Search PubMed⌕ Search

Biomedical subjects

Wyndham H Wilson

Publications and source records attributed to Wyndham H Wilson.

At least 19 recordsLinked to original sources
PubMed2022

The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee.

Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.

Advisory Committees↗
PubMed2006

Molecular diagnosis of Burkitt's lymphoma.

BACKGROUND: The distinction between Burkitt's lymphoma and diffuse large-B-cell lymphoma is crucial because these two types of lymphoma require different treatments. We examined whether gene-expression profiling could reliably distinguish Burkitt's lymphoma from diffuse large-B-cell lymphoma. METHODS: Tumor-biopsy specimens from 303 patients with aggressive lymphomas were profiled for gene expression and were also classified according to morphology, immunohistochemistry, and detection of the t(8;14) c-myc translocation. RESULTS: A classifier based on gene expression correctly identified all 25 pathologically verified cases of classic Burkitt's lymphoma. Burkitt's lymphoma was readily distinguished from diffuse large-B-cell lymphoma by the high level of expression of c-myc target genes, the expression of a subgroup of germinal-center B-cell genes, and the low level of expression of major-histocompatibility-complex class I genes and nuclear factor-kappaB target genes. Eight specimens with a pathological diagnosis of diffuse large-B-cell lymphoma had the typical gene-expression profile of Burkitt's lymphoma, suggesting they represent cases of Burkitt's lymphoma that are difficult to diagnose by current methods. Among 28 of the patients with a molecular diagnosis of Burkitt's lymphoma, the overall survival was superior among those who had received intensive chemotherapy regimens instead of lower-dose regimens. CONCLUSIONS: Gene-expression profiling is an accurate, quantitative method for distinguishing Burkitt's lymphoma from diffuse large-B-cell lymphoma.

Adolescent↗
PubMed2006

Drug resistance in diffuse large B-cell lymphoma.

Despite significant advances in the treatment of diffuse large B-cell lymphoma (DLBCL), drug resistance remains a major cause of treatment failure. Early strategies to improve outcome were mostly empiric or relied on classical mechanisms of drug resistance and were largely unsuccessful. More recent approaches have been aided by an understanding of the molecular pharmacology of drug action and tumor biology. Microarray profiling in particular has provided important insights into the complex biology of DLBCL and has led to a molecular taxonomy based on cell of origin and pathways of lymphomagenesis. It is now recognized that drug resistance is a complex and dynamic process related to cell cycle and apoptotic pathways, cellular differentiation, and the microenvironment. Drugs that target potential pathways of drug resistance, such as nuclear factor kappaB (NFkappaB), cyclin-dependent kinases (CDKs), and BCL-2 have entered clinical trials. However, the complexity of drug resistance requires that future clinical trials incorporate molecular translational endpoints to help identify the biologic basis of treatment failure.

Apoptosis↗
PubMed2006

International Central Nervous System and Ocular Lymphoma Workshop: recommendations for the future.

PURPOSE: To bring together multidisciplinary experts to discuss primary central nervous system lymphoma (PCNSL) and primary intraocular lymphoma (PIOL). METHODS: NIH campus workshop discussion focusing on future work in both clinical and basic lymphoma research. RESULTS: The discussion lead to recommendations on elucidating disease pathobiology, improving diagnostic accuracy and sensitivity, and novel therapeutic strategies. CONCLUSIONS: Approaches which have been successfully applied to other neoplasms, such as microarray, may be applied to improve diagnostic accuracy and sensitivity of PCNSL and PIOL and should be systematically incorporated into clinical trials of both. Development of animal models of PCNSL and PIOL may be useful in understanding the unique ocular and CNS milieu. Disease detection by radiological, nuclear medicine, molecular and flow cytometric approaches should be systematically studied to improve early diagnosis, accurate staging, and response evaluation. Improved therapy remains the ultimate goal. Efforts in these arenas should be coordinated on a national and international level.

