Biomedical subjects

Joseph M Connors

Publications and source records attributed to Joseph M Connors.

50 records · Page 3Linked to original sources

PubMed2003

Characterization of the recurrent translocation t(1;1)(p36.3;q21.1-2) in non-Hodgkin lymphoma by multicolor banding and fluorescence in situ hybridization analysis.

Aberrations of chromosomal bands 1p36 and 1q11-q23 are among the most common chromosomal alterations in non-Hodgkin lymphoma (NHL). In this study, 16 cases of NHL showing recurrent unbalanced translocation t(1;1)(p36;q11-23) by G-band analysis were selected for further analysis. To delineate the exact breakpoints, multicolor band analysis for chromosome 1 (M-BAND1), and locus-specific fluorescence in situ hybridization (LS-FISH) using human genome designated BAC clones were performed. In all but one dicentric case, the breakpoint was determined to involve chromosomal bands 1p36.3 and 1q21.1-2. LS-FISH analysis for the TP73, MEL1, SKI, and CASP9 loci at 1p36, and the loci IRTA1, IRTA2, BCL9, AF1Q, JTB, and MUC1 at 1q21, verified the MBAND1 results and further delineated the breakpoints. In band 1p36, two hybridization patterns were observed, one involving deletions of MEL1, TP73, and SKI, but not CASP9, and the second involving a breakpoint telomeric to TP73. In region 1q21, four hybridization patterns were observed, the first involving duplication/translocation of all five genes; the second involving duplication/translocation of BCL9, AF1Q, JTB, and MUC1; the third involving duplication/translocation of AF1Q, JTB, and MUC1; and the fourth with a breakpoint telomeric to MUC1. Using an alpha-satellite probe for chromosome 1 (D1Z5), centromeric involvement in the unbalanced translocation t(1;1)(p36.3;q21.1-2) was excluded in all but the one dicentric case, that is, dic(1;1)(p36.3;q10). In conclusion, deletion of 1p36 and duplication of 1q21 through formation of an unbalanced translocation t(1;1)(p36.3;q21.1-2) is a non-random event in NHL, suggesting a deletion-duplication mechanism involved in lymphoma progression and justifying further systematic research.

Adult↗

PubMed2003

The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma.

We used gene expression profiling to establish a molecular diagnosis of mantle cell lymphoma (MCL), to elucidate its pathogenesis, and to predict the length of survival of these patients. An MCL gene expression signature defined a large subset of MCLs that expressed cyclin D1 and a novel subset that lacked cyclin D1 expression. A precise measurement of tumor cell proliferation, provided by the expression of proliferation signature genes, identified patient subsets that differed by more than 5 years in median survival. Differences in cyclin D1 mRNA abundance synergized with INK4a/ARF locus deletions to dictate tumor proliferation rate and survival. We propose a quantitative model of the aberrant cell cycle regulation in MCL that provides a rationale for the design of cell cycle inhibitor therapy in this malignancy.

ADP-Ribosylation Factors↗

PubMed2003

Follicular lymphoma lacking the t(14;18)(q32;q21): identification of two disease subtypes.

The clinical and pathological features, including karyotype data and BCL2 protein expression pattern, of follicular lymphoma without a t(14;18)(q32;q21) have not been well defined. We have identified and conducted a detailed analysis of 50 cases with follicular lymphoma who lack the t(14;18). Fluorescent in situ hybridization (FISH) analysis was used to exclude cases with a cryptic IGH/BCL2 rearrangement. BCL2 protein expression level was assessed by immunohistochemistry. The karyotypes were assessed for recurrent sites of structural rearrangement, duplications and deletions on a band-by-band basis, and compared with a large cohort of cases with t(14;18). A distinct pattern of chromosomal alterations was identified in the cases without t(14;18). BCL2 protein overexpression was detected in 33% of 49 tested cases. In this minority, the karyotypes frequently showed increased copies of chromosome 18. The majority of cases (67%) did not show BCL2 overexpression and were characterized prominently by the presence of t(3;14)(q27;q32), implying a role for BCL6. Follicular lymphomas that lack a t(14;18) were segregated into two subgroups with distinct cytogenetic, phenotypic and possibly clinical features: one with BCL2 protein overexpression not related to an IGH/BCL2 rearrangement and a second without BCL2 overexpression. Objective identification of BCL2 expression level as well as BCL2 and BCL6 status by cytogenetic or FISH analysis has potential clinical utility and may yield insights into alternative genetic mechanisms associated with B-cell lymphomas with a follicular growth pattern.

