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R Munker

Publications and source records attributed to R Munker.

At least 19 recordsLinked to original sources
PubMed2006

Graft-versus-host and graft-versus-leukemia reactions: a summary of the Seventh International Symposium held in Garmisch-Partenkirchen, Germany, February 22nd-25th, 2006, Tolerance and Immunity, an update on lymphoid malignancies.

The Seventh International Symposium on graft-versus-host and graft-versus-leukemia reactions was held in Garmisch Partenkirchen (Germany, near Lake Riessersee) between January 22nd and 25th, 2006. A total of more than 100 invited participants (scientists and clinicians working in the area of allogeneic stem cell transplantation) discussed research in the area of lymphoid malignancies. Major topics of the 2006 meeting were lymphocyte biology, experimental systems, lymphoma pathogenesis, cellular therapy in vivo and vitro, idiotype-specific responses and graft-versus-malignancy reactions for lymphomas and multiple myeloma. Further highlights were immune responses to blasts of ALL, haploidentical transplantation, role of natural killer cells, clinical guidelines for allogeneic transplantation and adoptive immunotherapy in chronic lymphocytic leukemia and multiple myeloma, new antibody-mediated strategies. As can be seen in the summaries of the individual presentations, progress was made in the understanding of lymphoma biology and in the clinical application of graft-versus-lymphoma or graft-versus-myeloma effects. Each day was followed by round-table discussions, which summarized new data and challenged established concepts. The discussions resulted in new insights and projects for basic research and clinical transplantation.

Animals↗
PubMed2004

An update on graft-versus-host and graft-versus-leukemia reactions: a summary of the sixth International Symposium held in Schloss Ellmau, Germany, January 22-24, 2004.

The Sixth International Symposium on Graft-versus-Host and Graft-versus Leukemia Reactions was held in Schloss Ellmau (near Garmisch-Partenkirchen, Germany) between January 21 and 24, 2004. A total of 110 invited participants (scientists and clinicians working in the area of allogeneic stem cell transplantation) discussed current topics. Major topics of the 2004 meeting were: clinical results of donor lymphocyte infusions, basic biology, immunogenetics, function and clinical relevance of natural killer cells, haplo-identical stem cell transplantation, immune monitoring and immune modulation. Further highlights were: adoptive immunotherapy, vaccination and antibody-mediated strategies. As can be seen in the summaries of the individual presentations, important advances have occurred in our understanding of GVH and GVL reactions. Each session was followed by an animated discussion, which resulted in new ideas, insights and projects both for basic research and clinical transplantation. This year's symposium ('From Marrow Transplantation to Cell Therapy') was jointly organized by the Ludwigs-Maximilians-University of Munich (Sonderforschungsbereich 455), GSF (National Research Center for Environment and Health) and the EBMT Immunobiology Working Party. The organizers and authors of the conference proceedings would like to extend their gratitude to all participants for sharing their ideas, slides and manuscripts and making this event possible.

Graft vs Host Disease↗
PubMed2004

Treatment of advanced Hodgkin's disease with COPP/ABV/IMEP versus COPP/ABVD and consolidating radiotherapy: final results of the German Hodgkin's Lymphoma Study Group HD6 trial.

BACKGROUND: The purpose of this study was to compare the efficacy of the hybrid chemotherapeutic regimen COPP/ABV/IMEP (cyclophosphamide-vincristine-procarbazine-prednisone-doxorubicin-bleomycin-vinblastine-ifosfamide-methotrexate-etoposide) (CAI) with that of the standard regimen COPP/ABVD (COPP/ABV, dacarbacine) (CA) in the treatment of advanced-stage Hodgkin's disease (HD). PATIENTS AND METHODS: Between January 1988 and January 1993, 588 eligible patients with HD in stages IIIB and IV were randomly assigned to a treatment or control group. The treatment group received four cycles of CAI over a complete cycle duration of 43 days. The control group received four cycles of CA over 57 days. Both groups then received consolidating radiotherapy. RESULTS: Five hundred and eighty-four patients were suitable for arm comparison. Patients in each group were similar in age, sex, histological subtype and clinical risk factors. Complete remission rates, overall survival and freedom from treatment failure at 7 years were similar for the two groups: 77% versus 78%, 73% versus 73% and 54% versus 56% for CAI and CA, respectively. Differences in acute chemotherapy-related toxicity were significant, however. Prognostic factor analysis confirmed the relevance of the International Prognostic Index and revealed that stage IVB, low hemoglobin, low lymphocyte count, high age and male gender were associated with a poor prognosis CONCLUSION: The rapidly alternating hybrid CAI did not give superior results when compared with the standard regimen CA in advanced-stage HD.

