Nikhil C Munshi

VA Long Beach Healthcare System, Long Beach, California, United States

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Publications (439)3338.8 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: We have previously demonstrated that interleukin-17A (IL-17) producing Th17 cells are significantly elevated in blood and bone marrow (BM) in multiple myeloma (MM) and IL-17A promotes MM cell growth via the expression of IL-17 receptor. In this study, we evaluated anti-human IL-17A human monoclonal antibody (mAb), AIN457 in MM. We observe significant inhibition of MM cell growth by AIN457 both in the presence and absence of BM stromal cells (BMSC). While IL-17A induces IL-6 production, AIN457 significantly down-regulated IL-6 production and MM cell-adhesion in MM-BMSC co-culture. AIN-457 also significantly inhibited osteoclast cell-differentiation. More importantly, in the SCIDhu model of human myeloma administration of AIN-457 weekly for 4 weeks after the first detection of tumor in mice led to a significant inhibition of tumor growth and reduced bone damage compared to isotype control mice. To understand the mechanism of action of anti-IL-17A mAb, we report here, that MM cells express IL-17A. We also observed that IL-17A knock-down inhibited MM cell growth and their ability to induce IL-6 production in co-cultures with BMSC. These pre-clinical observations suggest efficacy of AIN 457 in myeloma and provide the rationale for its clinical evaluation for anti-myeloma effects and for improvement of bone disease.Leukemia accepted article preview online, 21 August 2015. doi:10.1038/leu.2015.228.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 08/2015; DOI:10.1038/leu.2015.228 · 9.38 Impact Factor
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    ABSTRACT: Despite recent therapeutic advances that have doubled the median survival time of patients with multiple myeloma (MM), intratumor genetic heterogeneity contributes to disease progression and emergence of drug resistance. MicroRNAs (miRs), are noncoding small RNAs that play important roles in the regulation of gene expression, and have been implicated in cancer progression and drug resistance. We investigated the role of the miR-221-222 family in dexamethasone(Dex)-induced drug resistance in MM using the isogenic cell lines, MM1R and MM1S, which represent models of resistance and sensitivity, respectively. Analysis of array comparative genome hybridization (aCGH) data revealed gain of chromosome X regions at band p11.3, wherein the miR-221-222 resides, in resistant MM1R cells but not in sensitive MM1S cells. DNA copy number gains in MM1R cells were associated with increased miR-221-222 expression and downregulation of p53-upregulated modulator of apoptosis (PUMA) as a likely pro-apoptotic target. We confirmed PUMA mRNA as a direct target of miR-221-222 in MM1S and MM1R cells by both gain- and loss- of function studies. In addition, miR-221-222 treatment rendered MM1S cells resistant to Dex, whereas anti-miR-221-222 partially restored the Dex sensitivity of MM1R cells. These studies have uncovered a role for miR-221-222 in MM drug resistance, and suggest a potential therapeutic role for inhibitors of miR-221-222 binding to PUMA mRNA as a means of overcoming Dex resistance in patients. The clinical utility of this approach is predicated on the ability of anti-sense miR-221-222 to increase survival while reducing tumor burden, and is strongly supported by the metastatic propensity of MM1R cells in preclinical mouse xenograft models of MM. Moreover, our observation of increased levels of miR-221-222 with decreased PUMA expression in MM cells from patients at relapse versus untreated controls suggests an even broader role for miR-221-222 in drug resistance, and provides a rationale for the targeting of miR-221-222 as a means of improving patient outcomes. Copyright © 2015, American Association for Cancer Research.
