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1.  Enabling a Genetically Informed Approach to Cancer Medicine: A Retrospective Evaluation of the Impact of Comprehensive Tumor Profiling Using a Targeted Next-Generation Sequencing Panel 
The Oncologist  2014;19(6):616-622.
To determine the clinical impact of extensive genetic analysis, the use of a targeted next-generation sequencing (NGS) platform (FoundationOne) in advanced cancer patients was reviewed. Mutational profiling using a targeted NGS panel identified potentially actionable alterations in a majority of the patients. The assay identified additional therapeutic options and facilitated clinical trial enrollment. As time progresses, NGS results will be used to guide therapy in an increasing proportion of patients.
Background.
Oncogenic genetic alterations “drive” neoplastic cell proliferation. Small molecule inhibitors and antibodies are being developed that target an increasing number of these altered gene products. Next-generation sequencing (NGS) is a powerful tool to identify tumor-specific genetic changes. To determine the clinical impact of extensive genetic analysis, we reviewed our experience using a targeted NGS platform (FoundationOne) in advanced cancer patients.
Patients and Methods.
We retrospectively assessed demographics, NGS results, and therapies received for patients undergoing targeted NGS (exonic sequencing of 236 genes and selective intronic sequencing from 19 genes) between April 2012 and August 2013. Coprimary endpoints were the percentage of patients with targeted therapy options uncovered by mutational profiling and the percentage who received genotype-directed therapy.
Results.
Samples from 103 patients were tested, most frequently breast carcinoma (26%), head and neck cancers (23%), and melanoma (10%). Most patients (83%) were found to harbor potentially actionable genetic alterations, involving cell-cycle regulation (44%), phosphatidylinositol 3-kinase-AKT (31%), and mitogen-activated protein kinase (19%) pathways. With median follow-up of 4.1 months, 21% received genotype-directed treatments, most in clinical trials (61%), leading to significant benefit in several cases. The most common reasons for not receiving genotype-directed therapy were selection of standard therapy (35%) and clinical deterioration (13%).
Conclusion.
Mutational profiling using a targeted NGS panel identified potentially actionable alterations in a majority of advanced cancer patients. The assay identified additional therapeutic options and facilitated clinical trial enrollment. As time progresses, NGS results will be used to guide therapy in an increasing proportion of patients.
doi:10.1634/theoncologist.2014-0011
PMCID: PMC4041676  PMID: 24797823
Next-generation sequencing; Genotype; Precision medicine; Molecular targeted therapy; Cancer; Mutation
2.  Profile of belinostat for the treatment of relapsed or refractory peripheral T-cell lymphoma 
OncoTargets and therapy  2014;7:1971-1977.
The peripheral T-cell lymphomas are a rare and heterogeneous group of mature T-cell lymphomas with limited available therapies. The outcome of frontline chemotherapy regimens has been disappointing, with a long-term survival of only 20%–30%. There is an urgent need to optimize induction therapy by incorporating novel agents that target the dysregulated pathways. Histone deacetylase inhibitors that induce acetylation of histones and enhance apoptosis have shown promising activity. In this article, we summarize the role of histone deacetylase inhibitors and specifically discuss pharmacokinetics, efficacy, and toxicity of the recently US Food and Drug Administration-approved agent belinostat for its use in patients with relapsed/refractory peripheral T-cell lymphoma.
doi:10.2147/OTT.S59269
PMCID: PMC4216035  PMID: 25368524
histone deacetylase inhibitor; pharmacokinetics; cutaneous T-cell lymphoma
3.  Consolidative autologous hematopoietic stem-cell transplantation in first remission for non-Hodgkin lymphoma: current indications and future perspective 
The non-Hodgkin lymphomas (NHLs) are a heterogeneous group of diseases with variable clinical outcomes. Autologous hematopoietic stem-cell transplantation (ASCT) as frontline, consolidative therapy has been evaluated based upon histological subtype of NHL. In this review, we summarize the major clinical trials guiding the use of frontline ASCT in NHL. With the constantly changing landscape of upfront therapy and multiple promising novel agents, the ability to conduct randomized trials to evaluate the benefit of consolidative ASCT is not only challenging but may be considered by some an inept utilization of resources. Our recommendation for consolidative ASCT is based on analyzing the current available data.
