsed CLL and DLBCL, and it supports the in vitro data implicating a critical role for tonic BCR signaling in the survival and growth of select B-cell lymphomas.


Many oncogenes and tumor suppressor genes encode transcription factors that, when deregulated owing to mutations or translocation, can promote tumorigenesis as well as enhance tumor cell proliferation and survival. (20) The NOTCH1 receptor is a ligand-activated signaling molecule and transcription factor that directly transduces extracellular signals at the cell membrane to changes in gene expression in the nucleus. Under normal, physiologic conditions, the binding of ligand to the extracellular domain of NOTCH1 initiates a series of proteolytic cleavages within the intracellular and transmembrane domains of the receptor. The final proteolytic cleavage is catalyzed by [gamma]-secretase, which liberates the intracellular domain of NOTCH1 (ICN1) from the plasma membrane. ICN1 then translocates to the nucleus and forms part of a large transcriptional activation complex that upregulates target genes in a context-specific manner. (21,22) Under normal conditions, NOTCH1-mediated gene expression is necessary and sufficient for the differentiation of hematopoietic progenitors into T cells. (23,24)

The first evidence of a role for NOTCH1 in oncogenesis came from cloning of the t(7;9)(q34; q34.3) breakpoint in T-lymphoblastic leukemia/lymphoma (T-ALL). This rare, recurrent translocation, seen in 1% of T-ALL cases, encodes truncated NOTCH1 under the control of TCRft locus; as a result, a constitutively active form of NOTCH1 is expressed in T lymphoblasts. (25) Mice transplanted with hematopoietic progenitor cells expressing ICN1 develop T-cell lymphoblastic tumors. (26-28) However, the most compelling evidence for a critical role of NOTCH1 in the pathogenesis of T-ALL arose from the discovery of activating point mutations in NOTCH1 in approximately 50% of T-ALLs. (29) Notably, the NOTCH1 mutations are found across all genetic subtypes of T-ALL, placing NOTCH1 at the center of T-ALL oncogenesis. (29-33)

The mutant forms of NOTCH1 in human T-ALL are dependent upon [gamma]-secretase for activation and, fortuitously, potent inhibitors of [gamma]-secretase (GSIs) were previously developed as a potential therapeutic for Alzheimer disease. (34) The treatment of T-ALL cell lines with GSI suppressed NOTCH1 activation, leading to the rapid clearance of ICN1 and the down-regulation of NOTCH1 target genes, most notably c-MYC (Figure). (29,35,36) As a result, T-ALL lines with activating NOTCH1 mutations undergo growth arrest.

On the basis of these encouraging data, a phase 1 clinical trial was initiated with the [gamma]-secretase inhibitor MK-0752 (Merck & Co), in 6 adult and 2 pediatric patients with relapsed T-ALL (n = 7) and acute myeloid leukemia (n = 1). Four of 7 patients with T-ALL were confirmed as harboring NOTCH1-activating mutations. Initial results showed promise, as treatment for 1 patient with a NOTCH1-activating mutation led to a 45% reduction in tumor mass at the end of 28 days, but with subsequent progression of the tumor by 56 days. (37) However, the trial was discontinued owing to dose-limiting toxicity, most notably gastrointestinal toxicity as a result of inhibition of NOTCH1 signaling in the gut. (37,38)

Recent data using animal models suggest that the addition of glucocorticoids to a GSI-based treatment regimen can provide additional therapeutic benefits and prevent the major toxicity associated with GSIs. (39) In vitro blocking of constitutive NOTCH1 signaling with GSIs renders previously resistant T-ALL cell lines and primary tumors sensitive to glucocorticoid-induced apoptosis. This effect is mediated by inactivation of the NOTCH1-dependent transcriptional repressor at the HES1 promoter of glucocorticoid receptor genes and subsequent upregulation of the glucocorticoid receptors. The relationship between NOTCH1 signaling and glucocorticoid activity appears specific, since GSIs do not potentiate the tumoricidal activities of other chemotherapeutic agents, such as etoposide or methotrexate in the same cells. (40)

An undesirable effect of NOTCH1 inhibition in the gut is to promote goblet cell differentiation at the expense of enterocyte differentiation, a major contributor to gut toxicity. Experiments in mice indicate that glucocorticoids can diminish this deleterious effect. Although the mechanisms are not entirely clear, glucocorticoids appear to promote the growth of Paneth cells at the expense of goblet cells at the base of the intestinal crypts. Thus, the combination of GSI with glucocorticoids provides 2 distinct advantages over treatment with GSI alone by (1) reestablishing the sensitivity of previously resistant tumor cells to glucocorticoid-induced apoptosis and (2) abrogating the gut toxicity associated with GSIs. (40)

