Biomedical subjects
Reza Parwaresch
Publications and source records attributed to Reza Parwaresch.
Differential expression of cancer testis genes in histological subtypes of non-Hodgkin's lymphomas.
PURPOSE: The purpose of this study was to determine the potentialof cancer testis (CT) antigens as vaccines for non-Hodgkin's lymphomas (NHLs). EXPERIMENTAL DESIGN: Ninety-three specimens of NHLs were analyzed for their composite expression of eight CT genes (MAGE-3, MAGE-4, CT-7, HOM-MEL-40/SSX-2, SSX-1, SSX-4, HOM-TES-14/SCP-1, and HOM-TES-85). Thirty-nine of these specimens were also analyzed for their NY-ESO-1 expression. RESULTS: Only 1 of 7 cases of chronic lymphocytic leukemia expressed a CT gene (HOM-TES-14/SCP-1), and 10 follicular lymphomas were negative for all of the CT genes tested. In B-cell lymphomas, the most frequent expression of CT genes was observed in diffuse large-cell lymphomas (HOM-TES-14/SCP-1: 7 of 28; SSX-1: 5 of 28; CT-7: 2 of 28; and HOM-MEL-40/SSX-2 and HOM-TES-85: 1 of 28 positive cases). Only 1 of 8 Burkitt's and 1 of 7 lymphoblastic lymphomas expressed a CT gene (CT7 and HOM-TES-14/SCP-1, respectively). A majority (9 of 15) of T- NHLs (9 peripheral T-cell lymphomas, 2 lymphoblastic T-cell lymphomas, and 4 cases of AILD) expressed HOM-TES-14/SCP-1. CONCLUSIONS: HOM-TES-14/SCP-1, and to some degree SSX-1 and CT-7 might be candidates for lymphoma vaccine development. However, the identification of additional tumor-specific antigens with a frequent expression in lymphomas is warranted to allow for the development of widely applicable polyvalent lymphoma vaccines.
repp86: A human protein associated in the progression of mitosis.
Human repp86 becomes detectable in the nucleoplasm of cycling cells at the G(1)-S boundary, condenses at the centrosomes with the onset of mitosis, during which it progressively locates to the mitotic spindle and to the midbody, and vanishes at the completion of cytokinesis. The repp86 cDNA was cloned and sequenced. Full-length repp86 and its COOH-terminal domain cosediment with polymerized microtubules, linking repp86 to the family of microtubule-associated proteins. During prophase and metaphase, repp86 interacts on the mitotic spindle with the putative motor protein Hklp2. Thus, repp86 may function in targeting Hklp2 to the microtubule minus ends, its activity being regulated by phosphorylation of serine/threonine residues. Exogenous overexpression of repp86 provokes accumulation of cells in G(2)-M phase and subsequent polyploidization, suggesting that excess repp86 may interfere with correct nuclear division.
Randomized study to evaluate the use of high-dose therapy as part of primary treatment for "aggressive" lymphoma.
PURPOSE: This trial of the German High-Grade Non-Hodgkin's Lymphoma Study Group compares the use of high-dose therapy (HDT) as part of primary treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus etoposide followed by involved-field (IF) radiotherapy in a randomized, multicenter, phase III study. PATIENTS AND METHODS: Three hundred twelve patients with "aggressive" non-Hodgkin's lymphoma aged <or= 60 years with elevated serum lactate dehydrogenase levels were included from 1990 to 1997. Patients with at least a minor response after two cycles of CHOEP (CHOP + etoposide 3 x 100 mg/m(2)) were to receive three further cycles of CHOEP followed by IF radiotherapy (arm A) or one further cycle of CHOEP followed by autologous stem-cell transplantation and IF radiotherapy (arm B). RESULTS: Among 158 patients randomized to arm B, 103 (65%) received HDT. The complete remission rate at the end of treatment was 62.9% in arm A and 69.9% in arm B. With a median observation time of 45.5 months, overall survival for all 312 patients was 63% after 3 years (63% for arm A, 62% for arm B; P =.68). Event-free survival was 49% for arm A versus 59% for arm B (P =.22). Relapse in arm B was associated with a significantly worse survival rate than relapse in arm A (P <.05). Relapse after HDT occurred early (median interval, 3 months). Six patients developed secondary neoplasia, three in arm A and three in arm B. CONCLUSION: Results of the randomized trial comparing CHOP-like chemotherapy with early HDT do not support the use of HDT with carmustine, etoposide, cytarabine, and melphalan following shortened standard chemotherapy.