Adult↗

PubMed2003

Multicolour fluorescence in situ hybridization analysis of t(14;18)-positive follicular lymphoma and correlation with gene expression data and clinical outcome.

In order fully to identify secondary chromosomal alterations, such as duplications, additions and marker chromosomes that remained unresolved by G banding, 60 cases of t(14;18)-positive follicular lymphoma (FL) were analysed by multicolour karyotyping techniques [multicolour fluorescence in situ hybridization (MFISH)/multicolour banding for chromosome 1 (MBAND1)]. A total of 165 additional structural chromosomal aberrations were delineated. An increased frequency of chromosomal gains involving X, 1q, 2, 3q27-q29, 5, 6p11-p21, 7, 8, 11, 12, 14q32, 17q, 18 and 21 and deletions of 1p36, 3q28-q29, 6q, 10q22-q24 and 17p11-p13 was revealed by the MFISH/MBAND1 analysis. Balanced translocations other than t(14;18) were uncommon, whereas unbalanced translocations were numerous. Deletion of 1p36 and duplication of 1p33-p35, 1p12-p21 and 1q21-q41 were regularly involved in chromosome 1 alterations, seen in 53% of the cases. A strong correlation was demonstrated between gains of individual chromosomal bands and increased gene expression, including 1q22/MNDA, 6p21/CDKN1A, 12q13-q14/SAS, 17q23/ZNF161, 18q21/BCL2 and Xq13/IL2RG. Unfavourable overall survival was associated with del(1)(p36) and dup(18q). These data support the notion that translocation events are primarily responsible for FL disease initiation, whereas the unbalanced chromosomal gains and losses that mirror the gene expression patterns characterize clonal evolution and disease progression, and thus provide further insights into the biology of FL.

Adult↗

PubMed2003

Hodgkin's lymphoma: biology and treatment strategies for primary, refractory, and relapsed disease.

Hodgkin's lymphomas belong to the most curable tumor diseases in adults. About 80% of patients in all anatomical stages and of all histological subtypes can be cured with modern treatment strategies. In spite of the great clinical progress, the pathogenesis of this peculiar lymphoproliferative entity has not been elucidated completely up until now. In Section I Drs. Stein, Hummel, and Zollinger describe the different pro-proliferative and antiapoptotic pathways and molecules involved in the transformation of the germinal center B-lymphocyte to the malignant Hodgkin-Reed-Sternberg cell. They use a comprehensive gene expression profiling (Affymetrix gene chip U133A) on B- and T-Hodgkin cell lines and state that the cell of origin is not the dominant determinant of the Hodgkin cell phenotype, but the transforming event. H-RS cells lack specific functional markers (B-T-cell receptors) and physiologically should undergo apoptosis. Why they do not is unclear and a matter of intensive ongoing research. In Section II Dr. Diehl summarizes the commonly used primary treatment strategies adapted to prognostic strata in early, intermediate and advanced anatomical stages using increasing intensities of chemotherapy (two, four, eight courses of chemotherapy such as ABVD) and additive radiation with decreased doses and field size. ABVD is without doubt the gold standard for early and intermediate stages, but its role as the standard regimen for advanced stages is challenged by recent data with time- and dose-intensified regimens such as the escalated BEACOPP, demonstrating superiority over COPP/ABVD (equivalent to ABVD) for FFTF and OS in all risk strata according to the International Prognostic Score. In Section III, Dr. Connors states that fortunately there is a considerably decreased need for salvage strategies in Hodgkin's lymphomas since primary treatment results in a more than 80% tumor control. Nevertheless, a significant number of patients experience either a tumor refractory to therapy or an early or late relapse. Therefore, one of the continuing challenges in the care for Hodgkin's lymphomas today is to find effective modes for a second tumor control. High-dose chemotherapy followed by autologous stem cell support has proved to be the treatment of choice when disseminated tumors recur after primary chemo- and or radiotherapy. Nodal relapses respond well to local radiation when they recur outfield of primary radiation without B-symptoms and in stages I-II at relapse. Allogeneic stem cell support needs further intensive evaluation in controlled studies to become an established alternative.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2003

Primary adrenal lymphoma.