    Cancer Research 08/2015; DOI:10.1158/0008-5472.CAN-15-0457 · 9.28 Impact Factor
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    ABSTRACT: The aim of this study was to describe FDG-PET/CT findings in extramedullary multiple myeloma (EMM) correlating them with clinical outcome. In this institutional review board-approved HIPAA-compliant retrospective study, we reviewed the FDG-PET/CT scans of 35 patients with EMM (16 women, 19 men; mean age, 56 years; median follow-up after the diagnosis of EMM, 14 months) out of 156 patients diagnosed with MM at our institute between 2004 and 2012. The distribution and metabolic activity of EMM on the scans were reviewed. Clinical data were extracted from electronic medical records. Statistical analysis was performed to determine differences in outcome based on time of detection and distribution of EMM. Extramedullary multiple myeloma was present at diagnosis in 12 of 35 patients and during disease progression in 23 of 35 patients. Indications for FDG-PET/CT were initial staging (12/35), restaging for disease progression (18/23), or assessment of response to therapy (5/23). Extramedullary multiple myeloma was FDG-avid (mean SUVmax, 8.4; range, 1.2-31), solitary in 10 patients (29%) and multifocal in 25 patients (71%). Two patterns of distribution were noted: direct extension of osseous plasmacytomas in 18 (51%) of 35 patients and hematogeneous/lymphangiogenic dissemination in 33 (94%) of 35 patients. Mean SUVmax in lesions with direct osseous extension was statistically higher than hematogeneous/lymphangiogenic EMM (Mann-Whitney U test, P = 0.03). The most common sites of hematogeneous/lymphangiogenic spread of EMM were lymph nodes (21/35 [60%]), liver (10/35 [29%]), lung (9/35 [26%]), muscles away from bones (7/35 [20%]), and peritoneum/mesentery (7/35 [20%]). There was no statistically significant difference in distribution of EMM at presentation and during disease progression (χ test, P > 0.05); 24 (69%) of 35 patients died (median interval after diagnosis of EMM, 7 months). There was no statistically significant difference in outcome for EMM at presentation and during disease progression (log-rank test, P = 0.068). Involvement of any of the following 3 sites: liver, lung, and muscles away from bones, was associated with statistically significant shorter survival (log-rank test, P = 0.0008). Extramedullary multiple myeloma is more often seen on FDG-PET/CT in the context of a hematogeneous/lymphangiogenic spread pattern and less commonly as a direct extension of osseous plasmacytomas. Extramedullary multiple myeloma has poor outcome whether detected at presentation or during follow-up. Extramedullary multiple myeloma involving the liver, lung, and muscles was associated with shorter survival in our study.
    Clinical nuclear medicine 08/2015; DOI:10.1097/RLU.0000000000000902 · 2.86 Impact Factor
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    ABSTRACT: Siltuximab (interleukin-6 [IL-6] antibody) is approved for the treatment of multicentric Castleman's disease (MCD). Effects of IL-6 inhibition on the inflammatory milieu accompanying MCD have not been characterized. Trends in inflammatory- and anemia-associated markers measured over the course of a placebo-controlled study of siltuximab (11 mg/kg q3w) in MCD patients (N = 79) were characterized. Baseline IL-6 and C-reactive protein (CRP) levels were significantly correlated (r = 0.708; P less than 0.0001). CRP levels decreased (median 92%) by Cycle 1 Day 8 (C1D8), remaining suppressed during siltuximab treatment, while remaining stable in the placebo group. There were no associations between baseline CRP or IL-6 and MCD symptom burden, histologic subtype, ethnicity, maximum CRP decrease, and response parameters. A hemoglobin response (change greater than or equal to 15 g/L at Week 13) was observed with siltuximab (61%; P = 0.0002). Median hepcidin decrease from baseline at C1D8 with siltuximab was 47% versus median 11% increase with placebo. Maximum post-baseline changes in hepcidin levels among siltuximab recipients were correlated with maximum changes for hemoglobin (r = -0.395; P = 0.00607), total iron binding capacity (TIBC; r = -0.354; P = 0.01694), and ferritin (r = 0.599, P = 0.0001). Greater median changes from baseline in ferritin, hemoglobin, and TIBC were observed in anemic siltuximab-treated patients. IL-6 neutralization with siltuximab resulted in sustained CRP suppression and improvement of anemia in part by hepcidin pathway inhibition. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 06/2015; DOI:10.1158/1078-0432.CCR-15-0134 · 8.19 Impact Factor
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    ABSTRACT: Proteasome inhibitors (PI) and immunomodulatory agents (IMIDs) have improved the overall survival (OS) of patients with multiple myeloma (MM), but concerns have been raised about increased incidence of extramedullary disease (EMD) after the combined use of PIs and IMIDs for upfront therapy. We evaluated whether the addition of lenalidomide to bortezomib-based front-line regimens precipitated earlier development of EMD. We reviewed the charts of 117 MM patients (median follow-up from diagnosis 6·1 years; range 0·1-10·2 years) enrolled in eight clinical trials of first-line treatment with bortezomib-based regimens, with or without lenalidomide. We assessed development of EMD as extraosseous (distant from bone) or osseous (originating from bone) plasmacytomas. The primary endpoint was time from diagnosis until development of EMD, based on imaging, biopsy and/or physical examination. Any form of EMD at progression was observed in 40 (34·2%) patients, including 21 (18%) osseous, 8 (7%) extraosseous and 11 (9%) both osseous and extraosseous. Median OS was 0·9 years (range 0·1-4·8 years) after extraosseous EMD development. Sensitivity analyses with follow-up times truncated at 5 years detected no statistically significant difference in rates of any EMD form between the two groups (P > 0·2 for each comparison). Therefore, we observed no evidence that bortezomib-lenalidomide-based front-line therapy precipitates earlier EMD. © 2015 John Wiley & Sons Ltd.