Proliferation marker KI-S5 discriminates between favorable and adverse prognosis in advanced stages of neuroblastoma with and without MYCN amplification.
BACKGROUND: The biologic behavior of neuroblastoma is notoriously variable, and even carefully elaborated prognostic models fail to predict the clinical course in a portion of cases. Because the proliferative activity is determined by the sum of all molecular imbalances that influence cell cycling, the authors investigated the potential prognostic relevance of the tumor growth fraction in neuroblastoma. METHODS: A retrospective analysis was conducted on a cohort of 161 neuroblastoma patients with a median follow-up period of 72.8 months. Tumors were classified according to Hughes typing and grading criteria. The proliferative index (PI) was assessed immunohistochemically on archival biopsy specimens using monoclonal antibody Ki-S5 (Ki-67), and the MYCN status was determined by means of Southern blot analysis. RESULTS: The PI, MYCN status, International Neuroblastoma Staging System (INSS) stage, International Neuroblastoma Pathology Classification grade, Hughes grade, and the patients' age at diagnosis were all found to be significant predictors of event free survival by univariate Kaplan-Meier analysis. However, the PI identified prognostically distinct subsets in higher tumor stages and Grade 2 and 3 neuroblastomas as well as tumors with unfavorable histology, and enabled risk stratification in tumors with and without MYCN amplification (P = 0.034 and 0.002, respectively). Multivariate Cox regression analysis selected INSS stage (relative risk [RR], 4.05; P < 0.0001) and the PI (RR, 2.49; P = 0.007) as the sole independent prognostic indicators, whereas MYCN entered the selection only after exclusion of the PI. CONCLUSIONS: It emerges that the PI as a single factor has greater predictive power than the MYCN status. Proliferation measurements therefore might significantly improve the accuracy of current prognostic models for neuroblastoma.
Preimplantation-stage stem cells induce long-term allogeneic graft acceptance without supplementary host conditioning.
Hematopoietic stem cells have been successfully employed for tolerance induction in a variety of rodent and large animal studies. However, clinical transplantation of fully allogeneic bone marrow or blood-borne stem cells is still associated with major obstacles, such as graft-versus-host disease or cytoreductive conditioning-related toxicity. Here we show that when rat embryonic stem cell-like cells of WKY origin are injected intraportally into fully MHC-mismatched DA rats, they engraft permanently (>150 days) without supplementary host conditioning. This deviation of a potentially alloreactive immune response sets the basis for long-term graft acceptance of second-set transplanted WKY cardiac allografts. Graft survival was strictly correlated with a state of mixed chimerism, which required functional thymic host competence. Our results provide a rationale for using preimplantation-stage stem cells as vehicles in gene therapy and for the induction of long-term graft acceptance.
Chronic sclerosing sialadenitis of the submandibular gland is mainly due to a T lymphocyte immune reaction.
The aim of our study was to investigate the role of immunopathological processes in the pathogenesis of chronic sclerosing sialadenitis of submandibular glands (Küttner tumor). For this purpose, biopsy specimens from submandibular glands of 22 patients with the histological diagnosis of chronic sclerosing sialadenitis were analyzed. Paraffin-embedded tissues were immunostained for T-lymphocyte subsets (CD3, CD4, CD8), cytotoxic T cells (granzyme B), B cells (CD20, Ki-B3), and macrophages (Ki-M1P). Polymerase chain reaction and capillary electrophoresis were used to detect rearrangements of the T-cell receptor gamma chain and the CDRIII region of the immunoglobulin heavy chain. In all cases, abundant cytotoxic T cells were found, especially in close association with ducts and acini. T-cell receptor gamma chain rearrangements showed a monoclonal pattern in 6 cases (27.3%), an oligoclonal pattern in 8 (36.4%), and a polyclonal pattern in 8 (36.4%). The B-cell reaction was less pronounced and largely restricted to lymph follicles. Molecular analysis of immunoglobulin heavy chain revealed a polyclonal rearrangement in 17 cases (77.3%). In conclusion, there is an intimate relationship between the T-cell-dominated inflammatory infiltrate and acinar and duct cells. This, together with the frequent demonstration of monoclonal and oligoclonal populations of cytotoxic T cells and their histopathological behavior, suggests that chronic sclerosing sialadenitis may be the result of an immune process triggered by intraductal agents.
