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Biomedical subjects

Bruce J Dezube

Publications and source records attributed to Bruce J Dezube.

At least 19 recordsLinked to original sources
PubMed2006

Morphologic and immunophenotypic evidence of in-situ Kaposi's sarcoma.

BACKGROUND: The spectrum of Kaposi's sarcoma (KS) has been expanded to include pre-KS lesions. CASE PRESENTATION: We report, for the first time, a case providing direct histological evidence of the development of early (in-situ) KS from mediastinal lymphatic vessels in the setting of chronic lymphedema in an HIV-positive patient. Spindle-shaped and endothelial cells in these early KS-appearing lesions were immunoreactive for HHV8, D2-40 and CD34. CONCLUSION: Our findings suggest that HHV8-infected spindle-shaped cells associated with lymphangiogenesis that evolve into KS lesions, acquire from the outset an aberrant mixed vascular and lymphatic endothelial cell phenotype.

Journal Article↗
PubMed2006

HIV-associated monoclonal gammopathy: a retrospective analysis of 25 patients.

BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) is unusual in the general population aged <60 years. Various reports indicate a much higher incidence of monoclonal gammopathy among human immunodeficiency virus (HIV)-infected patients and a significantly younger age at diagnosis. We sought to describe the laboratory findings and clinical course of MGUS, including association with plasma cell disorders, other malignancies, and infections, in 25 HIV-infected patients with a detectable serum monoclonal protein. METHODS: We reviewed the patients' demographic characteristics, stage of HIV infection, and clinical course. Laboratory studies included determination of CD4(+) T lymphocyte cell counts, HIV type 1 loads, and quantitative immunoglobulin levels; serum and urine protein immunoelectrophoresis; and determination of serum viscosity indices. Skeletal surveys and bone marrow biopsies were performed in selected cases. RESULTS: Twenty-four of 25 patients were male, and the median age of patients was 50 years (range, 21-69 years). The median CD4(+) T lymphocyte count was 350 cells/ microL (range, 40-1029 cells/ microL; mean, 355 cells/ microL), and the median HIV load was <75 copies/mL (range, <50 to 100,000 copies/mL; mean, 20,800 copies/mL). Thirteen of 25 patients had HIV viremia, despite receiving highly active antiretroviral therapy (HAART). After a mean follow-up duration of 21 months, 7 patients (28%) received a diagnosis of a malignancy (multiple myeloma, in 1 patient; non-Hodgkin lymphoma, in 1; Hodgkin lymphoma, in 1; Kaposi sarcoma, in 2; and plasmacytoma, in 2). Ten patients were coinfected with hepatitis B virus and/or hepatitis C virus; 6 were anemic. No patients developed renal failure or hypercalcemia. Nine (56%) of 19 evaluable patients had a decrease of serum monoclonal protein (mean, 0.5 g/dL) while receiving HAART. CONCLUSIONS: Patients in our study were characterized by the detection of a monoclonal protein at a younger age and the increased presence of other viral infections (infection with hepatitis B or C virus or Kaposi sarcoma herpesvirus) than is typically seen in an HIV-uninfected cohort. CD4(+) T lymphocyte counts were relatively robust. HAART appeared to have a favorable impact on the serum monoclonal protein level in 9 patients. Long-term follow-up is needed to better define the natural history of MGUS and the link to other possible contributing factors.

Adult↗
PubMed2006

A phase I study of ultra low dose interleukin-2 and stem cell factor in patients with HIV infection or HIV and cancer.

PURPOSE: Ultra low doses of interleukin-2 (IL-2) can activate the high-affinity IL-2 receptor constitutively expressed on CD56(bright) natural killer (NK) cells, the CD34+ NK cell precursor, and CD4+ CD25+ regulatory T cells (Tregs) in vivo. We have previously shown synergy between IL-2 and stem cell factor (SCF) in the generation of CD56(bright) NK cells from CD34+ hemopoietic progenitor cells in vitro and showed synergistic NK cell expansion in an in vivo preclinical model. To determine the safety, toxicity, and immune modulation of this combination of cytokines in vivo, we conducted a first-in-man phase I study. EXPERIMENTAL DESIGN: A phase I dose escalation study was conducted using IL-2 at 900,000 or 650,000 IU/m2/d for 8 weeks with 5 or 10 microg/kg/d of SCF given thrice a week for 8 weeks in patients with HIV infection and/or cancer. RESULTS: Ten of 13 patients completed therapy; four experienced the dose-limiting toxicities of grade 3 fatigue or urticaria. The maximum tolerated doses of IL-2 and SCF in combination is 650,000 IU/m2/d of IL-2 and 5 microg/kg/d thrice a week of SCF. NK cells were expanded over 2-fold on therapy; Tregs were expanded nearly 6-fold from baseline. CONCLUSIONS: Administration of IL-2 with SCF is safe and well tolerated and leads to expansion of lymphocyte subsets in patients with HIV or HIV and cancer; however, the changes in NK cell and Treg expansion seen with this cytokine combination were no different than those seen with a similar dose of IL-2 alone.

