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Find video protocols related to scientific articles indexed in Pubmed.
Cost-Effectiveness Analysis of Prognostic Gene Expression Signature-Based Stratification of Early Breast Cancer Patients.
Pharmacoeconomics
PUBLISHED: 11-19-2014
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The individual risk of recurrence in hormone receptor-positive primary breast cancer patients determines whether adjuvant endocrine therapy should be combined with chemotherapy. Clinicopathological parameters and molecular tests such as EndoPredict(®) (EPclin) can support decision making in patients with estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative cancer.
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Lenalidomide and dexamethasone for acute light chain-induced renal failure: a phase II study.
Haematologica
PUBLISHED: 11-16-2014
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We prospectively evaluated the activity and tolerance of lenalidomide-dexamethasone in 35 patients with acute light chain-induced renal failure. The lenalidomide dose was adapted to the estimated glomerular filtration rate and dexamethasone was given at high dose at cycle one and at low dose thereafter. Four patients died within the first 2 cycles, and 5 discontinued therapy leaving 26 patients for the per-protocol analysis. Responses were observed in 24/35 (68.6%) patients of the intent to treat population. Complete response was noted in 7 (20%), very good partial response in 3 (8.6%), partial response in 14 (40%), and minimal response in 1 (2.9%) patient. Renal response was observed in 16 (45.7%) patients, 5 (14.2%) achieved complete, 4 (11.4%) partial and 7 (20%) minor renal response, respectively. Five of 13 patients who were dialysis dependent at baseline became dialysis independent. Median time to myeloma and to renal response was 28 days for both parameters and median time to best myeloma and best renal response was 92 and 157 days, respectively. Median estimated glomerular filtration rate increased significantly in patients with partial response or better from 17.1 ml/min at baseline to 39.1 ml/min at best response (p=0.001). Median progression free and overall survival was 5.5 and 21.8 months in the intent to treat and 12.1 and 31.4 months in the per-protocol group. Infections, cardiotoxicity, anemia and thrombocytopenia were the most frequent toxicities. In conclusion, the lenalidomide-dexamethasone regimen achieved rapid and substantial myeloma and renal responses. The trial was registered under EUDRACT number 2008-006497-15.
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Preoperative Treatment with Capecitabine, Cetuximab and Radiotherapy for Primary Locally Advanced Rectal Cancer - A Phase II Clinical Trial.
Anticancer Res.
PUBLISHED: 11-05-2014
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To investigate the feasibility and safety of preoperative capecitabine, cetuximab and radiation in patients with MRI-defined locally advanced rectal cancer (LARC, cT3/T4).
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Adipocyte-derived players in hematologic tumors: useful novel targets?
Expert Opin Biol Ther
PUBLISHED: 10-14-2014
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Introduction: Adipocytes and their products play essential roles in tumor establishment and progression. As the main cellular component of the bone marrow, adipocytes may contribute to the development of hematologic tumors. Areas covered: This review summarizes experimental data on adipocytes and their interaction with various cancer cells. Special focus is set on the interactions of bone marrow adipocytes and normal and transformed cells of the hematopoietic system such as myeloma and leukemia cells. Current in vitro and in vivo data are summarized and the potential of novel therapeutic targets is critically discussed. Expert opinion: Targeting lipid metabolism of cancer cells and adipocytes in combination with standard therapeutics might open novel therapeutic avenues in these cancer entities. Adipocyte-derived products such as free fatty acids and specific adipokines such as adiponectin may be vital anti-cancer targets in hematologic malignancies. However, available data on lipid metabolism is currently mostly referring to peripheral fat cell/cancer cell interactions and results need to be evaluated specifically for the bone marrow niche.
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AID induces intraclonal diversity and genomic damage in CD86(+) chronic lymphocytic leukemia cells.
Eur. J. Immunol.
PUBLISHED: 09-01-2014
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The activation-induced cytidine deaminase (AID) mediates somatic hypermutation and class switch recombination of the Ig genes by directly deaminating cytosines to uracils. As AID causes a substantial amount of off-target mutations, its activity has been associated with lymphomagenesis and clonal evolution of B-cell malignancies. Although it has been shown that AID is expressed in B-cell chronic lymphocytic leukemia (CLL), a clear analysis of in vivo AID activity in this B-cell malignancy remained elusive. In this study performed on primary human CLL samples, we report that, despite the presence of a dominant VDJ heavy chain region, a substantial intraclonal diversity was observed at VDJ as well as at IgM switch regions (S?), showing ongoing AID activity in vivo during disease progression. This AID-mediated heterogeneity was higher in CLL subclones expressing CD86, which we identified as the proliferative CLL fraction. Finally, CD86 expression correlated with shortened time to first treatment and increased ?-H2AX focus formation. Our data demonstrate that AID is active in CLL in vivo and thus, AID likely contributes to clonal evolution of CLL.
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MDM2 promotor polymorphism and disease characteristics in chronic lymphocytic leukemia: results of an individual patient data-based meta-analysis.
Haematologica
PUBLISHED: 08-02-2014
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A number of single nucleotide polymorphisms have been associated with disease predisposition in chronic lymphocytic leukemia. A single nucleotide polymorphism in the MDM2 promotor region, MDM2SNP309, was shown to soothe the p53 pathway. In the current study, we aimed to clarify the effect of the MDM2SNP309 on chronic lymphocytic leukemia characteristics and outcome. We performed a meta-analysis of data from 2598 individual patients from 10 different cohorts. Patients' data and genetic analysis for MDM2SNP309 genotype, immunoglobulin heavy chain variable region mutation status and fluorescence in situ hybridization results were collected. There were no differences in overall survival based on the polymorphism (log rank test, stratified by study cohort; P=0.76; GG genotype: cohort-adjusted median overall survival of 151 months; TG: 153 months; TT: 149 months). In a multivariable Cox proportional hazards regression analysis, advanced age, male sex and unmutated immunoglobulin heavy chain variable region genes were associated with inferior survival, but not the MDM2 genotype. The MDM2SNP309 is unlikely to influence disease characteristics and prognosis in chronic lymphocytic leukemia. Studies investigating the impact of individual single nucleotide polymorphisms on prognosis are often controversial. This may be due to selection bias and small sample size. A meta-analysis based on individual patient data provides a reasonable strategy for prognostic factor analyses in the case of small individual studies. Individual patient data-based meta-analysis can, therefore, be a powerful tool to assess genetic risk factors in the absence of large studies.
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Treatment of aggressive B-cell lymphoma in elderly patients: influence of single nucleotide polymorphisms affecting pharmacodynamics of chemotherapeutics.
Leuk. Lymphoma
PUBLISHED: 05-07-2014
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Clinical and/or biological risk factors are needed to identify elderly patients with aggressive B-cell lymphoma able to receive full-dose R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) treatment. We present a retrospective analysis of 83 patients ? 75 years of age (range: 75-97) who were diagnosed with aggressive B cell lymphoma between 2004 and 2011 in our clinic. R-CHOP-like therapy was administered in 82% of these patients resulting in a median overall survival of 54 months. A median cumulative dose of 226 mg/m(2) doxorubicin and a median of six cycles were applied in these patients. Two genotypes of the CBR3 and MLH1 genes affecting the metabolism of cytostatics identified a subgroup with a favorable prognosis (median overall survival not reached vs. 30 months, p = 0.01). A treatment strategy aiming at full-dose R-CHOP was feasible and resulted in an encouraging treatment outcome in patients ? 75 years. Pharmacogenetic parameters, if independently validated, may be helpful in elderly patients.
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Valproic acid in combination with all-trans retinoic acid and intensive therapy for acute myeloid leukemia in older patients.
Blood
PUBLISHED: 05-05-2014
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The outcome of patients with acute myeloid leukemia who are older than 60 years has remained poor because of unfavorable disease characteristics and patient-related factors. The randomized German-Austrian AML Study Group 06-04 protocol was designed on the basis of in vitro synergistic effects of valproic acid (VPA) and all-trans retinoic acid with chemotherapy. Between 2004 and 2006, 186 patients were randomly assigned to receive 2 induction cycles with idarubicin, cytarabine, and all-trans retinoic acid either with VPA or without (STANDARD). In all patients, consolidation therapy was intended. Complete remission rates after induction tended to be lower in VPA compared with STANDARD (40% vs 52%; P = .14) as a result of a higher early death rate (26% vs 14%; P = .06). The main toxicities attributed to VPA were delayed hematologic recovery and grade 3/4 infections, observed predominantly during the second induction cycle. After restricting VPA to the first induction cycle and reducing the dose of idarubicin, these toxicities dropped to rates observed in STANDARD. After a median follow-up time of 84 months, event-free and overall survival were not different between the 2 groups (P = .95 and P = .57, respectively). However, relapse-free-survival was significantly superior in VPA compared with STANDARD (24.4% vs 6.4% at 5 years; P = .02). Explorative subset analyses revealed that AML with mutated Nucleophosmin 1 (NPM1) may particularly benefit from VPA. This trial was registered at www.clinicaltrials.gov as #NCT00151255.
