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Biomedical subjects

Michael E Williams

Publications and source records attributed to Michael E Williams.

13 recordsLinked to original sources
PubMed2006

Thrice-weekly low-dose rituximab decreases CD20 loss via shaving and promotes enhanced targeting in chronic lymphocytic leukemia.

Treatment of chronic lymphocytic leukemia (CLL) patients with standard dose infusion of rituximab (RTX), 375 mg/m2, induces clearance of malignant cells from peripheral blood after infusion of 30 mg of RTX. After completion of the full RTX infusion, substantial recrudescence of CLL cells occurs, and these cells have lost > 90% of CD20. To gain insight into mechanism(s) of CD20 loss, we investigated the hypothesis that thrice-weekly low-dose RTX (20 or 60 mg/m2) treatment for CLL over 4 wk would preserve CD20 and enhance leukemic cell clearance. During initial infusions in all 12 patients, the first 30 mg of RTX promoted clearance of > 75% leukemic cells. Four of six patients receiving 20 mg/m2 RTX retained > or = 50% CD20, and additional RTX infusions promoted further cell clearance. However, four of six patients receiving 60 mg/m2 had CD20 levels < 20% baseline 2 days after initial infusions, and additional RTX infusions were less effective, presumably due to epitope loss. Our results suggest that when a threshold RTX dose is exceeded, recrudesced RTX-opsonized cells are not cleared, due to saturation of the mononuclear phagocytic system, but instead are shaved of RTX-CD20 complexes by acceptor cells. Thrice-weekly low-dose RTX may promote enhanced clearance of circulating CLL cells by preserving CD20.

Administration, Oral↗
PubMed2006

The shaving reaction: rituximab/CD20 complexes are removed from mantle cell lymphoma and chronic lymphocytic leukemia cells by THP-1 monocytes.

Clinical investigations have revealed that infusion of immunotherapeutic mAbs directed to normal or tumor cells can lead to loss of targeted epitopes, a phenomenon called antigenic modulation. Recently, we reported that rituximab treatment of chronic lymphocytic leukemia patients induced substantial loss of CD20 on B cells found in the circulation after rituximab infusion, when rituximab plasma concentrations were high. Such antigenic modulation can severely compromise therapeutic efficacy, and we postulated that B cells had been stripped (shaved) of the rituximab/CD20 complex by monocytes or macrophages in a reaction mediated by FcgammaR. We developed an in vitro model to replicate this in vivo shaving process, based on reacting rituximab-opsonized CD20(+) cells with acceptor THP-1 monocytes. After 45 min at 37 degrees C, rituximab and CD20 are removed from opsonized cells, and both are demonstrable on acceptor THP-1 cells. The reaction occurs equally well in the presence and absence of normal human serum, and monocytes isolated from peripheral blood also promote shaving of CD20 from rituximab-opsonized cells. Tests with inhibitors and use of F(ab')(2) of rituximab indicate transfer of rituximab/CD20 complexes to THP-1 cells is mediated by FcgammaR. Antigenic modulation described in previous reports may have been mediated by such shaving, and our findings may have profound implications for the use of mAbs in the immunotherapy of cancer.

Antibodies, Monoclonal↗
PubMed2006

Hematologic disorders in critically ill patients.

Hematologic disorders are frequently encountered in the intensive care unit. Thrombocytopenia, often defined as a platelet count below 100,000/microL, is common in critically ill patients and may be associated with adverse outcomes. A systematic evaluation of clinical and laboratory findings is necessary to ascertain the cause of the thrombocytopenia and to determine the correct therapy. Recognition of heparin-induced thrombocytopenia (HIT) is particularly important, given the risk of thrombosis associated with this condition. Prompt cessation of all heparin products is required, and anticoagulation with a direct thrombin inhibitor is recommended if HIT is strongly suspected. Coagulopathies are also common in the critically ill, and are often due to vitamin K deficiency or disseminated intravascular coagulation (DIC). A careful history and interpretation of clotting studies are useful in defining the coagulation defect. Advances in understanding the pathogenesis of DIC have generated new treatment approaches, such as the use of recombinant activated protein C. Recombinant factor VIIa (rFVIIa) is a novel drug approved for use in patients with congenital hemophilia and inhibitors. Although its use as a hemostatic agent is currently being evaluated in several off-label scenarios, including trauma, intracerebral hemorrhage, and liver disease, there are limited data to guide therapy in these conditions.