Adult↗
PubMed2006

Ovarian carcinoma with thyroid metastases causing clinical hypothyroidism: a case report.

BACKGROUND: Ovarian cancer is known to metastasize to the thyroid gland. Despite an incidence of ovarian metastasis to the thyroid of 3-15%, clinical hypothyroidism resulting from such metastasis has not yet been reported. We present a case of metastatic ovarian cancer to the thyroid resulting in clinical hypothyroidism. CASE: A 55-year-old woman with recurrent papillary adenocarcinoma of the ovary presented with fatigue, abdominal distention, lymphedema, and depression. Thyroid stimulating hormone was markedly elevated, and thyroid biopsy demonstrated bilateral metastatic ovarian carcinoma. CONCLUSION: Although uncommon, metastatic disease to the thyroid should be considered when evaluating a patient with advanced ovarian cancer and clinical hypothyroidism.

Female↗
PubMed2006

Randomized phase II trial of matrix metalloproteinase inhibitor COL-3 in AIDS-related Kaposi's sarcoma: an AIDS Malignancy Consortium Study.

PURPOSE: Matrix metalloproteinases (MMPs) are involved in tumor metastasis and are overexpressed in Kaposi's sarcoma (KS) cells. In a phase I trial of the MMP inhibitor COL-3 in patients with AIDS-related KS, the drug was well tolerated, KS regression was observed, and MMP-2 levels decreased significantly in responders compared with nonresponders. The aim of this trial was to extend these initial observations. PATIENTS AND METHODS: This was a randomized, parallel-group, phase II study. COL-3 was administered orally once daily at one of two doses (group A received 50 mg and group B received 100 mg) to patients with AIDS-related KS. Antiretroviral therapy was permitted but not required. Serial tumor assessments and plasma levels of MMPs were obtained. Study end points were progressive KS and recurrent dose-limiting toxicity. RESULTS: Seventy-five patients received COL-3: 37 in group A and 38 in group B. Fifty-seven patients (76%) had received prior KS therapy. Thirty-three patients (44%) had more than 50 KS lesions. The response rate in group A was 41%, which was significantly greater than the prespecified target rate of 20% (95% CI, 25% to 58%; P = .003); the response rate of group B was 29% (P = not significant). There were significant declines in MMP-2 and MMP-9 plasma levels from baseline to minimum value with treatment (MMP-2, P < .001; MMP-9, P = .001). The most common adverse events were photosensitivity and rash. CONCLUSION: COL-3, when administered as 50 mg/d, is both active and well tolerated in the treatment of AIDS-related KS. COL-3 is a promising agent for the treatment of this opportunistic neoplasm of AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Emerging targets and novel strategies in the treatment of AIDS-related Kaposi's sarcoma: bidirectional translational science.

Through the mentorship process, Dr. Arthur Pardee emphasized the critical importance of bidirectional translational research-not only advancing drug development from bench to bedside, but also bringing back precious clinical material to the laboratory to assess the biologic effects of therapeutic agents on their targets. This mini-review focuses on the signal transduction pathways of Kaposi's sarcoma (KS) and on how the knowledge of such pathways has led to the rational development of molecularly targeted pathogenesis-driven therapies. Acquired immune deficiency syndrome (AIDS) related-KS results from co-infection with human immunodeficiency virus and KS herpesvirus/human herpesvirus-8 (KSHV/HHV8), which leads to the development of an angiogenic-inflammatory state that is critical in the pathogenesis of KS. KS is driven by KSHV/HHV8-specific pathways, which include viral G protein-coupled receptor (vGPCR), viral interleukin-6 (vIL-6), and viral chemokine homologues. In addition, cellular growth/angiogenic pathways, such as vascular endothelial growth factor (VEGF), insulin-like growth factor, platelet-derived growth factor (PDGF), angiopoietin and matrix metalloproteinases (MMPs) are "pirated" by KSHV/HHV8. As a very tangible example of how translational research has led to a marked improvement in patient outcome, the signal transduction inhibitor imatinib (a tyrosine kinase inhibitor of c-kit and PDGF) was administered to patients with KS whose tumors were serially biopsied. Not only did the patients' tumors regress, but also the regression was correlated with the inhibition of PDGF receptor (PDGFR) in the biopsy samples. Recent and future clinical trials of molecularly targeted therapy for the treatment of KS are a prelude to a shift in the paradigm of how KS is managed.