    British Journal of Haematology 06/2015; 169(6). DOI:10.1111/bjh.13382 · 4.96 Impact Factor
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    ABSTRACT: B cell malignancies frequently colonize the bone marrow. The mechanisms responsible for this preferential homing are incompletely understood. Here we studied multiple myeloma (MM) as a model of a terminally differentiated B cell malignancy that selectively colonizes the bone marrow. We found that extracellular CyPA (eCyPA), secreted by bone marrow endothelial cells (BMECs), promoted the colonization and proliferation of MM cells in an in vivo scaffold system via binding to its receptor, CD147, on MM cells. The expression and secretion of eCyPA by BMECs was enhanced by BCL9, a Wnt-β-catenin transcriptional coactivator that is selectively expressed by these cells. eCyPA levels were higher in bone marrow serum than in peripheral blood in individuals with MM, and eCyPA-CD147 blockade suppressed MM colonization and tumor growth in the in vivo scaffold system. eCyPA also promoted the migration of chronic lymphocytic leukemia and lymphoplasmacytic lymphoma cells, two other B cell malignancies that colonize the bone marrow and express CD147. These findings suggest that eCyPA-CD147 signaling promotes the bone marrow homing of B cell malignancies and offer a compelling rationale for exploring this axis as a therapeutic target for these malignancies.
    Nature medicine 05/2015; 21(6). DOI:10.1038/nm.3867 · 28.05 Impact Factor
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    ABSTRACT: Natural killer (NK) cells may play an important role in the immune response to multiple myeloma (MM); however, MM cells express killer immunoglobulin-like receptor (KIR) ligands to prevent NK cell cytotoxicity. Lenalidomide can expand and activate NK cells in parallel with its direct effects against MM; however, dexamethasone may impair these favorable immunomodulatory properties. IPH2101, a first-in-class anti-inhibitory KIR antibody, has acceptable safety and tolerability in MM as a single agent. The present work sought to characterize lenalidomide and IPH2101 as a novel, steroid-sparing, dual immune therapy for MM. A phase I trial enrolled 15 patients in three cohorts. Lenalidomide was administered per os at 10mg on cohort 1 and 25mg on cohorts 2 and 3 days 1-21 on a 28-day cycle with IPH2101 given intravenously on day 1 of each cycle at 0.2 mg/kg on cohort 1, 1mg/kg on cohort 2, and 2mg/kg on cohort 3. No corticosteroids were utilized. The primary endpoint was safety, secondary endpoints included clinical activity, pharmacokinetics (PK) and pharmacodynamics (PD). The biologic endpoint of full KIR occupancy was achieved across the IPH2101 dosing interval. PD and PK of IPH2101 with lenalidomide were similar to data from a prior single agent IPH2101 trial. Five serious adverse events (SAEs) were reported. Five objective responses occurred. No autoimmunity was seen. These findings suggest that lenalidomide in combination with anti-inhibitory KIR therapy warrants further investigation in MM as a steroid-sparing, dual immune therapy. This trial was registered at www.clinicaltrials.gov (reference: NCT01217203). Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 05/2015; DOI:10.1158/1078-0432.CCR-15-0304 · 8.19 Impact Factor