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Azacitidine in 302 patients with WHO-defined acute myeloid leukemia: results from the Austrian Azacitidine Registry of the AGMT-Study Group.
Ann. Hematol.
PUBLISHED: 04-08-2014
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Data on efficacy and safety of azacitidine in acute myeloid leukemia (AML) with >30 % bone marrow (BM) blasts are limited, and the drug can only be used off-label in these patients. We previously reported on the efficacy and safety of azacitidine in 155 AML patients treated within the Austrian Azacitidine Registry (clinicaltrials.gov identifier NCT01595295). We herein update this report with a population almost twice as large (n?=?302). This cohort included 172 patients with >30 % BM blasts; 93 % would have been excluded from the pivotal AZA-001 trial (which led to European Medicines Agency (EMA) approval of azacitidine for high-risk myelodysplastic syndromes (MDS) and AML with 20-30 % BM blasts). Despite this much more unfavorable profile, results are encouraging: overall response rate was 48 % in the total cohort and 72 % in patients evaluable according to MDS-IWG-2006 response criteria, respectively. Median OS was 9.6 (95 % CI 8.53-10.7)?months. A clinically relevant OS benefit was observed with any form of disease stabilization (marrow stable disease (8.1 months), hematologic improvement (HI) (9.7 months), or the combination thereof (18.9 months)), as compared to patients without response and/or without disease stabilization (3.2 months). Age, white blood cell count, and BM blast count at start of therapy did not influence OS. The baseline factors LDH >225 U/l, ECOG ?2, comorbidities ?3, monosomal karyotype, and prior disease-modifying drugs, as well as the response-related factors hematologic improvement and further deepening of response after first response, were significant independent predictors of OS in multivariate analysis. Azacitidine seems effective in WHO-AML, including patients with >30 % BM blasts (currently off-label use). Although currently not regarded as standard form of response assessment in AML, disease stabilization and/or HI should be considered sufficient response to continue treatment with azacitidine.
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A modified scoring of the NCCN-IPI is more accurate in the elderly and is improved by albumin and ?2 -microglobulin.
Br. J. Haematol.
PUBLISHED: 03-25-2014
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The International Prognostic Index (IPI) has been used for decades in diffuse large B-cell lymphoma (DLBCL). A retrospective cancer registry analysis in North America showed significantly improved results when an enhanced IPI, the National Comprehensive Cancer Network (NCCN)-IPI was applied. This novel score puts more weight on age and high levels of lactate dehydrogenase (LDH). Nevertheless, it remains unclear if these results can be extrapolated to the general population. This retrospective bi-centre analysis included 499 unselected DLBCL patients who were treated with rituximab and anthracycline-based chemoimmunotherapy between 2004 and 2013. In our cohort, the NCCN-IPI was more accurate in identifying patients at low or high risk, despite older age, and more patients with increased LDH. Nevertheless, a modified scoring of the risk factors was required to more accurately identify elderly patients with a very favourable diagnosis, suggesting an impaired value of the original NCCN-IPI in the elderly. Serum ?2 -microglobulin and albumin were retained as independent prognostic factors for survival in a multivariate analysis. Our data confirm, for the first time, the superior prognostic power of the NCCN-IPI in an unselected, middle-European cohort. We furthermore propose a modified NCCN-IPI for more accurate prognostication in the elderly. Albumin and ?2 -microglobulin levels are likely to add significant information to the NCCN-IPI.
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IOERT as anticipated tumor bed boost during breast-conserving surgery after neoadjuvant chemotherapy in locally advanced breast cancer-Results of a case series after 5-year follow-up.
Int. J. Cancer
PUBLISHED: 03-06-2014
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To evaluate retrospectively rates of local (LCR) and locoregional tumor control (LRCR) in patients with locally advanced breast cancer (LABC) who were treated with preoperative chemotherapy (primary systemic treatment, PST) followed by breast-conserving surgery (BCS) and either intraoperative radiotherapy with electrons (IOERT) preceding whole-breast irradiation (WBI) (Group 1) or with WBI followed by an external tumor bed boost (electrons or photons) instead of IOERT (Group 2). From 2002 to 2007, 83 patients with clinical Stage II or III breast cancer were enrolled in Group 1 and 26 in Group 2. All patients received PST followed by BCS and axillary lymph node dissection. IOERT boosts were applied by single doses of 9 Gy (90% reference isodose) versus external boosts of 12 Gy (median dose range, 6-16) in 2 Gy/fraction (ICRU). WBI in both groups was performed up to total doses of 51-57 Gy (1.7-1.8 Gy/fraction). The respective median follow-up times for Groups 1 and 2 amount 59 months (range, 3-115) and 67.5 months (range, 13-120). Corresponding 6-year rates for LCR, LRCR, metastasis-free survival, disease-specific survival and overall survival were 98.5, 97.2, 84.7, 89.2 and 86.4% for Group 1 and 88.1, 88.1, 74, 92 and 92% for Group 2, respectively, without any statistical significances. IOERT as boost modality during BCS in LABC after PST shows a trend to be superior in terms of LCR and LRCR in comparison with conventional boosts.
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Targeted therapy in advanced metastatic colorectal cancer: current concepts and perspectives.
World J. Gastroenterol.
PUBLISHED: 02-20-2014
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The introduction of new cytotoxic substances as well as agents that target vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) signaling has improved clinical outcome of patients with metastatic colorectal cancer (mCRC). In this review we summarize the most relevant clinical data on VEGF and EGFR targeting regimens in mCRC. The effects of available treatment strategies for mCRC are often temporary, with resistance and disease progression developing in most patients. Thus, new treatment strategies are urgently needed. Some GI peptides including gastrin and gastrin releasing peptide, certain growth factors such as insulin-like growth factor-I?and II and neuropeptides such as growth hormone releasing hormone (GHRH) are implicated in the growth of CRC. Experimental investigations in CRC with antagonistic analogs of bombesin/gastrin-releasing peptide, GHRH, and with cytotoxic peptides that can be targeted to peptide receptors on tumors, are summarized in the second part of the review.
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Tiam1/Rac1 signals contribute to the proliferation and chemoresistance, but not motility, of chronic lymphocytic leukemia cells.
Blood
PUBLISHED: 02-05-2014
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Signals from the tumor microenvironment promote the migration, survival, and proliferation of chronic lymphocytic leukemia (CLL) cells. Rho GTPases control various signaling pathways downstream of microenvironmental cues. Here, we analyze the function of Rac1 in the motility and proliferation of CLL cells. We found decreased transcription of the Rac guanine nucleotide exchange factors Tiam1 and Vav1 in unstimulated peripheral blood CLL cells with almost complete loss of Tiam1 but increased transcription of the potential Rac antagonist RhoH. Consistently, stimulation of CLL cells with the chemokine CXCL12 induced RhoA but not Rac1 activation, whereas chemokine-induced CLL cell motility was Rac1-independent. Coculture of CLL cells with activated T cells induced their activation and subsequent proliferation. Here, Tiam1 expression was induced in the malignant cells in line with increased Ki-67 and c-Myc expression. Rac1 or Tiam1 knockdown using siRNA or treatment with the Tiam1/Rac inhibitor NSC-23766 attenuated c-Myc transcription. Furthermore, treatment of CLL cells with NSC-23766 reduced their proliferation. Rac inhibition also antagonized the chemoresistance of activated CLL cells toward fludarabine. Collectively, our data suggest a dynamic regulation of Rac1 function in the CLL microenvironment. Rac inhibition could be of clinical use by selectively interfering with CLL cell proliferation and chemoresistance.
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Alternative splice variants of AID are not stoichiometrically present at the protein level in chronic lymphocytic leukemia.
Eur. J. Immunol.