Primary adrenal lymphoma is a rare extranodal lymphoma with characteristic clinical features including a high incidence of bilateral involvement, predominantly diffuse large B-cell histology, and a low incidence of extra-adrenal disease at diagnosis. Patients are most commonly older men presenting with fever, lumbar pain, and/or symptoms of adrenal insufficiency. Prolonged disease-free survival appears uncommon, which may reflect a publication bias and/or the presence of additional adverse prognostic factors at diagnosis in most patients. Given the rarity of this disease, no prospective chemotherapy studies have been reported. Unresolved therapeutic issues include the optimal chemotherapy regimen (with vs. without monoclonal antibody), the role of bilateral adrenalectomy and/or adjuvant radiation therapy, and the need for central nervous system prophylaxis, given recent reports raising the possibility of a high risk of parenchymal or meningeal relapse. Multicenter collaborative retrospective reviews and prospective trials are needed to address these issues.

Adrenal Gland Neoplasms↗

PubMed2002

The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma.

BACKGROUND: The survival of patients with diffuse large-B-cell lymphoma after chemotherapy is influenced by molecular features of the tumors. We used the gene-expression profiles of these lymphomas to develop a molecular predictor of survival. METHODS: Biopsy samples of diffuse large-B-cell lymphoma from 240 patients were examined for gene expression with the use of DNA microarrays and analyzed for genomic abnormalities. Subgroups with distinctive gene-expression profiles were defined on the basis of hierarchical clustering. A molecular predictor of risk was constructed with the use of genes with expression patterns that were associated with survival in a preliminary group of 160 patients and was then tested in a validation group of 80 patients. The accuracy of this predictor was compared with that of the international prognostic index. RESULTS: Three gene-expression subgroups--germinal-center B-cell-like, activated B-cell-like, and type 3 diffuse large-B-cell lymphoma--were identified. Two common oncogenic events in diffuse large-B-cell lymphoma, bcl-2 translocation and c-rel amplification, were detected only in the germinal-center B-cell-like subgroup. Patients in this subgroup had the highest five-year survival rate. To identify other molecular determinants of outcome, we searched for individual genes with expression patterns that correlated with survival in the preliminary group of patients. Most of these genes fell within four gene-expression signatures characteristic of germinal-center B cells, proliferating cells, reactive stromal and immune cells in the lymph node, or major-histocompatibility-complex class II complex. We used 17 genes to construct a predictor of overall survival after chemotherapy. This gene-based predictor and the international prognostic index were independent prognostic indicators. CONCLUSIONS: DNA microarrays can be used to formulate a molecular predictor of survival after chemotherapy for diffuse large-B-cell lymphoma.

Antibiotics, Antineoplastic↗

PubMed2002

Brief chemotherapy and involved-region irradiation for limited-stage diffuse large-cell lymphoma: an 18-year experience from the British Columbia Cancer Agency.

PURPOSE: To evaluate clinical outcome of patients with limited-stage diffuse large-cell lymphoma (DLCL) treated with three cycles of chemotherapy followed by involved-region irradiation (IRRT). PATIENTS AND METHODS: Adults with limited-stage DLCL were treated with brief doxorubicin-containing chemotherapy regimens between 1980 and 1998. IRRT was administered 3 to 4 weeks after the third chemotherapy treatment in a dose equivalent to 30 Gy in 10 fractions. RESULTS: Three hundred and eight patients (median age, 64 years) were included, and 299 experienced complete remission. After a median follow-up of 86 months, 64 patients developed progressive disease, and 104 patients died (43 from lymphoma, three from toxicity, and 58 from other causes). Actuarial overall and progression-free survival (PFS) rates were, respectively, 80% and 81% at 5 years and 63% and 74% at 10 years. For subgroups identified using the Miller modification of the International Prognostic Index (IPI), the overall survival rates at 5 and 10 years were, respectively, 97% and 89% (no factors), 77% and 56% (one or two factors), and 58% and 48% (three or four factors), and the 5-year and 10-year PFS rates were, respectively, 94% and 89% (no factors), 79% and 73% (one or two factors), and 60% and 50% (three or four factors). Men with testicular presentation, had a definitely inferior outcome. CONCLUSION: Long-term outcome with three cycles of doxorubicin-based chemotherapy and IRRT confirms that this is a successful approach for the majority of patients with limited-stage DLCL. Subgroups with worse prognoses can be identified, and these patients should be offered alternative treatment approaches.