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    ABSTRACT: Interferon regulatory factor 4 (IRF4) is an attractive therapeutic target in multiple myeloma (MM). We here report that expression of IRF4 mRNA inversely correlates with microRNA (miR)-125b in MM patients. Moreover, we provide evidence that miR-125b is downregulated in TC2/3 molecular MM subgroups and in established cell lines. Importantly, constitutive expression of miR-125b-5p by lentiviral vectors or transfection with synthetic mimics impaired growth and survival of MM cells and overcame the protective role of bone marrow stromal cells (BMSCs) in vitro. Apoptotic and autophagy-associated cell death were triggered in MM cells upon miR-125b-5p ectopic expression. Importantly, we found that the anti-MM activity of miR-125b-5p was mediated via direct downregulation of IRF4 and its downstream effector BLIMP-1. Moreover, inhibition of IRF4 translated into downregulation of c-Myc, caspase-10 and cFlip, relevant IRF4-downstream effectors. Finally, in vivo intra-tumor or systemic delivery of formulated miR-125b-5p mimics against human MM xenografts in SCID/NOD mice induced significant anti-tumor activity and prolonged survival. Taken together, our findings provide evidence that miR-125b, differently from other hematologic malignancies, has tumor suppressor activity in MM. Furthermore, our data provide proof-of-concept that synthetic miR-125b-5p mimics are promising anti-MM agents to be validated in early clinical trials.Leukemia accepted article preview online, 19 May 2015. doi:10.1038/leu.2015.124.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 05/2015; DOI:10.1038/leu.2015.124 · 9.38 Impact Factor
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    ABSTRACT: Immunomodulatory drugs (IMiDs) thalidomide, lenalidomide (Len) and pomalidomide trigger anti-tumor activities in multiple myeloma (MM) by targetting cereblon and thereby impacting IZF1/3, c-Myc and IRF4. Histone deacetylase inhibitors (HDACi) also downregulate c-Myc. We therefore determined whether IMiDs with HDACi trigger significant MM cell growth inhibition by inhibiting or downregulating c-Myc. Combination treatment of Len with non-selective HDACi suberoylanilide hydroxamic acid or class-I HDAC-selective inhibitor MS275 induces synergic cytotoxicity, associated with downregulation of c-Myc. Unexpectedly, we observed that decreased levels of cereblon (CRBN), a primary target protein of IMiDs, was triggered by these agents. Indeed, sequential treatment of MM cells with MS275 followed by Len shows less efficacy than simultaneous treatment with this combination. Importantly ACY1215, an HDAC6 inhibitor with minimal effects on class-I HDACs, together with Len induces synergistic MM cytotoxicity without alteration of CRBN expression. Our results showed that only modest class-I HDAC inhibition is able to induce synergistic MM cytotoxicity in combination with Len. These studies may provide the framework for utilizing HDACi in combination with Len to both avoid CRBN downregulation and enhance anti-MM activities.