Analysis of the human herpesvirus 8 (HHV-8) genome and HHV-8 vIL-6 expression in archival cases of castleman disease at low risk for HIV infection.
Lymph nodes from 44 patients with Castleman disease (CD) without risk factors for HIV infection were analyzed with polymerase chain reaction (PCR), in situ hybridization (ISH), and immunohistochemical analysis for human herpesvirus 8 (HHV-8) and viral interleukin-6 (vIL-6). PCR detected HHV-8 genome in 2 of 4 cases; ISH detected it in 9 of 16 cases. HHV-8 vIL-6 peptides were detected in 2 of 44 cases. vIL-6- and ISH-positive cells were found in large transformed and small lymphocytes of the follicular mantle, respectively. Of 9 cases of plasma cell (PC) CD that demonstrated HHV-8 genome by PCR or ISH, 1 expressed vIL-6. Clonal populations of PCs in CD by immunohistochemical analysis or immunoelectrophoresis of serum and urine were associated with neuropathy. HHV-8 vIL-6 detection was associated with poor survival and lack of HHV-8 IL-6, with low risk for subsequent lymphoma. Although HHV-8 genome was detected in a considerable number of patients with PC CD, vIL-6 expression was infrequent. Expression of HHV-8 vIL-6 in CD may indicate poor prognosis in patients at risk for lymphoma who may prospectively require more aggressive treatment. The lack of vIL-6 expression in CD with HHV-8 genome suggests that human IL-6 rather than vIL-6 may be the principal pathogenic cytokine.
[Detection and analysis of bcl-1/IgH rearrangement in mantle cell lymphoma]
OBJECTIVE: To investigate the specificity and sensitivity of the PCR technique in the identification of bcl-1/IgH gene rearrangement in mantle cell lymphoma (MCL) and to characterize the bcl-1/IgH junction DNA sequences. METHODS: A semi-nested PCR method to amplify bcl-1/IgH gene rearrangement in DNA from fresh frozen lymphonode specimen was established. Twenty-eight cases of mantle cell lymphoma were analyzed for the presence of bcl-1/IgH gene rearrangement. The rearrangement products was cloned and sequenced to recognize the junction sequences, the breakpoints in the bcl-1 region, and J(H) gene involved in the rearrangement. RESULTS: A bcl-1/IgH gene rearrangement was detected in 17 out of 28 cases of MCL, while only 9 cases was detected with single step PCR method (X(2)=4.59, P<0.05). The rearrangement product varied in size between 74 to 162 base pairs, and the length of the junction sequences ranged from 6 to 24 base pairs. Ten different bcl-1 breakpoints were clustered within 65 base-pair spans, among which, 5 breakpoints (located at 430, 440, 451, 486 and 492) were never reported by other authors. The most common J(H) gene segments utilized in the translocation were J(H) 4 (8/18), then J(H)5 (3/18), J(H)6 (2/18), J(H)4/5 (2/18). J(H)1 2/18, and J(H)3 (1/18). CONCLUSION: These results indicate that the semi-nested PCR is a specific and sensitive method for the detection of bcl-1/IgH gene rearrangement in mantle cell lymphoma, which has implications for both the diagnosis and clinical management of mantle cell lymphoma. The recognization the potential mechanism of bcl-1/IgH gene rearrangement will help us to know the exact pathogenic machanisms of MCL.