Clinical Trials as Topic↗
PubMed2005

Four human t(11;14)(q13;q32)-containing cell lines having classic and variant features of Mantle Cell Lymphoma.

The objectives of this study were foremost to further characterize pre-existing cell lines containing the t(11;14)(q13;q32) translocation. This translocation along with cyclin D1 overexpression is characteristic of Mantle Cell Lymphoma (MCL), an aggressive B cell neoplasm. Considerable variation in the abundance of cyclin D1 expression was observed. mRNA levels were examined by RT-PCR as differences in cyclin D1 mRNA abundance have been shown to synergize with INK4A/Arf deletions to dictate proliferation rate and survival in MCL patient samples. In this study, the cell lines, Z-138 and HBL-2, which exhibited the fastest growth rates and the shortest survival times in Rag2-M mice, had high expression of either one or both cyclin D1 mRNA isoforms and had negligible expression of p16. On the other hand, NCEB-1 and JVM-2 had low expression of both mRNA isoforms, retained p16 expression, and had slower growth rates and exhibited longer survival times in Rag2-M mice. Furthermore, JVM-2, which was found to have the lowest expression of cyclin D1, was the only cell line that expressed cyclin D2. The results of the characterization of Z-138, HBL-2, NCEB-1 and JVM-2 reveal that this group of cell lines represents both classic and variant features of MCL.

Animals↗
PubMed2005

Biology and therapy of mantle cell lymphoma.

PURPOSE OF REVIEW: Mantle cell lymphoma is an aggressive non-Hodgkin's lymphoma characterized by the t(11;14) chromosomal translocation and overexpression of cyclin D1. Constituting approximately 5 to 8% of all non-Hodgkin's lymphomas, it carries the poorest prognosis among non-Hodgkin's lymphoma subtypes. Standard and effective treatment approaches have yet to be established. RECENT FINDINGS: Several recent insights regarding the molecular pathogenesis and prognostic biomarkers have been realized by way of comparative genomic hybridization, cDNA microarray, and proteomic analysis. Clinical trials using chemotherapy plus rituximab have shown improved response rates, including complete remissions, but without cure in most cases, indicating a clear need for new treatment approaches. Novel therapies for relapsed disease using the proteasome inhibitor bortezomib, thalidomide plus rituximab, the cyclin inhibitor flavopiridol, or inhibitors of the mammalian target of rapamycin (mTOR) have shown encouraging clinical responses. Stem cell transplantation, including nonmyeloablative approaches, are being incorporated into therapeutic regimens and show promise in both the front-line and relapsed/refractory settings. SUMMARY: This review summarizes recent advances in the biology, pathogenesis, and therapy of mantle cell lymphoma and identifies ongoing areas of clinical investigation and new treatment approaches.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Rituximab infusion promotes rapid complement depletion and acute CD20 loss in chronic lymphocytic leukemia.

Complement plays an important role in the immunotherapeutic action of the anti-CD20 mAb rituximab, and therefore we investigated whether complement might be the limiting factor in rituximab therapy. Our in vitro studies indicate that at high cell densities, binding of rituximab to human CD20(+) cells leads to loss of complement activity and consumption of component C2. Infusion of rituximab in chronic lymphocytic leukemia patients also depletes complement; sera of treated patients have reduced capacity to C3b opsonize and kill CD20(+) cells unless supplemented with normal serum or component C2. Initiation of rituximab infusion in chronic lymphocytic leukemia patients leads to rapid clearance of CD20(+) cells. However, substantial numbers of B cells, with significantly reduced levels of CD20, return to the bloodstream immediately after rituximab infusion. In addition, a mAb specific for the Fc region of rituximab does not bind to these recirculating cells, suggesting that the rituximab-opsonized cells were temporarily sequestered by the mononuclear phagocytic system, and then released back into the circulation after the rituximab-CD20 complexes were removed by phagocytic cells. Western blots provide additional evidence for this escape mechanism that appears to occur as a consequence of CD20 loss. Treatment paradigms to prevent this escape, such as use of engineered or alternative anti-CD20 mAbs, may allow for more effective immunotherapy of chronic lymphocytic leukemia.