Animals↗
PubMed2006

Acquired immunodeficiency syndrome-related malignancies in the era of highly active antiretroviral therapy.

Since the beginning of the acquired immunodeficiency syndrome (AIDS) epidemic, malignancies have been an important feature of this disease. Several cancers, including Kaposi sarcoma (KS), certain aggressive B-cell lymphomas, and cervical cancer, are considered AIDS-defining when they occur in patients infected with human immunodeficiency virus. Most AIDS-defining tumors are associated with one of 3 DNA viruses: KS-associated herpesvirus, Epstein-Barr virus, or human papillomavirus. With the introduction of highly active antiretroviral therapy (HAART), the incidence of KS and certain lymphomas has decreased, whereas that of other tumors, such as cervical cancer, has undergone little change. Several new drugs and therapies have been developed for KS and AIDS-related lymphomas, and these treatments, plus the development of HAART, have contributed to improvements in morbidity and mortality. At the same time, the improved overall survival of patients with HAART has contributed to an increase in the number of patients living with AIDS in developed countries such as the United States. With the development of HAART and improved prevention and treatment of opportunistic infections, an increasing percentage of the deaths in AIDS patients have been from malignancies. Strategies for prevention, screening, and therapy remain important areas of research in this developing field.

AIDS-Related Opportunistic Infections↗
PubMed2005

The pharmacokinetics of rituximab following an intravitreal injection.

Rituximab is a monoclonal antibody directed against the CD20 B-cell antigen and is approved for the treatment of B-cell lymphoma. We investigated the pharmacokinetics of rituximab following intravitreal administration to assess the feasibility of treating primary intraocular lymphoma. Intravitreal injections of rituximab 0.1 ml (1 mg) were performed in rabbits. Drug concentrations in the aqueous and vitreous humor were measured at intervals from 2 to 17 days after administration. The half-life of the total amount of rituximab in the two compartments was calculated to be 4.7 days. The aqueous and vitreous humor drug levels decayed in parallel maintaining an average ratio of approximately seven. Fitting the data to a two-compartment model yielded a clearance from the aqueous humor of 1.2 microl/min. The clearance was less than the reported rate of aqueous humor outflow indicating that elimination by this route could have been sufficient to account for the disappearance of the drug from the eye. The duration of time over which sustained levels of rituximab were achieved suggest that intravitreal administration warrants further investigation as an approach to treating vitreous and anterior chamber infiltrates in patients with primary intraocular lymphoma.

Animals↗
PubMed2005

Radiofrequency ablation of lymphoma.

Percutaneous minimally invasive radiofrequency (RF) ablation has not been described for lymphoma. This image-guided modality is presented in 3 different settings for the treatment of refractory lymphoma. The first patient received RF ablation for the curative treatment of a solitary residual hepatic mass following rituximab-based chemotherapy for a posttransplantation lymphoproliferative disorder (PTLD) and is disease-free 4 years later. The second patient received RF ablation for successful palliation of progressive follicular lymphoma adjacent to the bladder wall following chemotherapy and maximum radiation. The third patient received RF ablation for prevention of airway obstruction from progressive diffuse large B-cell lymphoma of the right neck following chemotherapy and maximum radiation. RF ablation may be clinically beneficial and should be considered for the treatment of local lymphoma that is refractory or not amenable to standard approaches.

Adult↗
PubMed2005

Cyclin D1-negative mantle cell lymphoma: a clinicopathologic study based on gene expression profiling.

