Stephanie Mathews

Expression of six drug transporters in vaginal, cervical, and colorectal tissues: Implications for drug disposition in HIV prevention.

Effective antiretroviral (ARV)‐based HIV prevention strategies require optimizing drug exposure in mucosal tissues; yet factors influencing mucosal tissue disposition remain unknown. We hypothesized drug transporter expression in vaginal, cervical, and colorectal tissues is a contributing factor and selected 3 efflux (ABCB1/MDR1, ABCC2/MRP2, ABCC4/MRP4) and 3 uptake (SLC22A6/OAT1, SLC22A8/OAT3, SLCO1B1/OATP1B1) transporters to further investigate based on their affinity for 2 ARVs central to prevention (tenofovir, maraviroc). Tissue was collected from 98 donors. mRNA and protein expression were quantified using qPCR and immunohistochemistry (IHC). Hundred percent of tissues expressed efflux transporter mRNA. IHC localized them to the epithelium and/or submucosa. Multivariable analysis adjusted for age, smoking, and co‐medications revealed significant (P < 0.05) differences in efflux transporter mRNA between tissue types (vaginal ABCB1 3.9‐fold > colorectal; vaginal ABCC2 2.9‐fold > colorectal; colorectal ABCC4 2.0‐fold > cervical). In contrast, uptake transporter mRNA was expressed in <25% of tissues. OAT1 protein was detected in 0% of female genital tissues and in 100% of colorectal tissues, but only in rare epithelial cells. These data support clinical findings of higher maraviroc and tenofovir concentrations in rectal tissue compared to vaginal or cervical tissue after oral dosing. Quantifying mucosal transporter expression and localization can facilitate ARV selection to target these tissues.

Performance Comparison of Capillary and Agarose Gel Electrophoresis for the Identification and Characterization of Monoclonal Immunoglobulins

The objective of this study was to compare gel- and capillary-based serum protein electrophoresis methods to identify and characterize monoclonal immunoglobulins (M proteins). Five reviewers interpreted 149 consecutively ordered serum specimens following agarose gel electrophoresis (AGE), capillary electrophoresis (CE), immunofixation electrophoresis (IFE), and subtraction immunotyping (IT). As a screening test for detecting M proteins, AGE and CE displayed similar sensitivity (91% and 92%, respectively). CE was less specific (74%) than AGE (81%). An analysis of interinterpreter agreement revealed that interpretations were more consistent using gel-based methods than capillary-based methods, with 80% of the gel interpretations being in complete (5/5) agreement compared with 67% of the capillary interpretations. After implementing the capillary-based methods, the number of tests per reportable result increased (from 1.58 to 1.73). CE is an analytically suitable alternative to AGE, but laboratories implementing it will need to continue IFE testing to characterize all M proteins detected by CE.

Karyotypic abnormalities associated with Epstein-Barr virus status in classical Hodgkin lymphoma.

Classical Hodgkin lymphoma (CHL) is morphologically characterized by scattered malignant Hodgkin/Reed-Sternberg (HRS) cells that are far outnumbered by surrounding reactive hematolymphoid cells. Approximately half of all cases of CHL are associated with infection by Epstein-Barr virus (EBV), an oncogenic herpesvirus that expresses a number of proteins thought to contribute to transformation. While a small number of published studies have attempted to identify recurrent cytogenetic abnormalities in CHL, no large case series have explored karyotypic differences between EBV-positive and EBV-negative tumors. Here, we report a two-institution retrospective investigation of cytogenetic features characterizing CHL. In our cohort, cases of EBV-negative CHL were characterized by more complex routine karyotypes than their EBV-positive counterparts (24.6 versus 15.6 independent aberrations per case, P = 0.009). The increased complexity of EBV-negative cases was driven by a number of features suggestive of genomic instability, including a larger number of independent chromosomal breakpoints (P = 0.03) and apparently aneuploid autosomes (P = 0.008). Compelling but nonsignificant trends also suggest a larger modal number and increased marker chromosomes in EBV-negative cases (P = 0.13 and 0.06, respectively). While some of these differences are related to histologic subtype, others appear independent of histology. Finally, a significant subset of EBV-positive tumors has a surprisingly simple karyotype relative to what is normally seen in CHL, an observation suggesting considerable biological and genetic diversity in this disease.