Adolescent↗
PubMed2004

Contribution of PET imaging to the initial staging and prognosis of patients with Hodgkin's disease.

BACKGROUND: Positron emission tomographic (PET) scanning utilizing [18F]fluorodeoxyglucose (FDG) is a new method of tumor imaging based on the increased glucose metabolic activity of malignant tumors. In Hodgkin's disease (HD), PET has proven value for the evaluation of residual masses following treatment and for the early diagnosis of relapse. In the initial staging of HD, PET frequently shows a higher stage than conventional methods (upstaging by PET). In the present study, we evaluated the frequency of stage changes by PET in a multicenter setting and determined its prognostic relevance. PATIENTS AND METHODS: A total of 73 patients with newly diagnosed HD were staged with both conventional methods and whole-body PET scanning. All histological types and stages were represented. The median time of follow-up after the initial diagnosis was 25 months (range 1 month to 5 years). The response to treatment was determined by standard clinical and diagnostic criteria. For the purpose of this analysis, data from a PET center associated with a university medical center and a PET center associated with a group oncology practice were combined. RESULTS: A total of 21 patients (28.8%) were upstaged by PET compared with conventional methods. In two cases (2.7%), a lower stage was suggested by PET scanning. With one possible exception, the upstaging had no obvious clinical or biological correlate. Among 12 patients in stage I (A + B) by conventional methods, seven were upstaged by PET (58.3%), four to stage II, one to stage III and two to stage IV. Among 42 patients in stage II, eight were upstaged by PET (19.0%), six to stage III and two to stage IV. Among 12 patients in stage III, six (50%) were upstaged to stage IV by PET. If only early-stage patients and major changes are considered (stages IA-IIB to III or IV), among 49, 10 were upstaged to III or IV, whereas in 39 staging was unchanged following PET. In the former group, three relapsed or were refractory compared with none in the latter group (P<0.006). In advanced stage patients (IIIA or IIIB) a trend toward treatment failure was apparent in patients who were upstaged by PET. CONCLUSIONS: PET scanning is an interesting new modality for the accurate staging of patients with HD and frequently shows a higher stage than conventional methods. PET should be performed at initial diagnosis and should be included in prospective studies of patients with HD. Upstaging by PET may represent a risk factor for a more advanced stage or a biologically more aggressive tumor. Patients with early-stage disease as identified by conventional methods have a significant risk of treatment failure if a more advanced stage is indicated by PET. At present, major stage changes suggested by PET imaging should be confirmed by an independent diagnostic method.

Adult↗
PubMed2002

Monoclonal gammopathy after low-grade MALT lymphoma: evidence for a second neoplasm.

We report the case of a patient with lymphoma of the salivary gland, at first diagnosed as lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) but later found to infiltrate the bone marrow. At diagnosis, the patient had a polyclonal increase of gamma-globulins. Five years after initial diagnosis, the patient presented with monoclonal gammopathy and infiltration of the bone marrow with neoplastic cells. Initially, the patient had received chemotherapy with different protocols (including etoposide, cyclophosphamide, fludarabin, methotrexate, and vincristine), none of which induced a lasting response. Therapy with rituximab (chimeric anti-CD20 monoclonal antibody) finally led to partial remission. Eighteen months after rituximab, progressive lymphoma in the abdomen and a monoclonal gammopathy developed. The bone marrow showed infiltration by lymphoplasmacytoid cells (monoclonal expression of the light-chain type lambda, positive for CD20, heterogeneous expression of CD45). The patient achieved another short clinical response with 4 cycles of the CHOP-protocol, but soon the lymphoma progressed again. Five years and 8 months after the initial diagnosis, the patient died from septicemia and progressive lymphoma. By polymerase chain reaction (PCR) for the IgH gene it was shown that lymphoma cells were initially oligoclonal in the salivary gland and, later, biclonal in the bone marrow. Sequencing of two bands of apparently same length showed that these manifestations of lymphoma were not identical. Taken together, our data show that the initial low-grade oligoclonal MALT lymphoma was no longer present and a more aggressive biclonal lymphoma with plasmacytoid differentiation had developed. The new lymphoma was clonally distinct and produced high amounts of monoclonal IgG lambda by immunoelectrophoresis. The relationship of the second lymphoma to the initial MALT lymphoma is discussed.