Cyclin D1 overexpression is believed to be essential in the pathogenesis of mantle cell lymphoma (MCL). Hence, the existence of cyclin D1-negative MCL has been controversial and difficult to substantiate. Our previous gene expression profiling study identified several cases that lacked cyclin D1 expression, but had a gene expression signature typical of MCL. Herein, we report the clinical, pathologic, and genetic features of 6 cases of cyclin D1-negative MCL. All 6 cases exhibited the characteristic morphologic features and the unique gene expression signature of MCL but lacked the t(11;14)(q13; q32) by fluorescence in situ hybridization (FISH) analysis. The tumor cells also failed to express cyclin D1 protein, but instead expressed either cyclin D2 (2 cases) or cyclin D3 (4 cases). There was good correlation between cyclin D protein expression and the corresponding mRNA expression levels by gene expression analysis. Using interphase FISH, we did not detect chromosomal translocations or amplifications involving CCND2 and CCND3 loci in these cases. Patients with cyclin D1-negative MCL were similar clinically to those with cyclin D1-positive MCL. In conclusion, cases of cyclin D1-negative MCL do exist and are part of the spectrum of MCL. Up-regulation of cyclin D2 or D3 may substitute for cyclin D1 in the pathogenesis of MCL.

Cyclin D1↗
PubMed2005

Vaccine-induced tumor-specific immunity despite severe B-cell depletion in mantle cell lymphoma.

The role of B cells in T-cell priming is unclear, and the effects of B-cell depletion on immune responses to cancer vaccines are unknown. Although results from some mouse models suggest that B cells may inhibit induction of T cell-dependent immunity by competing with antigen-presenting cells for antigens, skewing T helper response toward a T helper 2 profile and/or inducing T-cell tolerance, results from others suggest that B cells are necessary for priming as well as generation of T-cell memory. We assessed immune responses to a well-characterized idiotype vaccine in individuals with severe B-cell depletion but normal T cells after CD20-specific antibody-based chemotherapy of mantle cell lymphoma in first remission. Humoral antigen- and tumor-specific responses were detectable but delayed, and they correlated with peripheral blood B-cell recovery. In contrast, vigorous CD4(+) and CD8(+) antitumor type I T-cell cytokine responses were induced in most individuals in the absence of circulating B cells. Analysis of relapsing tumors showed no mutations or change in expression of target antigen to explain escape from therapy. These results show that severe B-cell depletion does not impair T-cell priming in humans. Based on these results, it is justifiable to administer vaccines in the setting of B-cell depletion; however, vaccine boosts after B-cell recovery may be necessary for optimal humoral responses.

Adult↗
PubMed2005

Lymphomatoid granulomatosis: abnormalities of the brain at MR imaging.

PURPOSE: To retrospectively evaluate the magnetic resonance (MR) imaging features of lymphomatoid granulomatosis in the brain. MATERIALS AND METHODS: The study, including retrospective analysis of data, was approved by the institutional review board of the National Cancer Institute and complied with Health Insurance Portability and Accountability Act. All patients gave written informed consent. Thirty-one patients with pathologically confirmed lymphomatoid granulomatosis were enrolled in a natural history and treatment study at the National Institutes of Health. Twenty-five patients (median age, 50 years; range, 18-62 years; 18 men, seven women) were evaluated with MR imaging of the brain at study entry for the presence of brain lesions and enhancing characteristics. Patients with abnormal findings were reexamined at intervals ranging from 2 to 19 months, as medically indicated. Cytologic analysis and flow cytometry of cerebrospinal fluid (CSF) were performed. Statistical analysis was performed to compare neurologic and CSF findings in patients with brain MR imaging abnormalities and in patients without abnormalities. The sensitivity of brain MR imaging was compared with that of CSF studies. RESULTS: Thirteen (52%) of 25 patients evaluated with MR imaging had a variety of brain abnormalities. Multiple focal intraparenchymal lesions, which exhibited T2 prolongation and commonly punctate or linear enhancement, were the most frequent abnormalities, and they were encountered in seven patients. The second most common finding was involvement of leptomeninges and cranial nerves, which manifested as abnormal enhancement on MR images obtained after contrast agent administration. This abnormality was seen in six patients. Involvement of dura mater was noted in another. Four patients had brain masses. Two had abnormal engorgement and intense enhancement of the choroid plexus. Most lesions resolved after treatment, but seven resulted in lacunar infarctions. Abnormal B cells were detected in the CSF with either cytologic techniques or flow cytometry in five patients. CONCLUSION: Lymphomatoid granulomatosis has a high rate of central nervous system involvement and a variable spectrum of lesions at MR imaging. Findings in this study suggest that MR imaging is more sensitive than CSF cytologic analysis or flow cytometry for detection of central nervous system involvement from lymphomatoid granulomatosis.

