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Findings From Current Research

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Novel Therapeutic Targets in Mantle Cell Lymphoma

Authors: Martin P, Leonard JP.

Weill Medical College of Cornell University and New York Presbyterian Hospital, Center for Lymphoma and Myeloma, Division of Hematology and Medical Oncology, Starr Building Room 340, 520 East 70th Street, New York, NY 10021, USA +1 212 746 2932 ; +1 212 746 3844 ; jpleonar@med.cornell.edu.

Mantle cell lymphoma (MCL) is characterised by cell cycle dysregulation and a defective DNA damage response pathway. An evolving understanding of these processes has provided the rationale for development of novel agents targeting various steps that appear to be involved in lymphomagenesis and disease progression. Cyclin D1, overexpressed in nearly 100% of MCL, and the cyclin-dependent kinases were among the first rational targets identified. Therapies focusing on the PI3K/Akt pathway, the tumour microenvironment, and cell surface markers are also in various stages of exploration. Here, the authors discuss the rationale for developing targeted therapies and discuss future challenges in combining some of these agents.

Journal: Expert Opin Ther Targets. 2007 Jul;11(7):929-940.
Adapted from PubMed; click here to access full journal article.

ALK is a Novel Dependence Receptor: Potential Implications in Development and Cancer

Authors: Allouche M.

ALK (anaplastic lymphoma kinase) is a transmembrane receptor tyrosine kinase, initially discovered as part of the NPM-ALK fusion protein, resulting from a chromosomal rearrangement frequently associated with anaplastic large cell lymphomas. The native ALK protein is normally expressed in the developing and, at a weaker level, adult nervous system. We recently demonstrated that ALK is a novel dependence receptor. As such, in the absence of ligand, the ALK receptor is kinase inactive and its expression results in enhanced apoptosis, whereas kinase activation, due to a ligand or constitutive as in NPM-ALK, decreases apoptosis. Unligated/kinase unactivated ALK receptor facilitates apoptosis via its own cleavage by caspases, a phenomenon allowing the exposure of a proapoptotic juxta-membrane intra-cellular domain. This review summarizes the biological significance of the ALK receptor in cancer and development, in perspective with its dependence receptor function. The dual function of ALK in the physiology of development is illustrated in the visual system of Drosophila. In this part of the nervous system, ALK in the presence of ligand appears essential for axonal guidance, whereas in the absence of ligand, ALK expression can lead to developmental neuronal apoptosis. ALK is also found expressed in neural crest-derived tumors such as human neuroblastomas or glioblastomas but its role is not fully elucidated. However, an excessive or constitutive ALK tyrosine kinase activation can lead to deregulation of cell proliferation and survival, therefore to human cancers such as lymphomas and inflammatory myofibroblastic tumors. Our observations could have important implications in the therapy of ALK-positive tumors harboring the chimeric or wild type ALK protein.

Journal: Cell Cycle. 2007 May 14;6(13)
Adapted from PubMed; click here to access full journal article.

Proteome-Wide Changes Induced by the Hsp90 Inhibitor, Geldanamycin in Anaplastic Large Cell Lymphoma Cells

Authors: Schumacher JA, Crockett DK, Elenitoba-Johnson KS, Lim MS.

Associated and Regional University Pathologists (ARUP), Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA.

The molecular chaperone heat shock protein 90 (Hsp90) affects the function of many oncogenic signaling proteins including nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) expressed in anaplastic large cell lymphoma (ALCL). While ALK-positive ALCL cells are sensitive to the Hsp90 inhibitor and the geldanamycin (GA) analog, 17-allylamino-17-demethoxygeldanamycin (17-AAG), the proteomic effects of these drugs on ALK-positive ALCL cells are unpublished. In this study, we investigated the cellular, biologic, and proteomic changes occurring in ALK-positive ALCL cells in response to GA treatment. GA induced G(2)/M cell cycle arrest and caspase-3-mediated apoptosis. Furthermore, quantitative proteomic changes analyzed by cleavable isotope-coded affinity tagtrade mark-LC-MS/MS (cICATtrade mark-LC-MS/MS) identified 176 differentially expressed proteins. Out of these, 49 were upregulated 1.5-fold or greater and 70 were downregulated 1.5-fold or greater in GA-treated cells. Analysis of biological functions of differentially expressed proteins revealed diverse changes, including induction of proteins involved in the 26S proteasome as well as downregulation of proteins involved in signal transduction and protein and nucleic acid metabolism. Pathway analysis revealed changes in MAPK, WNT, NF-kappaB, TGFbeta, PPAR, and integrin signaling components. Our studies reveal some of the molecular and proteomic consequences of Hsp90 inhibition in ALK-positive ALCL cells and provide novel insights into the mechanisms of its diverse cellular effects.

Journal: Proteomics. 2007 Jul 3
Adapted from PubMed; click here to access full journal article.

Longitudinal Screening and Management of Fatigue, Pain, and Emotional Distress Associated with Cancer Therapy

Authors: Butt Z, Wagner LI, Beaumont JL, Paice JA, Straus JL, Peterman AH, Carro G, Von Roenn JH, Shevrin D, Cella D.

