Publications by authors named "James R Cook"

154 Publications

Impact of next generation sequencing results on clinical management in patients with hematological disorders.

Leuk Lymphoma 2021 Feb 3:1-15. Epub 2021 Feb 3.

Department of Laboratory Medicine, Robert J. Tomsich Institute of Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, OH, USA.

Application of next generation sequencing (NGS) has shed light on the molecular heterogeneity of hematological malignancies. NGS panels targeting recurrent mutations have become common in many large centers and commercial laboratories. However, its impact in clinical practice is unclear. We sought to characterize the use of NGS at a tertiary care center in an observational study of 343 patients with suspected hematological malignancies. We found that NGS changed or refined the clinical and pathologic diagnosis in 9% of patients and affected management decisions in 65% (including clinical trial eligibility, targeted therapy selection, and consideration for stem cell transplantation). This study emphasizes early incorporation of NGS in clinical practice while also highlighting the present limitations. As our understanding of these disorders increases and more clinically relevant genetic targets emerge, it will be important to refine the molecular testing strategy to deliver personalized medicine given the high cost associated with this technology.
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http://dx.doi.org/10.1080/10428194.2021.1876860DOI Listing
February 2021

Novel invariant features of Good syndrome.

Leukemia 2021 Jan 7. Epub 2021 Jan 7.

Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH, USA.

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http://dx.doi.org/10.1038/s41375-020-01114-zDOI Listing
January 2021

RNA-Based next generation sequencing complements but does not replace fluorescence in situ hybridization studies for the classification of aggressive B-Cell lymphomas.

Cancer Genet 2021 Apr 10;252-253:43-47. Epub 2020 Dec 10.

Department of Laboratory Medicine, Robert J Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, United States. Electronic address:

Aggressive B-cell lymphomas are currently classified based in part upon the presence or absence of translocations involving BCL2, BCL6, and MYC. Most clinical laboratories employ fluorescence in situ hybridization (FISH) analysis for the detection of these rearrangements. The potential role of RNA-based sequencing approaches in the evaluation of malignant lymphoma is currently unclear. In this study, we performed RNA sequencing (RNAseq) in 37 cases of aggressive B-cell lymphomas using a commercially available next generation sequencing assay and compared results to previously performed FISH studies. RNAseq detected 1/7 MYC (14%), 3/8 BCL2 (38%) and 4/8 BCL6 (50%) translocations identified by FISH. RNAseq also detected 1 MYC/IGH fusion in a case not initially tested by FISH due to low MYC protein expression and 2 BCL6 translocations that were not detected by FISH. RNAseq identified the partner gene in each detected rearrangement, including a novel EIF4G1-BCL6 rearrangement. In summary, RNAseq complements FISH for the detection of rearrangements of BCL2, BCL6 and MYC in the evaluation and classification of aggressive B-cell lymphomas by detecting rearrangements that may be cryptic by FISH methods and by identifying the rearrangement partner genes. Detection of these clinically important translocations may be optimized by combined use of FISH and RNAseq.
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http://dx.doi.org/10.1016/j.cancergen.2020.12.004DOI Listing
April 2021

A data-guided approach to supporting students' social-emotional development in pre-k.

Am J Orthopsychiatry 2020 Dec 14. Epub 2020 Dec 14.

Charlotte-Mecklenburg Schools.

The development of social-emotional competencies in early childhood is essential for long-term health and wellbeing, and these skills are particularly critical for children from disadvantaged backgrounds to set the foundation for success in school and in life. The present study examined the effects of an intervention to support prekindergarten (pre-k) teachers' ability to address the specific social-emotional needs of their students. Teachers in a publicly funded pre-k program completed the Devereux Early Childhood Assessment (DECA; LeBuffe & Naglieri, 1999; LeBuffe & Shapiro, 2004) to measure social-emotional functioning. "Intervention" teachers received summaries of their students' social-emotional strengths and needs based on the DECA and packets providing teaching strategies they could use to target the social-emotional domains assessed by the DECA. Teachers were encouraged to work with their coaches to interpret their classroom summaries and implement strategies to address their students' needs. Multilevel modeling revealed that students whose teachers received social-emotional feedback (classroom summaries and strategy packets) showed significantly greater social-emotional gains (across multiple domains) over the school year compared to students whose teachers did not receive feedback. Our findings suggest that having teachers complete social-emotional assessments of their students at the beginning of the school year and providing teachers with data-based feedback may build teachers' capacity to promote social-emotional development for children from disadvantaged backgrounds. We discuss the potential to build on this data-guided approach to better prepare children to succeed in elementary school and beyond. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
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http://dx.doi.org/10.1037/ort0000522DOI Listing
December 2020

The molecular landscape and other distinctive features of primary cutaneous follicle center lymphoma.

Hum Pathol 2020 Dec 9;106:93-105. Epub 2020 Oct 9.

Division of Hematopathology, Department of Pathology, University of Pittsburgh School of Medicine and UPMC, Hill Building, Room 359, 3477 Euler Way, Pittsburgh, PA, 15213, USA. Electronic address:

