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  • 1
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    Epidemiology of non-Hodgkin?s lymphoma (NHL): trends, geographic distribution, and etiology
    Springer Science and Business Media LLC ; 2005
    In:  Annals of Hematology Vol. 84, No. 1 ( 2005-1), p. 1-12
    Details
    In: Annals of Hematology, Springer Science and Business Media LLC, Vol. 84, No. 1 ( 2005-1), p. 1-12
    Type of Medium: Online Resource
    ISSN: 0939-5555 , 1432-0584
    URL: Article
    DOI: 10.1007/s00277-004-0939-7
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2005
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  • 2
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    Frequency, severity and risk factors for oral mucositis after BEAM conditioning and autologous peripheral blood stem cell transplantation: A single center analysis and review of the literature
    Informa UK Limited ; 2007
    In:  Leukemia & Lymphoma Vol. 48, No. 11 ( 2007-01), p. 2255-2260
    Details
    In: Leukemia & Lymphoma, Informa UK Limited, Vol. 48, No. 11 ( 2007-01), p. 2255-2260
    Type of Medium: Online Resource
    ISSN: 1042-8194 , 1029-2403
    URL: Article
    DOI: 10.1080/10428190701636492
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2007
    detail.hit.zdb_id: 2030637-4
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  • 3
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    Coincidence of Chronic Lymphocytic Leukemia (CLL) and Multiple Myeloma (MM) in One Patient: An Exceptional or Common Event? Summary of 4 Cases at a Single Center.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 4980-4980
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 4980-4980
    Abstract: The simultaneous appearance of B-CLL and MM in the same patient (pt) seems to be a rare phenomenon. In those cases - our experience included - 1. the myeloma exhibits an aggressive course, 2. with CLL-treatment, MM seems to emerge, 3. which, if well treated (e.g. high-dose chemotherapy [CTx] with autologous peripheral blood stem cell transplantation [auto-PBSCT] ), may lead to a slower myeloma course, improved clinical condition and CLL disapearance. Here we report on the simultaneous (n=2) and successive (n=2) occurrence of CLL and MM in four pts, who were diagnosed at our center during the last year. We suggest that the occurrence of CLL and MM, when carefully monitored, may be more frequent than assumed so far. Case 1. This 64-year-old male was evaluated due to weight loss, leukocytosis, anaemia, foamy urine and increased creatinine. Kappa (k) Bence-Jones (BJ) proteinuria and elevated k-serum free light chains (SFLC) were found. A bone survey was normal, but BM biopsy showed infiltrates of plasma- (PC) and B-CLL-cells. Due to Rai 0 CLL and MM stage IIIB, the pt received 2 cycles of VAD followed by an auto-PBSCT. Thereby, he obtained a PR. Maintenance with thalidomide stabilized both diseases. Case 2. This 77-year-old male was simultaneously diagnosed with RAI 0 CLL and stage IIIB MM. Diagnostics revealed a lambda (l)-paraprotein, BJ-l-proteinuria and lytic bone lesions. The BM showed monoclonal l-LC-expressing PCs, and k-LC-CLL-cells. The pt received melphalan/prednisone (MP) and thereby obtaining SD. Case 3. This 62-year old pt was diagnosed with RAI II B-CLL. Two years later, he showed increased splenomegaly, anemia, elevated l-SFLC and dense CLL-BM-infiltrates. Chlorambucil/prednisone-CTx was initiated, but failed to improve his condition. Further evaluation due to renal impairment revealed multiple lytic lesions and monoclonal l-LC-expressing PCs, coexisting with remaining CLL infiltrates in his BM. Cyclophosphamide-CTx, 2 cycles of VAD and auto-PBSCT were performed and Bortezomib maintenance, improving the pt’s general condition, his PB counts and l-SFLC secretion. Despite these efforts, MM relapse occurred 5 months later with persisting absence of his preceding CLL and the pt eventually died due to myeloma progression. Case 4. This 73-year-old male was diagnosed with B-CLL, showing moderate splenomegaly, lymphocytosis, initially not requiring any therapy. Two years later, he showed a deteriorating clinical condition, multiple osteolytic lesions, anemia, hypercalcemia, monoclonal IgA paraprotein and k-BJ-proteinuria. A BM biopsy confirmed k-LC B-CLL- and k-PC-infiltrates. The diagnosis of stage IIIA IgA k-MM, and RAI II B-CLL led to MP-CTx that induced SD of his MM and CLL. In summary, our 4 pts had a median age of 69 years (range; 62–77) and showed a median time interval of their CLL and MM diagnosis of 11 months (0–31). All pts had stage III MM and renal impairment in 3/4, whereas CLL showed an indolent course. LCs of CLL and MM were different in all except one pt. Cytogenetic and genomic analyses are currently ongoing and will be reported at the meeting. We conclude that the elucidation of the coincidence of CLL and MM will allow to understand why and how often both occur and also, how they can be efficiently treated. The question of their clonal relationship should be answered via genomic analyses that will allow to gain further insight into the origin of both diseases.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.4980.4980