Adolescent↗
PubMed2005

Phase I trial of recombinant immunotoxin RFB4(dsFv)-PE38 (BL22) in patients with B-cell malignancies.

PURPOSE: To conduct a phase I trial of recombinant immunotoxin BL22, an anti-CD22 Fv fragment fused to truncated Pseudomonas exotoxin. PATIENTS AND METHODS: Forty-six pretreated patients with CD22+ non-Hodgkin's lymphoma (NHL; n = 4), chronic lymphocytic leukemia (CLL; n = 11), and hairy cell leukemia (HCL; n = 31) received 265 cycles at 3 to 50 microg/Kg every other day x 3 doses. RESULTS: BL22 was active in HCL, with 19 complete remissions (CRs; 61%) and six partial responses (PRs; 19%) in 31 patients. Of 19 CRs, 11 were achieved after one cycle and eight after two to 14 cycles. All 25 responders benefited clinically with one cycle. The CR rate was 86% in patients enrolled at > or = 40 microg/Kg every other day x 3, and 41% at lower doses (P = .011). The median duration for CR was 36 months (range, 5 to 66 months), and eight patients remain in CR at 45 months (range, 29 to 66 months). Lower but significant activity occurred in CLL. Neutralizing antibodies occurred in 11 (24%) of 46 patients (all HCL). A reversible hemolytic uremic syndrome requiring plasmapheresis was observed in one patient with NHL during cycle 1 and in four patients with HCL during cycle 2 or 3. The maximum-tolerated dose (MTD) evaluated at cycle 1 was 40 microg/Kg IV. QOD x 3. The most common toxicities at 30 to 50 microg/Kg every other day x 3 included hypoalbuminemia, transaminase elevations, fatigue, and edema. CONCLUSION: BL22 was well tolerated and highly effective in HCL, even after one cycle. Phase II testing is underway to define the efficacy with one cycle and to study safety when additional cycles are needed for optimal response.

Adult↗
PubMed2005

Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction.

Gene-expression profiling has identified 3 major subgroups of diffuse large B-cell lymphoma (DLBCL): germinal center B-cell-like (GCB), activated B-cell-like (ABC), and primary mediastinal DLBCL (PMBCL). Using comparative genomic hybridization (CGH), we investigated the genetic alterations of 224 cases of untreated DLBCL (87 GCB-DLBCL, 77 ABC-DLBCL, 19 PMBCL, and 41 unclassified DLBCL) previously characterized by gene-expression profiling. The DLBCL subgroups differed significantly in the frequency of particular chromosomal aberrations. ABC-DLBCL had frequent trisomy 3, gains of 3q and 18q21-q22, and losses of 6q21-q22, whereas GCB-DLBCL had frequent gains of 12q12, and PMBCL had gains of 9p21-pter and 2p14-p16. Parallel analysis of CGH alterations, locus-specific gene-expression profiles, and global gene-expression signatures revealed that DNA amplifications and gains had a substantial impact on the expression of genes in the involved chromosomal regions, and some genes were overexpressed in a DLBCL subgroup-specific fashion. Unexpectedly, specific chromosomal alterations were associated with significant changes in gene-expression signatures that reflect various aspects of lymphoma cell biology as well as the host response to the lymphoma. In addition, gains involving the chromosomal region 3p11-p12 provided prognostic information that was statistically independent of the previously defined gene-expression-based survival model, thereby improving its predictive power.

Chromosomes, Human↗
PubMed2005

B-cell recovery following rituximab-based therapy is associated with perturbations in stromal derived factor-1 and granulocyte homeostasis.

The occurrence of delayed neutropenia following rituximab is poorly defined and of unknown cause. We hypothesized it may be related to perturbations of stromal derived factor-1 (SDF-1) and granulocyte homeostasis. Late-onset neutropenia (LON) was investigated in 130 patients with untreated aggressive B-cell lymphoma receiving DA-EPOCH (dose-adjusted etoposide, prednisone, Oncovin [vincristine], cyclophosphamide, and hydroxydaunorubicin) chemotherapy with or without rituximab. All patients were in remission and had no known causes for neutropenia. LON occurred in 6 (8%) of 76 patients receiving rituximab and 0 of 54 patients not receiving rituximab (P = .04). The median onset was 175 days (range, 77-204 days) after treatment with a median duration of 14 days (range, 11-16 days). In a subset of 24 patients, a significant correlation was found between rapid B-cell recovery and granulocyte decline over the 6-month recovery period (R = -0.53; P = .04). Rapid B-cell recovery directly correlated with prerecovery SDF-1 levels (R = 0.65; P = .015) and SDF-1 decline (R = -0.67; P = .013) after recovery. Our results suggest that early B-cell lymphopoiesis is important for B-cell recovery following rituximab, and that perturbation of SDF-1 during B-cell recovery retards neutrophil egress from the bone marrow. These findings illustrate the dual role of SDF-1 in human B-cell and granulocyte homeostasis.

Adult↗
PubMed2005

Efficacy of reduced-intensity allogeneic stem cell transplantation in chemotherapy-refractory non-hodgkin lymphoma.

Chemotherapy sensitivity has been identified as an important prognostic factor in reduced-intensity allogeneic stem cell transplantation (RIST) for non-Hodgkin lymphoma (NHL). However, the effect of uniform salvage chemotherapy before RIST has not been studied prospectively. We examined whether the response to prospectively administered uniform salvage therapy (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and fludarabine) influenced the subsequent outcome of RIST in 28 patients with relapsed or refractory NHL. After RIST, overall survival (OS) at 36 months is 49%, whereas event-free survival (EFS) is 32%. In Cox model analyses, the response to chemotherapy was the best predictor of OS (P = .0006) and EFS (P = .0006) after RIST. Differentiating stable disease from progressive disease after salvage chemotherapy strengthened the association with survival. Among chemotherapy-sensitive patients, the median OS and EFS have not been reached. In patients with stable disease, OS and EFS at 24 months are 50% and 25%, respectively. In contrast, only 1 patient with progressive disease during salvage therapy survived longer than 12 months. These prospective data confirm the favorable prognosis for chemotherapy-sensitive NHL after RIST and suggest that chemotherapy resistance is not an absolute contraindication to RIST for NHL patients with stable disease during salvage therapy.

Adult↗
PubMed2004

Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells.

BACKGROUND: Patients with follicular lymphoma may survive for periods of less than 1 year to more than 20 years after diagnosis. We used gene-expression profiles of tumor-biopsy specimens obtained at diagnosis to develop a molecular predictor of the length of survival. METHODS: Gene-expression profiling was performed on 191 biopsy specimens obtained from patients with untreated follicular lymphoma. Supervised methods were used to discover expression patterns associated with the length of survival in a training set of 95 specimens. A molecular predictor of survival was constructed from these genes and validated in an independent test set of 96 specimens. RESULTS: Individual genes that predicted the length of survival were grouped into gene-expression signatures on the basis of their expression in the training set, and two such signatures were used to construct a survival predictor. The two signatures allowed patients with specimens in the test set to be divided into four quartiles with widely disparate median lengths of survival (13.6, 11.1, 10.8, and 3.9 years), independently of clinical prognostic variables. Flow cytometry showed that these signatures reflected gene expression by nonmalignant tumor-infiltrating immune cells. CONCLUSIONS: The length of survival among patients with follicular lymphoma correlates with the molecular features of nonmalignant immune cells present in the tumor at diagnosis.

Adult↗