PUBLISHED: 02-03-2014
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Activation-induced deaminase (AID) is a DNA-mutating enzyme that mediates class-switch recombination as well as somatic hypermutation of antibody genes in B cells. Due to off-target activity, AID is implicated in lymphoma development by introducing genome-wide DNA damage and initiating chromosomal translocations such as c-myc/IgH. Several alternative splice transcripts of AID have been reported in activated B cells as well as malignant B cells such as chronic lymphocytic leukemia (CLL). As most commercially available antibodies fail to recognize alternative splice variants, their abundance in vivo, and hence their biological significance, has not been determined. In this study, we assessed the protein levels of AID splice isoforms by introducing an AID splice reporter construct into cell lines and primary CLL cells from patients as well as from WT and TCL1(tg) C57BL/6 mice (where TCL1 is T-cell leukemia/lymphoma 1). The splice construct is 5'-fused to a GFP-tag, which is preserved in all splice isoforms and allows detection of translated protein. Summarizing, we show a thorough quantification of alternatively spliced AID transcripts and demonstrate that the corresponding protein abundances, especially those of splice variants AID-ivs3 and AID-?E4, are not stoichiometrically equivalent. Our data suggest that enhanced proteasomal degradation of low-abundance proteins might be causative for this discrepancy.
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The CXCR4 and adhesion molecule expression of CD34+ hematopoietic cells mobilized by "on-demand" addition of plerixafor to granulocyte-colony-stimulating factor.
Transfusion
PUBLISHED: 01-24-2014
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Granulocyte-colony-stimulating factor (G-CSF) is routinely used for mobilization of hematopoietic stem and progenitor cells preceding autologous transplantation after high-dose chemotherapy in hematologic malignancies. However, due to high mobilization failure rates, alternative mobilization strategies are required.
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Human immunodeficiency virus type 2 infections in Austria.
Wien. Klin. Wochenschr.
PUBLISHED: 01-18-2014
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The first case of human immunodeficiency virus type 2 (HIV-2) seropositivity in Austria was confirmed in 1993 in a dually human immunodeficiency virus type 1 (HIV-1)- and HIV-2-infected patient from Ghana, who died in 2001. Before this investigation, no further HIV-2 infection was published.
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Performance characteristics of the COBAS Ampliprep/COBAS TaqMan v2.0 and the Abbott RealTime hepatitis C assays - implications for response-guided therapy in genotype 1 infections.
Antivir. Ther. (Lond.)
PUBLISHED: 01-16-2014
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With the advent of the protease inhibitors boceprevir and telaprevir a novel therapy approach for HCV genotype 1 infected subjects has become standard of care. Quantification of HCV viral load (VL) represents an important predictor of treatment response.
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Hypertension as a predictive marker for bevacizumab in metastatic breast cancer: results from a retrospective matched-pair analysis.
Anticancer Res.
PUBLISHED: 01-10-2014
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Several phase-III studies have shown improvements in terms of progression-free survival (PFS) with bevacizumab when added to chemotherapy in advanced breast cancer. However, the extent of improvement varied and none of the trials showed benefit in terms of overall survival (OS).
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Azacitidine in CMML: matched-pair analyses of daily-life patients reveal modest effects on clinical course and survival.
Leuk. Res.
PUBLISHED: 01-07-2014
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Recent data suggest that azacitidine may be beneficial in CMML. We report on 48 CMML-patients treated with azacitidine. Overall response rates were high (70% according to IWG-criteria, including 22% complete responses). Monocyte count and cytogenetics adversely affected survival, whereas age, WHO-type, FAB-type, and spleen size did not. Matched-pair analyses revealed a trend for higher two-year-survival for azacitidine as compared to best supportive care (62% vs. 41%, p=0.067) and longer OS for azacitidine first-line vs. hydroxyurea first-line (p=0.072, median OS 27.7 vs. 6.2 months). This report reinforces existing evidence that azacitidine is safe and efficacious in both myelodysplastic and myeloproliferative CMML.
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Lenalidomide in combination with vorinostat and dexamethasone for the treatment of relapsed/refractory peripheral T cell lymphoma (PTCL): report of a phase I/II trial.
Ann. Hematol.
PUBLISHED: 01-05-2014
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Given the poor outcome of relapsed and refractory peripheral T cell lymphoma (PTCL), we explored a combination of lenalidomide, vorinostat, and dexamethasone to test the feasibility of this therapy in relapsed and refractory PTCL. Eight patients were accrued: two peripheral T cell lymphoma, unspecified; five angioimmunoblastic T cell lymphoma; and one ALK-negative anaplastic large-cell lymphoma. A dose escalation of lenalidomide (days 1-21, q28) was planned using a 3?+?3 design. As two patients treated with 10 mg/day experienced dose-limiting toxicity (thrombocytopenia grade 3, stroke grade 4), the primary end point of our trial was reached; the maximal tolerable dose of lenalidomide was 5 mg/day (level -I). Adverse events grade ?3 were observed as thrombocytopenia (23 %), leukocytopenia (15 %), anemia (8 %), and neutropenia (8 %). One complete remission (10.3 months), one partial remission (11.3 months), one stable disease (11.9 months), and four progressive disease (overall response rate 25 %) were observed. The median progression-free survival was 2.2 months and the median OS was 6.7 months. In conclusion, the poor results obtained with lenalidomide in combination with vorinostat and dexamethasone provide no arguments that could justify further investigation of this drug combination for the treatment of relapsed PTCL.
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Liver toxicity during temozolomide chemotherapy caused by Chinese herbs.
BMC Complement Altern Med
PUBLISHED: 01-03-2014
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Complementary and alternative medicine is often used by patients with malignant glioma. Although several interactions of various alternative agents with chemotherapy are known, none has been described for temozolomide so far.
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Bendamustine-bortezomib-dexamethasone is an active and well tolerated regimen in patients with relapsed or refractory multiple myeloma.
Blood
PUBLISHED: 11-13-2013
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Bendamustine with bortezomib and dexamethasone was evaluated in 79 patients with relapsed/refractory multiple myeloma. Median age was 64 (range 40-80) years and patients had a median of 2 (range 1-6) prior treatment lines. Bendamustine 70 mg/m(2), day 1 and 4, bortezomib 1.3mg/m(2) days 1, 4, 8, 11 intravenously, and dexamethasone 20 mg, days 1, 4, 8, and 11, q 28 days, was given for up to 8 cycles. Primary endpoint was response rate (ORR) and secondary endpoints were progression-free survival (PFS), overall survival (OS), time to response and toxicity. ORR was 60.9%, and when minor responses were included, 75.9%. Median time to response was 31 days (111 to best response). ORR rate was similar in patients previously exposed to bortezomib, lenalidomide and to both bortezomib and lenalidomide. PFS was 9.7 and OS 25.6 months. Multivariate analysis showed high LDH, ?3 prior treatment lines and low platelet counts correlating with short survival. Grade 3/4 thrombopenia and G 3/4/5 infections were noted in 38% and 23% respectively. Grade ? 2 polyneuropathy increased from 19% at baseline to 52% at cycle 8 and grade 4 from 0 to 7%. Bendamustine-bortezomib-dexamethasone is active and well tolerated in patients with relapsed/refractory myeloma. This study is registered in the EudraCT data base (Nr. 2008-006421-13).
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Female gender may predict response to FOLFIRINOX in patients with unresectable pancreatic cancer: A single institution retrospective review.
Int. J. Oncol.
PUBLISHED: 08-25-2013
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FOLFIRINOX is a highly active regimen for the treatment of patients with unresectable pancreatic cancer. However, treatment with FOLFIRINOX is associated with relevant toxicity and predictors for response to therapy are warranted. We retrospectively analyzed 49 patients with unresectable pancreatic cancer treated with FOLFIRINOX in order to evaluate a possible predictive role of clinical parameters and tumor characteristics for response to chemotherapy. Tumor samples were characterized histopathologically before treatment and expression of p53 and Ki67 was analyzed using automated immunohistochemistry. Overall survival (OS) and progression-free survivall (PFS) were estimated by the Kaplan-Meier method. The overall objective response rate was 55.1%, the disease control rate was 70.6%. Female gender was associated with a significantly higher disease control rate of 91.7 compared to 48.0% in male patients (p=0.001) which reached 100% in female patients when primarily treated compared to treatment after surgical resection and relapse (77.8%, p=0.057). For all patients median PFS was 3.5 months (95% CI, 2.7-4.3 months) and median OS was 13 months (95% CI, 9.4-16.6 months). Female patients showed a tendency towards a longer median PFS (5.0 months, 95% CI, 3.6-6.4 months) compared to males (3.0 months, 95% CI, 2.4-3.6 months) (p=0.099). Serum levels of CA19.9 and CEA were significantly higher in female patients compared to male patients (p=0.037, p=0.05). Tumors of patients with response to FOLFIRINOX showed a higher expression level of p53 and Ki67 as well as higher serum levels of CA19.9 compared to non-responders, which was statistically not significant. Our study indicates that female gender is a positive predictor for therapy response to FOLFIRINOX in patients with unresectable pancreatic cancer. Female gender in turn was associated with increased levels of tumor markers CEA and CA19.9 and patients with higher serum levels of CA19.9 were more responsive to FOLFIRINOX.