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
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  • 4
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    Bone Marrow Hypocellularity, Decreased Platelet Counts and Colony Forming Units Serve as Prognostics Parameters for Early Complications after Autologous Peripheral Blood Stem Cell Transplantation.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 5514-5514
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 5514-5514
    Abstract: High-dose chemotherapy with autologous peripheral blood stem cell transplantation (auto-PBSCT) offers a valid treatment option in cancer patients (pts) with advanced, relapsed or high-risk (HR) disease. Auto-PBSCT is in general a safe procedure, however, some pts may have a dismal outcome due to treatment related mortality (TMR), early relapse (ER) and/or failure of blood cell reconstitution (FBR). Risk factors predisposing for early complications after PBSCT have not yet been clearly assessed. From a total of 796 pts having been transplanted over a 10 year (y) period (6/93-5/03), we determined 50 pts (group A, m:f=29:21), who had primary FBR or died within 3 months after PBSCT. As a control group, 50 pts who had undergone PBSCT over the same period, were randomly selected (group B; m:f=25:25). Pre-PBSCT-parameters associated with early complications were examined by univariate analysis. Median age at transplant was similar in group A (52y) and group B (54y). Group A vs. B had underlying lymphoma in 31 vs. 17, solid tumors in 13 vs. 21 and leukemias in 6 vs. 12 pts, respectively. Notable differences were a lower performance status, more pretreatment chemotherapy (CX)-cycles, higher LDH levels, lower platelet counts, hypocellular bone marrow (BM) and lower colony forming units (CFU) in group A. Treatment before PBSCT in group A consisted of a median number of 7 CX (group B: 4 CX) cycles. Median number of retransfused CD34+-cells were similar (group A 4.1 vs. group B 3.7x10e6/kg bw). Total CFUs/1.5e5, determined by methylcellulose culture of PBSC grafts in group A were considerably decreased with 128 vs. 187 (group B), and BFU-E, CFU-GM, and CFU-GEMM were 51 vs. 79, 55 vs. 87 and 5 vs. 4, respectively. Hypocellular BM was observed in group A and B in 46% vs. 4% of pts (odds ratio 20.44 [p & lt;0.001]), platelet counts were 98 vs. 170x10e9/L (odds ratio 13.5 [p & lt;0.001]), respectively. Advanced stage at transplant was present in 90% vs. 78%, and residual BM-infiltration in 36% vs. 58% in group A and B, respectively. Age, number of CX-cycles and CD34+-transfused cells showed no significantly increased risk. Of pts in group A, 21 had early TRM (group A1: sepsis and multi-organ failure in 81%, fatal bleeding in 14%, CX-toxicity in 5%, leading to early death after a median of 23 days [d] ). 26 pts (52%) died of early progression (group A2: after a median of 62d) and 3 pts (6%) had FBR (group A3). Median BFU-E, CFU-GM and CFU-GEMM were similar in group A1 and A2 and correlated with comparable CD34+-numbers. However, in group A1, 29% reached no WBC and 81% no platelet engraftment, whereas in group A2 only 12% and 23% did not reach WBC- and platelet reconstitution, respectively. Engraftment in group B (control pts) was regular with median WBC and platelet reconstitution on d+10. With a TRM of 2.64% and FBR in 0.38% in this HR-pt cohort, auto-PBSCT is in general a well tolerable treatment option. Nevertheless, distinct risk factors for early transplant complications can be determined and should be considered. We identified BM-hypocellularity and a decreased platelet count & lt;100x10e9/L as the strongest prognostic parameters. Our analysis also suggests, that other pre-transplant parameters, including CFUs - more reliably than CD34+-cell numbers - provide additional valuable information on engraftment and complications after auto-PBSCT.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.5514.5514