Primary cutaneous follicle center lymphoma (PCFCL) is distinguished from other follicular lymphomas (FLs) based on its clinicopathologic features including diminished CD10 and frequent lack of BCL2 rearrangements (R). Whether newer germinal center-associated markers would also be less commonly expressed and whether mutational studies would support its segregation from classic FL and FL subsets, including those which also typically lack BCL2R, are uncertain. To address these questions, 22 PCFCLs were stained for myocyte enhancer factor 2B (MEF2B) and human germinal center-associated lymphoma (HGAL), and targeted next-generation sequencing was performed with results compared to a meta-analysis of FL, pediatric-type FL (PTFL), low stage FL (LSFL) and other FL subsets. Selected fluorescence in situ hybridization studies were also performed. Although 27% of cases lacked CD10, all tested were MEF2B+ and HGAL+. The most common somatic mutations in the 12 to 19 analyzable PCFCL were TNFRSF14 (40%, plus 10% with 1p36 deletions), followed by CREBBP, TNFAIP3, KMT2D, SOCS1, EP300, STAT6, and FOXO1 (17-25%). Three of the most commonly mutated genes in FL (KMT2D, CREBBP, and BCL2) were significantly less commonly mutated in PCFCL than in FL, and TNFAIP was more commonly mutated with no difference for TNFRSF14 between PCFCL and FL or PTFL. CREBBP was also less frequently mutated than in LSFL but more frequently mutated than in PTFL. MAP2K1 mutations were much more common in PTFL (44% versus 0%). Two of 22 of the PCFCL had a BCL2 rearrangement and zero of 12 had a BCL6 rearrangement. These findings, while showing well-recognized and new shared features between PCFCL and other FL, highlight a distinctive mutational profile further supporting its recognition as a distinct entity.
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http://dx.doi.org/10.1016/j.humpath.2020.09.014DOI Listing
December 2020

Extranodal Marginal Zone Lymphoma of the Central Nervous System Includes Parenchymal-Based Cases With Characteristic Features.

Am J Clin Pathol 2020 06;154(1):124-132

Department of Laboratory Medicine, Robert J. Tomisch Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH.

Objectives: To define the clinicopathologic features of extranodal marginal zone lymphoma (EMZL) of the central nervous system (CNS), including cases arising in CNS parenchyma, which have been reported only rarely.

Methods: Twelve cases of CNS EMZL were identified, including 5 based in CNS parenchyma and 7 nonparenchymal cases arising in dura or choroid plexus.

Results: Histologically, parenchymal cases were perivascular infiltrates without a dominant lymphoid mass, whereas nonparenchymal cases were masses of small lymphocytes. Plasma cells were a larger component of the infiltrate in parenchymal cases (median, 30%; range, 20%-50%) than nonparenchymal cases (median, 0%; range, 0%-5%; P < .001), and plasma cells were clonal by immunohistochemistry in 4 of 5 parenchymal vs 1 of 7 nonparenchymal cases (P = .07). Fluorescence in situ hybridization for MALT1 rearrangement was positive in 1 of 3 parenchymal and none of 3 nonparenchymal cases. Chromosomal microarray was abnormal in 5 of 7 cases (71%), with chromosome 6/6q alterations identified in 3 cases. No patients with parenchymal disease but all 6 (100%) with nonparenchymal disease achieved complete remission.

Conclusions: This case series, the first to include multiple parenchymal cases, clarifies the spectrum of clinical, pathologic, and genetic findings in CNS EMZL and suggests that parenchymal-based lesions may show less favorable prognosis than dural-based disease.
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http://dx.doi.org/10.1093/ajcp/aqaa032DOI Listing
June 2020

Primary effusion lymphoma in human immune deficiency (HIV)-negative non-organ transplant immunocompetent patients.

Diagn Cytopathol 2020 Apr 17;48(4):380-385. Epub 2019 Dec 17.

Department of Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio.

Primary effusion lymphoma (PEL) is a rare non-Hodgkin's lymphoma most commonly occurring in the context of human immune deficiency (HIV) infection. Herpes virus 8 (HHV-8) has been associated with PEL and considered to be the etiologic agent. In addition, most cases (60%-90%) also show evidence of Epstein-Barr virus (EBV) infection. We describe here an elderly man who was HIV seronegative and immunocompetent, and presented with worsening weakness and ascites. The diagnosis of PEL was rendered cytologically and supported by the results of flow cytometry. The presence of HHV-8 was demonstrated by immunohistochemistry, whereas EBV-associated genetic material was absent by EBER ISH. No lymphadenopathy or organ involvement with lymphoma was found. Systemic chemotherapy with lenalidomide was started given the poor prognosis and commodities of severe coronary artery disease; however, the patient did not respond and succumbed to his disease in 4 months. We present detailed cytologic and clinical findings of this very rare occurrence, and review literature of all reported PEL cases of HIV-negative, nontransplant, immunocompetent patients.
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http://dx.doi.org/10.1002/dc.24371DOI Listing
April 2020

As the world turns, evolving lymphoma classifications-past, present and future.

Hum Pathol 2020 01 5;95:55-77. Epub 2019 Sep 5.

Department of Laboratory Medicine, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address:

The last century and a half has seen first the recognition of lymphomas, and then the publication of one lymphoma classification after another often together with highly critical comments about preceding classifications or a welcome that was less than warm. The introduction of HUMAN PATHOLOGY in 1970 came just before one of the very acrimonious periods in lymphoma classification, as we were learning more about the normal immune system and with the proposed functional lymphoma classifications of Lukes/Collins and Kiel in 1974 relating the lymphomas to their normal B-cell or T-cell 'counterparts'. Those difficult times were followed by the regressive strictly morphologic NCI Working Formulation in 1982, with the REAL classification in 1994 putting us back on a rational path, once again grouping the lymphoid neoplasms first into those of B-cell and T- and putative NK-cell origin, and then using multiple parameters to define specific entities. Planning for the first modern WHO lymphoma classification began soon afterward, with concordance and collegiality leading to the 2001 WHO classification, which then evolved with publication of the 2008 and 2016 WHO classifications. While this review looks at these important past developments which have gotten us to where we are today, it also concentrates on where we are now, what has been learned since the most recent WHO classification and 'Blue Book' were published and on some of the unanswered questions that remain as we look to the future.
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http://dx.doi.org/10.1016/j.humpath.2019.08.019DOI Listing
January 2020

Myeloid neoplasm with eosinophilia and fusion.

Leuk Lymphoma 2020 01 4;61(1):213-216. Epub 2019 Sep 4.

Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.

