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Paul J Kurtin

Publications and source records attributed to Paul J Kurtin.

At least 19 recordsLinked to original sources
PubMed2006

Randomized phase II study of interleukin-12 in combination with rituximab in previously treated non-Hodgkin's lymphoma patients.

PURPOSE: Rituximab is a chimeric antibody that induces B-cell apoptosis and recruits immune effector cells to mediate cell lysis. Interleukin-12 (IL-12) facilitates cytolytic responses by T cells and natural killer cells. This phase II study was done to determine the efficacy and toxicity of IL-12 in combination with rituximab in patients with B-cell non-Hodgkin's lymphoma (NHL). EXPERIMENTAL DESIGN: Fifty-eight patients with histologically confirmed relapsed B-cell NHL were randomized to receive concurrent treatment with rituximab and IL-12 (arm A) or rituximab with subsequent treatment with IL-12 after documented nonresponse or progression after rituximab (arm B). Treatment consisted of 375 mg/m2 rituximab on days 1, 8, 15, and 22 and 300 ng/kg IL-12 given s.c. twice weekly starting on day 2 for arm A or upon progression for arm B. RESULTS: The overall response rate was 37% (11 of 30) in arm A and 52% (13 of 25) in arm B. All of the responses seen in arm B occurred while patients received rituximab, and no responses occurred during treatment with subsequent IL-12. The median duration of response was 16 months for arm A and 12 months for arm B. Biopsy specimens were serially obtained in a subset of patients and showed that changes in gene expression were different when cells from the peripheral blood were compared with cells from lymph node biopsies. CONCLUSIONS: The concomitant use of IL-12 and rituximab had modest disease activity in patients with B-cell NHL, but the sequential administration of IL-12 after rituximab did not result in additional clinical responses.

Adult↗
PubMed2006

Tumor suppressor p16 methylation in multiple myeloma: biological and clinical implications.

The biological and clinical implications of p16 gene methylation in multiple myeloma (MM) are still unclear despite previous studies. In this comprehensive study, using methylation-specific PCR (MS-PCR), we show that p16 methylation is relatively common and occurs in monoclonal gammopathy of undetermined significance (MGUS; n=17), smoldering multiple myeloma (SMM; n=40), and MM (n=522) at a prevalence of 24%, 28%, and 34%, respectively. However, p16 methylation does not appear to affect gene expression level. In a large cohort of patients with long-term follow-up information (n=439), there was no difference in overall survival between patients with or without p16 methylation. We also found no association between p16 methylation and the main cytogenetic categories, although it was more common among patients with 17p13.1 deletions (p53 locus), a genetic progression event in MM. In addition, p16 methylation has no apparent effect on the cycle because there was also no difference in the plasma cell labeling index (a direct measurement of proliferation) between patients with and without p16 methylation. Our results question a major role for p16 methylation in the oncogenesis of the PC neoplasm, and we now believe p16 methylation may be a marker for overall epigenetic changes associated with disease progression, with no obvious direct biological or clinical consequences.

Cell Cycle↗
PubMed2006

Expression of CXCL13, a chemokine highly upregulated in germinal center T-helper cells, distinguishes angioimmunoblastic T-cell lymphoma from peripheral T-cell lymphoma, unspecified.