In addition to combination chemotherapy, the development of new classes of NOTCH1 inhibitory molecules may result in more specific and less toxic treatment of this disease. For example, recent studies (41,42) have described antibodies that selectively inhibit NOTCH1 and NOTCH3. A similar approach could be used for inhibition of NOTCH1 signaling, which could be designed to specifically block the NOTCH1 receptor in the leukemic clone. (40)


Apoptosis is an intrinsic cell death program that maintains tissue homeostasis and is characterized by activation of intracellular proteases, known as caspases. (43) Several pathways for triggering caspase activation exist; however, the 2 major pathways are commonly referred to as the intrinsic and extrinsic pathways. (44) The intrinsic pathway, also known as the mitochondrial pathway, regulates cell death in response to numerous stimuli, including the cellular damage induced by most chemotherapeutic agents. Initiation of the intrinsic pathway is catalyzed by activator proteins, such as BIM and BID, which promote the oligomerization of the proapoptotic members of the Bcl2 family, such as BAX and BAK, at the mitochondrial membrane. (45,46) Subsequent permeabilization of the outer mitochondrial membrane results in the release of proapoptotic proteins into the cytoplasm, such as cytochrome c, which in turn promotes caspase activation. Importantly, 1 or more anti-apoptotic members of the Bcl-2 family, including Bcl-2, Bcl-XL, Bcl-W, and Mcl-1, can inhibit this apoptotic machinery. (45-47)

There is extensive evidence that a wide array of tumors suppress the intrinsic apoptotic pathway to ensure survival. The prototypic example is follicular lymphoma, the tumor type from which BCL2 was first discovered. (45,48) In most instances, follicular lymphoma harbors a balanced chromosomal abnormality, t(14; 18), which results in the juxtaposition of the immunoglobulin heavy-chain gene enhancer with the BCL2 locus. This genetic defect results in the constitutive, aberrant overexpression of the BCL2 protein, which inhibits tumor cell death. (49)

Many, if not most, other lymphomas adapt to escape apoptosis by several mechanisms that fit into 3 broad categories: (1) down-regulation or loss of activator proteins, (2) down-regulation or loss of the proapoptotic effector proteins, and (3) upregulation of anti-apoptotic proteins. (45,50) Strikingly, the dominant mechanism of dysregulation is not always consistent among individual tumor types, a finding that complicates the designand use of novel therapeutics that seek to reactivate the apoptotic machinery of tumor cells. (45,51)

ABT-737 and its derivative, ABT-263 (Navitoclax, F. Hoffmann-La Roche), are small molecule mimics of the critical BH3 domain in the activating members of BCL2 family members. (52,53) By binding to BCL2, BCL-XL, and BCL-W with high affinity, these compounds competitively displace the sequestered BH3 domain-containing activator proteins and allow them to catalyze the oligomerization and activation of the proapoptotic effector proteins BAX and BAK and induce cell death (Figure). Several laboratories have shown that ABT-737 is highly effective as a single agent in killing primary tumor cells in vitro, including tumor cells from patients with CLL, FL, and marginal zone lymphoma. (51,54) Furthermore, the orally available ABT-263 has been able to effect a complete regression of acute lymphoblastic leukemia in a xenograft tumor model. (46,55,56)

ABT-263 is in clinical trials for CLL, non-Hodgkin lymphomas, and small cell lung cancer. (46) As part of an ongoing phase 1 study, 27 patients with CLL/small lymphocytic lymphoma were treated with ABT-263, resulting in 3 radiographically confirmed partial responses and 2 regressions in lymphadenopathy not further characterized by radiologic means. (57) Remarkably, 6 patients had a sustained, greater than 50% reduction in circulating tumor cells for more than 2 months. Among additional patients with FL who were enrolled in the trial, treatment has led to a partial response in 3 patients and to a minor response (49% regression) in 1 patient. Thrombocytopenia was the most prominent side effect. (57)

Despite the promising results seen upon treating patients with CLL/small lymphocytic lymphoma and other low-grade B-cell lymphomas with ABT-263 in the clinical setting, various in vitro experiments suggest limitations to its use. Most notably, the BH3 mimetic has the highest affinity for BCL2, BCL-XL, and BCL-W, but only a poor affinity for MCL1 and BCL2A1. (45) Thus, not surprisingly, resistance to ABT-263 has been linked to high MCL1 expression in tumor cells. (52,58) Of additional concern is the interactions between CLL tumor cells and nonneoplastic stromal cells in the tumor microenvironment, which can trigger a marked upregulation of BCL-XL and BCL2A1 in the tumor cells, thus conferring drug resistance. (54) Further experiments indicate that ligation of CD40 on CLL tumor cells by CD40L expressed on stromal cells is partially responsible for this effect. Thus, the combination of ABT-263 with an antagonist of CD40-CD40L interactions (such as the humanized anti-CD40 monoclonal antibody CHIR-12.12, also known as lucatumumab, Novartis International) may further enhance the anti-tumor activities of ABT-263. (59) These data suggest that multiple strategies and targeted therapies may be necessary to achieve maximum and durable responses in lymphoid malignancies.