AIDS-Related Opportunistic Infections↗
PubMed2006

Signal transduction targets in Kaposi's sarcoma.

PURPOSE OF REVIEW: AIDS-related Kaposi's sarcoma results from co-infection with HIV and Kaposi's sarcoma herpesvirus/human herpesvirus-8, which leads to the development of an angiogenic-inflammatory state that is critical in the pathogenesis of the condition. Recent discoveries regarding Kaposi's sarcoma herpesvirus/human herpesvirus-8 infection and its activation of signal transduction have led to a greater understanding into Kaposi's sarcoma pathogenesis and have identified potential targets for therapy. RECENT FINDINGS: Kaposi's sarcoma is driven by Kaposi's sarcoma herpesvirus/human herpesvirus-8-specific pathways, which include viral G protein-coupled receptor, viral IL-6, and viral chemokine homologues. In addition, cellular growth/angiogenic pathways such as vascular endothelial growth factor, insulin growth factor, platelet-derived growth factor, angiopoietin and matrix metalloproteinases are 'pirated' by Kaposi's sarcoma herpesvirus/human herpesvirus-8. Recent findings show Kaposi's sarcoma herpesvirus/human herpesvirus-8 specific signaling pathways and pirated pathways to be important therapeutic targets. SUMMARY: Numerous advances have been made recently that expand the understanding of Kaposi's sarcoma pathogenesis. These findings and recent clinical trials of targeted therapy for treatment are a prelude to a shift in the paradigm of how AIDS-related Kaposi's sarcoma is managed.

Cell Transformation, Viral↗
PubMed2006

The growing problem of non-AIDS-defining malignancies in HIV.

PURPOSE OF REVIEW: The incidence and spectrum of non-AIDS-defining cancers has continued to grow. As HIV-infected individuals live longer due to highly active antiretroviral therapy, their risk of dying from one of these cancers is increased. The recent literature pertaining to non-AIDS-defining cancers is reviewed. RECENT FINDINGS: Recent epidemiological studies have identified higher rates of carcinoma of the anus, lung, breast, skin, conjunctiva, liver and prostate; hematopoietic malignancies such as Hodgkin's lymphoma, plasma-cell neoplasia and leukemia; and other neoplasms like melanoma and leiomyosarcoma in HIV-positive patients. The role of HIV-induced immunosuppression in the development of these non-AIDS-defining cancers appears less important than lifestyle habits like smoking and sun exposure, as well as coinfection with human papilloma, hepatitis B, hepatitis C and Epstein-Barr viruses. SUMMARY: It is unclear whether the growing number of reports on non-AIDS-defining cancers reflects a true increased incidence or merely the product of increased surveillance, detection and reporting. Highly active antiretroviral therapy not only promotes longevity in the HIV-positive population, but may increase their risk of developing cancer like Hodgkin's lymphoma. Assertive prevention strategies are needed to adequately deal with non-AIDS-defining cancers in an aging and growing HIV-positive population.

Anti-Retroviral Agents↗
PubMed2006

Matrix metalloproteinases in the progression and regression of Kaposi's sarcoma.

BACKGROUND: Matrix metalloproteinases (MMPs) are associated with Kaposi's sarcoma (KS) tumorigenesis. To date, only a few MMPs have been studied in KS lesions. Their role in KS regression has not been investigated. The aim of this study was to evaluate the expression of multiple MMPs in developing and pharmacologically regressed KS lesions. METHODS: Nine samples of acquired immune deficiency syndrome (AIDS)-related and classic cutaneous KS lesions at various histological stages were studied. Regressing KS lesions from three patients treated with systemic therapy were procured after one and two cycles of chemotherapy. Tissue sections from all specimens were immunostained using monoclonal antibodies to MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-13, and MMP-14. RESULTS: KS lesional cells were immunoreactive for all MMPs, except MMP-14. Admixed inflammatory cells were immunoreactive for MMP-1, MMP-2, MMP-7, MMP-9, and MMP-13. The MMP immunoprofile in residual KS lesional cells was unaltered in regressed lesions. Increased extracellular matrix (ECM) and macrophage immunoreactivity for MMPs was identified in regressed specimens. CONCLUSIONS: These data show that developing KS lesional cells express collagenases (MMP-1, MMP-13), gelatinases (MMP-2, MMP-9), stromelysin-1 (MMP-3), and matrilysin (MMP-7) but not the membrane-type MMP-14. This MMP expression profile is retained by residual KS cells and also expressed by infiltrating macrophages in regressed KS lesions. Pantanowitz L, Dezube BJ, Hernandez-Barrantes S, Tahan SR, Dabbous MK. Matrix metalloproteinases in the progression and regression of Kaposi's sarcoma.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Case of fatal sickle cell intrahepatic cholestasis despite use of exchange transfusion in an African-American patient.