The germinal center T-helper cell has been proposed as the cell of origin for angioimmunoblastic T-cell lymphoma. Our recent report of expression of CXCL13, a chemokine critical for germinal center formation and one of the most highly upregulated genes in the germinal center T-helper cell subset, in the majority of angioimmunoblastic T-cell lymphoma cases, provided further support for this theory. To determine the specifity of this marker for angioimmunoblastic T-cell lymphoma, we evaluated CXCL13 expression in 26 nodal-based peripheral T-cell lymphomas and 14 lymph nodes showing paracortical lymphoid hyperplasia. No significant paracortical CXCL13 staining was seen in the reactive lymph nodes. By WHO classification criteria, 20 of the lymphoma cases were considered peripheral T-cell lymphoma, unspecified, and six were reclassified as angioimmunoblastic T-cell lymphoma after immunohistochemical detection of disorganized follicular dendritic cell meshworks. Combining the results of our studies, 31 of 35 angioimmunoblastic T-cell lymphoma cases (89%) showed CXCL13 expression, in contrast to two out of 20 peripheral T-cell lymphoma, unspecified cases (10%). The two peripheral T-cell lymphoma, unspecified cases that were positive for CXCL13 showed a Lennert lymphoma-like histology. While these cases did not meet all histologic criteria for angioimmunoblastic T-cell lymphoma, they did show an increase in EBV-positive B cells, suggesting they may be histologic variants of angioimmunoblastic T-cell lymphoma. In conclusion, CXCL13 expression is a distinctive feature of angioimmunoblastic T-cell lymphoma, providing further support for the germinal center T-helper cell as the cell of origin for this neoplasm. Given its specificity when compared to cases of peripheral T-cell lymphoma, unspecified as well as paracortical lymphoid hyperplasia, it may be a useful marker in the diagnosis of angioimmunoblastic T-cell lymphoma.

Biomarkers, Tumor↗
PubMed2006

Prognostic significance of Bcl-6 protein expression in DLBCL treated with CHOP or R-CHOP: a prospective correlative study.

Bcl-6 protein expression, a marker of germinal center origin, has been associated with a favorable prognosis in diffuse large B-cell lymphoma (DLBCL). To determine the prognostic significance of this marker when rituximab (R) was added to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy, we prospectively studied Bcl-6 protein expression by immunohistochemical staining of 199 paraffin-embedded specimens from patients enrolled in the US Intergroup phase 3 trial comparing R-CHOP to CHOP with or without maintenance R. In Bcl-6(-) patients, failure-free survival (FFS) and overall survival (OS) were prolonged for those treated with R-CHOP alone compared to CHOP alone (2-year FFS 76% versus 9%, P < .001; 2-year OS 79% versus 17%, P < .001). In contrast, no differences in FFS and OS were detected between treatment arms for Bcl-6(+) cases. In the multivariate analysis, treatment arm (CHOP versus R-CHOP) was the major determinant of both FFS (P < .001) and OS (P < .001) for the Bcl-6(-) subset, whereas the International Prognostic Index risk group was the only significant predictor of outcome among Bcl-6(+) cases. Bcl-2 protein expression was not predictive of outcome in either group. In this study, we observed a reduction in treatment failures and death with the addition of R to CHOP in Bcl-6(-) DLBCL cases only. Our finding that Bcl-6(+) cases did not benefit from the addition of R to CHOP requires independent confirmation.

Aged↗
PubMed2006

The incidence and anatomic site specificity of chromosomal translocations in primary extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) in North America.

Several balanced translocations have been identified in extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) but there are few data regarding their frequency in different anatomic sites or the frequency of translocations involving BCL6 or kappa or lambda immunoglobulin light chain genes (IGK or IGL), particularly in patients from geographic regions other than Europe and Japan. One hundred thirty-three paraffin-embedded North American primary MALT lymphoma specimens from diverse anatomic sites were studied by fluorescence in situ hybridization (FISH) using probes for API2-MALT1, IGH-MALT1, IGH-BCL10, IGH-FOXP1, IGH, +/- centromeres 3, 7, 12, and 18, and a subset (n=74) were analyzed using FISH probes for IGK, IGL, and BCL6. Translocations were mutually exclusive and were detected in 26% of cases (17% API2-MALT1, 5% IGH-MALT1, 3% IGH-unknown translocation partner, and 1% IGH-BCL10). Aneuploidy was associated with IGH-MALT1 and IGH-BCL10 but only rarely with API2-MALT1. There was striking site specificity, with API2-MALT1 showing a marked predilection for lung and intestine, and IGH-MALT1 and IGH-BCL10 occurring almost exclusively in lung. Twenty-three percent of translocation-negative primary MALT lymphomas from diverse sites showed complete/partial trisomy 18. No MALT lymphomas with translocations involving IGK, IGL, BCL6, or FOXP1 were identified. This FISH panel detected cytogenetic abnormalities in half of all MALT lymphomas, and translocations arose preferentially in MALT lymphomas of the lung and gastrointestinal tract. Differences in incidence and anatomic site specificity of translocations between North American and non-North American cases may reflect geographic variability of infectious or other etiologic factors.

