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* Context.--Large B-cell lymphomas represent the most common non-Hodgkin lymphomas and often present as extranodal masses with advanced stage similar to meta-static tumors. Without proper intraoperative, microscopic, immunophenotypic, and cytogenetic evaluation they may be mistaken for other hematopoietic or even nonhematopoietic tumors. Also, diffuse large B-cell lymphomas often have clinical, morphologic, immunophenotypic, and cytogenetic clinical features that are similar to those of other less common B-cell lymphomas. Furthermore, classification of these neoplasms is continually becoming more refined. Objective.--To provide a rational, methodic approach to the evaluation of large B-cell lymphomas for community practice pathologists who provide general pathology services. Data Sources.--This review incorporates guidelines detailed in the 2017 update to the World Health Organization's Classification of Tumours of Haematopoietic and Lymphoid Tissues in addition to other recent peer-reviewed publications. Conclusions.--Many large B-cell neoplasms respond favorably to current treatments, but these cases also require accurate and timely diagnoses. We propose a process following a brief checklist that focuses on diffuse large B-cell lymphoma, the most common entity, and rules out other similar lymphomas in a stepwise fashion. (Arch Pathol Lab Med. 2020;144:160-167; doi: 10.5858/arpa.2019-0182-RA), Non-Hodgkin B-cell lymphomas with enlarged cell size and diffuse patterns of growth are common and often present with clinically aggressive behavior. Among these, diffuse large B-cell lymphomas (DLBCLs) are most [...]

Background: Systemic adenoviral (Ad) gene therapy for renal disorders is largely hampered by the unique architecture of the kidney. Consequently, currently available Ad vectors are of only limited therapeutic utility in the context of glomerular and fibroproliferative renal diseases., Methods: The Ad vectors studied in the context of blocking renal fibrosis were AdTbeta-ExR and AdCATbeta-TR. AdTbeta-ExR encodes a chimeric soluble molecule comprising the entire ectodomain of the human type II TGF-beta receptor, genetically fused to the Fc fragment of the human IgG1 (sTbetaRII), while AdCATbeta-TR encodes only the dominant-negative truncated ectodomain of the human type II TGF-beta receptor. The biologic activity of the type II TGF-beta receptor was evaluated in vitro by its ability to inhibit cellular proliferation and in vivo in a unilateral ureter obstruction fibrosis model. Renal targeting with sTbetaRII was evaluated immunohistochemically after intramuscular (IM) delivery of AdTbeta-ExR. The renal antifibrotic effect of the Ad vectors was evaluated in a lupus murine model with both light and electron microscopy and urinalysis., Results: sTbetaRII was detected in the glomeruli after remote IM injection of AdTbeta-ExR, but not the control AdCATbeta-TR, indicating renal deposition of the heterologous soluble fusion protein after its expression in the muscle and secretion into the circulation. AdTbeta-ExR, but not AdCATbeta-TR, could transiently inhibit mesangial expansion, glomerular hypercellularity, proteinuria and cortical interstitial fibrosis in a murine lupus model. However, the autoimmune renal disease eventually surpassed the antifibrotic effect., Conclusions: These results indicate the superiority of a soluble type II TGF-beta receptor over a dominant-negative, non-soluble type II TGF-beta receptor in the context of blocking renal fibrosis in murine models., (Copyright 2003 John Wiley & Sons, Ltd.)

Adenovirus (Ad) serotype 5 (Ad5) continues to be the predominant vector used for cancer gene therapy. However, many tumor types are reported to be relatively refractory to Ad5 infection because of low surface expression of the native Ad5 receptor, CAR. The observation that many tumor cells are CAR deficient has necessitated the development of CAR-independent infection strategies, including the introduction of heterologous ligand sequences into the virus fiber gene and immunological or chemical modifications of the capsid proteins. Alternatively, native Ad5 tropism can be modified by substituting the knob region from other Ad serotypes such as Ad type 3 (Ad3) into the Ad5 knob region. To date, the effect(s) of tropism modification on the replication and oncolytic capacity of these chimeric Ad vectors has not been fully evaluated. To address this issue, Ad5 vectors and isogenically matched chimeric vectors with Ad3 tropism (Ad5/3) were compared in this study. Various parameters of virus infection were compared, including binding, nuclear translocation, E1A transcription, transgene expression, de novo virus production, and oncolysis. Overall, the chimeric Ad5/3 virus was progressively more efficient at each step of the replication cycle compared with its Ad5 counterpart. The higher replication efficiency of the chimeric Ad5/3 vector translated into improved therapeutic efficacy in a murine in vivo tumor rejection model. These findings suggest that in addition to the initial target cell interaction, multiple mechanisms contribute to the enhanced replication of the chimeric Ad5/3 vector. Furthermore, the data demonstrate that alternative Ad serotype receptors can be used to improve infection and subsequent oncolytic replication, which is particularly relevant in gene therapy applications for tumors that are inefficiently infected with Ad5.

Ad5-Delta 24RGD is an adenovirus that is selectively replication competent in cells defective in the Rb/p16 pathway, such as ovarian cancer cells. The fiber of Ad5-Delta 24RGD contains an integrin binding RGD-4C motif, allowing Coxsackie adenovirus receptor-independent infection of cancer cells. Oncolysis of cell lines was similar to that of a wild-type control, and replication in primary tumor material was shown using a novel three-dimensional spheroid model. Finally, an orthotopic murine model of peritoneally disseminated ovarian cancer was used to test i.p. administration to tumor-bearing animals. Injection of the agent resulted in eradication of i.p. disease, whereas control animals expired (P < 0.0001). These results suggest that Ad5-Delta 24RGD could be useful for treatment of ovarian cancer in humans.

Gene delivery efficiency in clinical cancer gene therapy trials with recombinant adenoviruses (Ads) based on serotype 5 (Ad5) has been limited partly because of variable expression of the primary Ad5 receptor, the coxsackie and adenovirus receptor (CAR), on human primary cancer cells. As a means of circumventing CAR deficiency, Ad vectors have been retargeted by creating chimeric fibers possessing knob domains of alternate Ad serotypes. In this study, we have constructed an Ad5-based vector, Ad5/3luc1, with a chimeric fiber protein featuring a knob domain derived from Ad3. This virus is retargeted to the Ad3 receptor and, therefore, has different tissue tropism. A novel knob binding assay was used to measure expression of CAR and the Ad3 receptor. Further, to evaluate the correlation of receptor expression and infectivity by Ad, a panel of ovarian cancer cell lines and purified primary cancer cells were infected with Ad5luc1 and Ad5/3luc1 at 50, 200, and 1000 viral particles/cell. Our results confirm that Ad5/3luc1 is retargeted to the Ad3 receptor. Furthermore, the Ad3 receptor is present at higher levels than CAR on ovarian adenocarcinoma cells. Also, the amount of binding to primary receptor appears to be the major factor determining the efficiency of transgene expression. The Ad5/3 chimera displays enhanced infectivity for ovarian cancer cell lines and purified primary tumor cells, which could translate into increased efficacy in clinical trials.