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http://dx.doi.org/10.1080/10428194.2019.1658105DOI Listing
January 2020

Class-switched Primary Cutaneous Marginal Zone Lymphomas Are Frequently IgG4-positive and Have Features Distinct From IgM-positive Cases.

Am J Surg Pathol 2019 10;43(10):1403-1412

Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA.

Primary cutaneous marginal zone lymphoma (PCMZL) can be subdivided into 2 groups based on immunoglobulin (Ig) heavy chain usage: IgM-positive cases that constitute a less common and more T-helper type 1-driven process, and more common heavy chain class-switched cases that are predominantly T-helper type 2-driven. Although some report a significant IgG4-positive subset, others have found a much smaller proportion. To further evaluate the proportion of IgG4-positive PCMZL, to address whether IgG4-positive cases have any distinctive characteristics, and to assess whether additional features separating IgM-positive and class-switched cases could be identified, the clinicopathologic features of 26 PCMZL obtained from 19 patients were investigated. Twenty of 26 (77%) PCMZL were heavy chain class-switched (19 IgG-positive, 1 IgA-positive), including 9 that were IgG4-positive (35%). IgG4-positive and other class-switched PCMZL were morphologically similar. IgM-positive cases occurred in older individuals (median: 69 vs. 46.5 y; P=0.0001), more often involved the subcutis (P=0.002), demonstrated plasma cells diffusely scattered versus at the periphery of the lymphoid infiltrate (P=0.005), uniformly showed follicular colonization (P=0.0001), contained more numerous B cells (P=0.0004), and were more likely to have a T-cell CD4:CD8 ratio of <3:1 (P=0.03). None of the IgM-positive PCMZL harbored a MYD88 L265P mutation. No significant differences in clinical outcome were documented. These results highlight the high frequency of IgG4-positive PCMZL, which are otherwise similar to other class-switched cases, provide additional evidence supporting the distinction between class-switched and IgM-positive cases, and emphasize the indolent nature of at least the class-switched PCMZL, which may warrant their categorization as a clonal chronic lymphoproliferative disorder.
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http://dx.doi.org/10.1097/PAS.0000000000001363DOI Listing
October 2019

Molecular and Cytogenetic Education in Hematopathology Fellowship.

Am J Clin Pathol 2019 09;152(4):438-445

Oncology Diagnostics, Janssen Research and Development, Spring House, PA.

Objectives: Given the increased complexity of molecular and cytogenetic testing (MOL-CG), the Society for Hematopathology Education Committee (SH-EC) was interested in determining what the current expectations are for MOL-CG education in hematopathology (HP) fellowship training.

Methods: The SH-EC sent a questionnaire to HP fellowship program directors (HP-PDs) covering MOL-CG training curricula, test menus, faculty background, teaching, and sign-out roles. These findings were explored via a panel-based discussion at the 2018 SH-EC meeting for HP-PDs.

Results: HP fellows are expected to understand basic principles, nomenclature, and indications for and limitations of testing. Interpretation of common assays is within that scope, but not necessarily proficiency in technical troubleshooting of testing or analysis of complex raw data.

Conclusions: The consensus was that HP fellows should understand the components of MOL-CG testing necessary to incorporate those results into an accurate, clinically relevant, and integrated HP report.
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http://dx.doi.org/10.1093/ajcp/aqz048DOI Listing
September 2019

Comparison of real-time PCR vs PCR with fragment length analysis for the detection of CALR mutations in suspected myeloproliferative neoplasms.

Int J Lab Hematol 2019 12 3;41(6):e139-e141. Epub 2019 May 3.

Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio.

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http://dx.doi.org/10.1111/ijlh.13040DOI Listing
December 2019

Very rare lineage switch from acute myeloid leukemia to mixed phenotype acute leukemia, B/Myeloid, during chemotherapy with no clonal evolution.

Int J Lab Hematol 2019 08 1;41(4):e86-e88. Epub 2019 Feb 1.

Department of Laboratory Medicine, Cleveland Clinic, Cleveland, Ohio.

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http://dx.doi.org/10.1111/ijlh.12977DOI Listing
August 2019

Autologous transplantation as consolidation for high risk aggressive T-cell non-Hodgkin lymphoma: a SWOG 9704 intergroup trial subgroup analysis.

Leuk Lymphoma 2019 08 10;60(8):1934-1941. Epub 2019 Jan 10.

a Cardinal Bernardin Cancer Center, Loyola University Medical Center , Maywood , IL , USA.

Phase II data suggest a benefit to autotransplantation for aggressive T-cell non-Hodgkin lymphoma (T-NHL) in first remission; randomized trials have yet to validate this. We performed a retrospective analysis of aggressive T-NHL patients in the intergroup randomized consolidative autotransplant trial (SWOG 9704). Of the 370 enrolled, 40 had T-NHL: 12 were not randomized due to ineligibility ( = 1), choice ( = 2), or progression ( = 9), leaving 13 randomized to control and 15 to autologous stem cell transplantation (ASCT). Two ASCT patients refused transplant and one failed mobilization. The 5-year landmark PFS/OS estimates for ASCT vs. control groups were 40% vs. 38% ( = .56), and 40% vs. 45% ( = .98), respectively. No difference was seen based on IPI, or histologic subtype. Only 1/7 receiving BCNU-based therapy survived vs. 4/5 receiving TBI. Aggressive T-NHL autotransplanted in first remission did not appear to benefit from consolidative ASCT. This and the 30% who dropped out pre-randomization mostly to progression, suggests that improved induction regimens be developed.
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http://dx.doi.org/10.1080/10428194.2018.1563691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620162PMC
August 2019

IRTA1 and MNDA Expression in Marginal Zone Lymphoma: Utility in Differential Diagnosis and Implications for Classification.

Am J Clin Pathol 2019 02;151(3):337-343

Department of Laboratory Medicine, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH.