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The pathogenic relevance of the prognostic markers CD38 and CD49d in chronic lymphocytic leukemia.
Ann. Hematol.
PUBLISHED: 07-26-2013
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The interactions of chronic lymphocytic leukemia cells with the microenvironment in secondary lymphoid tissues and the bone marrow are known to promote CLL cell survival and proliferation. CD38 and CD49d are both independent prognostic risk parameters in CLL with important roles in shaping these interactions. Both are reported to influence CLL cell trafficking between blood and lymphoid organs as well as their survival and proliferation within the lymphoid organs, thereby impacting the pathophysiology of the disease. The expression of CD38 and CD49d is associated in the majority of cases, and they exist as part of macromolecular complexes. Here, we review the current evidence for the individual and associated contributions of these molecules to CLL pathophysiology.
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Phase III trial of sunitinib in combination with capecitabine versus capecitabine monotherapy for the treatment of patients with pretreated metastatic breast cancer.
J. Clin. Oncol.
PUBLISHED: 07-15-2013
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Metastatic breast cancer (MBC) remains an incurable illness in the majority of cases, despite major therapeutic advances. This may be related to the ability of breast tumors to induce neoangiogenesis, even in the face of cytotoxic chemotherapy. Sunitinib, an inhibitor of key molecules involved in neoangiogenesis, has an established role in the treatment of metastatic renal cell and other cancers and demonstrated activity in a phase II trial in MBC. We performed a randomized phase III trial comparing sunitinib plus capecitabine (2,000 mg/m2) with single-agent capecitabine (2,500 mg/m2) in patients with heavily pretreated MBC.
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Neoadjuvant Chemotherapy and Targeted Therapy in Breast Cancer: Past, Present, and Future.
J Oncol
PUBLISHED: 07-11-2013
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Traditionally, neoadjuvant treatment for breast cancer was preserved for locally advanced and inflammatory disease, converting an inoperable to a surgical resectable cancer. In recent years, neoadjuvant therapy has become an accepted treatment option also for lower tumor stages in order to increase the rate of breast conserving therapy and to reduce the extent of surgery. Furthermore, treatment response can be monitored, and therefore, patient compliance may be increased. Neoadjuvant trials, additionally, offer the opportunity to evaluate new treatment options in a faster way and with fewer patients than large adjuvant trials. Compared to the metastatic setting, the issue of acquired resistance and pretreatments, which may distort treatment efficacy, can be avoided. New trial designs like window-of-opportunity trials or postneoadjuvant trials provide the chance to identify tumor sensitivity or to overcome tumor resistance in early tumor stages. In particular, in HER2-positive breast cancer, the neoadjuvant approach yielded great successes. The dual HER2 blockade with trastuzumab and pertuzumab recently showed the highest pCR rates ever reported. Many new drugs are in clinical testing with the aim to further increase pCR rates. Whether this endpoint really represents a surrogate for long-term outcome is not answered yet and will be discussed in this review.
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Randomized phase II study of the anti-epidermal growth factor receptor monoclonal antibody cetuximab with cisplatin versus cisplatin alone in patients with metastatic triple-negative breast cancer.
J. Clin. Oncol.
PUBLISHED: 06-03-2013
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Epidermal growth factor receptor is overexpressed in metastatic triple-negative breast cancers (mTNBCs), an aggressive subtype of breast cancer. Our randomized phase II study investigated cisplatin with or without cetuximab in this setting.
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Differential survival trends of stage II colorectal cancer patients relate to promoter methylation status of PCDH10, SPARC, and UCHL1.
Mod. Pathol.
PUBLISHED: 05-29-2013
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Surgical excision of colorectal cancer at early clinical stages is highly effective, but 20-30% of patients relapse. Therefore, it is of clinical relevance to identify patients at high risk for recurrence, who would benefit from adjuvant chemotherapy. The objective of this study was to identify prognostic and/or predictive methylation markers in stage II colorectal cancer patients. Therefore, we selected six gene promoters (FZD9, PCDH10 (protocadherin 10), SFRP2, SPARC (secreted protein acidic and rich in cysteine), UCHL1 (ubiquitin carboxyl-terminal hydrolase 1), and WIF1) for methylation analysis in formalin-fixed, paraffin-embedded primary tumor samples of colorectal cancer patients (n=143) who were enrolled in a prospective randomized phase III trial of the Austrian Breast and Colorectal cancer Study Group. Patients were randomized to adjuvant chemotherapy with 5-fluorouracil and leucovorin or surveillance only. Survival analyses revealed that combined evaluation of three promoters (PCDH10, SPARC, and UCHL1) showed differential effects with regard to disease-free survival and overall survival in the two treatment groups (significance level 0.007). In the chemotherapy arm, a statistically insignificant trend for patients without methylation toward longer survival was observed (P=0.069 for disease-free survival and P=0.139 for overall survival). Contrary, patients in the surveillance arm without methylation in their gene promoters had shorter disease-free survival and overall survival (P=0.031 for disease-free survival and P=0.003 for overall survival), indicating a prognostic effect of methylation in this group (test for interaction, P=0.006 for disease-free survival and P=0.018 for overall survival). These results indicate that promoter methylation status of PCDH10, SPARC, and UCHL1 may be used both as prognostic and predictive molecular marker for colorectal cancer patients and, therefore, may facilitate treatment decisions for stage II colorectal cancer.Modern Pathology advance online publication, 6 December 2013; doi:10.1038/modpathol.2013.204.
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Clinical impact of DNMT3A mutations in younger adult patients with acute myeloid leukemia: results of the AML Study Group (AMLSG).
Blood
PUBLISHED: 04-30-2013
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In this study, we evaluated the frequency and prognostic impact of DNMT3A mutations (DNMT3A(mut)) in 1770 younger adult patients with acute myeloid leukemia (AML) in the context of other genetic alterations and the European LeukemiaNet (ELN) classification. DNMT3A(mut) were found in 20.9% of AMLs and were associated with older age (P < .0001), higher white blood cell counts (P < .0001), cytogenetically normal AML (CN-AML; P < .0001), NPM1 mutations (P < .0001), FLT3 internal tandem duplications (P < .0001), and IDH1/2 mutations (P < .0001). In univariable and multivariable analyses, DNMT3A(mut) did not impact event-free, relapse-free (RFS), or overall survival (OS) in either the entire cohort or in CN-AML; a negative prognostic effect was found only in the ELN unfavorable CN-AML subset (OS, P = .011). In addition, R882 mutations vs non-R882 mutations showed opposite clinical effects-unfavorable for R882 on RFS (all: hazard ratio [HR], 1.29 [P = .026]; CN-AML: HR, 1.38 [P = .018]) and favorable for non-R882 on OS (all: HR, 0.77 [P = .057]; CN-AML: HR, 0.73 [P = .083]). In our statistically high-powered study with minimized selection bias, DNMT3A(mut) represent a frequent genetic lesion in younger adults with AML but have no significant impact on survival end points; only moderate effects on outcome were found, depending on molecular subgroup and DNMT3A(mut) type.
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AVEREL: a randomized phase III Trial evaluating bevacizumab in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer.