    Blood Cancer Journal 05/2015; 5(5):e312. DOI:10.1038/bcj.2015.38 · 2.88 Impact Factor
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    ABSTRACT: PD1/PD-L1 signaling promotes tumor growth while inhibiting effector cell-mediated anti-tumor immune responses. Here we assessed the impact of single and dual blockade of PD1/PD-L1, alone or in combination with lenalidomide, on accessory and immune cell function as well as multiple myeloma (MM) cell growth in the BM milieu. Surface expression of PD1 on immune effector cells, and PD-L1 expression on CD138+MM cells and myeloid derived suppressor cells (MDSC) were determined on tumor cells from newly diagnosed (ND)-MM and relapsed/refractory (RR)-MM BM versus healthy donor (HD). We defined the impact of single and dual blockade of PD1/PD-L1, alone and with lenalidomide, on autologous anti-MM immune response and tumor cell growth. Both ND and RR patient MM cells have increased PD-L1 mRNA and surface expression compared to HD. There is also a significant increase in PD1 expression on effector cells in MM. Importantly, PD1/PD-L1-blockade abrogates BM-stroma cell (BMSC)-induced MM growth, and combined blockade of PD1/PD-L1 with lenalidomide further inhibits BMSC-induced tumor growth. These effects are associated with induction of intracellular expression of IFNγ and Granzyme-B in effector cells. Importantly, PD-L1 expression in MM is higher on MDSC than on antigen presenting cells, and PD1/PD-L1-blockade inhibits MDSC-mediated MM growth. Finally, lenalidomide with PD1/PD-L1-blockade inhibits MDSC-mediated immune suppression. Our data therefore demonstrates that checkpoint signaling plays an important role in providing the tumor-promoting, immune-suppressive microenvironment in MM, and that PD1/PD-L1-blockade induces anti-MM immune response that can be enhanced by lenalidomide, providing the framework for clinical evaluation of combination therapy. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 05/2015; DOI:10.1158/1078-0432.CCR-15-0200 · 8.19 Impact Factor
  • Raphaël Szalat · Nikhil C Munshi
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    ABSTRACT: Multiple myeloma (MM) is an incurable malignancy in majority of patients characterized by clonal proliferation of plasma cells. To date, treatment is established based on general conditions and age of patients. However, MM is a heterogeneous disease, featured by various subtypes and different outcomes. Thus, the understanding of MM biology is currently a major challenge to eventually cure the disease. During the last decade, karyotype studies and gene expression profiling have identified robust prognostic markers as well as a widespread genomic landscape. More recently, studies of epigenetic, transcriptional modifications and next generation sequencing have allowed characterization of critical genes and pathways, clonal heterogeneity and mutational profiles involved in myelomagenesis. Altogether, these findings constitute important tools to develop new targeted and personalized therapies in MM. Copyright © 2015. Published by Elsevier Ltd.
    Current opinion in genetics & development 05/2015; 30:56-65. DOI:10.1016/j.gde.2015.03.008 · 8.57 Impact Factor
  • Giada Bianchi · Nikhil C Munshi
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    ABSTRACT: Over the past four decades, basic research has provided crucial information regarding the cellular and molecular biology of cancer. In particular, the relevance of cancer microenvironment, including both cellular and non-cellular elements, and the concept of clonal evolution and heterogeneity have emerged as important in cancer pathogenesis, immunological escape and resistance to therapy. Multiple myeloma, a cancer of terminally differentiated plasma cells, is emblematic of the impact of cancer microenvironment and the role of clonal evolution. Indeed, while genetic and epigenetic aberrations occur in multiple myeloma and evolve over time under the pressure of exogenous stimuli, they are also largely present in premalignant plasma cell dyscrasia such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma, suggesting that genetic mutations alone are necessary, but not sufficient for myeloma transformation. The role of bone marrow (BM) microenvironment in mediating survival, proliferation and therapy resistance in myeloma is well established. Vice versa, while it is an appealing speculation, its role in fostering evolution of MGUS or SMM into MM has still to be proven. In this review we will discuss MM pathogenesis with a particular emphasis on the role of cancer microenvironment. Copyright © 2015 American Society of Hematology.
    Blood 04/2015; 125(20). DOI:10.1182/blood-2014-11-568881 · 10.43 Impact Factor
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    ABSTRACT: Extramedullary disease (EMD), defined as an infiltrate of clonal plasma cells at an anatomic site distant from the bone marrow, is an uncommon manifestation of multiple myeloma. Six hundred and sixty-three consecutive patients with multiple myeloma who underwent stem cell transplantation between January 2005 and December 2011 were assessed for the presence of EMD. A cohort of 55 patients with biopsy-proven EMD was identified, comprising 8·3% of the total study population. EMD was present at the time of diagnosis in 14·5% of cases and at the time of relapse in 76% of patients. The most common EMD presentations at relapse were liver involvement and pleural effusions. EMD specimens had high expression of CD44 (92%) and moderate expression of CXCR4. The median overall survival from time of myeloma diagnosis was 4·1 years (95% CI: 3·1, 5·1) and the median overall survival from time of EMD diagnosis was 1·3 years (95% CI: 0·8, 2·3). This report demonstrates that the incidence of EMD has not increased with the introduction of novel agents and stem cell transplantation. The most common EMD presentations in the relapsed setting were liver and pleural fluid. The presence of CD44 and CXCR4 expression may represent new markers of EMD that warrant further investigation. © 2015 John Wiley & Sons Ltd.