Human herpesvirus 6 lymphadenitis in drug rash with eosinophilia and systemic symptoms syndrome: a lymphoma mimic

Lymphadenopathy, haematological abnormalities and constitutional symptoms are among the non‐specific manifestations seen in drug rash with eosinophilia and systemic symptoms (DRESS), an uncommon but potentially fatal cutaneous adverse drug reaction. The ubiquitous human herpesvirus 6 (HHV‐6) plays a unique role in the pathogenesis of DRESS, with emerging data suggesting that reactivation occurs in most cases and contributes to the clinical manifestations, including lymphadenopathy. Further, in the appropriate clinical context, demonstration of HHV‐6 reactivation may lend support to a diagnosis of DRESS. The histopathology of DRESS‐associated HHV‐6 lymphadenitis is reported rarely, with morphologic and immunophenotypic characteristics concerning for T cell lymphoma. The aim is to characterize the histopathology of HHV‐6 lymphadenitis in the context of DRESS and to highlight this as an important cause of lymphadenopathy that may be a clinical, morphologic and immunophenotypic mimic of lymphoma.

Transformation in Low-grade B-cell Neoplasms.

Low-grade B-cell leukemias/lymphomas are a diverse group of indolent lymphoproliferative disorders that are typically characterized by good patient outcomes and long life expectancies. A subset of cases, however, undergo histologic transformation to a higher-grade neoplasm, a transition associated with a more aggressive clinical course and poor survival. Transformation of follicular lymphoma to diffuse large B-cell lymphoma and Richter transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma are best characterized in the literature. This article reviews clinical and pathologic characteristics of these most common forms of transformation, with an emphasis on salient histologic, immunophenotypic, and genetic features.

Complex karyotype in patients with mantle cell lymphoma predicts inferior survival and poor response to intensive induction therapy

Risk stratification of newly diagnosed patients with mantle cell lymphoma (MCL) primarily is based on the MCL International Prognostic Index (MIPI) and Ki‐67 proliferative index. Single‐center studies have reported inferior outcomes in patients with a complex karyotype (CK), but this remains an area of controversy.

Deferred treatment is a safe and viable option for selected patients with mantle cell lymphoma.

Abstract Prospective identification of candidates for deferred therapy is not standardized and many patients receive immediate therapy regardless of risk. We conducted a retrospective, multi-center cohort analysis of MCL patients with comprehensive clinical data to examine the use and safety of deferred therapy for newly diagnosed patients. Previously untreated patients ≥18 years-old with MCL diagnosed in 1993–2015 at five academic sites were included. Of 395 patients, 72 (18%) received deferred therapy (defined as receipt of first treatment >90 days following initial diagnosis). Patients receiving deferred therapy were more likely to have an ECOG performance status of 0 (67 versus 44% p = .001), have no B symptoms (83 versus 65% p = .003) and have normal LDH levels at diagnosis (87 versus 55% p < .001). In multivariable analysis, deferred therapy was not associated with a significant difference in OS (HR 0.64: 95% CI 0.22–1.84, p = .407).

Acute promyelocytic leukemia and chronic lymphocytic leukemia diagnosed concurrently

A 57-year-old male with history of type 2 diabetes presented with 2 weeks of malaise and hyperglycemia. Complete blood counts were notable for a newly elevated WBC count of 58.3 3 10/L with 62% abnormal promyelocytes and 16% lymphocytes, hemoglobin of 11.2 g/dL, and platelet count of 60 310/L (Image 1, panel A, original magnification 31000, Wright–Giemsa stain). Coagulation testing IMAGE 1 Histopathologic findings of concurrent microgranular APL and CLL. A. Peripheral blood smear showed circulating matureappearing lymphocytes and abnormal promyelocytes (Wright-Giemsa; 10003). B–F. Bone marrow biopsy demonstrated presence of both microgranular APL and CLL. Panel B: Wright-Giemsa at 4003; Panel C: Hematoxylin and eosin at 4003; Panel D: CD117 at 4003; Panel E: Pax-5 at 4003; and Panel F: CD5 at 4003.

Clonal karyotypic abnormalities associated with reactive lymphoid hyperplasia

Cytogenetic abnormalities are important in the diagnosis and prognosis of hematolymphoid neoplasms. Although many recurrent karyotypic abnormalities are well-defined and known to underlie pathophysiologic processes contributing to malignancy, the significance of other cytogenetic changes is less clear. This uncertainty reflects an incomplete understanding of the frequency with which karyotypic abnormalities arise in benign processes. Numerous case reports and a small number of retrospective series have noted clonal cytogenetic changes in association with reactive-appearing lymph nodes. However, the incidence of such abnormalities has varied widely in published series. Here, we report the largest retrospective series of karyotypic abnormalities in association with reactive lymphoid hyperplasia published to date. Clonal karyotypic abnormalities were present in 6.3% of reactive lymph nodes with informative karyotypes and 5.1% of all reactive lymphoid tissues. These data suggest that karyotypic abnormalities are less frequently found in association with reactive lymphoid tissue than previously reported and provide a clearer picture of the baseline incidence of cytogenetic changes in benign lymphoid processes.