Adaptor Proteins, Signal Transducing↗
PubMed2005

BLyS and APRIL in rheumatoid arthritis.

The cytokines B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) enhance autoimmune disease by sustaining B cell activation. In RA, B cells contribute to the formation of 3 functionally distinct types of lymphoid microarchitectures in the inflamed synovium: ectopic GCs; T cell-B cell aggregates lacking GC reactions; and unorganized, diffuse infiltrates. We examined 72 tissues representing the 3 types of synovitis for BLyS and APRIL production and for expression of APRIL/BLyS receptors. Biologic effects of BLyS and APRIL were explored by treating human synovium-SCID mouse chimeras with the APRIL and BLyS decoy receptor transmembrane activator and CAML interactor:Fc (TACI:Fc). GC+ synovitis had the highest levels of APRIL, produced exclusively by CD83+ DCs. BLyS was present in similar levels in all tissue types and derived exclusively from CD68+ macrophages. In GC+ synovitis, treatment with TACI:Fc resulted in GC destruction and marked inhibition of IFN-gamma and Ig transcription. In contrast, inhibition of APRIL and BLyS in aggregate and diffuse synovitis left Ig levels unaffected and enhanced IFN-gamma production. These differential immunomodulatory effects correlated with the presence of TACI+ T cells in aggregate and diffuse synovitis and their absence in GC+ synovitis. We propose that BLyS and APRIL regulate B cell as well as T cell function and have pro- and antiinflammatory activities in RA.

Adult↗
PubMed2005

Rituximab therapy for patients with newly diagnosed, advanced-stage, follicular grade I non-Hodgkin's lymphoma: a phase II trial in the North Central Cancer Treatment Group.

PURPOSE: Patients with newly diagnosed, advanced-stage, follicular grade 1 non-Hodgkin's lymphoma (NHL) are often asymptomatic and can be observed without immediate chemotherapy. The goals of this study were to assess the overall response rate (ORR) to rituximab in this patient population and to determine the time-to-progression (TTP) and time-to-subsequent-chemotherapy (TTSC). PATIENTS AND METHODS: Eligible patients had untreated follicular grade 1 NHL, and measurable stage III/IV disease. Patients received rituximab 375 mg/m(2) intravenous weekly x 4 doses and were then followed for response and progression; no maintenance therapy was provided. RESULTS: Thirty-seven patients were accrued; one patient was ineligible. The median age was 59 years (range, 29 to 83 years). Six patients (18%) had elevated lactate dehydrogenase levels. The ORR was 72%, with 36% complete remissions. Fourteen (39%) of 36 patients remain in unmaintained remission, two died without disease progression, and three died with disease progression. Twenty (56%) of 36 patients have disease progression. The median TTP was 2.2 years (95% CI, 1.3 to not yet reached). Eighteen patients have subsequently been treated with chemotherapy, with a median TTSC of 2.3 years (95% CI, 1.6 to not yet reached). Patients with a high lactate dehydrogenase level had a lower ORR of 33% and a short TTP of only 6 months. CONCLUSION: Rituximab can be safely administered to patients with advanced-stage follicular grade 1 NHL with efficacy and minimal toxicity. This therapy is highly active and offers an acceptable alternative to observation in this patient population. Patients with high LDH should not be considered for rituximab monotherapy.

Adult↗
PubMed2005

Clinical significance of monoclonal B cells in cerebrospinal fluid.