    British Journal of Haematology 04/2015; 169(6). DOI:10.1111/bjh.13383 · 4.96 Impact Factor
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    ABSTRACT: Multicentric Castleman's disease (MCD) is a rare lymphoproliferative disorder driven by dysregulated interleukin-6 production. MCD has a poor prognosis, and treatment is generally noncurative and aimed at symptom relief. Siltuximab is a novel, monoclonal interleukin-6 antibody recently shown to be effective in a registration clinical trial. MCD symptoms, such as fatigue, pain, and weakness, are most appropriately quantified using patient-reported outcome (PRO) measures. We assessed the effect of siltuximab on patient perception of symptoms, functional status, and wellbeing using PRO instruments. We analyzed results of a randomized, double-blind trial comparing siltuximab 11 mg/kg every 3 weeks with placebo to treat MCD. Subjects (N = 79) completed the recently developed MCD-Symptom Scale (MCD-SS), the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale, and the Short Form (SF)-36 at predetermined time points throughout the treatment period. Scores were compared at baseline and over time between the treatment arms and PRO instruments. At baseline, the mean number of symptoms reported was 9.2 (standard deviation 3.76) out of 16 total, as measured by the MCD-SS. Fatigue was a key symptom across all PRO instruments. Siltuximab-treated subjects reported early improvements in symptoms compared with subjects in the placebo arm on both the MCD-SS and FACIT-Fatigue scale. Statistically significant improvements in five SF-36 domains were observed in siltuximab-treated patients, namely role physical, role emotional, vitality, bodily pain, and mental health. Patients with MCD commonly report impairments in functioning, wellbeing, and fatigue at baseline. Siltuximab-treated patients reported significant improvements in these outcomes after treatment.
    The patient 03/2015; 8(2). DOI:10.1007/s40271-015-0120-5 · 1.96 Impact Factor
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    ABSTRACT: Objectives: To analyze imaging features of subtypes of Castleman Disease (CD), emphasizing differentiating features from lymphoma. Methods: IRB-approved, HIPAA compliant, retrospective study examined 30 patients with CD. 30 patients (20 women, mean age: 46 years, range 22-87) with histopathologically confirmed CD and pre-treatment imaging formed the analytic cohort. Imaging at presentation in all patients (30 CT, 5 PET/CT, 4 MR, 3 US) and subsequent imaging in three cases that developed lymphoma was reviewed by two radiologists in consensus. Results: Subtypes: hyaline-vascular(n=18); multicentric not otherwise specified (NOS)(n=6); HHV-8 associated( n=2); mixed unicentric(n=2); pure plasma-cell variant(n=1); unicentric NOS(n=1). Distribution: unicentric(n=17); multicentric(n=13). Nodal sites: unicentric: 13thoracic, 3abdominal and 1 cervical; multicentric: 9abdominal, 8thoracic, 6cervical, 5inguinal, 4axillary and 4supraclavicular. On CT, differentiating features from lymphoma were calcification(n=8; 26.7%) and heterogeneous enhancement(n=5; 19.2%). No association between CD subtype, degree or enhancement pattern, or calcification was noted. On PET/CT(n=5), nodes were typically FDG-avid(n=4). On ultrasound(n=3), nodes were hypoechoic, homogeneous with posterior acoustic enhancement. On MR(n=4), nodes were hypointense(n=2) to isointense(n=2) on T1-weighted images and isointense(n=1) to hyperintense(n=3) on T2-weighted images. All(n=4) demonstrated homogeneous enhancement. Three cases developed non-Hodgkin's lymphoma, 2 of the 3 had larger spleens, and these cases had effusions/ascites. Conclusions: CD can be unicentric or multicentric, and involve nodes above and below the diaphragm. Patients with CD can develop lymphoma. Advances in knowledge: Assessing individual risk of developing lymphoma in patients with CD is difficult, though the findings of splenomegaly, pleural effusion and ascites may be suggestive.