doi:10.1177/2040620714547327
PMCID: PMC4199091  PMID: 25324956
autologous transplantation; diffuse large B cell; follicular; mantle cell; non-Hodgkin lymphoma; peripheral T cell; primary central nervous system
4.  Optimizing Personalized Bone Marrow Testing Using an Evidence-based, Interdisciplinary Team Approach 
Personalized medicine requires physicians to employ complex and expensive diagnostic analyses. However, without evidence-based standards, there is over-utilization of testing that complicates patient care, diminishes quality, and increases costs. To address this, we implemented the diagnostic management team (DMT), a multi-disciplinary system for development and deployment of diagnostic testing guidelines for hematologic malignancies. The team created evidence-based standard ordering protocols (SOPs) for cytogenetic and molecular testing that were applied by pathologists to bone marrow biopsies on adult patients. Testing on 780 biopsies performed during the 6 months before SOP implementation was compared with 1,806 biopsies performed during the subsequent 12 months. After implementation, there were significant decreases in tests discordant with SOPs, omitted tests, and the estimated cost of testing to payers. The fraction of positive tests increased. Clinicians reported acceptance of the new procedures and perceived time savings. This process is a model for optimizing complex and personalized diagnostic testing.
doi:10.1309/AJCP8CKE9NEINQFL
PMCID: PMC4159763  PMID: 24124142
Hematopathology; informatics; molecular diagnostics; genetics
5.  Immunomodulatory nonablative conditioning regimen for B-cell lymphoid malignancies 
Experimental hematology  2012;40(6):431-435.
Twenty-six patients with recurrent CD20+ B-cell lymphoid malignancies received fludarabine, cyclophosphamide, and rituximab–based nonablative conditioning followed by either matched related (n = 18) or unrelated (n = 8) donor allogeneic stem cell transplantation (allo-SCT) between March 2008 and May 2011. Median age of patients at transplantation was 59 years (range, 41–64 years). At diagnosis, 20 (77%) had stage IV disease; 23 (88%) received ≥3 regimens, 14 (54%) received ≥4 regimens, and 4 (15%) had earlier autologous-SCT. All patients had either chemosensitive or stable disease and nine (35%) were in complete remission before transplantation. At the time of analysis, 17 patients were alive with an estimated 2-year overall survival and progression-free survival rate of 63% and nonrelapse mortality of 25%. Grade II to IV acute graft-vs-host-disease occurred in 8 (31%) and chronic graft-vs-host-disease in 6 (23%) patients (extensive, n = 3). Causes of death include progressive disease in four, acute graft-vs-host-disease in two (both after receiving donor lymphocyte infusion for mixed chimerism with residual disease), infection in one, and other (e.g., substance abuse, leukoencephalopathy) in two. Six patients required rehospitalization within 100 days of SCT (mean = 10 days; range, 3–18 days). Our data support fludarabine, cyclophosphamide, and rituximab–based nonablative conditioning allo-SCT in CD20+ B-cell lymphoid malignancies and it is time to compare this regimen with an alternative reduced-intensity conditioning regimen in B-cell malignancies.
doi:10.1016/j.exphem.2012.01.014
PMCID: PMC4067702  PMID: 22269114
6.  Strategies to Prevent EBV Reactivation and Posttransplant Lymphoproliferative Disorders (PTLD) after Allogeneic Stem Cell Transplantation in High-Risk Patients 
Epstein-Barr virus (EBV)-associated postallogeneic stem cell transplantation (SCT) lymphoproliferative disorder (PTLD) is often life threatening. The risk of EBV reactivation is highest in older patients, T cell-depleted SCT (in vivo or vitro), and in unrelated or mismatched SCT. Cumulative numbers of patients with EBV reactivation and PTLD are rising as more patients at high risk for EBV reactivation and PTLD are receiving allo-SCT. Novel but easily applicable strategies are needed to prevent EBV reactivation and PTLD to serve the needs of the increasingly enlarging population of high-risk SCT recipients across the globe.