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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  • 5
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    Bortezomib, Intravenous Cyclophosphamide and Dexamethasone (VelCD) for Previously Untreated Multiple Myeloma: An Interim Analysis of the German DSMM XIa Trial
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 2776-2776
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 2776-2776
    Abstract: Introduction. Autologous stem cell transplantation (ASCT) after cytoreductive induction is considered standard of care for younger patients (pts) with multiple myeloma (MM). However, 40% of pts fail to achieve remission to standard cytotoxic regimens obviously necessitating improvement. Bortezomib (Vel) is considered the most potent single agent MM therapy. Bortezomib-containing induction treatments have already been shown to be superior to vincristine, adriamycine, and dexamethasone. Methods. As previously reported, 30 pts were included in the dose finding study to determine the optimum dose of intravenous cyclophosphamide (C) in conjunction with Vel and dexamethasone (D). Here we report on the results of the planned interim analysis with an additional 70 pts up to 60 years of age with untreated MM. They were enrolled between 03/2006 and 03/2008 to receive a maximum of 3 three-week cycles of induction treatment with Vel 1.3 mg/m2 IV d1,4,8,11; D 40 mg/d d1,2,4,5,8,9,11,12; and C 900mg/m2 IV d1 before scheduled ASCT as a consolidation. Primary study objective is response rate (≥ PR) to VelCD before ASCT according to the stringent EBMT criteria. Results. Data from the first consecutively completed 100 pts (mean age, 52 years; 78% stage III) from 22 German centers were analyzed. Molecular cytogenetic analysis was available for 79% with the most frequent cytogenetic abnormalities being 13q− (34%), 17p− (14%) and t[4;14] (8%). All 100 pts (84% of whom completed three cycles) were included in the intent-to-treat analysis. Overall response rate was 79% with 11% CR and 68% PR + VGPR; only 2 subjects (2%) progressed. Typically VAD induces app. 60% response. Additionally, response by cytogenetic risk group was assessed. Response was documented in 73.5% of the subjects with 13q−, in 100% with t(4;14) and in 57.1% with 17p−. 42 SAEs were reported: 18 pts had a SAE associated with Vel, 17 had a SAE associated with C, and for 10 pts SAE associated with D was established. One patient died due to gastric hemorrhage possibly related to dexamethasone. This is a remarkably low rate of early deaths (1%) in this setting. 53% of the patients experienced grade 3 + 4 AE with leucopenia (34%), thrombocytopenia (6%), neutropenia (5%), anaemia (4%), nausea (3%) and bone pain (3%) being the most frequent. Infections of grade 3 and 4 have been reported in 2% and a low incidence of grade 3 (2%) but no grade 4 paraesthesia occurred while 13% of pts developed peripheral neuropathy (only of grades 1 and 2). Conclusion. This analysis demonstrates Bortezomib combined with D and intravenous C is a highly effective treatment regimen regardless of cytogenetic risk factors for newly diagnosed MM with acceptable toxicity. Given the importance of high-quality response prior to ASCT, VelCD is considered a very active induction regimen. Table 1. Response to study therapy (intent-to-treat set, n=100) Response to VelCD n (%) CR 11 PR + VGPR 68 MR 8 SD 11 PD 2 Table 2. Response by result of cytogenetic analysis (intent-to-treat set, n=100) Responding patients (≥ PR) N % No FISH abnormality 15/17 88.2 13q− 25/34 73.5 t(4;14) 8/8 100 17p− 8/14 57.1 Other 26/29 89.7
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.2776.2776
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 6
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    Bortezomib Retreatment in Relapsed Multiple Myeloma (MM): Results from a Binational, Multicenter Retrospective Survey
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 2775-2775
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 2775-2775