BACKGROUND: Morphologically malignant lymphocytes in the cerebrospinal fluid (CSF) are highly suggestive of central nervous system involvement by lymphoid malignancy. Although flow cytometry is increasingly used to detect a monoclonal B-cell population in the CSF, the significance of this finding in the absence of morphologically identifiable malignant cells is unknown. METHODS: We reviewed CSF flow cytometric results in 32 patients studied at a single institution over 5 years and identified patients who had monoclonal B-cells in the CSF. Clinical presentation and course were reviewed. RESULTS: Twelve patients had a monoclonal B-cell population in the CSF, but only three had clinical evidence of malignant CNS disease. Of the other nine patients, 4 had nonmalignant neurologic disease and five had a lymphoproliferative disorder: chronic lymphocytic leukemia (n = 4) and mantle cell lymphoma (n = 1). In patients who had chronic lymphocytic leukemia and mantle cell lymphoma, the monoclonal B-cell population was small and had an immunophenotype identical to that of circulating malignant B cells. None of these nine patients developed clinical evidence of malignant CNS involvement during follow-up. CONCLUSION: In patients who have indolent B-cell malignancies, the presence of monoclonal B cells in the CSF may not be diagnostic of clinically significant CNS involvement by a lymphoid malignancy.

B-Lymphocytes↗
PubMed2005

A survey of clusterin and fascin expression in sarcomas and spindle cell neoplasms: strong clusterin immunostaining is highly specific for follicular dendritic cell tumor.

Clusterin, a glycoprotein implicated in many cellular functions including apoptosis, has recently been shown to be strongly expressed in follicular dendritic cell tumors, and to be absent or only weakly expressed in other dendritic cell tumors. Fascin has also been investigated as a potential marker of dendritic cell neoplasms. We evaluated staining for antibodies directed against these two antigens in 202 spindle cell tumors, including cases of follicular dendritic cell tumor (n=14), interdigitating dendritic cell tumor (n=7), leiomyosarcoma (n=17), inflammatory myofibroblastic tumor (n=13), inflammatory pseudotumor (n=2), spindle cell thymoma (n=17), synovial sarcoma (n=11), fibrosarcoma (n=14), liposarcoma (n=27), gastrointestinal stromal tumor (n=13), malignant fibrous histiocytoma (n=18), angiomatoid fibrous histiocytoma (n=4), angiosarcoma (n=10), malignant peripheral nerve sheath tumor (n=8), malignant melanoma (n=16), and spindle cell carcinoma (n=11). Among these spindle cell neoplasms, strong diffuse clusterin staining had an overall specificity of 93% and a sensitivity of 100% for follicular dendritic cell tumor. Clusterin staining was least reliable in distinguishing follicular dendritic cell tumor from spindle cell thymoma or malignant fibrous histiocytoma, but these are entities that usually can be distinguished by clinical and morphologic data. Rare cases of leiomyosarcoma, fibrosarcoma and angiosarcoma may show strong clusterin staining. Fascin staining was very nonspecific among spindle cell tumors and thus does not imply a dendritic cell lineage.

Carrier Proteins↗
PubMed2005

Diffuse large B-cell lymphoma with distinctive patterns of splenic and bone marrow involvement: clinicopathologic features of two cases.

Two unusual cases of large B-cell lymphoma with predominant splenic and bone marrow (BM) involvement and similar clinical and histopathologic features are described. Both patients presented with nonspecific constitutional symptoms, unexplained cytopenias, and splenomegaly. Splenectomy revealed diffuse red pulp involvement by large B-cell lymphoma. The perisplenic lymph nodes were also involved diffusely with effacement of normal nodal architecture, excluding a diagnosis of intravascular large B-cell lymphoma. BM biopsies revealed striking erythroid hyperplasia without overt morphologic evidence of involvement by lymphoma. Immunoperoxidase staining of the marrow biopsies with antibodies to CD20 and erythroid-associated antigens revealed involvement by large B-cell lymphoma morphologically resembling the early pronormoblasts. In both cases there was prominent, but not exclusive, intravascular/intrasinusoidal lymphomatous marrow infiltration. These cases represent an unusual variant of large B-cell lymphoma with distinctive patterns of splenic and BM involvement. Furthermore, they underscore the difficulties in identifying intrasinusoidal marrow infiltration by lymphoma in H&E-stained biopsy slides and demonstrate that this pattern of marrow infiltration may be seen in cases of large B-cell lymphoma distinct from the intravascular variant.

