Management of patients with post-transplant lymphoproliferative disorder: the role of rituximab.

Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ and bone marrow transplantations. Rituximab (Rituxan, Mabthera), a chimeric monoclonal antibody to the CD20 antigen on the surface of B-cell lymphocytes, has been used increasingly in the treatment of PTLD. Rituximab was initially approved for the treatment of low-grade non-Hodgkin lymphomas, but multiple case studies, retrospective analyses, and phase II trials demonstrate the benefit of rituximab in PTLD.

In vitro hypoxia-conditioned colon cancer cell lines derived from HCT116 and HT29 exhibit altered apoptosis susceptibility and a more angiogenic profile in vivo.

Hypoxia is an important selective force in the clonal evolution of tumours. Through HIF-1 and other transcription factors combined with tumour-specific genetic alterations, hypoxia is a dominant factor in the angiogenic phenotype. Cellular adaptation to hypoxia is an important requirement of tumour progression independent of angiogenesis.

PERK and GCN2 contribute to eIF2alpha phosphorylation and cell cycle arrest after activation of the unfolded protein response pathway.

Exposure of cells to endoplasmic reticulum (ER) stress leads to activation of PKR-like ER kinase (PERK), eukaryotic translation initiation factor 2alpha (eIF2alpha) phosphorylation, repression of cyclin D1 translation, and subsequent cell cycle arrest in G1 phase. However, whether PERK is solely responsible for regulating cyclin D1 accumulation after unfolded protein response pathway (UPR) activation has not been assessed. Herein, we demonstrate that repression of cyclin D1 translation after UPR activation occurs independently of PERK, but it remains dependent on eIF2alpha phosphorylation.

Serum protein electrophoresis abnormalities in adult solid organ transplant patients with post-transplant lymphoproliferative disorder.

Post-transplant lymphoproliferative disorder (PTLD) is an Epstein-Barr virus (EBV) associated malignancy that occurs in the setting of pharmacologic immunosuppression used after organ transplantation. The presence of monoclonal gammopathy (MG) after organ transplantation is a risk factor for the development of PTLD. We retrospectively explored the characteristics of serum protein electrophoresis (SPEP) in 38 adult solid organ transplant patients with biopsy proven PTLD and SPEP.

An Internet-based cancer clinical trials matching resource.

Background: Many patients are now accessing the Internet to obtain cancer clinical trials information. However, services offering clinical trials recruitment information have not been well defined.

Objectives: This study describes one of the first Web-based cancer clinical trials matching resources and the demographics of users who were successfully matched.

Successful treatment of T-cell post-transplant lymphoproliferative disorder with the retinoid analog bexarotene.

T-cell post-transplant lymphoproliferative disorder (PTLD) is a rare life threatening complication of organ transplantation. It is usually resistant to treatment with reduction in immunosuppression or chemotherapy and carries a poor prognosis. We report on a combined kidney and pancreas transplant patient with Epstein-Barr virus (EBV) positive T-cell PTLD that had recurred after chemotherapy and reduction in immunosuppression.

17-Allylamino-17-demethoxygeldanamycin overcomes TRAIL resistance in colon cancer cell lines.

Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is a promising candidate for treatment of cancer, but displays variable cytotoxicity in cell lines. The mechanisms of sensitivity and resistance have not been fully elucidated; both AKT and NF-kappaB pathways may modulate cytotoxic responses. We have shown that the Hsp90 inhibitor 17-AAG enhances the cytotoxicity of oxaliplatin in colon cancer cell lines through inhibition of NF-kappaB.

Intensive graft-versus-host disease prophylaxis is required after unrelated-donor nonmyeloablative stem cell transplantation.

Nonmyeloablative stem cell transplantation (NST) harnesses the graft-versus-tumor effect while minimizing regimen-related toxicity, and can result in donor chimerism and remission. Acute graft-versus-host disease (GVHD) and infections are major complications after sibling NST. Toxicity of unrelated-donor (UD) NST and the most appropriate GVHD prophylaxis in this setting remain poorly defined.

Phase I trial of combretastatin a-4 phosphate with carboplatin.

Purpose: Preclinical evidence of synergy led to a phase I trial employing combretastatin A-4 phosphate (CA4P), a novel tubulin-binding antivascular drug, in combination with carboplatin.

Experimental Design: Based on preclinical scheduling studies, patients were treated on day 1 of a 21-day cycle. Carboplatin was given as a 30-minute i.

Identification of genes associated with platinum drug sensitivity and resistance in human ovarian cancer cells.

Platinum-based chemotherapeutic regimens are ultimately unsuccessful due to intrinsic or acquired drug resistance. Understanding the molecular basis for platinum drug sensitivity/resistance is necessary for the development of new drugs and therapeutic regimens. In an effort to identify such determinants, we evaluated the expression of approximately 4000 genes using cDNA microarray screening in a panel of 14 unrelated human ovarian cancer cell lines derived from patients who were either untreated or treated with platinum-based chemotherapy.