Compartment analysis of T cell receptor gamma--and immunoglobulin V(H) rearrangements by microdissection in patients with malt lymphoma and chronic gastritis with lymphatic hyperplasia.
The interpretation of clonality within H. pylori-associated gastritis and low-grade MALT lymphoma remains controversial. Due to the observation of MALT lymphoma regression after H. pylori eradication, new definitions concerning the border between benign reactive lesions and malignant gastric lymphoma are needed. Gene rearrangements for immunoglobulin heavy-chain in low-grade MALT lymphoma (N= 12) and H. pylori-associated chronic gastritis with lymphatic hyperplasia (N= 13) were analyzed by microdissection and polymerase chain reaction. Furthermore, T cell receptor-gamma chain rearrangements were analyzed by gene scan analysis. In 11 of 12 cases with initial low-grade MALT lymphoma, intraepithelial and subepithelial B cell rearrangements showed a restricted usage of the immunoglobulin heavy-chain 3. In H. pylori-associated chronic gastritis, the intraepithelial B cell compartment showed an oligoclonal the immunoglobulin heavy-chain rearrangement pattern with a predominance of VH3. The subepithelial compartment did not show any restrictive immunoglobulin heavy-chain gene usage. Additionally a mono- to oligoclonal rearrangement pattern of the T cell receptor-y chain was observed in low-grade MALT lymphoma, whereas an oligoclonal pattem was observed in chronic gastritis. Our data provide evidence that low-grade MALT lymphoma may start within the epithelium and subsequently infiltrate the subepithelial compartment. The observation of a mono- to oligoclonal TCR-gamma rearrangement suggests that an antigen selecting process also takes place within reactive T cells. Combining TCR-gamma gene scan analysis with IgH chain rearrangement analysis might help in discriminating between chronic gastritis and initial MALT lymphoma in questionable cases.
Ki-S1--a prognostic marker for hypopharyngeal carcinoma with potential predictive value for response to chemotherapy.
BACKGROUND: It has previously been shown that the proliferative activity, determined by means of the monoclonal antibody Ki-S11 against the Ki-67 protein, is a significant prognostic factor for squamous cell carcinoma of the hypopharynx (SCCH). We now investigated the prognostic and the predictive impact of Ki-S1, a monoclonal antibody which detects an epitope of topoisomerase II alpha, another proliferation-associated antigen. MATERIALS AND METHODS: The proliferation index (PI) in terms of Ki-S1 immunolabeling was evaluated on tumor specimens from 131 patients with SCCH. Survival probabilities over an observation time of 72 months were calculated by Kaplan-Meier analysis. RESULTS: Patients with low PI (< or = 45%) had a significantly improved 5-year survival (33.2%) compared with patients with high PI (> 45%), of whom only 11% survived after 5 years (p = 0.001). Since there was no significant difference between the results obtained with Ki-S1 and Ki-S11, the present data confirm the prognostic significance of the proliferative activity in SCCH. CONCLUSION: Topoisomerase II alpha is also the target of many antineoplastic drugs and it has been proposed that its expression in tumor cells correlates with chemosensitivity. The high average topoisomerase II alpha content in SCCH therefore promises a good responsiveness to topoisomerase inhibitors. Because Ki-S1 directly measures cellular topoisomerase II alpha expression, it might be exploited not only as a prognostic indicator but also as a predictive marker for patients with SCCH.
Telomere biology and the molecular basis of aging.
Process of aging is regulated on the level of organism, clones and cellular level. Genes regulating aging on the individual (organism) level are detected in unicellular fungi. Mutations of such genes may lead to life lengthening by 60%. A similar gene is found in mice. Aging at the clonal level takes place by means of telomere shortening--that of DNA regions close to chromosome endings. Telomere shortening results in the chromosomes instability, their breaks and mutations, this apparently being a mechanism responsible for the increase of cancer incidence at advanced age. Telomerase is an enzyme responsible for the stability of the telomere length, supporting proliferation and by this that of life. This explains the increase of telomerase activity practically in all cases of malignant tumors. Aging is regulated by molecular components of cell cycle on cellular level.