Adolescent↗

PubMed2002

Cytogenetic findings in reactive lymphoid hyperplasia: significance of non-clonal t(3;14) and t(3;22).

Despite several reports of the molecular detection of recurrent lymphoma translocations in reactive lymph nodes (LN), cytogenetic analysis is seldom performed on such cases. We report the clinical and cytogenetic analysis results on 30 reactive LN. Of these, 17 cases yielded either no growth (n = 9) or normal metaphases only (n = 8), and seven of the 17 patients subsequently developed lymphoma. Lymphoma developed in all 10 patients with a clonal karyotype (median of 2.6 months). Three patients (1 HIV-positive) had non-clonal t(3;14) or t(3;22). Their lymphadenopathy resolved spontaneously, and none progressed to lymphoma at 4-6 years of follow-up. Molecular methods detected a small B-cell clone in one case and an oligoclonal B-cell population in the other. Cytogenetic analysis may be useful for interpreting cases of lymphoid hyperplasia. A clonal abnormality is highly predictive of concurrent and/or subsequent lymphoma. A lymphoma-specific but non-clonal abnormality does not necessarily herald the development of subsequent lymphoma.

Adult↗

PubMed2002

Uncovering novel inter- and intrachromosomal chromosome 1 aberrations in follicular lymphomas by using an innovative multicolor banding technique.

Follicular lymphoma (FL) is characterized by t(14;18)(q32;q21), which is the initial genetic perturbation in this disease. Additional genetic mutations are required to generate a fully malignant phenotype. Secondary chromosomal alterations seen in FL include prominent involvement of chromosome 1 in the form of balanced or unbalanced translocations, insertions, deletions, and duplications involving both the p and q arms. We investigated a diagnostically well defined set of 55 t(14;18)-positive FL cases with complex karyotypes by means of multicolor karyotyping. Sixteen cases showed involvement of chromosome 1 and were analyzed in further detail by a novel multicolor banding technique for this chromosome. We defined three groups showing varying complexity of chromosome 1 alterations. The first group revealed simple translocations, such as t(1;2), t(1;6), t(1;8), and t(1;17), involving breakpoints on either the p or the q arm of chromosome 1. The second group showed more complex rearrangements with translocations, insertions, regional duplications, and involvement of more than one partner chromosome with either the p or the q arm of chromosome 1. The third group was defined by highly complex rearrangements involving translocations, regional duplications, amplifications, and intrachromosomal band relocations affecting the entire chromosome 1. All three groups shared interchromosomal rearrangements of chromosome 1 with chromosome 8, often involving the MYC protooncogene site, amplification involving region 1q21-q31, and deletion involving region 1p36. Thus, the use of sophisticated multicolor molecular cytogenetic assays in the investigation of malignant lymphoma allows precise characterization of chromosomal alterations and will provide a better understanding of their biology.

Aged↗

PubMed2002

Cytogenetic analysis in mantle cell lymphoma: a review of 214 cases.

Cytogenetic (CG) analysis was performed in 78 consecutive cases of mantle cell lymphoma (MCL) at the British Columbia Cancer Agency (BCCA). A clone containing a t(11;14) translocation was identified in 53 cases. Data from 47 cases with sufficient CG details were reviewed along with 167 cases of t(11; 14)-associated lymphoproliferative diseases (LPD) from the literature. Common aneuploidies included -Y, -13, -9, -18, +3 and +12. Common structural changes included: +3q, +12q, del(6q), del(1p), del(13q), del(10q), del(11q), del(9p) and del(17p). The commonest breakpoints clusters were 1p21-22, 1p31-32, 1q21, 6q11-q15, 6q23-25, 8q24, 9p21-24, 11q13-23, 13q12-14, and 17p12-13. When analyzed separately as lymph node-based disease (LN group) and peripheral blood disease (PB group), deletions and chromosomal losses were more common in the LN group, while gains of chromosome segments 3q and 12q were similar. The LN group was cytogenetically more complex. CG analysis is useful for confirming the diagnosis of MCL. Almost all cases will have t(11; 14), but poor quality and number of metaphases may render a difficult analysis. CG evolution in MCL follows a complex but defined pattern. Regions affected by recurrent changes are similar to other B cell lymphomas. The LN and PB groups of t(11;14)-associated LPD may have subtle differences in clonal evolution.

Adult↗

PubMed2002

A literature review of single agent treatment of multiply relapsed aggressive non-Hodgkin's lymphoma.