    Abstract: In myeloma therapy retreatment after successful therapy is frequently considered. Here we present pooled data from a German and Swiss multicenter, retrospective survey (26866138MMY4014). The survey started in Germany and was later extended to Switzerland. German data have already been published before. Here we report on the entire cohort of patients for the first time. For inclusion into this analysis, patients with MM had to have had preceding bortezomib treatment, resulting in at least partial remission and a second therapy with Bortezomib on relapse. The intention of this trial was to provide further evidence of the value of a retreatment with bortezomib, description of predisposing factors and comparison of response quality and remission duration in this predefined patient group of bortezomib responders. Data from 36 centers and 94 patients were available for safety analysis. 34 patients had to be excluded from the efficacy analysis due to major deviations from the inclusion criteria, i.e. concomitant antineoplastic treatment, retreatment with bortezomib not being completed, no response during initial bortezomib treatment or missing information about MM-specific interim therapy. Thus 60 patients were left for the per protocol population (PP). Patients had a mean age of 65.5 years (40–89), 56.4% being male. Patients had received a mean of 3.7 prior therapies for multiple myeloma before initial bortezomib therapy, most frequently melphalan-prednisone (44.7%), dexamethasone (38.3%) and/or vincristine-adriamycin-dexamethasone (31.9%). Stem cell transplantation was undertaken in 26.6% of the patients. Mean cycle numbers for initial bortezomib therapy and retreatment were 5.8 and 4.5, respectively. The majority of patients (85.1% and 78.7%, respectively) received a bortezomib dose of 1.3 mg/m2. Concomitant dexamethasone therapy was administered to 43.6% and 62.8% of the patients, respectively. Between the initial bortezomib therapy and bortezomib retreatment 13.8% of the patients received other MM-specific interim therapy. The efficacy analysis was based on the PP population and revealed very encouraging responses. Overall response (OR) was defined as complete response (CR), nearly complete response (nCR) and partial response (PR). With a pre-defined OR of 100% for the initial bortezomib therapy, 63% (49.9–75.4%) responded again to retreatment. Best response is summarized in the table below. Subgroup analyses of the rates of clinical benefit (CR, nCR, PR or SD) were performed by treatment free interval (TFI) after initial bortezomib therapy ( & lt;= 6 months versus & gt; 6 months) and by concomitant dexamethasone treatment. In patients with TFI & gt; 6 months a higher rate of clinical benefit (89.7%) could be achieved as compared to TFI & lt;= 6 months (61.9%). Concomitant dexamethasone treatment was associated with a lower rate of clinical benefit (76.5%) than without (84.6%). For 44 patients (46.8%) a total of 125 adverse drug reactions (ADRs) were documented. 21 serious ADRs were documented in 11 (11.7%) patients. 30 patients had died at the time of analysis. 2 patients died due to adverse events (pneumonia and pulmonary oedema) assessed as at least possibly related to bortezomib. For one fatal outcome (pneumonia) causality assessment has not been provided. This binational retrospective survey suggests that the safety profile is in line with the current summary of product characteristics of Velcade and that high remission rates and durable TFIs can be achieved by bortezomib retreatment. A TFI & gt; 6 months could be a good clinical marker for a higher rate of clinical benefit. Results of an ongoing prospective trial on bortezomib retreatment are awaited to confirm these results. Initial bortezomib therapy (N=60) Bortezomib retreatment (N=60) * based on n=47 patients responding to bortezomib retreatment. Complete response (CR) 12 (20%) 8 (13.3%) Nearly complete response (nCR) 7 (11.7%) 3 (5%) Partial response (PR) 41 (68.3%) 27 (45%) Stable disease (SD) - (not allowed by selection criteria) 10 (16.7%) Progressive disease (PD) - (not allowed by selection criteria) 12 (20%) Median time to response 3.1 months 3.3 months* Median duration of response 6.9 months 6.1 months* Median treatment free interval 8.6 months 5.7 months
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.2775.2775
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 7
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    High-Dose Chemotherapy in Small Cell Neuroendocrine Carcinoma: Favorable Long-Term Outcome for Extrapulmonary Primary Localization.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 3075-3075
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 3075-3075