Aged↗
PubMed2005

Clinical outcome of patients with subcutaneous panniculitis-like T-cell lymphoma.

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare form of cytotoxic T-cell lymphoma. The objective of this study was to characterize the clinical presentation, treatment, and prognosis of patients with SPTCL. Twenty-one patients with SPTCL were seen at Mayo Clinic (Rochester, Minnesota, USA) between July 1973 and June 2004. The median age at diagnosis was 42 years (range 23-80 years) and 15 (71%) were women. Constitutional symptoms occurred in 14 (67%) patients, including fever, serositis, arthralgias and myalgias. The Eastern Cooperative Oncology Group performance score was poor (3-4) in 3 (15%) patients. Liver enzymes (at least 2 enzymes, Aspartate aminotransferase (AST), alkaline phosphatase and/or lactate dehydrogenase) were elevated in 11 (52%) patients. Therapy consisted of chemotherapy in 13 (62%) patients, or other therapeutic interventions in 8 (38%) patients, including surgical excision, corticosteroids alone or in combination with either plaquenil, colchicine, hydroxychoroquine, or azathioprine. Bone marrow transplantation was performed in 5 (24%) patients, 3 autologous and 2 allogeneic. The median overall survival from diagnosis was 15 months (range 0.1-104 months). Two groups of patients were identified and categorized as having a favorable or unfavorable disease course. The factors associated with an unfavorable disease course were a low white blood cell count or elevated lactate dehydrogenase. Patients treated aggressively with stem cell transplantation appeared to have an improved overall survival.

Adult↗
PubMed2005

Adult B-cell lymphomas with burkitt-like morphology are phenotypically and genotypically heterogeneous with aggressive clinical behavior.

Adult, de novo B-cell lymphomas meeting the WHO morphologic criteria for atypical Burkitt/Burkitt-like lymphoma cause diagnostic difficulty for pathologists because the genetic and clinical characteristics of this group of lymphomas have not been clearly defined. Thirty-one such lymphomas, designated as Burkitt-like lymphomas (BLL), were selected based on morphologic features and evaluated for immunophenotype, MYC and BCL2 status, and clinical features. Nine childhood Burkitt lymphomas (BL) and 87 adult, de novo diffuse large B-cell lymphomas (DLBL) were similarly evaluated for comparison. The BL group demonstrated uniform characteristics: all had Burkitt lymphoma morphology, an identical immunophenotype (positive for CD20, CD10, bcl-6, CD43, and p53; negative for CD138, CD23, bcl-2), high MIB-1 positivity, IGH/MYC translocation, no IGH/BCL2 translocation, and all patients were alive at the last follow-up. The BLL and DLBL groups were heterogeneous. Burkitt-like morphology alone correlated with decreased survival. IGH/MYC or IGL/MYC fusion was identified in 11 of 27 (41%) BLL and 4 of 76 (5%) DLBL and was associated with decreased survival in both groups. MIB-1 positivity did not correlate with morphology, MYC abnormalities, or survival. We propose that adult B-cell lymphomas with BLL morphology are a phenotypically and genetically heterogeneous group of aggressive lymphomas, biologically distinct from childhood BL. Until biologically accurate subgroups within this morphologically defined group are identified, it is appears that both recognition of BLL morphology and direct evaluation for the presence of MYC fusion to immunoglobulin genes are important for identification of adult patients with poorer prognosis than those with DLBL.

Adolescent↗
PubMed2005

FISH is superior to PCR in detecting t(14;18)(q32;q21)-IgH/bcl-2 in follicular lymphoma using paraffin-embedded tissue samples.