    British Journal of Radiology 02/2015; 88(1049):20140670. DOI:10.1259/bjr.20140670 · 2.02 Impact Factor
  • A Ray · D S Das · Y Song · P Richardson · N C Munshi · D Chauhan · K C Anderson
    Leukemia 01/2015; 29(6). DOI:10.1038/leu.2015.11 · 9.38 Impact Factor
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    ABSTRACT: In multiple myeloma, cytogenetic changes display important value for patients' outcome. In this setting, the most important changes are the del(17p), and the t(4;14), conferring a poor outcome. However, a certain heterogeneity is observed in survival of these high-risk patients. We hypothesized that other chromosomal changes may impact the outcome. We retrospectively analyzed a large series of 242 patients displaying either the t(4;14) (157 patients), or the del(17p) (110 patients), 25 patients presenting both abnormalities, using SNP-array. In patients with t(4;14), del(1p32) (p<0.001), del22q (p<0.05) and more than 30 chromosomal structural changes (p=0.01) negatively impacted PFS. For OS, del(13q14) (p=0.01), del(1p32) (p<0.001), and the number of chromosomal structural changes (p<0.05 and p=0.01 for [10;30[and more than 30 structural changes, respectively) worsened the prognosis of patients. For patients with del(17p), del6q (p=0.01) worsened the prognosis of patients, whereas trisomy 15 (p=0.01) and monosomy 14 (p=0.03) were found to have a protective effect on PFS. For OS, del(1p32) (p=0.01) worsened the prognosis of patients, whereas more than 8 numerical changes (p=0.004) was found to have a protective effect on survival. This study, which is the largest series of high-risk patients, analyzed with the most modern genomic technique, identified one main factor negatively impacting survival: del(1p32). Copyright © 2015 American Society of Hematology.
    Blood 01/2015; 125(13). DOI:10.1182/blood-2014-07-587964 · 10.43 Impact Factor
  • Jill Corre · Nikhil Munshi · Hervé Avet-Loiseau
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    ABSTRACT: Our knowledge of myeloma genetics remained limited and lagged behind many other hematologic malignancies due to the inherent difficulties in generating metaphases within the malignant plasma cell clone. With the development of molecular techniques (micro-arrays, next-generation sequencing), our understanding has been highly improved in the past five years. These studies have not only confirmed the prevalence of wide heterogeneity in myeloma at the molecular level, but has also provided a much clearer picture of the disease pathogenesis and progression. Whether these data will enable improvements in the therapeutic approach is still a matter of debate. The next improvement will come from detailed analyses of these molecular features to try to move from a treatment fitted to every patient to individualized therapies, taking into account the complexity of the chromosomal changes, the mutation spectrum, and subclonality evolution. Copyright © 2015 American Society of Hematology.
    Blood 01/2015; 125(12). DOI:10.1182/blood-2014-10-567370 · 10.43 Impact Factor
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    ABSTRACT: Once-weekly administration of bortezomib has reduced bortezomib-induced peripheral neuropathy without affecting response rates, but this has only been demonstrated prospectively in three- and four- drug combinations. We report a phase II trial of alternate dosing and schedule of bortezomib and dexamethasone in newly diagnosed multiple myeloma patients who are not eligible for or refused autologous stem cell transplantation. Bortezomib 1·6 mg/m2 intravenously was given once-weekly for six cycles, together with dexamethasone 40 mg on the day of and day after bortezomib. Fifty patients were enrolled; 58% did not require any dose modification. The majority of patients had multiple co-morbidities, including cardiovascular (76%) and renal insufficiency (54%), and the median number of medications prior to enrollment was 13. Of all evaluable patients, the overall response rate was 79% and at least 45% had at least a very good partial response. The median time to first response was 1·3 months (range, 0·25–2·4 months). The progression-free and overall survivals were 8 months and 46·5 months, respectively. Twenty-four percent developed worsening neuropathy. We conclude that alternate dosing and scheduling of bortezomib and dexamethasone is both safe and effective for management of newly diagnosed multiple myeloma in frail patients. (ClinicalTrials.gov number, NCT01090921).