J. Clin. Oncol.
PUBLISHED: 04-08-2013
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PURPOSE The AVEREL trial [A Study of Avastin (Bevacizumab) in Combination With Herceptin (Trastuzumab)/Docetaxel in Patients With HER2-Positive Metastatic Breast Cancer] evaluated first-line bevacizumab-containing therapy for human epidermal growth factor receptor 2 (HER2) -positive locally recurrent/metastatic breast cancer (LR/MBC). PATIENTS AND METHODS Patients with measurable/evaluable HER2-positive LR/MBC who had not received trastuzumab or chemotherapy for LR/MBC were stratified by prior adjuvant trastuzumab, prior (neo)adjuvant taxane, hormone receptor status, and measurable disease and were randomly assigned to receive docetaxel 100 mg/m(2) plus trastuzumab 8 mg/kg loading dose followed by 6 mg/kg either with bevacizumab 15 mg/kg or without bevacizumab, all administered every 3 weeks. The primary end point was progression-free survival (PFS). Additional end points included overall survival, response rate (RR), safety, quality of life, and translational research. Results Baseline characteristics of the 424 patients were balanced between treatment arms. Most patients had visceral metastases, 43% had a disease-free interval less than 12 months, and 85% had measurable disease. Median follow-up was 26 months. The hazard ratio for investigator-assessed PFS was 0.82 (95% CI, 0.65 to 1.02; P = .0775; median PFS, 13.7 v 16.5 months in the non-bevacizumab and bevacizumab arms, respectively; PFS events in 72%). The Independent Review Committee-assessed PFS hazard ratio was 0.72 (95% CI, 0.54 to 0.94; P = .0162; median PFS, 13.9 v 16.8 months, respectively; PFS events in 53%). The RR was 70% versus 74%, respectively (P = .3492). Grade ? 3 febrile neutropenia and hypertension were more common with bevacizumab-containing therapy. High baseline plasma vascular endothelial growth factor A (VEGF-A) concentrations were associated with greater bevacizumab benefit (not statistically significant). CONCLUSION Combining bevacizumab with docetaxel and trastuzumab did not significantly improve investigator-assessed PFS. The potential predictive value of plasma VEGF-A is consistent with findings in HER2-negative LR/MBC, warranting prospective evaluation.
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ABVD in older patients with early-stage Hodgkin lymphoma treated within the German Hodgkin Study Group HD10 and HD11 trials.
J. Clin. Oncol.
PUBLISHED: 03-18-2013
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Older patients with Hodgkin lymphoma (HL) account for approximately 20% of all HL patients. ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy is regarded as standard of care in these patients. However, little is known on feasibility and efficacy of ABVD in this age group.
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Complications of 5-azacytidine: Three cases of severe ischemic colitis in elderly patients with myelodysplastic syndrome.
Oncol Lett
PUBLISHED: 03-12-2013
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5-Azacytidine (5-AZA) was the first drug to be approved for the treatment of high-risk myelodysplastic syndrome (MDS). The adverse event profile of this drug appears favorable compared with the conventional intensive chemotherapy that is used for MDS or acute myeloid leukemia. However, uncommon adverse events may have remained undetected in the limited number of patients that have been treated to date. The present study describes three cases/66.8 person-years (4,491 cases/100,000 person-years) of severe ischemic colitis in a single center cohort of 95 patients who were consecutively treated using subcutaneous 5-AZA. The results demonstrated a much higher incidence of colitis compared with the rates in the general population or in patients of greater ages and co-morbidities. The present study investigated whether the combination of anemia and constipation due to the co-medication of 5-HT3 receptor antagonists may explain the three cases of ischemic colitis.
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Azacitidine in patients with WHO-defined AML -- results of 155 patients from the Austrian Azacitidine Registry of the AGMT-Study Group.
J Hematol Oncol
PUBLISHED: 02-11-2013
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OBJECTIVE: The Austrian Azacitidine Registry is a multi-center database (ClinicalTrials.gov: NCT01595295). The nature and intent of the registry was to gain a comprehensive view of the use, safety and efficacy of the drug in a broad range of AML-patients treated in real-life scenarios.Patients and methods: The sole inclusion criteria were the diagnosis of WHO-AML and treatment with at least one dose of azacitidine. No formal exclusion criteria existed. A total of 155 AML-patients who were mostly unfit/ineligible for intensive chemotherapy, or had progressed despite conventional treatment, were included. True ITT-analyses and exploratory analyses regarding the potential prognostic value of baseline-variables/performance-/comorbidity-/risk-scores on OS, were performed. RESULTS: In this cohort of 155 pretreated (60%), and/or comorbid (87%), elderly (45% >=75 years) AML-patients, azacitidine was well tolerated and efficacious, with an overall response rate (CR, mCR, PR, HI) of 45% in the total cohort (ITT) and 65% in patients evaluable according to IWG-criteria, respectively. Pre-treatment with conventional chemotherapy (P = .113), age <=/>80 years (P = .853), number of comorbidities (P = .476), and bone marrow (BM) blast count (P = .663) did not influence overall survival (OS). In multivariate analysis hematologic improvement alone (without the requirement of concomitant bone marrow blast reduction), although currently not regarded as a standard form of response assessment in AML, was sufficient to confer OS benefit (18.9 vs. 6.0 months; P = .0015). Further deepening of response after first response was associated with improved OS (24.7 vs. 13.7 months; P < .001). CONCLUSIONS: In this large cohort of AML-patients treated with azacitidine, age >80a, number of comorbidities and/or BM-blasts >30% did not adversely impact OS.
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Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer: interim efficacy results of the randomised, open-label, non-inferiority, phase 3 TURANDOT trial.
Lancet Oncol.
PUBLISHED: 01-10-2013
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Randomised phase 3 trials in metastatic breast cancer have shown that combining bevacizumab with either paclitaxel or capecitabine significantly improves progression-free survival and response rate compared with chemotherapy alone but the relative efficacy of bevacizumab plus paclitaxel versus bevacizumab plus capecitabine has not been investigated. We compared the efficacy of the two regimens.
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Viral infections and their management in patients with chronic lymphocytic leukemia.
Leuk. Lymphoma
PUBLISHED: 01-03-2013
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Over the past decade, the treatment of patients with chronic lymphocytic leukemia (CLL) has been improved by several new cytostatic agents and monoclonal antibodies. This development has resulted in higher response rates and more profound levels of immunosuppression than with previously used treatments. With the intrinsic immune defect of CLL, the degree and quality of immunosuppression is thus substantially different from that observed during the treatment of other indolent lymphomas and warrants special consideration. Infection with or reactivation of viral diseases such as herpes simplex, varicella zoster, cytomegalovirus (CMV), Epstein-Barr virus (EBV), hepatitis B and C or JC virus has become a more frequent problem in the management of these patients. However, most data are derived from observational studies, and only a few interventional trials have been planned and reported. In this review, we summarize the available data, discuss several treatment and management options and offer some recommendations.
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Cobas ampliprep/cobas TaqMan HIV-1 v2.0 assay: consequences at the cohort level.
PLoS ONE
PUBLISHED: 01-01-2013
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High-sensitive real-time PCR assays are routinely used to monitor HIV-1 infected subjects. Inter-assay discrepancies have been described at the low viral load (VL) end, where clinical decisions regarding possible virological rebound are based.
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Oxaliplatin, irinotecan and cetuximab in advanced gastric cancer. A multicenter phase II trial (Gastric-2) of the Arbeitsgemeinschaft Medikamentose Tumortherapie (AGMT).
Anticancer Res.
PUBLISHED: 12-27-2011
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Patients suffering from advanced gastric cancer still have a poor prognosis and treatment options are limited. In our previous phase II trial (AGMT-Gastric-1), we showed that the combination of oxaliplatin and irinotecan was well tolerated and effective. The same chemotherapy regimen was now tested in combination with cetuximab in a multicenter phase II trial.
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Adjuvant sequencing of tamoxifen and anastrozole is superior to tamoxifen alone in postmenopausal women with low proliferating breast cancer.
Clin. Cancer Res.
PUBLISHED: 10-13-2011
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To assess the predictive value of Ki67 expression in postmenopausal hormone receptor-positive early-breast cancer patients, who were either treated with adjuvant tamoxifen (TAM) alone or with TAM followed by anastrozole (ANA).
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Eight cycles of escalated-dose BEACOPP compared with four cycles of escalated-dose BEACOPP followed by four cycles of baseline-dose BEACOPP with or without radiotherapy in patients with advanced-stage hodgkins lymphoma: final analysis of the HD12 trial of
J. Clin. Oncol.
PUBLISHED: 10-11-2011
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Eight cycles of BEACOPP(escalated) (escalated dose of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) followed by radiotherapy (RT) to initial bulk or residual tumor mass is the German Hodgkin Study Group standard of care for advanced-stage Hodgkins lymphoma (HL). However, treatment-related toxicity is a concern, and the role of RT in this setting is unclear. The HD12 study thus aimed to reduce toxicity while maintaining efficacy.