Concurrent RT with 5-FU/epirubicin and cisplatin or irinotecan for locally advanced upper GI adenocarcinoma.

From the results of recent studies, it is likely that multimodality therapy with chemotherapy and radiation treatment may improve the overall outcome of locally advanced upper gastrointestinal (GI) malignancies, including esophageal, gastric, pancreatic, and biliary tract carcinomas. However, more effective, more optimal, and less toxic chemotherapy regimen(s) with concomitant radiotherapy are needed beyond the concurrent continuous-infusion fluorouracil (5-FU) with radiation that is commonly applied in general practice. Epirubicin (Ellence), cisplatin, and irinotecan (Camptosar) are all active cytotoxic chemotherapy agents in upper GI cancers.

Effect of bupropion on depression symptoms in a smoking cessation clinical trial.

Bupropion is an antidepressant shown to be efficacious for smoking cessation. This study examined the short- and long-term effects of bupropion (300 mg/day for 10 weeks) versus placebo on depression symptoms among 497 smokers attempting to quit in a randomized trial of bupropion plus behavioral counseling. Depression symptoms were assessed via the Center for Epidemiological Studies Depression Scale (L.

Recombinant Listeria vaccines containing PEST sequences are potent immune adjuvants for the tumor-associated antigen human papillomavirus-16 E7.

Previous work in our laboratory has established that the fusion of tumor-associated antigens to a truncated form of the Listeria monocytogenes virulence factor listeriolysin O (LLO) enhances the immunogenicity and antitumor efficacy of the tumor antigen when delivered by Listeria or by vaccinia. LLO contains a PEST sequence at the NH(2) terminus. These sequences, which are found in eukaryotic proteins with a short cellular half-life, target proteins for degradation in the ubiquitin-proteosome pathway.

Proteasome inhibition for treatment of multiple myeloma: clinical update.

Multiple myeloma is an incurable hematologic cancer affecting over 50,000 Americans. Current treatment approaches employ various chemotherapeutic regimens; however, relapse is inevitable. A novel treatment for multiple myeloma is bortezomib, a proteasome inhibitor that has shown significant in vitro and in vivo activity.

Future directions with angiogenesis inhibitors in colorectal cancer.

The recent US Food and Drug Administration's approval of bevacizumab has reinvigorated antiangiogenic research and has moved colorectal cancer to the forefront of study for the most promising drug candidates in this class. Predicting future directions in this field requires a return to the challenges of the past. Antiangiogenic drugs have necessitated new study design paradigms and imaging techniques in the assessment of drug activity and in dose selection.

The Keap1-BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3 ligase: oxidative stress sensing by a Cul3-Keap1 ligase.

The Nrf2 transcription factor promotes survival following cellular insults that trigger oxidative damage. Nrf2 activity is opposed by the BTB/POZ domain protein Keap1. Keap1 is proposed to regulate Nrf2 activity strictly through its capacity to inhibit Nrf2 nuclear import.

Phase I trial of the novel taxane BMS-184476 administered in combination with carboplatin every 21 days.

The aim of the study was to determine the maximum-tolerated dose and dose-limiting toxicities for BMS-184476, in combination with carboplatin, in patients with advanced solid tumours and to describe any preliminary antitumour activity associated with this regimen. Patients received combination therapy with BMS-184476 given intravenously over 1 h followed by carboplatin administered over 30 min on day 1 of a 21-day cycle. In all, 28 patients received 146 cycles of BMS-184476 and carboplatin.

Use of iodine 131I-tositumomab radioimmunotherapy in a patient with Waldenstrom's macroglobulinemia.

Waldenstrom's macroglobulinemia is an indolent B-cell malignancy that is characterized by high levels of IgM paraprotein production and is incurable with standard chemotherapy. Iodine 131I-Tositumomab (iodine-131-labeled murine anti-CD20 monoclonal antibody; Bexxar) is a novel radioimmunotherapeutic agent that has a high response rate in relapsed or chemotherapy refractory, CD20-positive, low grade or transformed B-cell non-Hodgkin's lymphomas. There are no data on the use of radioimmunotherapy in Waldenstrom's macroglobulinemia.

Extensive replicative capacity of human central memory T cells.

To characterize the replicative capacity of human central memory (T(CM)) CD4 T cells, we have developed a defined culture system optimized for the ex vivo expansion of Ag-specific CD4(+) T cells. Artificial APCs (aAPCs) consisting of magnetic beads coated with Abs to HLA class II and a costimulatory Ab to CD28 were prepared; peptide-charged HLA class II tetramers were then loaded on the beads to provide Ag specificity. Influenza-specific DR*0401 CD4 T(CM) were isolated from the peripheral blood of normal donors by flow cytometry.