Antibodies, Monoclonal↗
PubMed2004

Complement activation and C3b deposition on rituximab-opsonized cells substantially blocks binding of phycoerythrin-labeled anti-mouse IgG probes to rituximab.

Binding of rituximab (RTX) to CD20+ B cells activates complement and promotes covalent deposition of C3b fragments on the cells. Previously, we reported that the deposited C3b is substantially co-localized with cell-bound RTX, and therefore C3b may block access of antibody probes specific for RTX. We examined the ability of several commercially available phycoerythrin (PE)-labeled anti-Mouse IgG antibodies to bind to B cells opsonized in milieu which allow or preclude complement activation. Even when large amounts of fluorescently labeled RTX are bound to the cells, binding of the anti-Mouse IgG probes is substantially inhibited if C3b is deposited on the cells. However, cell-bound RTX is still demonstrable on development with a monoclonal antibody (mAb) specific for the human Fc region of RTX. Our findings may provide an alternative explanation for data presented in recent reports suggesting that binding of RTX to cells in plasma leads to internalization of RTX and CD20.

Animals↗
PubMed2003

Mantle cell lymphoma.

Mantle cell lymphoma is an aggressive non-Hodgkin's lymphoma that remains incurable with current chemotherapeutic approaches. Despite response rates to many regimens of 50% to 70%, the disease typically progresses after chemotherapy with a median survival time of approximately 3 years. There is no clear standard approach for treating mantle cell lymphoma, making it critical that appropriate patients be enrolled in clinical trials. Off protocol, chemotherapy with chlorambucil, CVP (cyclophosphamide, vincristine, and prednisone), or CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) can be used in patients who are not candidates for aggressive therapy. Intensive combination chemotherapy regimens have high response rates and may prolong time to progressive disease. High-dose therapy with autologous stem cell transplantation may, but does not appear to, provide longer time to progression, although it may improve survival. For young patients with matched donors, allogeneic transplant is promising in the limited numbers of patients treated. Other agents, including rituximab, fludarabine, and cladribine, have demonstrated activity, but these agents do not appear to offer survival advantages over combination chemotherapy.

Humans↗
PubMed2002

From centrocytic to mantle cell lymphoma: a clinicopathologic and molecular review of 3 decades.

Mantle cell lymphoma (MCL), described almost 3 decades ago as centrocytic lymphoma and by a variety of other names, was initially recognized morphologically. MCL is a classic illustration of how the field of hematopathology and our basic understanding of neoplasia have evolved. The advent of immunophenotypic and increasingly sophisticated genotypic and cytogenetic studies, together with clinical investigations, have led to a better practical and biologic understanding of MCL and have broader implications as well. MCL is now recognized as an aggressive, difficult to treat, B-cell lymphoma with a broader morphologic spectrum than was initially appreciated and a characteristic phenotype (CD5+, CD10-, CD23-, FMC7+). Virtually all MCLs carry the translocation t(11;14)(q13;q32) with overexpression of the involved CCND1 (cyclin D1) gene. Additional cytogenetic and molecular abnormalities have been identified, including some that are early events (such as ATM gene deletion and mutation) and others that appear to be late events (such as deletions and mutations in the negative cell cycle regulatory elements p53, p16, and p18). The latter are often associated with a blastoid morphology and more aggressive clinical course. Ongoing clinical and basic investigations including microarray analysis will undoubtedly provide additional insights into MCL and perhaps more effective and specific therapeutic modalities.

Chromosomes, Human, Pair 11↗
PubMed2002

Testicular lymphoma: a literature review and report of a case with a zoster-like cutaneous recurrence.

Testicular lymphoma accounts for approximately 1% of all cases of non-Hodgkin's lymphoma. This distinct clinical entity can have an aggressive course with a high rate of systemic relapse. We describe a unique case of a diffuse large B-cell lymphoma, T-cell-rich variant with cutaneous dermatomal zosteriform recurrence presenting as neuralgia. This case represents a unique pattern of treatment failure in this aggressive extranodal lymphoma.

Antineoplastic Combined Chemotherapy Protocols↗