Antibodies, Monoclonal↗
PubMed2002

New concepts about graft-versus-host and graft-versus-leukaemia-reactions. A summary of the 5th International Symposium held in Munich, 21 and 22 March 2002.

The Fifth International Symposium on Graft-versus-Host and Graft-versus-Leukemia Reactions was held on 21 and 22 March 2002 in the University Hospital (Klinikum Grosshadern) of the University of Munich. As in previous years, it was dedicated to the encounter of scientists and clinicians involved in hematopoietic cell transplantation. This year's symposium focused on the characterization of stem cells potentially expanding the use of hematopoietic stem cells and on gene therapy. The immunology section dealt with mechanisms of tolerance, and the characterization of minor histocompatibility antigens presented by major histocompatibility molecules. Further important topics were cytokines and dendritic cells. In 1 and 1/2 days of intense work, the invited speakers, chairmen, authors and an active audience experienced an exciting exchange of ideas and collaboration. Again, new impulses were given for basic research and clinical transplantation. The authors would like to express their deep appreciation and thanks to all participants of this symposium.

Animals↗
PubMed2001

Different types of human leukemias express the message for TNF-alpha and interleukin-10.

Leukemic cells proliferate under the influence of cytokines. In particular, the colony-stimulating factors stimulate the growth and proliferation of myeloid leukemia cells. Under normal conditions, tumor necrosis factor-alpha (TNF-alpha) is produced by activated monocytes, whereas interleukin- 10 (IL-10) is produced by several cell types like monocytes and lymphocytes. The autocrine production of cytokines by leukemic cells may have a pathogenic role in the progression of leukemia or may be an epiphenomenon. In this study, we investigated the expression of TNF-alpha and IL-10 in human leukemic cells by RT-PCR and by a cytoplasmic protein assay. Most cases of acute myelogenous leukemia (AML) (7/8 cases) and all cases of acute lymphoblastic leukemia (ALL) (n = 2), chronic myelogenous leukemia (CML) (n = 5), both in chronic phase and during blast crisis, expressed the mRNA for TNF-alpha and IL-10. A patient whose blasts were positive for IL-10 and negative for TNF-alpha, had high circulating levels of IL-10 and failed to respond to donor lymphocyte infusions. Using a cytoplasmic protein assay, generally low levels of cytoplasmic TNF-alpha and IL-10 were found which increased in case of TNF-alpha following stimulation with lipopolysaccharide. Taken together, our data show that most leukemic cells express the mRNA for a proinflammatory cytokine (TNF-alpha) and an immunosuppressive cytokine (IL-10). More work is necessary to determine under which conditions these cytokines actually paralyze the immune system and thereby permit the progression of leukemia.

Gene Expression Profiling↗
PubMed2001

Levels of insulin-like growth factor after stem cell transplantation.

Some cytokines, i.e. tumor necrosis factor-, interleukin-6 and soluble interleukin-2 receptors are associated with complications of stem cell transplantation. Insulin-like growth factors (IGFs) are a family of peptides essential for the proliferation of normal and malignant cells. Recently increased levels of IGFs have been associated with the development of malignant tumors. In this communication we report on 96 measurements of insulin-like growth factor-I (IGF-1), insulin-like growth factor-II (IGF-2), and insulin-like growth factor-binding protein-3 (IGFBP-3) performed in 19 patients following stem cell transplants. Seventeen patients had allogeneic and 2 patients autologous transplants. Most IGF determinations were made at days 0, 7, 14, 21 and 28, some at other time points. The baseline values (day 0) of IGF-1 and IGFBP-3 were not different from controls. IGF-2 values were slightly lower than controls. Following transplantation, a consistent increase of IGF-1 was observed in 9/16 patients at days 7 and 14. Later the values decreased again. IGF-2 and IGFBP-3 did not change significantly after transplantation. No direct correlation could be established with the severity of graft-versus-host disease, levels of interleukin-6 and the time to hematopoietic recovery. A potential relevance of IGFs following stem cell transplantation may be the early diagnosis of liver damage and the development of second malignancies. More studies are necessary to investigate the pathophysiology and the clinical relevance of the increase of IGF-1 following stem cell transplantation.