Epigenetics is the study of genetic modifications that result in changes in gene expression and function without a corresponding alteration in the DNA sequence. (60) These changes are heritable and potentially reversible, providing many possibilities for targeted epigenetic therapy of cancer. So far, such therapy lacks the specificity to target individual genes, but instead, attempts either to reactivate or silence large cohorts of genes critical for tumor cell survival and proliferation. Currently, the major avenues of intervention in the epigenetic therapy of cancer involve inhibitors of histone deacetylases (HDACs) and DNA methyltransferases.

Histone acetylation plays a critical role in the regulation of gene transcription. In general, hyperacetylated histones are associated with transcriptionally active genes, whereas hypoacetylated histones are associated with suppressed transcription. (61) These changes are mediated by histone acetyltransferases and deacetylases, respectively. (62,63) Histones that have been acetylated by histone acetyltransferases have a more neutral charge and, therefore, lower affinity for negatively charged DNA, contributing to relaxed chromatin structure and facilitating transcriptional activation. Conversely, when histone acetylation is reversed by HDACs, the more positively charged histones interact more tightly with DNA contributing to transcriptional repression. (64)

Vorinostat (Zolinza, Merck & Co), a member of the hydroxamic acid subclass of HDAC inhibitors, has been approved by the US Food and Drug Administration for the treatment of relapsed or refractory cutaneous T-cell lymphoma (CTCL). In this tumor type, nuclear chromatin appears hypoacetylated, which leads to decreased expression of genes responsible for cell differentiation, cell-cycle control, and apoptosis (Figure). (65) Through inhibition of deacetylase activity, vorinostat induces hyperacetylation of histones and transcription of genes that promote cell differentiation and senescence. (66)

A phase 2 clinical study with the single agent vorinostat enrolled 33 patients with CTCL who were intolerant or refractory to conventional treatments. This trial showed an overall response rate of 24%, with a reduction of pruritus in 58% of patients. The average time to response was 11.9 weeks; the average time to progression was 30.2 weeks. (67) Another phase 2 clinical study enrolled 74 patients with CTCL for whom 2 or more prior systemic therapies had failed, 1 of which was bexarotene. (68) The time to response in this study was 7.9 weeks, the overall response rate was 29.7%, and a reduction in pruritus was reported in 32% of patients. The time to progression ranged from 11.1 weeks to 67.1 weeks. Currently, there is an ongoing phase 3 (NCT00419367) clinical study for patients with advanced CTCL. (69) Based on the studies thus far, while vorinostat has not definitively demonstrated an improved outcome in patients with CTCL, the therapy provides a relatively safe alternative to the currently existing systemic treatments.

Inhibitors of HDACs, including vorinostat, have been used as single agents or in combination with more conventional treatments in many small, additional clinical studies, with notable patient responses in a subset of peripheral T-cell lymphomas, Hodgkin lymphomas, DLBCLs, and acute myeloid leukemias (70) (Table). Given the results of the clinical trials and experiments performed in vitro, it is likely that in the future HDAC inhibitors will be used as part of combination chemotherapy regimens. For example, preclinical studies have shown synergistic interactions between bortezomib (Velcade, Takeda Pharmaceutical Company, Tokyo, Japan) and HDAC inhibitors in multiple myeloma cells. (71,72)


In an era in which targeted therapies will play an increasing role in cancer care, the relative importance of the diagnostic tests available to the pathologist is destined to change and is likely to introduce advanced molecular and genetic analyses into routine clinical practice. Indeed, this evolution is well underway; for instance, the genetic testing of tumor tissue for EGFR mutations has now become routine to qualify patients with lung cancer for EGFR inhibitor therapy. (73-75) Although the clinical trials that have been described in this review have enrolled or are currently enrolling patients on the basis of standard pathologic diagnoses, advanced genetic and molecular testing are being used for correlative scientific studies in almost all cases.