Center on Outcomes, Research and Education (CORE), Evanston Northwestern Healthcare, 1001 University Place, Suite 100, Evanston, IL, 60201, USA.

GOALS OF WORK: Fatigue, pain, and emotional distress are common symptoms among patients with cancer. We sought to learn about patient perceptions of these symptoms and their treatment. MATERIALS AND METHODS: At a baseline assessment and two monthly follow-up assessments, we asked a diverse sample of patients with solid tumor or lymphoma (N = 99) about their fatigue, pain and distress, their treatment for these symptoms, and their satisfaction with treatment via standardized questionnaires and semistructured interviews. MAIN RESULTS: In this observational study, patients reported fatigue, pain, emotional distress, and general quality of life at expected levels. Across all assessments, at least half of our sample experienced at least some fatigue, pain, or distress. On the whole, patients and providers do communicate about these concerns, and at least 75% of patients found these discussions helpful when they occurred. CONCLUSIONS: Improved symptom identification and communication may optimize the detection of those at risk of morbidity and decreased quality of life because of excess symptom burden.

Journal: Support Care Cancer. 2007 Jul 3
Adapted from PubMed; click here to access full journal article.

ECP versus PUVA for the Treatment of Cutaneous T-Cell Lymphoma

Authors: Geskin L.

Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, USA.

Extracorporeal photopheresis (ECP) and psoralen plus ultraviolet A therapy (PUVA) are widely accepted types of photochemotherapy used for the treatment of cutaneous T-cell lymphomas (CTCL). PUVA and ECP utilize a photosensitizing agent, that can be taken orally (PUVA) or added to the concentrated sample of white blood cells extracorporeally (ECP) prior to UVA exposure. Both therapies have been shown to be safe and effective for the treatment of CTCL. As a monotherapy, PUVA is preferentially used for treatment of patients at earlier stages with skin involvement alone (T1 and T2). ECP is usually used for patients with erythrodermic skin involvement (T4) in advanced stages (Stage III and IVA) with peripheral blood involvement as in Sézary syndrome (SzS). Use of ECP in earlier stages is controversial and is currently under investigation. Both PUVA and ECP are rarely used as monotherapy, though long-term remissions after PUVA monotherapy for early disease have been reported. CTCL is a rare disease and randomized prospective clinical trials are difficult. The best efficacy data derived from prospective case studies and meta-analysis are reviewed here.

Journal: Skin Therapy Lett. 2007 May;12(5):1-4.
Adapted from PubMed; click here to access full journal article.

Successful Intermittent Prophylaxis With Trimethoprim/Sulfamethoxazole 2 Days per Week for Pneumocystis carinii (jiroveci) Pneumonia in Pediatric Oncology Patients

Authors: Lindemulder S, Albano E.

Children's Hospital, Center for Cancer and Blood Disorders, 1056 E 19th Ave, B115, Denver, CO 80218. lindemulder.susan@tchden.org.

OBJECTIVE. This study was conducted to determine the efficacy of dosing trimethoprim/sulfamethoxazole on 2 consecutive days per week for the prevention of Pneumocystis carinii (jiroveci) pneumonia in a pediatric leukemia and lymphoma population and to determine whether trimethoprim/sulfamethoxazole contributes to neutropenia during maintenance therapy. METHODS. Charts were reviewed for all pediatric patients with leukemia and lymphoma diagnosed between January 1, 1993, and December 31, 2002. Data were collected through April 1, 2004. RESULTS. A total of 575 charts were reviewed; 529 patients were included in the analysis. A total of 482 (345 leukemia, 137 lymphoma) patients were evaluated on trimethoprim/sulfamethoxazole dosed 2 consecutive days per week for 268074 patient-days. No breakthrough cases were documented in compliant patients; 2 noncompliant patients developed P carinii pneumonia. A total of 238 patients who were on trimethoprim/sulfamethoxazole prophylaxis and 13 patients who were receiving an alternative medication prophylaxis were evaluated for neutropenia during maintenance therapy. The median number of maintenance days on trimethoprim/sulfamethoxazole was 605.5 days and on alternative drug was 617 days. The median number of neutropenic maintenance days on trimethoprim/sulfamethoxazole was 15.5 days and on the alternative drug was 16 days. The median proportion of neutropenic days per patient was 0.029 on trimethoprim/sulfamethoxazole and 0.022 on the alternative drug. CONCLUSIONS. Intermittent dosing of trimethoprim/sulfamethoxazole on 2 consecutive days per week is an effective alternative prophylactic regimen for P carinii pneumonia in pediatric patients with leukemia and lymphoma. This analysis does not support a difference in neutropenia during maintenance therapy between patients who are treated with trimethoprim/sulfamethoxazole versus an alternative drug.

Journal: Pediatrics. 2007 Jul;120(1):e47-51. Epub 2007 Jun 4.
Adapted from PubMed; click here to access full journal article.




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