Sickle cell intrahepatic cholestasis (SCIC) is a rare complication of sickle cell anemia, characterized by marked hyperbilirubinemia and acute hepatic failure with an often fatal course. However, the few reported adult cases that were treated with exchange transfusion had a favorable outcome. We herein describe a 48-year-old African-American man with hemoglobin S/B thalassemia and previously treated hepatitis C with compensated cirrhosis, who presented with a total bilirubin of 59.7 mg/dL and direct bilirubin of 43.6 mg/dL in the absence of choledocholithiasis. Despite an exchange transfusion and aggressive packed red blood cell transfusions, which successfully decreased the hemoglobin S levels to <15%, he perished from progressive hepatic and renal failure. Autopsy demonstrated extensive intrahepatocellular and intracanalicular cholestasis in a background of cirrhosis. Our case suggests that poor prognostic factors for adult SCIC patients treated with exchange transfusion may include older age and underlying hepatic disease.

Black or African American↗
PubMed2006

Higher prevalence of monoclonal gammopathy of undetermined significance in African Americans than whites--the unknown role of underlying HIV infection.

The age-adjusted prevalence rate of monoclonal gammopathy of undetermined significance (MGUS) is three-fold higher in African Americans than whites. Similarly, there is a higher preponderance of multiple myeloma (MM) in African-American patients. Since the risk of progression of MGUS to MM is equal in both races, identification of exogenous and genetic risk factors of MGUS [such as genetic pre-disposition; diet; and chronic antigenic exposure related to sexually transmitted diseases, including human immunodeficiency virus (HIV) infection] is essential for unraveling the etiology of the racial disparity for MM. HIV infection, a well-documented risk factor for MGUS, is more frequent in African-American patients. Future epidemiologic studies dealing with plasma cell disorders should carefully examine the relationship between race, HIV infection status, prevalence of MGUS and its ultimate progression to MM.

Black or African American↗
PubMed2005

Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1.

We assessed the efficacy and safety of 10-d monotherapy with the orally administered CCR5 antagonist maraviroc in 63 HIV-1-positive individuals prescreened for the absence of CXCR4-using virus. Maximum reduction in viral load occurred at a median of 10-15 d, with a mean reduction of >or=1.6 log(10) copies/ml at all twice daily doses >or=100 mg. These results provide proof of concept that CCR5 antagonism is a viable antiretroviral therapeutic approach.

Anti-HIV Agents↗
PubMed2005

Novel cellular genes essential for transformation of endothelial cells by Kaposi's sarcoma-associated herpesvirus.

Kaposi's sarcoma-associated herpesvirus (KSHV) is involved in the development of lymphoproliferative diseases and Kaposi's sarcoma. The oncogenicity of this virus is reflected in vitro by its ability to transform B cells and endothelial cells. Infection of dermal microvascular endothelial cells (DMVEC) transforms the cells from a cobblestone-like monolayer to foci-forming spindle cells. This transformation is accompanied by dramatic changes in the cellular transcriptome. Known oncogenes, such as c-Kit, are among the KSHV-induced host genes. We previously showed that c-Kit is an essential cellular component of the KSHV-mediated transformation of DMVEC. Here, we test the hypothesis that the transformation process can be used to discover novel oncogenes. When expression of a panel of KSHV-induced cellular transcripts was inhibited with antisense oligomers, we observed inhibition of DMVEC proliferation and foci formation using antisense molecules to RDC1 and Neuritin. We further showed that transformation of KSHV-infected DMVEC was inhibited by small interfering RNA directed at RDC1 or Neuritin. Ectopic expression of Neuritin in NIH 3T3 cells resulted in changes in cell morphology and anchorage-independent growth, whereas RDC1 ectopic expression significantly increased cell proliferation. In addition, both RDC1- and Neuritin-expressing cells formed tumors in nude mice. RDC1 is an orphan G protein-coupled receptor, whereas Neuritin is a growth-promoting protein known to mediate neurite outgrowth. Neither gene has been previously implicated in tumorigenesis. Our data suggest that KSHV-mediated transformation involves exploitation of the hitherto unrealized oncogenic properties of RDC1 and Neuritin.

Adaptor Proteins, Signal Transducing↗