Objectives: To evaluate the clinical utility of immune receptor translocation-associated protein 1 (IRTA1) and myeloid nuclear differentiation antigen (MNDA) expression in the diagnosis and classification of marginal zone lymphomas (MZLs).

Methods: IRTA1 was examined using a novel RNA in situ hybridization assay and MNDA expression determined by immunohistochemistry in 127 small B-cell neoplasms, including 80 cases of MZL.

Results: IRTA1 expression was detected in 31 (42%) of 74 MZLs vs one (2%) of 43 other small B-cell neoplasms (P < .001). MNDA staining was positive in 51 (64%) of 79 MZLs vs 21 (45%) of 46 non-MZLs (P = .06). MNDA expression was particularly uncommon in follicular lymphoma (3/14, 21%; P = .003 vs MZL). There was no association between MNDA and IRTA1 expression and the presence of monocytoid cytology. IRTA1 expression was less frequent in cases with a diffuse growth pattern.

Conclusions: IRTA1 and MNDA are useful markers in the differential diagnosis of MZLs.
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http://dx.doi.org/10.1093/ajcp/aqy144DOI Listing
February 2019

Molecular classification of primary mediastinal large B-cell lymphoma using routinely available tissue specimens.

Blood 2018 11 26;132(22):2401-2405. Epub 2018 Sep 26.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ.

Primary mediastinal large B-cell lymphoma (PMBCL) is recognized as a distinct entity in the World Health Organization classification. Currently, the diagnosis relies on consensus of histopathology, clinical variables, and presentation, giving rise to diagnostic inaccuracy in routine practice. Previous studies have demonstrated that PMBCL can be distinguished from subtypes of diffuse large B-cell lymphoma (DLBCL) based on gene expression signatures. However, requirement of fresh-frozen biopsy material has precluded the transfer of gene expression-based assays to the clinic. Here, we developed a robust and accurate molecular classification assay (Lymph3Cx) for the distinction of PMBCL from DLBCL subtypes based on gene expression measurements in formalin-fixed, paraffin-embedded tissue. A probabilistic model accounting for classification error, comprising 58 gene features, was trained on 68 cases of PMBCL and DLBCL. Performance of the model was subsequently evaluated in an independent validation cohort of 158 cases and showed high agreement of the Lymph3Cx molecular classification with the clinicopathological diagnosis of an expert panel (frank misclassification rate, 3.8%). Furthermore, we demonstrate reproducibility of the assay with 100% concordance of subtype assignments at 2 independent laboratories. Future studies will determine Lymph3Cx's utility for routine diagnostic purposes and therapeutic decision making.
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http://dx.doi.org/10.1182/blood-2018-05-851154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265647PMC
November 2018

Natural Environments Near Schools: Potential Benefits for Socio-Emotional and Behavioral Development in Early Childhood.

Am J Community Psychol 2018 12 17;62(3-4):419-432. Epub 2018 Sep 17.

University of North Carolina at Charlotte, Charlotte, NC, USA.

Features of the natural environment such as tree canopy and green space have been found to promote health and well-being; however, minimal research has investigated potential benefits of nature near schools for early childhood development. This study examined differences in teacher ratings of preschoolers' socio-emotional and behavioral functioning in relation to the presence of natural elements (e.g., trees, parks) near children's homes and schools. Students' development of emotional and behavioral regulatory skills was the greatest when there were high levels of tree canopy either at home or school. Additionally, students developed greater independence and social skills when their schools were in neighborhoods with limited impervious surface (e.g., concrete); this trend was the most pronounced for students from neighborhoods low in impervious surface. Further, results suggested that associations with tree canopy may fluctuate seasonally (i.e., stronger relationships in the spring) and that the potential impact of school nature may depend on levels of home nature exposure. Although not yielding causal evidence regarding the impact of nature exposure or the effectiveness of greening interventions, findings suggest that school administrators and city planners could collaborate to maximize potential benefits of greening efforts near schools or within their catchment zones.
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http://dx.doi.org/10.1002/ajcp.12272DOI Listing
December 2018

Development of a Behavioral Health Stigma Measure and Application of Machine Learning for Classification.

Innov Clin Neurosci 2018 Jun;15(5-6):34-42

Drs. Tokmic and Hadzikadic are with the Department of Software & Information Systems at the University of North Carolina, in Charlotte, North Carolina.

Given the growing public health importance of measuring the change in mental health stigma over time, the goal of this study was to demonstrate the potential for using machine learning as a tool to analyze patterns of social stigma as a complement to traditional research methods. A total of 1,904 participants were recruited through Sona Systems, Ltd (Tallinn, Estonia), an experiment management system for online research, to complete a self-reported survey. The collected data were used to develop a new measure of mental (behavioral) health stigma. To build a classification predictive model of stigma, a decision tree was used as the data mining tool, wherein a set of classification rules was generated and tested for its ability to examine the prevalence of stigma. A three-factor stigma model was supported and confirmed. Results indicate that the measure is content-valid and internally consistent. Performance evaluation of the machine learning-based classification algorithm revealed a sufficient inter-rater reliability with a predictive accuracy of 92.4 percent. This study illustrates the potential for applying machine learning to derive a data-driven understanding of the extent to which stigma is prevalent in society. It establishes a framework for the development of an index to track stigma over time and to assist healthcare decision-makers with improving the health of populations and the experience of care for patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040723PMC
June 2018

Brain-targeted stem cell gene therapy corrects mucopolysaccharidosis type II via multiple mechanisms.