doi:10.1016/j.bbmt.2010.08.007
PMCID: PMC3763478  PMID: 20732435
EBV reactivation; PTLD; Stem cell transplantation; Rituximab; Sirolimus; Long-term survivors
7.  Immune surveillance and lymphoid malignancy in immunocompromised host 
Immune surveillance is a dynamic process that involves an intact immune system to identify and protect the host against tumor development. The increased understanding of the genetics, infections and hematological malignancies in congenital immune deficiency states supports the concept that impaired T cells and Natural-killer/T cells leads to B-cell lymphoma. Furthermore, severe combined immunodeficient mice are prone to spontaneous tumor development and therefore serve as experimental models. Here we discuss the acquired conditions and mechanisms involved in dysregulation of the immune system that lead to lymphoma. Preemptive strategies to improve immune regulation and response and restore a competent immune system may lead to a decrease in lymphoid malignancies.
PMCID: PMC3649811  PMID: 23675561
Lymphoma; immune surveillance; immune deficiency
8.  Treatment Options for Transformed Lymphoma: Incorporating Allogeneic Stem Cell Transplantation in a Multimodality Approach 
Transformed non-Hodgkin’s lymphoma (TL) arising from follicular lymphoma carries a poor prognosis and the median survival time after transformation is approximately 10-12 months. Standard chemotherapy and radioimmunotherapy have offered promising responses however; the duration of response does not appear to last long. Several studies evaluating the role of autologous stem cell transplantation (auto-SCT) as a salvage regimen have been reported and a subset of patients benefit from this modality of treatment. With an improvement in supportive care, outcome after allogeneic stem cell transplantation (allo-SCT) has been improved significantly over past decades, however very limited data are available in TL. In the era of emerging novel therapies, the actual timing, optimal conditioning regimens and long term impact of the type of stem cell transplantation (auto-SCT vs. allo-SCT) is unclear. This review addresses the approaches to the management of patients with TL.
doi:10.1016/j.bbmt.2011.05.002
PMCID: PMC3156833  PMID: 21621630
Transformed lymphoma; autologous stem cell transplant; allogeneic stem cell transplant; radioimmunotherapy
9.  Advances and application of radioimmunotherapy in non-Hodgkin lymphoma 
The activity of radio-immuno conjugate in Non-Hodgkin Lymphoma (NHL) has resulted in FDA approval of two antibodies, Y90 Ibritumomab tiuxetan and I131 tositumomab. Both these agents target CD20, a receptor widely expressed in B-Cell NHL. These immunoconjugates deliver their radioactive payload to the malignant clone in the bone marrow and lymph node. Their use has been associated with modest improvement in survival end points among several lymphoma histologies. The promising effect on disease control as well as their efficacy in disease relapse is encouraging in low grade lymphoma. Radioimmunotherapy (RIT) is increasingly being explored in the setting of consolidation as well as conditioning regimens prior to stem cell transplantation. Here, we summarize the clinical use, complications and future applications of RIT in NHL.
PMCID: PMC3384399  PMID: 22762027
Radioimmunotherapy; non-Hodgkin lymphoma; stem cell transplantation; CD20 target
10.  High Prevalence of Obesity in Acute Promyelocytic Leukemia (APL): Implications for Differentiating Agents in APL and Metabolic Syndrome 
Background:
Between January 1999 and December 2008, 469 patients treated for acute myeloid leukemia (AML) were included in this single-institution study.
Methods:
We performed a case-control analysis to study the rate of obesity among patients with acute promyelocytic leukemia (APL) and non-APL AML.
Results:
A total of 81% of APL patients analyzed were obese compared with 41.7% in the non-APL group (p < 0.001). Body mass index (BMI) >30 was seen in 57% of APL patients compared with 31% for the non-APL group (p = 0.01). Neither obesity nor the chemotherapy dosing based on ideal body weight affected survival.
Conclusions:
Our findings generate the hypothesis that APL and metabolic syndromes may share a common pathogenic pathway via retinoic acid receptors (RARs), the ligand-controlled transcription factors that function as heterodimers with retinoid X receptors (RXRs) to regulate cell growth and survival. If this link is confirmed in larger studies, our data will instigate further studies using RXR and RAR modulators as a preventive strategy among obese individuals.
doi:10.1177/2040620711408490
PMCID: PMC3573402  PMID: 23556085
acute promyelocytic leukemia; body mass index; obesity; prevention; RAR; RXR

Results 1-10 (10)