Adolescent↗
PubMed2001

Advanced head and neck cancer: long-term results of chemo-radiotherapy, complications and induction of second malignancies.

BACKGROUND: Chemo-radiotherapy is superior to radiotherapy alone in the treatment of advanced, inoperable head and neck cancer. The long-term treatment results, the induction of second malignant tumors, and other long-term toxicities are not well defined. PATIENTS AND METHODS: 100 consecutive patients with advanced head and neck cancer who were treated at our center were studied. Treatment results, survival, the occurrence of late complications, and second malignant tumors (SMT) were investigated. 78 patients were treated with a protocol combining cisplatinum, 5-fluorouracil, folinic acid and hyperfractionated irradiation. 22 patients were treated with other chemo-radiotherapy protocols. The relative risk of developing an SMT was compared with that within the normal population. RESULTS: The cumulative total probability of survival was 51.1% at 2 years and 38.7% at 4 years. The probability of relapse-free survival was 39.9% at 2 years and 36.7% at 4 years. A total of 7 patients developed SMT (4 cases of lung cancer, 2 colon cancers, 1 skin cancer). After 6 years, a cumulative risk of SMT of 8.7% was observed. The relative risk of developing an SMT was significantly increased (4.45-fold in males) compared with a normal population. 13 of 38 evaluable patients (34.2%) had severe late complications like fibrosis of soft tissues, nerve lesions, or were dependent on tracheal cannulas. CONCLUSIONS: The treatment results and long-term prognoses in our population of unselected high-risk patients are unsatisfactory, but comparable to those from multicenter studies. About 35% of patients become long-term (> 4 years) survivors. SMT generally occur early, have a poor prognosis and, most likely, are not treatment-related. Approximately 30% of long-term survivors have severe, often incapacitating late effects. The treatment and - if possible - prevention of these late effects is important for the quality of life of patients who survived advanced head and neck cancer.

Aged↗
PubMed2000

Modulation of CD95 in leukemia and lymphoma cells by retinoids.

Retinoids are highly active for the treatment of acute promyelocytic leukemia, but have effects on many different types of normal and transformed cells. CD95 is a member of the TNF-receptor superfamily and can mediate apoptosis. In this study, we screened a series of 7 myeloid and 12 lymphoid cell lines for the expression of CD95 and for the induction of CD95 by retinoids. A differential response was observed: in 3/7 myeloid cell lines a significant down-regulation of CD95 happened which correlated with the induction of differentiation. A significant induction of CD95 was observed in 4/ 12 lymphoid lines (2 HHV8+ cell lines, one Burkitt line and another lymphoma line). The modulation of CD95 was both time- and dose- dependent (maximum reached after 3-5 days of culture with 10-6 M retinoid). The 3 retinoid compounds studied (all-trans retinoic acid, 9-cis retinoic acid and 13-cis retinoic acid) had comparable activity. Taken together, we describe a new mode of induction of CD95 in lymphoma cells. More work is needed to define the functional consequences of these changes in CD95 surface expression.

Apoptosis↗
PubMed1999

Novel 20-epi-vitamin D3 analog combined with 9-cis-retinoic acid markedly inhibits colony growth of prostate cancer cells.