EMBO Mol Med 2018 07;10(7)

Stem Cell and Neurotherapies, Division of Cell Matrix Biology & Regenerative Medicine, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK

The pediatric lysosomal storage disorder mucopolysaccharidosis type II is caused by mutations in IDS, resulting in accumulation of heparan and dermatan sulfate, causing severe neurodegeneration, skeletal disease, and cardiorespiratory disease. Most patients manifest with cognitive symptoms, which cannot be treated with enzyme replacement therapy, as native IDS does not cross the blood-brain barrier. We tested a brain-targeted hematopoietic stem cell gene therapy approach using lentiviral IDS fused to ApoEII (IDS.ApoEII) compared to a lentivirus expressing normal IDS or a normal bone marrow transplant. In mucopolysaccharidosis II mice, all treatments corrected peripheral disease, but only IDS.ApoEII mediated complete normalization of brain pathology and behavior, providing significantly enhanced correction compared to IDS. A normal bone marrow transplant achieved no brain correction. Whilst corrected macrophages traffic to the brain, secreting IDS/IDS.ApoEII enzyme for cross-correction, IDS.ApoEII was additionally more active in plasma and was taken up and transcytosed across brain endothelia significantly better than IDS via both heparan sulfate/ApoE-dependent receptors and mannose-6-phosphate receptors. Brain-targeted hematopoietic stem cell gene therapy provides a promising therapy for MPS II patients.
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http://dx.doi.org/10.15252/emmm.201708730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034129PMC
July 2018

Identification of "Double Hit" Lymphomas Using Updated WHO Criteria: Insights From Routine MYC Immunohistochemistry in 272 Consecutive Cases of Aggressive B-Cell Lymphomas.

Appl Immunohistochem Mol Morphol 2019 07;27(6):410-415

Department of Laboratory Medicine, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH.

Aggressive lymphomas with MYC and BCL2 and/or BCL6 translocations ("double hit" lymphomas, DHL) represent a distinct diagnostic category in the updated World Health Organization (WHO) classification. The diagnostic yield of MYC immunohistochemistry (IHC) for the identification of DHL is currently uncertain. MYC IHC was performed in 272 consecutive cases of aggressive B-cell lymphoma, and results correlated with fluorescence in situ hybridization (FISH) for MYC translocations. Among 156 patients with IHC and FISH data, MYC IHC identified MYC translocations with 89% sensitivity, 38% specificity, 92% negative predictive value, and 29% positive predictive value. Three of 15 (20%) of DHL were MYC IHC negative. One case contained a MYC translocation detectable IGH/MYC fusion probes but not MYC break-apart probes. A subset of DHL lack MYC protein expression, and recognition of this subset of cases requires FISH testing. These results provide an appropriate diagnostic algorithm for implementation of 2016 WHO diagnostic criteria.
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http://dx.doi.org/10.1097/PAI.0000000000000657DOI Listing
July 2019

Tandem Autologous Hematopoietic Cell Transplantation for Patients with Primary Progressive or Recurrent Hodgkin Lymphoma: A SWOG and Blood and Marrow Transplant Clinical Trials Network Phase II Trial (SWOG S0410/BMT CTN 0703).

Biol Blood Marrow Transplant 2018 04 28;24(4):700-707. Epub 2017 Dec 28.

Hematology/Oncology, Loyola University Medical Center, Maywood, Illinois.

Based on promising pilot data a phase II tandem autologous hematopoietic stem cell transplant (AHSCT) trial for relapsed/refractory Hodgkin lymphoma (HL) was performed in the US intergroup setting to determine if long-term progression-free survival (PFS) could be improved. Patients were enrolled after salvage therapy and stem cell collection. Sensitivity to salvage was defined by 1999 Standardized Response Criteria and did not include fluorodeoxyglucose-positron emission tomography. Cycle 1 consisted of melphalan 150 mg/m with half of the stem cells. For stable disease or better, patients received cycle 2 consisting of single doses of etoposide 60 mg/kg and cyclophosphamide 100 mg/kg and either total body radiation 12 Gy in 8 fractions over 4 days or BCNU 150 mg/m/day for 3 days with the remaining stem cells. Of 98 enrolled patients, 89 were eligible and treated: 82 completed both cycles of AHSCT, 47 (53%) had primary refractory HL, and 72 (81%) were resistant to salvage therapy. There were no treatment-related deaths in the first year after AHSCT. With a median follow-up of 6.2 years (range, 2 to 7.7) for eligible patients who remained alive, the 2-year and 5-year PFS were 63% (95% CI, 52% to 72%) and 55% (95% CI, 44% to 64%) respectively; the 2-year and 5-year overall survival were 91% (95% CI, 83% to 95%) and 84% (95% CI, 74% to 90%), respectively. Univariate Cox regression analysis showed Zubrod performance status and lactate dehydrogenase levels > 1 times upper limit of normal at the time of enrollment were significantly associated with PFS. The observed 5-year PFS of 55% suggests the tandem approach appears to be effective in treating HL patients demonstrated to have poor prognosis in prior single AHSCT trials. This trial was registered at www.clinicaltrials.gov as NCT00233987.
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http://dx.doi.org/10.1016/j.bbmt.2017.12.798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5965270PMC
April 2018

Ultrasensitive automated RNA in situ hybridization for kappa and lambda light chain mRNA detects B-cell clonality in tissue biopsies with performance comparable or superior to flow cytometry.

Mod Pathol 2018 03 20;31(3):385-394. Epub 2017 Oct 20.

Department of Laboratory Medicine, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.