Among patients with de novo DLBCL treated with FosD, the overall response rate was 24%, a result that suggests differential sensitivity among DLBCLs to inhibition of BCR signaling. Given that only a subset of DLBCL cell lines are dependent upon constitutive BCR signaling for proliferation and survival and are sensitive to FosD in vitro, it is reasonable to expect that only those primary DLBCLs with constitutive BCR signaling will be sensitive to the drug in vivo. A study comparing the histologic, phenotypic, and genetic characteristics of the tumors from patients enrolled in FosD trial is ongoing, but a possible challenge for pathologists in the future might be to determine whether an individual tumor exhibits constitutive BCR activity on a routine basis. Two possible means to accomplish this goal are via gene expression profiling of primary tumors to identify a BCR signaling "signature," or via standard immunohistochemical analyses of biopsy samples by using phosphoepitope-specific antibodies that indicate constitutive activation of the BCR signaling cascade. Both approaches are currently being investigated by using primary tumor samples (J. Kutok and S. Rodig, unpublished data, 2010).

Similarly, in the phase 1 clinical trial using a GSI in patients with relapsed T-ALL, the patient with the most dramatic response to the drug had a tumor with an activating mutation in NOTCH1. This finding is also in agreement with in vitro data in which T-ALL cell lines harboring activating NOTCH1 mutations are selectively responsive to GSIs. These data suggest that pathologists may one day be required to routinely identify the approximately 50% of T-ALLs that harbor pathologic NOTCH mutations in order to qualify a patient for GSI therapy. This requirement poses a unique set of challenges. To date, dozens of different activating mutations have been identified in a total of 4 exons in the NOTCH1 gene, and new activating mutations continue to be discovered. Thus, direct identification of mutations will require sequencing a large portion of NOTCH1 by using a multiplex polymerase chain reaction-based strategy. In theory, alternative diagnostic tools include a limited gene expression profile to detect the upregulation of NOTCH1-specific target genes in tissue biopsies or the direct detection of activated NOTCH1 in formalin-fixed, paraffin-embedded tissue samples by immunohistochemistry, using antibodies specific for activated forms of the protein.

We are in the midst of a revolution in cancer care in which the genetic bases for neoplasia are giving rise to disease-specific, targeted therapies. Given the remarkable successes of using targeted therapy for the treatment of myeloid neoplasms, there is every reason to be optimistic that such an approach will lead to improved care for patients with lymphoid malignancies in the near future.

The authors would like to thank Jon Aster, MD, PhD, Tony Letai, MD, PhD, and Jay Bradner, MD, for critical readings of this manuscript and helpful discussions.


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Olga Pozdnyakova, MD, PhD; Jeffery L. Kutok, MD, PhD; Scott J. Rodig, MD, PhD

Accepted for publication October 4, 2010.

From the Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Scott J. Rodig, MD, PhD, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115 (e-mail:
Major Phase 2 Trials of Single-Agent Histone Deacetylase Inhibitors
for Hematologic Malignancies

Agent Source, y Disease Response

Vorinostat Duvic et al, CTCL (n = 33) PR 8
 (67) 2007
 Olsen et al, CTCL (n =74) CR1; PR21
 (68) 2007
 Kirschbaum et al, HL (n = 25) PR 1
 (76) 2007

Romidepsin Piekarz et al, CTCL (n = 71) CR 6; PR 24;
 (77) 2009 SD 19
 Kim et al, CTCL (n = 92) CR 7; PR 10
 (78) 2008
 Piekarz et al, PTCL (n = 43) PR 10;CR 7
 (79) 2008

MGCD0103 Bociek et al, HL (n = 20) CR 2; PR 6
 (80) 2008
 Younes et al, HL (n = 21) CR 2; PR 6
 (81) 2007
 Crump et al, DLBCL/FL CR 1; PR 4;
 (82) 2008 (n = 50) SD 22
 Blum et al, CLL (n = 21) SD 20
 (83) 2009
 Younes et al, DLBCL (n = 19), PR 2; CR 1;
 (84) 2007 FL (n = 19) PR 1

Panobinostat Duvic et al, CTCL (n = 95) CR 2; skin CR 2
 (85) 2008

Abbreviations: CLL, chronic lymphocytic leukemia; CTCL, cutaneous
T-cell lymphoma; CR, complete response; DLBCL, diffuse large B-cell
lymphoma; FL, follicular lymphoma; HL, Hodgkin lymphoma; PR, partial
response; PTCL, peripheral T-cell lymphoma; SD, stable disease.
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Author:Pozdnyakova, Olga; Kutok, Jeffery L.; Rodig, Scott J.
Publication:Archives of Pathology & Laboratory Medicine
Date:May 1, 2012
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