    British Journal of Haematology 01/2015; 169(1). DOI:10.1111/bjh.13243 · 4.96 Impact Factor
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    ABSTRACT: XBP1 is a critical transcriptional activator of the unfolded protein response (UPR), which increases tumor cell survival under prolonged endoplasmic reticulum (ER) stress and hypoxic conditions.This study was designed to evaluate the immunogenicity of heteroclitic XBP1 unspliced (US)184-192 (YISPWILAV) and heteroclictic XBP1 spliced (SP)367-375 (YLFPQLISV) HLA-A2 peptides, and to characterize the specific activities of XBP1 peptides-specific cytotoxic T lymphocytes (XBP1-CTL) against breast cancer, colon cancer, and pancreatic cancer cells.The XBP1-CTL had upregulated expression of critical T cell markers and displayed HLA-A2-restricted and antigen-specific activities against breast cancer, colon cancer and pancreatic cancer cells. XBP1-CTL were enriched withCD45RO+ memory CTL, which showed high expression of critical T cell markers (CD28, ICOS, CD69, CD40L), cell proliferation and antitumor activities as compared to CD45RO− non-memory CTL. The effector memory (EM: CD45RO+CCR7−) subset had the highest level of cell proliferation while the central memory (CM: CD45RO+CCR7+) subset demonstrated enhanced functional activities (CD107a degranulation, IFNγ/IL-2 production) upon recognition of the respective tumor cells. Furthermore, both the EM and CM XBP1-CTL subsets expressed high levels of Th1 transcription regulators Tbet and Eomes. The highest frequencies of IFNγ or granzyme B producing cells were detected within CM XBP1-CTL subset that were either Tbet+ or Eomes+ in responding to the tumor cells.These results demonstrate the immunotherapeutic potential of a cocktail of immunogenic HLA-A2 specific heteroclitic XBP1 US184-192 and heteroclictic XBP1 SP367-375 peptides to induce CD3+CD8+ CTL enriched for CM and EM cells with specific antitumor activities against a variety of solid tumors.
    OncoImmunology 01/2015; 3(12):e970914. DOI:10.4161/21624011.2014.970914 · 6.28 Impact Factor

Publication Stats

24k Citations
3,338.80 Total Impact Points

Institutions

  • 2015
    • VA Long Beach Healthcare System
      Long Beach, California, United States
  • 2002–2015
    • Dana-Farber Cancer Institute
      • Department of Medical Oncology
      Boston, Massachusetts, United States
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2011
    • National and Kapodistrian University of Athens
      • Division of Clinical Therapeutics
      Athínai, Attica, Greece
  • 2008–2010
    • Karmanos Cancer Institute
      Detroit, Michigan, United States
  • 2009
    • National Institutes of Health
      Maryland, United States
  • 2007
    • University of Pennsylvania
      • Division of Hematology/Oncology
      Filadelfia, Pennsylvania, United States
  • 2005–2007
    • Universita' degli Studi "Magna Græcia" di Catanzaro
      Catanzaro, Calabria, Italy
  • 2006
    • Brigham and Women's Hospital
      Boston, Massachusetts, United States
  • 1996–2005
    • University of Arkansas at Little Rock
      Little Rock, Arkansas, United States
  • 2004
    • University of Leeds
      • School of Medicine
      Leeds, ENG, United Kingdom
  • 2003–2004
    • Cornell University
      Итак, New York, United States
  • 1997–2002
    • University of Arkansas for Medical Sciences
      Little Rock, Arkansas, United States
  • 2001
    • Harbor-UCLA Medical Center
      Torrance, California, United States
  • 1999–2001
    • Central Arkansas Veterans Healthcare System
      Washington, Washington, D.C., United States
    • Arkansas Children's Hospital
      Little Rock, Arkansas, United States
  • 1990–1995
    • Indiana University-Purdue University Indianapolis
      • Department of Medicine
      Indianapolis, IN, United States
  • 1992
    • Indiana University East
      Indiana, United States