    Abstract: Small cell neuroendocrine carcinomas (SCNC) are composed of round to spindle-shaped cells with features of both neuroendocrine and epithelial neoplasms. SCNC can be found in basically all epitheloid organs; however, the vast majority arises in the lung, while extrapulmonary (EP) localization is rare. Small cell lung cancer (SCLC) and EP SCNC are considered one histological entity and are treated similarly. Despite the high initial response to chemo- and radiotherapy, most patients relapse after short remission, and overall prognosis is dismal. Clinical trials employing high-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (auto-SCT) neither demonstrated a clear benefit nor clarified its significance in SCLC. The role of intensified treatment in EP SCNC has not been specifically addressed in detail. Conversely to SCLC, some subgroup analyses indicated that patients with EP SCNC might benefit from intensive treatment. We analyzed a total of 22 patients: 8 with EP SCNC (group A; m:f 3:5; median age 36 years (y) [range 22–56]) and 14 patients with SCLC (group B; m:f 10:4; median age 55 y [40–63] ), all undergoing HDCT with auto-SCT at our single center from 07/90–01/05. A control group C consisted of 30 patients with EP SCNC (m:f 21:9, median age 66 years [32–81], who received different standard treatments without auto-SCT. All group A patients had stage IV disease (liver n=5, lymph nodes n=4, pancreas n=1, orbita n=1, bone n=1, kidney n=1). Two of these patients received additional local radiotherapy. In group B, 7 patients had limited and 7 patients extensive disease, (stage I (n=1), II (n=2), III (n=10), IV (n=1). HDCT with VIC (etoposide, ifosfamide, carboplatin; n=21), or CCT (carboplatin, cyclophosphamide, thiotepa; n=1) was followed by infusion of a median 3.2x10^6 CD34+ cells. Prophylactic radiotherapy was performed in 12 patients (mediastinum n=11; brain n=10). With a median follow-up (FU) of 48 months (7–152) for group A and 85 months (0–170) for group B, 5/8 (63%) of patients with EP SCNC (group A) are alive and in complete remission (CR), compared to 5/14 (36%) SCLC patients (group B). Best response ever achieved after HDCT was a CR in 5/8 (63%), a partial remission (PR) in 2/8 (25%) and stable disease (SD) in 1/8 (12%) in group A. In group B, a CR was attained in 11/14 (79%), a PR and a SD in 1/14 (7%) patients, respectively. In the conventionally treated control group C, a transient PR was achieved in 5/30 (16%), and after a median FU of 9.7 months, only 2/30 (6.7%) EP SCNC patients are alive. Our analysis suggests that selected SCNC patients may benefit from HDCT, particularly when integrated into multimodal treatment concepts. The remarkably favorable outcome in patients with EP primary site, even when HDCT was implemented as salvage treatment warrants further studies on the role of HDCT in SCNC. Careful attention will have to be paid to prognostic clinical features, such as primary site and/or histological parameters including neuroendocrine marker profiles and mitotic indices. These may help to predict which patients will benefit from intensified treatment. In addition, further histological studies should address the identification of markers specific for lung- vs. extrapulmonary primary localization. For this purpose all available tumor tissue from our study is currently under histological re-analysis, assessing the expression of the novel tumor testis antigens.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.3075.3075
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
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  • 8
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    Spindle Checkpoint Insufficiency in Acute Myeloid Leukemia.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 873-873
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 873-873
    Abstract: Chromosomal instability and aneuploidy are hallmarks of most human malignancies. Various mechanisms have been shown to give rise to numerical chromosome aberrations. Compromised function of the spindle assembly checkpoint (SAC) is generally regarded as one of the most powerful ways to drive genome instability. The SAC is a mitotic checkpoint mechanism ensuring the equal segregation of the mitotic chromosomes onto the developing daughter cells. Unfaithful mitotic surveillance by the SAC favors chromosomal misdistribution as error-prone chromosome attachment to the mitotic spindle does not induce a strong mitotic arrest by interference with anaphase promoting complex (APC)-dependent proteolysis. The APC is an important ubiquitin ligase that triggers the transition from mitosis into G1-phase by targeted proteolysis of mitotic regulators such as cyclin B and securin. The SAC prevents the proteolysis of those regulator proteins in the presence of mitotic aberrancies by inhibition of the APC. This leads to a delayed progression through mitosis and provides time to recover from defective chromosomal spindle attachment. SAC malfunction