BACKGROUND: 1,25 dihydroxyvitamin D3 (1,25D) and retinoids may play an important role in preventing progression of prostate cancer. METHODS: We examined the ability of four novel 20-epi-vitamin D3 analogs (CB1093, KH1060, KH1266, and CB1267), either alone or in combination with 9-cis retinoic acid (RA) to inhibit colony growth of a human prostate cancer cell line, LNCaP, using soft agar as well as bone marrow stroma. Also, the effect of these analogs on the cell cycle and expression of Ki-67, p21(waf-1), and p27(kip1) in LNCaP cells was examined. RESULTS: The analog CB1267 was the most potent, with 8 x 10(-10) M of the analog inhibiting 50% colony growth (ED50) of LNCaP. 9-cis-RA also inhibited colony growth of LNCaP (ED50, 5 x 10(-7) M). Combined, CB1267 and 9-cis-RA synergistically inhibited colony growth and significantly increased the number of LNCaP cells in G0/G1 phase. Cell cycle arrest was associated with increased levels of p21(waf-1) and p27(kip1) and decreased expression of Ki-67 protein. Pulse-exposure to this combination (5 x 10(-8) M) irreversibly inhibited colony growth, both in soft agar and on normal human bone marrow stroma. CONCLUSIONS: Combination of a new vitamin D3 analog (CB1267) and a retinoid (9-cis-RA) potently inhibited colony formation of LNCaP prostate cancer cells in vitro, suggesting further studies in animal models. This combination may afford an interesting therapeutic approach to low-burden prostate cancer.

Alitretinoin↗
PubMed1999

Second malignancies after Hodgkin's disease: the Munich experience.

The occurrence of second malignancies (SM) is an important late event following the treatment of Hodgkin's disease (HD). We sought to determine the incidence, the risk factors, and the prognosis of SM in our population of patients with HD. A total of 1120 patients diagnosed with HD were registered at six participating institutions in Munich (calendar period 1974-1994). The mean follow-up for the development of SM was 9.1 years. A cumulative treatment score was calculated for both radio- and chemotherapy. The relative and absolute risks of SM were established. All SM were investigated for response to treatment and outcome. We observed 85 SM [eight leukemias, 22 non-Hodgkin's lymphomas (NHL), two plasma cell neoplasias, and 53 solid tumors]. Five patients developed third malignancies. The relative risk of developing a second neoplasm was compared with that within the normal population and was 3.1-fold. The risk varied according to the category of SM. Higher relative risks (20.5 and 25.9-fold), but lower absolute risks were observed for leukemias and non-Hodgkin's lymphomas. Solid tumors had lower relative risks (1.8-fold). Splenectomy increased the risk of SM (relative risk 4.4-fold versus 2.7-fold). The risk of SM did not correlate with the initial treatment (radio- or chemotherapy) and did not decrease with prolonged follow-up. The cumulative intensity of radiotherapy, chemotherapy, or the two modalities combined correlated with the risk of SM. Since some cases occurred early after diagnosis, not all second neoplasms can be considered treatment-associated. After 15 years, an actuarial risk of 11.7% was calculated for all SM, of 1.0% for leukemias, of 3.0% for NHL, and of 7.7% for solid tumors. The prognosis of SM varied between good (thyroid cancer, melanoma: median survival 5+ years), average (breast cancer, NHL), and poor (acute myeloid leukemias, lung cancers: median survival 9 months). With the exception of NHL, second cancers often occurred in topographic relation to the field of previous radiotherapy. Taken together, in our patient population, we observed all three categories of SM (solid tumors, leukemias, NHL). The risk for second leukemias is lower than in previous studies, whereas the risk of second NHL is somewhat higher. We confirm that splenectomy is a possible risk factor for SM. Even after correction for the age-specific cancer incidence, treatment intensity is associated with the development of second malignant tumors. Continued follow-up is mandatory after treatment for HD. Since the prognosis of most SM is unfavorable, early recognition and prevention are of the utmost importance.

Adolescent↗
PubMed1998

Mechanisms of growth control of Kaposi's sarcoma-associated herpes virus-associated primary effusion lymphoma cells.

Primary effusion lymphoma (PEL) is a distinct clinicopathologic entity associated with Kaposi's sarcoma-associated herpes virus (KSHV). Several cytokines, including interleukin-6 (IL-6), basic fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF) may be important for survival of KS cells. However, little is known about the interaction of cytokines with KSHV-infected lymphocytes from PEL. Therefore, we investigated what cytokines were produced by KSHV-infected PEL cell lines (KS-1, BC-1, BC-2), what cytokine receptors were expressed by these cells, what response these cells had to selected cytokines, and what was the effect of IL-6 antisense phosphorothioated oligonucleotides. Reverse transcriptase-polymerase chain reaction (RT-PCR) and protein studies showed that these three cell lines produced IL-10, IL-6, and the receptors for IL-6. The granulocyte macrophage colony-stimulating factor (GM-CSF), IL-1beta, IL-8, IL-12, bFGF, PDGF, and c-kit transcripts were not detected in the cell lines. High levels (0.7 to 5 ng/mL/10(6) cells/48 hours) of IL-6 protein were consistently detected in supernatants of the cell lines by enzyme-linked immunosorbent assay (ELISA) tests. In clonogenic assays, interferon-alpha (IFN-alpha) and IFN-gamma suppressed the clonal growth of the PEL cells, but GM-CSF, IL-4, IL-6, IL-8, IL-10, and oncostatin M did not change it. We examined for several autocrine loops that have been suggested to occur in KS. Experiments using antisense oligonucleotides showed that the clonal growth of KS-1 and BC-1 was nearly 100% inhibited by IL-6 antisense oligonucleotides (10 micromol/L), but not at all by either oligonucleotides (</=10 micromol/L) to IL-6 sense, IL-6 scrambled, viral IL-6 (vIL-6) antisense, or IL-10 antisense. Furthermore, the IL-6 antisense oligonucleotides had no effect on two B-cell lymphoma cell lines, which were not infected with KSHV. Addition of IL-6 antibody did not inhibit clonal growth of any of the cell lines. Taken together, we have defined the cytokines and their receptors expressed on PEL cells and have found that these cells synthesized IL-6 and IL-6 receptors; interruption of this pathway by IL-6 antisense oligonucleotides specifically prevented the growth of these cells. These findings will offer potential new therapeutic strategies for PEL.

Cell Division↗
PubMed1998

Further characterization of cyclophosphamide resistance: expression of CD95 and of bcl-2 in a CML cell line.

Drug resistance is a common cause of treatment failure in oncology. In addition to the resistance caused by over-expression of p-glycoprotein and similar molecules other mechanisms are involved in the selection or induction of drug resistant tumor cells. In this study, we characterized a CML cell line made resistant to cyclophosphamide (KBM7-B5-1803) further for the expression of apoptosis promoting and inhibiting molecules. We found that KBM7-B5-1803 has a 3 4-fold over-expression of the receptor CD95 (Fas/Apo-1) compared with the parent line. The regulation of CD95 by cytokines was comparable to other types of cells. Despite the inducibility and over-expression of CD95, CD95 failed to trigger apoptosis in both the parent and the drug resistant line. The drug resistant line has a particular pattern of the expression of bcl-2 family members: bcl-2 protein and message were expressed to a similar extent, however, compared with the parent line, the message for bclx short was decreased. P-glycoprotein was not expressed in either cell line. Taken together we show here in a leukemia cell line that the phenotype of cyclophosphamide resistance is associated with a particular pattern of apoptosis-related molecules.

Apoptosis↗
PubMed1998

Methylation of the p16INK4A gene in multiple myeloma.

The p16INK4A (p16) binds to both cyclin D-CDK4 and cyclin D-CDK6 and inhibits the progression of the cell cycle from G1 to S phase. Loss of expression of this protein can occur by several mechanisms including structural alterations. Recent studies have suggested that the loss of expression of p16 can occur by hypermethylation of the gene. The methylation status of the p16 gene in multiple myeloma was examined in three myeloma cell lines (U266, RPMI8226 and IM9) and 16 primary myeloma samples using methylation-specific polymerase chain reaction (MSP). The U266 and RPMI8226 cell lines contained a completely methylated p16 gene and the IM9 line had a partially methylated p16 gene. Identical results were obtained by another polymerase chain reaction (PCR)-based methylation assay system as well as Southern blotting after using a methylation-sensitive restriction enzyme. The U266 cell line expressed no p16, and the IM9 had weak expression as determined by reverse transcript (RT-)PCR. The U266 cells began to express, and IM9 increased the accumulation of, the p16 RNA after treatment with the demethylating agent 5'-aza-2-deoxycytidine (10(-6)-10(-5) M). This suggested that the levels of methylation of the p16 gene detected by the MSP technique correlated with the regulation of transcription of this gene. Examination of the primary myeloma samples showed that eight of 16 (50%) contained a methylated p16 gene. We have previously found that alterations of the p16 gene, such as deletions and point mutations, are rare in primary multiple myeloma; none of the 16 samples included in this study had p16 gene alterations. Our results suggest that methylation of the p16 gene may contribute to the development and/or progression of multiple myeloma.

Aged↗