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A new molecular predictor of distant recurrence in ER-positive, HER2-negative breast cancer adds independent information to conventional clinical risk factors.
Clin. Cancer Res.
PUBLISHED: 08-01-2011
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According to current guidelines, molecular tests predicting the outcome of breast cancer patients can be used to assist in making treatment decisions after consideration of conventional markers. We developed and validated a gene expression signature predicting the likelihood of distant recurrence in patients with estrogen receptor (ER)-positive, HER2-negative breast cancer treated with adjuvant endocrine therapy.
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Prognostic value of number of removed lymph nodes, number of involved lymph nodes, and lymph node ratio in 7502 breast cancer patients enrolled onto trials of the Austrian Breast and Colorectal Cancer Study Group (ABCSG).
Ann. Surg. Oncol.
PUBLISHED: 07-19-2011
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The number of removed axillary lymph nodes and the ratio of involved to removed lymph nodes are described as independent prognostic factors beside the absolute number of involved lymph nodes in breast cancer patients. The correlation between these factors and prognosis were investigated in trials of the Austrian Breast and Colorectal Cancer Study Group (ABCSG).
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Antimyeloma activity of the sesquiterpene lactone cnicin: impact on Pim-2 kinase as a novel therapeutic target.
J. Mol. Med.
PUBLISHED: 07-05-2011
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Despite recent advances in therapy, multiple myeloma, the second most common hematologic tumor in the Western world, is still incurable. Identification of substances that display a wide range of tumor-killing activities and target cancer-specific pathways constitute a basis for the development of novel therapies. In this study, we investigate the cytotoxic effect of the natural substance cnicin in multiple myeloma. Cnicin treatment reveals potent antiproliferative effects and induces cell death in cell lines and primary myeloma cells even in the presence of survival cytokines and the tumor microenvironment. Other cell lines of hematopoietic origin also succumb to cell death whereas stromal cells and endothelial cells are unaffected. We show that activation of caspases, accumulation of reactive oxygen species and downregulation of nuclear factor kappa-light-chain-enhancer of activated B cell contribute to the cytotoxic effects of cnicin. Microarray analysis reveals downregulation of Pim-2, a serine/threonine kinase. We provide evidence that Pim-2 constitutes a new survival kinase for myeloma cells in vitro and is highly expressed in malignant but not in normal plasma cells in vivo. Combining cnicin with current standard or experimental therapeutics leads to enhanced cell death. Thus, our data indicate that cnicin induces myeloma cell death via several pathways and reveals Pim-2 as a novel target. These findings provide a rational for further evaluation of cnicin as a new anti-tumor drug and underline the potential of sesquiterpene lactones in tumor therapy.
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Novel therapeutic options in anaplastic large cell lymphoma: molecular targets and immunological tools.
Mol. Cancer Ther.
PUBLISHED: 06-28-2011
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Anaplastic large cell lymphoma (ALCL) is a CD30-positive, aggressive T-cell lymphoma, and about half of the patients with this disease harbor the t(2;5)(p21;q35) translocation. This chromosomal aberration leads to fusion of the NPM gene with the ALK tyrosine kinase, leading to its constitutive activation. To date, treatment options include polychemotherapy (e.g., cyclophosphamide, doxorubicin, vincristine, and prednisone), which is sometimes combined with radiation in the case of bulky disease, leading to remission rates of ?80%. However, the remaining patients do not respond to therapy, and some patients experience chemo-resistant relapses, making the identification of new and better treatments imperative. The recent discovery of deregulated ALK in common cancers such as non-small cell lung cancer and neuroblastoma has reinvigorated industry interest in the development of ALK inhibitors. Moreover, it has been shown that the ALK protein is an ideal antigen for vaccination strategies due to its low expression in normal tissue. The characterization of microRNAs that are deregulated in ALCL will yield new insights into the biology of ALCL and open new avenues for therapeutic approaches in the future. Also, CD30 antibodies that have been tested in ALCL for quite a while will probably find a place in forthcoming treatment strategies.
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Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial.
Lancet Oncol.
PUBLISHED: 06-05-2011
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Analysis of the Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) at 48 months follow-up showed that addition of zoledronic acid to adjuvant endocrine therapy significantly improved disease-free survival. We have now assessed long-term clinical efficacy including disease-free survival and disease outcomes in patients receiving anastrozole or tamoxifen with or without zoledronic acid.
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Impact of body mass index on the efficacy of endocrine therapy in premenopausal patients with breast cancer: an analysis of the prospective ABCSG-12 trial.
J. Clin. Oncol.
PUBLISHED: 05-09-2011
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Aromatase inhibitors are effective as endocrine treatment for patients with hormone receptor-positive breast cancer. According to the hypothesis that overweight patients have higher levels of aromatase enzyme availability, we investigated the influence of body mass index (BMI) on the efficacy of adjuvant endocrine therapy in premenopausal patients in a retrospective analysis of the Austrian Breast and Colorectal Cancer Study Group (ABCSG) 12 trial.
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Combination therapy of lapatinib and Capecitabine for ErbB2-positive metastatic or locally advanced breast cancer: results from the Lapatinib Expanded Access Program (LEAP) in Central and Eastern Europe.
Onkologie
PUBLISHED: 04-26-2011
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The Lapatinib Expanded Access Program (LEAP) was initiated in 45 countries to provide lapatinib in combination with capecitabine to patients with ErbB2 (HER2)-positive breast cancer already treated with anthracyclines, taxanes and trastuzumab. We report the results from 12 Central and Eastern European countries.
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Clinical outcome with bevacizumab in patients with recurrent high-grade glioma treated outside clinical trials.
Acta Oncol
PUBLISHED: 04-18-2011
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Patients with recurrent high-grade glioma (HGG) have a poor prognosis and there is no defined standard of care. High levels of vascular endothelial growth factor (VEGF) expressed in HGG make the anti-VEGF monoclonal antibody bevacizumab (BEV) of particular interest.
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Sentinel node biopsy after primary chemotherapy in breast cancer: a note of caution from results of ABCSG-14.
Breast J
PUBLISHED: 03-31-2011
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Over the past years, experience has been increasing with lymphatic mapping and sentinel node biopsy (SNB) after preoperative chemotherapy for breast cancer, with a wide range of results reported in the literature and final conclusions on the diagnostic value and clinical consequences of this sequential approach still missing. Between 1999 and 2002, the Austrian Breast and Colorectal Cancer Study Group (ABCSG) conducted a prospective randomized multicenter trial comparing three versus six preoperative cycles of epirubicin/docetaxel + granulocyte colony-stimulating factor for operable breast cancer. Of the 292 patients recruited to the trial overall, 111 were enrolled in a prospective subprotocol for performing LM and SNB in addition to obligatory axillary lymph node dissection (ALND) after PC. SNB after PC identified at least one sentinel node in 100 of 111 patients (identification rate 90%). In six cases, a false-negative SN was identified, resulting in a false-negative rate of 13% (6 of 47). We only found little correlation between patients and tumor characteristics and the identification rate or false-negative rate. Lymphatic mapping and SNB after primary chemotherapy failed to predict histologic infiltration of the sentinel node with sufficient sensitivity. The routine use of SNB after primary chemotherapy should therefore be discouraged.
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First-line panitumumab plus irinotecan/5-fluorouracil/leucovorin treatment in patients with metastatic colorectal cancer.
J. Cancer Res. Clin. Oncol.
PUBLISHED: 03-28-2011
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Panitumumab monotherapy is approved for KRAS wild-type (WT) metastatic colorectal cancer (mCRC) progressing after standard chemotherapy. This study evaluated first-line panitumumab plus FOLFIRI in patients with mCRC.
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Zoledronic acid for adjuvant use in patients with breast cancer.