weakens the tight control on chromosome attachment and tension across the kinetochore favoring chromosomal misdistribution. We performed expression analyses of key proteins in SAC signaling in acute myeloid leukemia (AML). We found the SAC-components Bub1 and BubR1 to be down-regulated in most of the investigated AML cell lines. Functional assays revealed a defective mitotic arrest mechanism in comparison to SAC-competent cell lines after exposure to the microtubule disrupting agent nocodazole. This finding was accompanied by the observation of a decline in cyclin B and securin levels despite severe damage to the mitotic spindle induced by nocodazole. Expression of cyclin B and securin in the presence of spindle damage could be stabilized by proteasome inhibition. We established a shRNA-based model to evaluate the effects of BubR1- and/or Bub1-repression to levels found among AML cell lines to directly compare the Bub1/BubR1 knockdown phenotype with the investigated AML cell lines. Interestingly, BubR1 knockdown was sufficient to generate a phenotype resembling the behavior of our AML cell lines. Further experiments revealed a strong relation between premature degradation of cyclin B and the degree of BubR1 downregulation. Given the potent role of BubR1 in the generation of a mitotic arrest deficient phenotype, we addressed the BubR1 expression levels in a number of patients exhibiting karyotype abnormalities. Primary myeloid blast cells were stimulated with cytokines to force the largely resting cells into an actively dividing state. The maximum expression level of BubR1 in G2/M was used to define SAC-compentent and SAC-deficient populations. Strikingly, six out of eight (6/8) primary AML samples exhibited BubR1 expression patterns resembling the BubR1-knockdown model suggesting deficient mitotic surveillance in most of the primary AML samples. Since SAC deficiency is an important mechanism in creating numerical chromosomal aberrations and genetic instability, our findings underline a role for impaired SAC function in rise and progression of AML.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.873.873
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 9
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    Allogeneic Stem Cell Transplant Versus Tandem High-Dose Melphalan for Front-Line Treatment of Deletion 13q14 Myeloma – An Interim Analysis of the German DSMM V Trial.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 51-51
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 51-51
    Abstract: Abstract 51 Background Allogeneic stem cell transplantation (allo SCT), a treatment modality based on transfer of immunocompetent donor lymphocytes offers curative potential to subjects with a variety of hematological cancers. In multiple myeloma (MM), high-dose melphalan followed by autologous stem cell transplantation (auto SCT) is adopted as a standard of care. However, it remains palliative since virtually all patients (pts) relapse and renders allo SCT an option of interest. Deletion of chromosome 13q14 (13q-) in MM has been shown to negatively impact prognosis. Therefore, improvement of therapy for 13q- pts is highly desirable. Patients and methods A prospective two-arm multi-center trial (DSMM V) was set up by our group to compare tandem high-dose melphalan 200 mg/m2 (HD Mel) with a reduced intensity conditioning allo-SCT after one cycle of HD Mel for 13q- MM. Eligibility criteria were 13q- on bone marrow FISH analysis; age up to 60 years; newly diagnosed MM in Salmon and Durie stages II and III; and measurable disease. Allocation to either treatment arm was by availability of an HLA-matched (one mismatch allowed) volunteer related (VRD) or unrelated donor (VUD). Initially, all pts received four cycles of anthracycline/dexamethasone-based induction followed by chemomobilization of peripheral blood stem cells (PBSCT) and one cycle of HD Mel. Allogeneic SCT was performed after preparation with fludarabine (30 mg/m2 for 3 consecutive days) and melphalan 140 mg/m2. ATG was administered for VUD transplants. Results 199 pts with a median age of 53 (range, 30 – 60) years were enrolled between October 2002 and March 2007 and included in this interim analysis. Sixty-seven percent had stage III disease. Allo SCT was performed in 126 of 199 pts (63%), 76 of whom (60%) received VUD allografts. The remaining 73 subjects uniformely received tandem HD Mel. Pts following allo SCT were more likely to achieve CR (59%) when compared to tandem HD Mel (32%; p=.003) within one year after end of therapy. Similarly, overall response rate was