The assessment of B-cell clonality is a critical component of the evaluation of suspected lymphoproliferative disorders, but analysis from formalin-fixed, paraffin-embedded tissues can be challenging if fresh tissue is not available for flow cytometry. Immunohistochemical and conventional bright field in situ hybridization stains for kappa and lambda are effective for evaluation of plasma cells but are often insufficiently sensitive to detect the much lower abundance of light chains present in B-cells. We describe an ultrasensitive RNA in situ hybridization assay that has been adapted for use on an automated immunohistochemistry platform and compare results with flow cytometry in 203 consecutive tissues and 104 consecutive bone marrows. Overall, in 203 tissue biopsies, RNA in situ hybridization identified light chain-restricted B-cells in 85 (42%) vs 58 (29%) by flow cytometry. Within 83 B-cell non-Hodgkin lymphomas, RNA in situ hybridization identified restricted B-cells in 74 (89%) vs 56 (67%) by flow cytometry. B-cell clonality could be evaluated in only 23/104 (22%) bone marrow cases owing to poor RNA preservation, but evaluable cases showed 91% concordance with flow cytometry. RNA in situ hybridization allowed for recognition of biclonal/composite lymphomas not identified by flow cytometry and highlighted unexpected findings, such as coexpression of kappa and lambda RNA in 2 cases and the presence of lambda light chain RNA in a T lymphoblastic lymphoma. Automated RNA in situ hybridization showed excellent interobserver reproducibility for manual evaluation (average K=0.92), and an automated image analysis system showed high concordance (97%) with manual evaluation. Automated RNA in situ hybridization staining, which can be adopted on commonly utilized immunohistochemistry instruments, allows for the interpretation of clonality in the context of the morphological features in formalin-fixed, paraffin-embedded tissues with a clinical sensitivity similar or superior to flow cytometry.
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http://dx.doi.org/10.1038/modpathol.2017.142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5843495PMC
March 2018

Design, Validation, and Clinical Implementation of a Gap-Polymerase Chain Reaction Method for α-Thalassemia Genotyping Using Capillary Electrophoresis.

Hemoglobin 2017 Mar 9;41(2):124-130. Epub 2017 Jun 9.

a Robert J. Tomsich Pathology and Laboratory Medicine Institute , Cleveland Clinic , Cleveland , OH , USA.

α-Thalassemia (α-thal) is genetically heterogeneous with most cases caused by variably sized deletions of the HBA1 and/or HBA2 loci. In this report, we describe the development, validation, and implementation of a novel gap-polymerase chain reaction (gap-PCR)/capillary electrophoresis (CE).

Method: This assay utilizes two multiplex reactions and CE to detect the following deletions: -α (rightward), -α (leftward), -(α), - - (Southeast Asian), - -, - - and - -. Validation studies using 36 previously characterized patient samples and plasmid controls demonstrated 100.0% accuracy. Following clinical implementation, 423 patients were analyzed over 24 months. Two hundred and twenty-seven cases (46.0%) showed abnormal results including heterozygous -α (n = 114, 27.0%), homozygous -α (n = 96, 23.0%), heterozygous - - (n = 9, 2.0%), heterozygous -α (n = 5, 1.0%), heterozygous - - (n = 1, <1.0%), and compound heterozygous -α/-α (n = 2, <1.0%) deletions. Correlation with red blood cell (RBC) parameters showed that patients with a deletion of two or more genes were associated with significantly lower mean corpuscular volume (MCV) and mean corpuscular hemoglobin (Hb) (MCH) levels than patients with wild-type results. This novel multiplex gap-PCR protocol reliably detects the seven most common deletions giving rise to α-thal. Use of the fluorescently labeled CE method provides for a high throughput workflow suitable to a clinical diagnostic laboratory serving a multiethnic population.
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http://dx.doi.org/10.1080/03630269.2017.1327868DOI Listing
March 2017

What Is the Clinical Utility of Repeat SNP Array Testing in the Follow-up of Myeloid Neoplasms?: A Retrospective Analysis of 44 Patients With Serial SNP Arrays.

Am J Clin Pathol 2017 Mar;147(3):278-284

From the Department of Laboratory Medicine, Cleveland Clinic, Cleveland, OH.

Objectives: Single-nucleotide polymorphism (SNP) arrays have been shown to identify cytogenetic abnormalities in myeloid neoplasms that may be missed by metaphase cytogenetics alone at initial diagnosis. This study examines the utility of serial SNP arrays in follow-up testing of myeloid neoplasms.

Methods: We retrospectively reviewed results of SNP array testing in 44 patients with myeloid neoplasms and more than one SNP array study (n = 133 SNP arrays total; median, three per patient; range, two to eight per patient).

Results: Baseline abnormalities were identified by SNP array in 35 (79%) of 44 (79%) compared with 18 (50%) of 36 by metaphase karyotype. In follow-up studies, clonal evolution was found by both SNP array and karyotyping in seven (15.9%), by metaphase karyotyping alone in six (13.6%), and SNP arrays alone in two (4.5%). Overall survival was not significantly different between patients with or without clonal evolution detected by SNP array.

Conclusions: This study, the first systematic examination of serial SNP arrays in myeloid neoplasms, confirms the clinical utility of SNP arrays at initial diagnosis but shows that clonal evolution of the karyotype can be detected by metaphase cytogenetics alone in most patients. Follow-up SNP array testing is not required in routine clinical use in most cases.
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http://dx.doi.org/10.1093/ajcp/aqx003DOI Listing
March 2017

PDCD1LG2 (PD-L2) RNA in situ hybridization is a sensitive, specific, and practical marker of primary mediastinal large B-cell lymphoma.

Br J Haematol 2018 05 3;181(4):564-566. Epub 2017 Apr 3.

Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.

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http://dx.doi.org/10.1111/bjh.14670DOI Listing
May 2018

New Molecular Assay for the Proliferation Signature in Mantle Cell Lymphoma Applicable to Formalin-Fixed Paraffin-Embedded Biopsies.

J Clin Oncol 2017 May 14;35(15):1668-1677. Epub 2017 Mar 14.

David W. Scott, Pau Abrisqueta, Graham W. Slack, Anja Mottok, Diego Villa, Merrill Boyle, Fong Chun Chan, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, BC Cancer Agency; Anja Mottok, Christian Steidl, and Randy D. Gascoyne, University of British Columbia, Vancouver, British Columbia; Jan Delabie, University of Toronto, Toronto, Ontario, Canada; Pau Abrisqueta, Vall d'Hebron University Hospital; Pedro Jares, Cristina Royo, Guillem Clot, Magda Pinyol, and Elias Campo, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; George W. Wright, Elaine S. Jaffe, and Louis M. Staudt, National Institutes of Health, Bethesda, MD; Hilka Rauert-Wunderlich and Andreas Rosenwald, University of Würzburg, Würzburg; German Ott, Robert Bosch Hospital and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; Rita M. Braziel, Oregon Health & Sciences University, Portland, OR; Wing C. Chan and Dennis D. Weisenburger, City of Hope, Duarte, CA; James R. Cook, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH; Timothy C. Greiner and Kai Fu, University of Nebraska Medical Center, Omaha, NE; Erlend B. Smeland and Harald Holte, Oslo University Hospital, Oslo, Norway; and Lisa M. Rimsza, Mayo Clinic, Phoenix, AZ.

Purpose Mantle cell lymphoma is an aggressive B-cell neoplasm that displays heterogeneous outcomes after treatment. In 2003, the Lymphoma/Leukemia Molecular Profiling Project described a powerful biomarker-the proliferation signature-using gene expression in fresh frozen material. Herein, we describe the training and validation of a new assay that measures the proliferation signature in RNA derived from routinely available formalin-fixed paraffin-embedded (FFPE) biopsies. Methods Forty-seven FFPE biopsies were used to train an assay on the NanoString platform, using microarray gene expression data of matched fresh frozen biopsies as a gold standard. The locked assay was applied to pretreatment FFPE lymph node biopsies from an independent cohort of 110 patients uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. Seventeen biopsies were tested across three laboratories to assess assay reproducibility. Results The MCL35 assay, which contained a 17-gene proliferation signature, yielded gene expression of sufficient quality to assign an assay score and risk group in 108 (98%) of 110 archival FFPE biopsies. The MCL35 assay assigned patients to high-risk (26%), standard-risk (29%), and low-risk (45%) groups, with different lengths of overall survival (OS): a median of 1.1, 2.6, and 8.6 years, respectively (log-rank for trend, P < .001). In multivariable analysis, these risk groups and the Mantle Cell Lymphoma International Prognostic Index were independently associated with OS ( P < .001 for both variables). Concordance of risk assignment across the three independent laboratories was 100%. Conclusion The newly developed and validated MCL35 assay for FFPE biopsies uses the proliferation signature to define groups of patients with significantly different OS independent of the Mantle Cell Lymphoma International Prognostic Index. Importantly, the analytic and clinical validity of this assay defines it as a reliable biomarker to support risk-adapted clinical trials.
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http://dx.doi.org/10.1200/JCO.2016.70.7901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455765PMC
May 2017

Langerhans Cell Histiocytosis Shows Distinct Cytoplasmic Expression of Major Histocompatibility Class II Antigens.

J Hematop 2016 Sep 10;9(3):107-112. Epub 2016 Mar 10.

Department of Laboratory Medicine and Pathology, Mayo Clinic, AZ.

Objectives: Langerhans cell histiocytosis (LCH) is a monoclonal proliferation of antigen presenting cells (APC). In benign APCs, antigen loading occurs in the Major Histocompatibility class II (MHCII)-lysosomal compartment of the endocytic pathway followed by transport to the cell surface upon antigen stimulation. The pattern of MHC II expression in LCH is not well characterized.

Methods: The cellular localization of MHCII was determined using immunohistochemisty (IHC). Staining pattern for the representative MHCII molecule, HLA-DR, (cell surface, cytoplasmic granular, or cytoplasmic globular) and intensity (0 to 3+) were recorded for normal tissues and 44 LCH samples along with available clinicopathologic features. Results were confirmed with a different antibody to confirm the appearance.

Results: In the normal tissue survey, strong HLA-DR cell surface expression was present on APCs, benign B cells, some T cells, and pulmonary macrophages. A granular cytoplasmic staining pattern (without surface expression) was seen in benign Langerhans cells (LCs) in the skin and histiocytes. Strikingly, all 44 LCH samples demonstrated both cytoplasmic granular and an unusual "globular" staining pattern with no surface staining.

Conclusion: This is the first report of a highly specific HLA-DR staining pattern in LCH detected by IHC. The cytoplasmic perinuclear globular localization of MHCII may possibly be useful in diagnostics and may result from an immature/antigen-naïve differentiation state of the neoplastic cell.
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http://dx.doi.org/10.1007/s12308-016-0272-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191044PMC
September 2016

pSTAT3/pSTAT5 Signaling Patterns in Molecularly Defined Subsets of Myeloproliferative Neoplasms.

Appl Immunohistochem Mol Morphol 2018 Feb;26(2):147-152

Department of Laboratory Medicine, Cleveland Clinic, Cleveland, OH.

BCR/ABL1-negative myeloproliferative neoplasms (MPNs) are characterized by recurrent mutations in JAK2, CALR, and MPL, each of which has been reported to alter JAK/STAT signaling pathways. This report characterizes JAK/STAT signaling patterns in molecularly defined subsets of MPN utilizing immunohistochemistry for pSTAT3 and pSTAT5. Analysis of 30 BCR/ABL1-negative, nonpolycythemia vera MPN identified 15 (50%) with JAK2 V617F, 2 with MPL mutations (7%), and 8 with CALR mutations (27%). All mutations were mutually exclusive, except for 1 case with concurrent JAK2 V617F and CALR mutations. pSTAT3 staining in megakaryocyte nuclei was found in 4 cases (13%) and was not significantly associated with mutation status. pSTAT5 staining in megakaryocyte nuclei was found in 16 cases (53%), as was significantly associated with JAK2 V617F versus CALR mutation (P=0.009). Erythroid staining for pSTAT5 was seen exclusively in "triple-negative (TN)" cases lacking JAK2 V617F, MPL, and CALR mutations (P=0.006, TN vs. other genotypes), and pSTAT5 staining in megakaryocyte nuclei was seen in 2 TN cases. pSTAT5 staining in TN MPN suggests that other unknown abnormalities in this pathway may contribute to the pathogenesis of these cases. Furthermore, the demonstration of distinct STAT staining patterns in molecularly defined MPN suggests that these mutations result in divergent signaling events that may contribute to the biological and prognostic differences in these molecular subsets of MPN.
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http://dx.doi.org/10.1097/PAI.0000000000000391DOI Listing
February 2018

Outcomes of MYC-associated lymphomas after R-CHOP with and without consolidative autologous stem cell transplant: subset analysis of randomized trial intergroup SWOG S9704.

Br J Haematol 2016 Sep 13;174(5):686-91. Epub 2016 Apr 13.

University of Chicago, Chicago, IL, USA.

Double hit lymphoma (DHL) and double protein-expressing (MYC, BCL2) lymphomas (DPL) fare poorly with R-CHOP (rituximab + cyclophosphamide, doxorubicin, vincristine, prednisolone); consolidative autologous stem cell transplant (ASCT) may improve outcomes. S9704, a phase III randomized study of CHOP +/-R with or without ASCT enabled evaluation of intensive consolidation. Immunohistochemistry (IHC) identified 27 of 198 patients (13·6%) with MYC overexpression; 20 (74%) harboured concurrent BCL2 overexpression. Four had DHL and 16 had DPL only. With median 127 months follow-up, there is a trend favouring outcomes after ASCT in DPL and MYC protein overexpressing patients, whereas all DHL patients have died irrespective of ASCT.
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http://dx.doi.org/10.1111/bjh.14100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125530PMC
September 2016

US Intergroup Trial of Response-Adapted Therapy for Stage III to IV Hodgkin Lymphoma Using Early Interim Fluorodeoxyglucose-Positron Emission Tomography Imaging: Southwest Oncology Group S0816.

J Clin Oncol 2016 06 11;34(17):2020-7. Epub 2016 Apr 11.

Oliver W. Press, Fred Hutchinson Cancer Research Center, and the University of Washington; Hongli Li and Michael LeBlanc, Fred Hutchinson Cancer Research Center, Seattle, WA; Heiko Schöder, David J. Straus, Craig H. Moskowitz, and Ariela Noy, Memorial Sloan Kettering Cancer Center; John P. Leonard, Weill Cornell Medical College and New York Presbyterian Hospital, New York City; Paul M. Barr and Jonathan W. Friedberg, University of Rochester Medical Center, Rochester, NY; Lisa M. Rimsza, University of Arizona, Tucson, AZ; Nancy L. Bartlett and Brad S. Kahl, Washington University School of Medicine, St. Louis, MO; Andrew M. Evens, Tufts Medical Center; Ann S. LaCasce, Dana-Farber Cancer Institute, Boston, MA; Erik S. Mittra, Stanford University Medical Center, Stanford, CA; John W. Sweetenham, Huntsman Cancer Hospital, Salt Lake City, UT; Michelle A. Fanale, University of Texas MD Anderson Cancer Center, Houston, TX; Michael V. Knopp, The Ohio State University, Columbus; Eric D. Hsi, Cleveland Clinic Foundation; James R. Cook, Cleveland Clinic, Cleveland, OH; Mary Jo Lechowicz, Winship Cancer Institute of Emory University, Atlanta, GA; Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, BC; Bruce D. Cheson, Georgetown University Hospital, Washington DC; and Richard I. Fisher, Fox Chase Cancer Center, Philadelphia, PA.

Purpose: Four US National Clinical Trials Network components (Southwest Oncology Group, Cancer and Leukemia Group B/Alliance, Eastern Cooperative Oncology Group, and the AIDS Malignancy Consortium) conducted a phase II Intergroup clinical trial that used early interim fluorodeoxyglucose positron emission tomography (FDG-PET) imaging to determine the utility of response-adapted therapy for stage III to IV classic Hodgkin lymphoma.

Patients And Methods: The Southwest Oncology Group S0816 (Fludeoxyglucose F 18-PET/CT Imaging and Combination Chemotherapy With or Without Additional Chemotherapy and G-CSF in Treating Patients With Stage III or Stage IV Hodgkin Lymphoma) trial enrolled 358 HIV-negative patients between July 1, 2009, and December 2, 2012. A PET scan was performed after two initial cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and was labeled PET2. PET2-negative patients (Deauville score 1 to 3) received an additional four cycles of ABVD, whereas PET2-positive patients (Deauville score 4 to 5) were switched to escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) for six cycles. Among 336 eligible and evaluable patients, the median age was 32 years (range, 18 to 60 years), with 52% stage III, 48% stage IV, 49% International Prognostic Score 0 to 2, and 51% score 3 to 7.

Results: Three hundred thirty-six of the enrolled patients were evaluable. Central review of the interim PET2 scan was performed in 331 evaluable patients, with 271 (82%) PET2-negative and 60 (18%) PET2-positive. Of 60 eligible PET2-positive patients, 49 switched to eBEACOPP as planned and 11 declined. With a median follow-up of 39.7 months, the Kaplan-Meier estimate for 2-year overall survival was 98% (95% CI, 95% to 99%), and the 2-year estimate for progression-free survival (PFS) was 79% (95% CI, 74% to 83%). The 2-year estimate for PFS in the subset of patients who were PET2-positive after two cycles of ABVD was 64% (95% CI, 50% to 75%). Both nonhematologic and hematologic toxicities were greater in the eBEACOPP arm than in the continued ABVD arm.

Conclusion: Response-adapted therapy based on interim PET imaging after two cycles of ABVD seems promising with a 2-year PFS of 64% for PET2-positive patients, which is much higher than the expected 2-year PFS of 15% to 30%.
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http://dx.doi.org/10.1200/JCO.2015.63.1119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966513PMC
June 2016