Detection of t(14;18)(q32;q21)-IgH/bcl-2, which is present in 70% to 95% of follicular lymphomas (FLs), might aid in diagnosing FL. The efficacy of routine polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH) techniques in detecting t(14;18) in paraffin-embedded tissue samples was compared on 5 normal tonsils and 28 FLs demonstrated to be t(14;18)+ by previous karyotyping. There was technical failure in 14 (50%) of the FLs by PCR, likely due to B-5 fixation, and 4 (14%) of FLs by FISH, likely due to advanced specimen age. In the remaining successful cases, 5 (36%) of 14 were positive by PCR and 24 (100%) of 24 were positive by FISH. All 5 normal tonsils were negative by both methods. FISH is superior to PCR for detecting t(14;18) from paraffin-embedded tissue samples because it is more sensitive and equally specific.

Chromosomes, Human, Pair 14↗
PubMed2004

Clinical characteristics of familial vs. sporadic non-Hodgkin lymphoma in patients diagnosed at the Mayo Clinic (1986-2000).

There are few data on the clinical characteristics of familial vs. sporadic non-Hodgkin lymphoma (NHL). Using the NHL registry at the Mayo Clinic, we compared age of diagnosis, gender, tumor site and histologic subtype between patients with sporadic and familial NHL. In 2001, we identified all new cases of adult NHL diagnosed between 1986 and 2000 in the Mayo Clinic NHL database (n = 2289) and mailed out a family history questionnaire to all living patients with a current address (n = 1043). Each NHL patient was categorized according to their self-report of leukemia or lymphoma in first-degree (1 degree) relatives. We received complete FH information on 740 patients (71%). Age at diagnosis of NHL ranged from 18-88 years (mean = 59 years) and 53% of our cases were male. First-degree FH of lymphoma was reported by 43 patients (6%), 1 degree FH of leukemia by 27 patients (4%) and 1 degree FH of both in 4 (1%). There was a nonstatistically significant later age at diagnosis for cases with any family history of lymphoma or leukemia (mean age = 61.3 and 61.7 years, respectively) vs. no family history (59.0 years) (P = 0.58). The male to female ratio for those with a FH of leukemia (ratio = 2.9) was higher compared to those with FH lymphoma (0.95) or no FH (1.1) (P = 0.08). No differences were apparent between 1 degree FH and site of NHL (nodal vs. extranodal) (P = 0.53). Among recently diagnosed cases (since 1995), there was some suggestion of a greater proportion of aggressive tumors for those with any family history (69% and 55%) vs. none (50%) (P = 0.20). We found little evidence of large differences between familial and sporadic NHL with regard to age, gender, site or histologic subtype.

Adolescent↗
PubMed2004

Clusterin expression distinguishes follicular dendritic cell tumors from other dendritic cell neoplasms: report of a novel follicular dendritic cell marker and clinicopathologic data on 12 additional follicular dendritic cell tumors and 6 additional interdigitating dendritic cell tumors.

While tumors of dendritic cell lineage may have overlapping histomorphologic features, most but not all cases can be classified using an immunohistochemical panel, including CD21, CD23, CD35, CD1a, and S-100. Based on observations that clusterin is expressed in benign follicular dendritic cells, clusterin expression in 32 dendritic cell tumors was evaluated. Diffuse strong staining for clusterin was seen in 12 of 12 follicular dendritic cell tumors. Two of these cases were negative for traditional markers (CD21, CD23, CD35); they were classified based on characteristic ultrastructural features. Three of 6 interdigitating dendritic cell tumors were negative for clusterin and 3 showed focal weak positivity. Clusterin staining in Langerhans cell histiocytosis ranged from negative (6 of 14) to weak/moderate (8 of 14). Follicular dendritic cell tumors behaved as benign tumors or low-grade sarcomas. Interdigitating dendritic cell tumors demonstrated a widely variable behavior, ranging from benign to rapidly fatal disease. Based on this initial study, strong clusterin staining supports a diagnosis of follicular dendritic cell tumor. Thus, staining for clusterin is useful in classification of dendritic cell tumors, particularly when the more common markers of follicular dendritic cells are not expressed.

Adolescent↗