significantly higher with allo SCT (91% versus 86%; p=.003). Of note, depth of response to allo SCT was not associated with presence of acute graft-versus-host disease (GVHD): 62% CR with grades II to IV GVHD vs 58% CR with grades 0 and I (p=.75). Treatment-related mortality (TRM) at 2 years from allo SCT was 16/126 (12.7%). At a median follow up of 25 months for tandem HD Mel and 34 months for allo SCT, projected 3-year overall survival is 72% (auto) and 60% (auto/allo SCT; p=0.22), respectively. Conclusions This is the largest trial on first-line allogeneic stem cell transplant in MM so far. Our interim results show a higher CR rate in FISH 13q- subjects undergoing allo SCT when compared to tandem HD Mel. Despite a majority of allografts in our study being delivered from unrelated donors, TRM was comparable to trials confined to sibling transplants. At a relatively short follow-up, there is not yet a difference between both arms regarding OS, albeit longer follow-up may be important as previously described. This as well as analysis of the impact of donor type and chronic GVHD on outcome will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.51.51
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 10
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    Establishment of a Metastasizing Human Cell Line Based Multiple Myeloma Model in Immunodeficient Mice.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 4784-4784
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 4784-4784
    Abstract: Multiple myeloma (MM) accounts for 10% of all hematological malignancies, leads to devastating bone destruction, bone pain, renal failure, and hematopoietic insufficiency. In order to allow a better understanding of MM, the establishment of functional and reproducible in vivo models is pursued worldwide. Of available models, xenograft models in immunodeficient mice (IDM) reproduce the clinical situation best. Using the different MM cell lines (MMCLs) L363 and RPMI8226, we tested their ability to engraft in IDM under different conditions. As the supportive effect of bone marrow (BM) stroma has been suggested to be vital, we injected L363 or RPMI8226 into a freshly prepared mouse tibia which was implanted subcutaneously (sc) into IDM. In a second approach, we injected MMCLs directly into the tibia of the recipient mouse. Furthermore, the influence of IL-6, matrigel, pre-treatment with an anti-mouse CD122-antibody (Ab) and/or the use of NOD/SCID-IL2-receptor-gamma-chain−/− (IL2−/−) mice, instead of conventional NOD/SCID mice, was evaluated. Tumor growth was monitored by a) multiparameter flow-cytometry (FACS; detection of human HLA-DR, HLA-A,B,C, CD45 and CD138), b) immunohistological detection of human CD138+ cells in tumor implants, BM and spleen and c) a fluorescence-based in vivo imaging system. L363 and RPMI8226 engrafted reliably at the injection site and in distant organs, independent of the experimental conditions (using IL-6, matrigel and/or pre-treatment with anti-CD122-Ab). L363 cells showed higher take- and metastases-rates compared to RPMI8226. The knock-down of NK cell activity, either by Ab-treatment or by genetic engineering, enhanced the tumor take rate with both MMCLs in 8/8 mice. With RPMI8226, the BM infiltration rate was 1.5–1.8% in all examined murine models. In contrast, BM-infiltration rates of L363 cells negatively correlated with the NK cell activity of the host: L363 cells metastasized particularly well to the BM when injected into anti-CD122-pretreated mice or intratibialy into IL-2−/− mice. Engraftment of circulating cells into the peripheral blood and spleen was found with both MMCLs irrespective of the mouse strain, pretreatment or implantation site. Matrigel or IL-6 showed no relevant engraftment effect, neither sc, nor with the intratibial approach. We conclude that the establishment of a metastasizing cell line-based human MM in vivo model was successfully pursued. We observed that the knock-down of NK cell activity was essential for both MMCLs, whereas the influence of matrigel or IL-6 treatment could be neglected. Furthermore, the intratibial approach optimized especially the L363 model in terms of infiltration rate to clinically relevant sites. With this optimized transplant approach, we aim to determine whether this allows MM engraftment using primary patient specimens, which should also enable us to test novel anti-myeloma agents.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.4784.4784
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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