Expert Rev Anticancer Ther
PUBLISHED: 03-23-2011
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Zoledronic acid, a nitrogen-containing bisphosphonate, is firmly established in the management of metastatic bone disease. It inhibits farnesyl diphosphonate synthase within the mevalonate pathway and, through this mechanism, is a potent inhibitor of osteoclast-mediated bone resorption. In addition, there are preclinical data suggesting that farnesyl diphosphonate synthase inhibition by zoledronic acid has anti-tumor effects in breast cancer. Adjuvant therapies for early breast cancer are associated with substantial decreases in bone mineral density. Results from three clinical trials, ABCSG-12, Z-FAST and ZO-FAST, indicate that the addition of twice-yearly zoledronic acid to standard adjuvant endocrine therapy in premenopausal and postmenopausal patients with hormone receptor-positive breast cancer prevents cancer treatment-induced bone loss. Moreover, it is becoming evident that it may also exert anticancer effects in an estrogen-deprived state in the adjuvant and neoadjuvant setting. However, long-term side effects need to be taken into consideration for treatment decisions.
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Randomized phase II study of lapatinib plus capecitabine or lapatinib plus topotecan for patients with HER2-positive breast cancer brain metastases.
J. Neurooncol.
PUBLISHED: 03-08-2011
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Approximately one-third of patients with advanced, HER2-positive breast cancer develop brain metastases. A significant proportion of women experience central nervous system (CNS) progression after standard radiation therapy. The optimal treatment in the refractory setting is undefined. This study evaluated the toxicity and efficacy of lapatinib in combination with chemotherapy among patients with HER2-positive, progressive brain metastases. Patients with HER2-positive breast cancer with progressive brain metastases after trastuzumab and cranial radiotherapy were included. The primary endpoint was CNS objective response, defined as a ? 50% volumetric reduction of CNS lesion(s) in the absence of new or progressive CNS or non-CNS lesions, or increasing steroid requirements. The study was closed early after 22 of a planned 110 patients were enrolled due to excess toxicity and lack of efficacy in the lapatinib plus topotecan arm. The objective response rate (ORR) in the lapatinib plus capecitabine arm was 38% (exact 95% confidence interval [CI] 13.9-68.4). No responses were observed in the lapatinib plus topotecan arm. Although the study was stopped prior to full enrollment, some promising indications of CNS activity were noted for lapatinib plus capecitabine. The combination of lapatinib plus topotecan was not active and was associated with excess toxicity.
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Differential bone marrow homing capacity of VLA-4 and CD38 high expressing chronic lymphocytic leukemia cells.
PLoS ONE
PUBLISHED: 03-02-2011
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VLA-4 and CD38 predict a poor clinical outcome in chronic lymphocytic leukemia (CLL). We used CLL samples with discordant VLA-4/CD38 risk to address their individual roles in human bone marrow infiltration (BM), CLL cell homing to murine BM, and in supportive CLL cell-stromal cell interactions.
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Nilotinib as frontline and second-line therapy in chronic myeloid leukemia: open questions.
Crit. Rev. Oncol. Hematol.
PUBLISHED: 03-01-2011
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Nilotinib is a second generation ABL tyrosine kinase inhibitor (TKI) that exerts major anti-leukemic effects in newly diagnosed patients with chronic myeloid leukemia (CML) as well as in most patients with imatinib-resistant CML. In freshly diagnosed patients, the anti-leukemic activity of nilotinib exceeds the efficacy of imatinib, and although long-term data for nilotinib are not available yet, the drug has recently been approved for firstline treatment of chronic phase CML in various countries. Still however, several questions concerning the optimal dose, follow-up parameters, long-term safety, and patient selection remain open. Likewise, it remains uncertain whether both Sokal low-risk and high-risk patients should receive nilotinib as frontline therapy in the future. Another question is whether nilotinib can completely eradicate CML in a subset of patients. Furthermore, it remains unclear whether and what comorbidity must be regarded as relative or absolute contra-indication for this TKI. To discuss these issues, the Austrian CML Working Group organized a series of meetings in 2010. In the current article, the outcomes from these discussions are summarized and presented together with recommendations for frontline use of TKIs in various groups of patients with CML. These recommendations should assist in daily practice as well as in the preparation and conduct of clinical trials.
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Successful alemtuzumab retreatment in progressive B-cell chronic lymphocytic leukemia: a multicenter survey in 30 patients.
Ann. Hematol.
PUBLISHED: 02-07-2011
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Although retreatment with alemtuzumab in relapsing B-cell chronic lymphocytic leukemia (CLL) may be beneficial, there has thus far been no thorough analysis available on this topic. Data were collected from 30 chemotherapy-pretreated patients with progressive CLL who had received alemtuzumab twice in consecutive, distinct therapy lines. The median dose of alemtuzumab retreatment was 402 mg (range, 43-1,090 mg). Retreatment with alemtuzumab induced an overall response rate of 47%. From the start of alemtuzumab retreatment, median progression-free survival (PFS) and overall survival (OS) were 6.3 and 20.0 months, respectively. Response rates, PFS and OS upon alemtuzumab retreatment were correlated with response to initial alemtuzumab treatment, the time interval between the initial course of alemtuzumab and start of retreatment, and the hemoglobin concentration prior to retreatment. Reported toxicities from 24 cases included infections (50%), febrile reactions upon alemtuzumab administration (38%), exanthema (21%), and grade 4 neutropenia (13%) and thrombocytopenia (17%). We conclude that alemtuzumab retreatment represents an effective and tolerable therapeutic option for selected patients with CLL.
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Efficacy of temsirolimus after previous treatment with sunitinib, sorafenib or everolimus in advanced renal cell cancer.
Oncology
PUBLISHED: 01-26-2011
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Temsirolimus inhibits the mammalian target of rapamycin with demonstrated efficacy in patients with advanced renal cell cancer.
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Preoperative oxaliplatin, capecitabine, and external beam radiotherapy in patients with newly diagnosed, primary operable, cT?NxM0, low rectal cancer: a phase II study.
Strahlenther Onkol
PUBLISHED: 01-21-2011
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In patients with locally advanced rectal cancer (LARC), preoperative chemoradiation is known to improve local control, and down-staging of the tumor serves as a surrogate for survival. Intensification of the systemic therapy may lead to higher downstaging rates and, thus, enhance survival. This phase II study investigated the efficacy and safety of preoperative capecitabine and oxaliplatin in combination with radiotherapy.
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Liposomal cytarabine is effective and tolerable in the treatment of central nervous system relapse of acute lymphoblastic leukemia and very aggressive lymphoma.
Haematologica
PUBLISHED: 10-15-2010
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Treatment of central nervous system relapse in adult acute lymphoblastic leukemia is a challenge and outcome is poor. Liposomal cytarabine has a prolonged half-life and, given intrathecally, has produced high response rates in patients with central nervous system relapse of non-Hodgkins lymphoma. The aim of this study was to evaluate the efficacy and tolerability of liposomal cytarabine in central nervous system relapse of acute lymphoblastic leukemia or Burkitts lymphoma/leukemia.
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Reduced treatment intensity in patients with early-stage Hodgkins lymphoma.
N. Engl. J. Med.
PUBLISHED: 09-08-2010
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Whether it is possible to reduce the intensity of treatment in early (stage I or II) Hodgkins lymphoma with a favorable prognosis remains unclear. We therefore conducted a multicenter, randomized trial comparing four treatment groups consisting of a combination chemotherapy regimen of two different intensities followed by involved-field radiation therapy at two different dose levels.
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Light chain-induced acute renal failure can be reversed by bortezomib-doxorubicin-dexamethasone in multiple myeloma: results of a phase II study.
J. Clin. Oncol.
PUBLISHED: 09-07-2010
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To assess the efficacy of bortezomib-doxorubicin-dexamethasone (BDD) therapy in patients with multiple myeloma with light chain-induced acute renal failure.
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Modifying akt signaling in B-cell chronic lymphocytic leukemia cells.
Cancer Res.
PUBLISHED: 09-07-2010
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Emerging evidence suggests that the survival of B-cell chronic lymphocytic leukemia (CLL) cells is dependent on microenvironmental influences such as antigenic stimulation and support by stromal cells. Akt, also known as protein kinase B, is a central component in prosurvival signaling downstream of these events. We investigated the role of Akt and its modulation by the protooncogene T-cell leukemia 1a (Tcl1a) in the survival pathways of primary CLL samples and CLL-derived prolymphocytic cell lines MEC-1 and MEC-2. Akt activation was increased by the protective presence of human bone marrow stromal cells and B-cell receptor mimicking signals but antagonized by direct Akt blockade with the novel specific inhibitor AiX, with preferential apoptosis induction in CLL cells with an unmutated immunoglobulin status, which predicts poor clinical outcome. In addition, we found a direct interaction of Akt with Tcl1a in an endogenous coimmunoprecipitation assay. Confirming the critical role of Tcl1a in modulating Akt signaling, Akt activation was enhanced by overexpressing Tcl1a in CLL. In contrast, decreasing Tcl1a levels by small interfering RNA reduced Akt activation in the fludarabine-insensitive CLL cell line MEC-2 and sensitized the malignant cells to fludarabine treatment. In summary, our data reveal a significant role for the Akt-Tcl1a axis in CLL survival and propose a further evaluation of this interplay for targeting chemoresistance phenomena.
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Fludarabine modulates composition and function of the T cell pool in patients with chronic lymphocytic leukaemia.
Cancer Immunol. Immunother.
PUBLISHED: 09-06-2010
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The combination of cytotoxic treatment with strategies for immune activation represents an attractive strategy for tumour therapy. Following reduction of high tumour burden by effective cytotoxic agents, two major immune-stimulating approaches are being pursued. First, innate immunity can be activated by monoclonal antibodies triggering antibody-dependent cellular cytotoxicity. Second, tumour-specific T cell responses can be generated by immunization of patients with peptides derived from tumour antigens and infused in soluble form or loaded onto dendritic cells. The choice of cytotoxic agents for such combinatory regimens is crucial since most substances such as fludarabine are considered immunosuppressive while others such as cyclophosphamide can have immunostimulatory activity. We tested in this study whether fludarabine and/or cyclophosphamide, which represent a very effective treatment regimen for chronic lymphocytic leukaemia, would interfere with a therapeutic strategy of T cell activation. Analysis of peripheral blood samples from patients prior and during fludarabine/cyclophosphamide therapy revealed rapid and sustained reduction of tumour cells but also of CD4(+) and CD8(+) T cells. This correlated with a significant cytotoxic activity of fludarabine/cyclophosphamide on T cells in vitro. Unexpectedly, T cells surviving fludarabine/cyclophosphamide treatment in vitro had a more mature phenotype, while fludarabine-treated T cells were significantly more responsive to mitogenic stimulation than their untreated counterparts and showed a shift towards T(H)1 cytokine secretion. In conclusion, fludarabine/cyclophosphamide therapy though inducing significant and relevant T cell depletion seems to generate a micromilieu suitable for subsequent T cell activation.
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Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)+ and ALK- anaplastic large-cell lymphoma.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 08-30-2010
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Aberrant anaplastic lymphoma kinase (ALK) expression is a defining feature of many human cancers and was identified first in anaplastic large-cell lymphoma (ALCL), an aggressive non-Hodgkin T-cell lymphoma. Since that time, many studies have set out to identify the mechanisms used by aberrant ALK toward tumorigenesis. We have identified a distinct profile of micro-RNAs (miRNAs) that characterize ALCL; furthermore, this profile distinguishes ALK(+) from ALK(-) subtypes, and thus points toward potential mechanisms of tumorigenesis induced by aberrant ALK. Using a nucleophosmin-ALK transgenic mouse model as well as human primary ALCL tumor tissues and human ALCL-derived cell lines, we reveal a set of overlapping deregulated miRNAs that might be implicated in the development and progression of ALCL. Importantly, ALK(+) and ALK(-) ALCL could be distinguished by a distinct profile of "oncomirs": Five members of the miR-17-92 cluster were expressed more highly in ALK(+) ALCL, whereas miR-155 was expressed more than 10-fold higher in ALK(-) ALCL. Moreover, miR-101 was down-regulated in all ALCL model systems, but its forced expression attenuated cell proliferation only in ALK(+) and not in ALK(-) cell lines, perhaps suggesting different modes of ALK-dependent regulation of its target proteins. Furthermore, inhibition of mTOR, which is targeted by miR-101, led to reduced tumor growth in engrafted ALCL mouse models. In addition to future therapeutical and diagnostic applications, it will be of interest to study the physiological implications and prognostic value of the identified miRNA profiles.
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Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkins lymphoma: final analysis of the German Hodgkin Study Group HD11 trial.
J. Clin. Oncol.
PUBLISHED: 08-16-2010
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Combined-modality treatment consisting of four to six cycles of chemotherapy followed by involved-field radiotherapy (IFRT) is the standard of care for patients with early unfavorable Hodgkins lymphoma (HL). It is unclear whether treatment results can be improved with more intensive chemotherapy and which radiation dose needs to be applied.
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Regulatory T cells predict the time to initial treatment in early stage chronic lymphocytic leukemia.
Cancer
PUBLISHED: 07-18-2010
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Early stage chronic lymphocytic leukemia is characterized by a highly variable course of disease. Because it is believed that regulatory T cells (T(regs) ) are potent suppressors of antitumor immunity, the authors hypothesized that increased T(regs) may favor disease progression.
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Interdependent regulation of p53 and miR-34a in chronic lymphocytic leukemia.
Cell Cycle
PUBLISHED: 07-03-2010
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Chronic lymphocytic leukemia (CLL) has an incidence 4/1,00,000 people in the western world and is one of the first cancers reported to be associated with deregulated miRNA expression. microRNAs are small non coding RNAs that are important regulators of protein expression through binding to their untranslated 3-UTR region. The miR-34 family was demonstrated to be induced by the tumor suppressor p53 and to elicit p53-like responses like senescence, cell cycle arrest and apoptosis depending on the cell type. We have shown in a recent paper that miR-34a is severely increased in the TCL1-mouse model of CLL. This finding was reflected in human CLL. Moreover, it is demonstrated that its expression is dependent on the presence of the SNP309 in the intronic promoter of the MDM2 gene. In addition, low miR-34a expression was associated with shorter time to treatment (log-rank p = 0.003) in CLL. When reintroduced into CLL cells, miR-34a was able to induce apoptosis. Interestingly, this was dependent on an intact p53 pathway. Here, we present data showing that knockdown of p53 in HCT-116 cells severely reduces miR-34a induced apoptosis. In conclusion, miR-34a is proposed as a marker for the activity of the p53 pathway in CLL.
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An uncommon cause of anaemia: Sheehans syndrome.
Wien. Klin. Wochenschr.
PUBLISHED: 04-05-2010
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Ischemic pituitary necrosis due to severe postpartum haemorrhage called Sheehans syndrome is a rare cause of hypopituitarism in the western world, but much more common in developing countries. A 45-year-old female patient being a war refugee from Chechnya with severe anaemia and fatigue was diagnosed at our outpatient department with Sheehans syndrome after severe postpartum haemorrhage and emergency hysterectomy 15 years ago. Panhypopituitarism was adequately treated with substitution of hydrocortisone, thyroxine and transdermal oestrogen which resulted in haemoglobin increase to nearly normal levels and symptoms improved immediately. Severe anaemia caused by panhypopituitarism shows the importance of the hormonal system for erythropoiesis. Clinical and basic scientific evidence indicates thyroidal hormones to be the main cause.
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PLZF/ZBTB16, a glucocorticoid response gene in acute lymphoblastic leukemia, interferes with glucocorticoid-induced apoptosis.
J. Steroid Biochem. Mol. Biol.
PUBLISHED: 03-29-2010
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Glucocorticoids (GCs) cause cell cycle arrest and apoptosis in lymphoid cells which is exploited to treat lymphoid malignancies. The mechanisms of these anti-leukemic GC effects are, however, poorly understood. We previously defined a list of GC-regulated genes by expression profiling in children with acute lymphoblastic leukemia (ALL) during systemic GC monotherapy and in experimental systems of GC-induced apoptosis. PLZF/ZBTB16, a transcriptional repressor, was one of the most promising candidates derived from this screen. To investigate its role in the anti-leukemic GC effects, we performed overexpression and knock-down experiments in CCRF-CEM childhood ALL cells. Transgenic PLZF/ZBTB16 alone had no detectable effect on cell proliferation or survival, but reduced sensitivity to GC-induced apoptosis but not apoptosis induced by antibodies against Fas/CD95 or 3 different chemotherapeutics. Knock-down of ZBTB16 entailed a small, but significant, increase in cell death induction by GC. Affymetrix Exon array-based whole genome expression profiling revealed that PLZF/ZBTB16 induction did not significantly alter the expression profile, however, it interfered with the regulation of numerous GC response genes, including BCL2L11/Bim, which has previously been shown to be responsible for cell death induction in CCRF-CEM cells. