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Matthew J Maurer,
Ivana N M Micallef,
James R Cerhan,
Jerry A Katzmann,
Brian K Link,
Joseph P Colgan,
Thomas M Habermann,
David J Inwards,
Svetomir N Markovic,
Stephen M Ansell,
Luis F Porrata,
Patrick B Johnston,
Grzegorz S Nowakowski,
Carrie A Thompson,
Mamta Gupta, Sergei I Syrbu,
Paul J Kurtin,
William R Macon,
Daniel A Nikcevich,
Thomas E Witzig
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ABSTRACT: The serum free light chain (FLC) assay quantitates free kappa (κ) and free lambda (λ) immunoglobulin light chains. This assay has prognostic value in plasma cell proliferative disorders. There are limited data on serum FLC in B-cell malignancies.
The association of pretreatment FLC with event-free survival (EFS) and overall survival (OS) in diffuse large B-cell lymphoma (DLBCL) was evaluated in 76 patients from the North Central Cancer Treatment Group trial N0489 (NCT00301821) and 219 patients from the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource (MER). Published reference ranges were used to define an elevated FLC or an abnormal κ:λ FLC ratio.
Elevated FLC or abnormal κ:λ FLC ratio was present in 32% and 14% of patients, respectively. Patients with elevated FLC had an inferior OS and EFS in both cohorts compared with patients with normal FLC (N0489: EFS hazard ratio [HR], 3.06; OS HR, 3.16; both P < .02; MER: EFS HR, 2.42; OS HR, 3.40; both P < .001; combined EFS HR, 2.57; OS HR, 3.74; both P < .001). All associations remained significant for EFS and OS after adjusting for the International Prognostic Index (IPI). Abnormal κ:λ FLC ratio was modestly associated with outcome in the combined group (EFS HR, 1.61; OS HR, 1.67; both P = .07), but not in patients without corresponding elevated κ or λ. Elevated FLC was the strongest predictor of outcome in multivariable models with the IPI components.
Increased serum FLC is an independent, adverse prognostic factor for EFS and OS in DLBCL and warrants further evaluation as a biomarker in DLBCL.
Journal of Clinical Oncology 03/2011; 29(12):1620-6. · 18.37 Impact Factor
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ABSTRACT: Although the topic is somewhat contentious, fine-needle aspiration (FNA) is frequently used in conjunction with flow cytometry (FC) to evaluate lymphoid proliferations. Despite the fact that the FNA and FC are often analyzed independently, no previous large-scale study has independently analyzed FC of FNA specimens. FC reports of 511 FNAs were retrospectively reviewed and FC diagnoses categorized as monoclonal, atypical, normal/reactive, or insufficient cellularity (3.9%). Abnormal immunophenotype was considered a positive test result. "Gold standard" diagnoses were established by histologic examination, treatment based on FNA, or clinical features. In 92.2% (451/489), there was adequate follow-up. The diagnostic accuracy of FC was 88.4%, sensitivity was 85.8%, and specificity was 92.9%. In addition, FC accuracy for classes of non-Hodgkin lymphoma was assessed. We conclude that FC is an independently accurate ancillary test in the evaluation of FNA. However, the presence of false-negative and false-positive cases supports the common practice of correlating FC with cytomorphologic findings even if performed independently.
American Journal of Clinical Pathology 02/2011; 135(2):304-9. · 2.60 Impact Factor
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ABSTRACT: Formalin is the most commonly used fixative for light microscopy because of its preservation of -morphological details. A major adverse effect of formalin fixation is formation of cross-linkages between epitopes (amino acid residues) and unrelated proteins by formaldehyde groups. The great majority of monoclonal and polyclonal antibodies used for immunohistochemical (IHC) staining of formalin-fixed, paraffin-embedded (FFPE) tissues necessitate unmasking antigens for antigen retrieval. There are currently two major antigen-retrieval procedures based on treatment of deparaffinized tissue sections with heat or, less commonly, with enzymatic digestion. The use of various antigen-retrieval solutions and heating sources does not allow standardization of IHC staining and minimalization of interlaboratory discrepancies. We developed a novel modified antigen-retrieval protocol for reversing the effect of -formalin fixation. The key feature of this protocol is treatment of deparaffinized tissue sections at reduced constant heat (97(o)C in a water bath) for 40 min in 25 mM Tris-HCl (pH 8.5), 1 mM EDTA, and 0.05% SDS (Tris-EDTA-SDS) buffer. Sections are then immunostained with primary and secondary antibodies conjugated with polymer-labeled Horse Radish Peroxidase. Compared to conventional antigen-retrieval procedures, this protocol more efficiently reverses the effect of formalin fixation of a wide variety of cellular antigens and in most instances decreases the use of primary antibody by 2-40 times, resulting in cost savings. Moreover, this protocol eliminates the need for using different antigen-retrieval methods in the laboratory, which reduces both time and labor for medical technologists.
Methods in molecular biology (Clifton, N.J.) 01/2011; 717:101-10.
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ABSTRACT: PU.1 is a transcription factor restricted to the hematopoietic system. It is expressed in myeloid lineage and B lymphocytes but is absent in mature T cells and nonhematopoietic cells. Among myeloid lineage-derived cells, PU.1 is overexpressed in monocytes, histiocytes, and dendritic cells. We evaluated PU.1 expression in 78 cases of primary skin neoplasms, including 9 reticulohistiocytomas, 9 Langerhans cell histiocytoses, 7 juvenile xanthogranulomas, 9 fibrous papules, 8 dermatofibromas, 12 dermatofibrosarcoma protuberans, 9 Spitz nevi, and 15 malignant melanomas. Strong nuclear staining for PU.1 was seen in all cases of histiocyte and dendritic cell origin, including 9/9 reticulohistiocytomas, 9/9 Langerhans cell histiocytoses, and 7/7 juvenile xanthogranulomas. No staining for PU.1 was seen in any studied cases of fibrous papules, dermatofibrosarcoma protuberans, dermatofibromas, Spitz nevi, or malignant melanomas. This study indicates that PU.1 is a valuable immunohistochemical marker for identifying cutaneous histiocyte- and dendritic cell-derived lesions. PU.1 staining is easily interpreted due to the sharp nuclear staining as compared with the irregular and often variable cytoplasmic staining seen with CD68.
The American Journal of dermatopathology 08/2009; 31(5):432-5. · 1.30 Impact Factor
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ABSTRACT: Analysis of B-cell-specific transcription factors is useful in understanding of the differentiation-linked phenotype in Hodgkin's as well as in non-Hodgkin's lymphomas. We analyzed the expression profiling of transcription factors Pax-5, Oct-1, Oct-2, BOB.1, and PU.1 in 109 cases, including non-Hodgkin's lymphomas of B- and T-lineage, classical Hodgkin's lymphomas, and nodular lymphocyte predominant Hodgkin's lymphomas. Our study revealed that all transcription factors were universally expressed in all cases of nodular lymphocyte predominant Hodgkin's and variably expressed in non-Hodgkin's lymphomas of B-lineage. Cases of classical Hodgkin's lymphoma variably expressed the Pax-5, Oct-1, Oct-2, and BOB.1. However, in contrast to nodular lymphocyte predominant Hodgkin's lymphoma, the transcription factor PU.1 was consistently absent in all cases of classical Hodgkin's lymphoma. Transcription factors Pax-5, BOB.1, and PU.1 were not detectable in cases of anaplastic large cell lymphoma. However, the Oct-1 was detected in all anaplastic large cells lymphoma cases, indicating that expression of this transcription factor was not restricted to B-lineage lymphoid malignancies. Our findings suggest that inclusion of the PU.1 antibody may prove useful in separating classical Hodgkin's lymphomas from nodular lymphocyte predominant Hodgkin's lymphomas in problematic cases.
Modern Pathology 08/2006; 19(7):1010-8. · 4.79 Impact Factor
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ABSTRACT: We and others have previously described that the androgen-responsive human prostatic carcinoma cell line LNCaP is resistant to TRAIL and that TRAIL-mediated apoptosis in LNCaP is PI3K/Akt-dependent. In this study, we found that LNCaP remained resistant to treatment with TRAIL after androgen deprivation even in the presence of the PI3K/Akt pathway inhibitor wortmannin. This resistance was determined by failure to form the TRAIL-DISC and by decreased TRAIL-R1 and TRAIL-R2 levels after androgen deprivation; the capacity of TRAIL to induce DISC formation was completely restored in the presence of DHT. TRAIL and wortmannin together accelerated processing of caspase-8 on the DISC and apparently the release of caspase-8 from the DISC into the cytoplasm. Surprisingly, we found that wortmannin decreased the total amount of TRAIL-R1, but not TRAIL-R2, in the cells as well as the amount of TRAIL-R1 precipitated by TRAIL. Our data suggest that TRAIL-DISC formation and sensitivity to TRAIL treatment are androgen-dependent in LNCaP.
Cancer biology & therapy 1(6):631-7. · 2.64 Impact Factor