To analyze the available literature describing the treatment of relapsed aggressive non-Hodgkin's lymphoma (NHL) with single-agent chemotherapies, several comprehensive electronic and manual inspections of the literature were performed for the period from 1966 to the present. Each paper was examined to capture the following data: study type; patient demographics and characteristics; study endpoints, including responses, and method used to evaluate response; toxicities, and the power of the study. A wide variety of single-agent protocols continue to be studied, indicating no currently accepted standard therapy in this patient population. Reported response rates varied between 0 and 67%. The majority of trials were small, uncontrolled studies that used widely varying inclusion/exclusion criteria and had limited reporting of histology, response, prior treatments, and other key parameters. We were able to find only four agents, etoposide, vincristine, vinorelbine and possibly rituximab, with sufficient reproducible evidence to suggest greater than 30% activity (CR + PR rate) when given to patients with second or greater relapse of aggressive NHL. Consequently, the usefulness of the agents in these reports remains to be established in larger trials with more detailed reporting. The advantages that would be brought by an active non-myelosuppressive agent for patients having this condition emerge clearly from this review.

Antineoplastic Agents↗

PubMed2002

Treatment of elderly Hodgkin's lymphoma patients with a novel 5-drug regimen (ODBEP): a phase II study.

Elderly patients with Hodgkin's lymphoma (HL) have a worse outcome than young patients. In an effort to improve the outcome in elderly HL patients, we used a 5-drug chemotherapy regimen called ODBEP (vincristine, doxorubicin, bleomycin, etoposide, prednisone) from 1986-1995. We hoped that by increasing dose intensity through delivery of treatment without delays, and increasing the number of non-cross-resistant chemotherapeutic drugs that were selected for minimal cumulative myelotoxicity, we might improve the cure rate in elderly patients with Hodgkin's lymphoma. Comparison was made with a similar group of patients treated from 1981-1986 with MOPP/ABV-variant chemotherapy. Ninety-nine patients who were 65 years or older, were diagnosed with HL from 1981-1995. Seventy-one patients had advanced disease and 55 of this group were treated with curative intent using multi-agent chemotherapy (ODBEP = 38; MOPP/ABV-variant = 17). ODBEP and MOPP/ABV-type treatment gave a median survival of 43 and 39 months, with 5-year overall survival (OS) of 42 and 32%, respectively. There was no statistically significant difference in OS or disease specific survival between the treatments. Both treatments were well tolerated, but ODBEP was less myelotoxic. ODBEP patients had a relative risk of 0.47 of developing febrile neutropenia compared to the MOPP/ABV-variant patients. In conclusion, treatment of elderly Hodgkin's lymphoma patients with ODBEP resulted in a similar OS and disease-specific survival compared to those treated with MOPP/ABV type chemotherapy, but appeared to be less toxic.

Aged↗

PubMed2002

Lymphoma of the skin.

This chapter describes the various ways in which the non-Hodgkin's lymphomas can involve the skin, how these diseases should be assessed, standard treatments available in 2002, and new directions in research. The goal of the session is to succinctly review recent developments in lymphoma classification and treatment as they apply to the unique aspects of lymphoma when manifest in the skin. In Section I, Dr. Eric Hsi reviews the special characteristics of the lymphomas seen when they proliferate in the skin and the application of the new World Health Organization classification system to the cutaneous lymphomas, emphasizing the unique challenges of recognizing and correctly classifying these diseases. He summarizes the evidence in favor of including the skin lymphomas in the overall lymphoma classification scheme and concludes with a practical description of the specific skin lymphoma entities. In Section II, Dr. Joseph Connors describes the current optimal treatment of the B-cell lymphomas when they present in or metastasize to the skin. Building on the classification scheme described by Dr. Hsi, Dr. Connors outlines a treatment approach based on current understanding of pathophysiology of these diseases and application of each of the effective modalities available for cutaneous lymphoma including radiation, chemotherapy, and immunotherapy. In Section III, Dr. Francine Foss concludes the session with a discussion of the different T-cell lymphomas that start in or spread to the skin concentrating on mycosis fungoides, cutaneous anaplastic large cell lymphoma and peripheral T-cell lymphoma. She includes comments on the newer anti-T-cell chemo- and immuno-therapeutics focusing on agents and techniques specific for cutaneous T-cell lymphomas.

Antineoplastic Agents↗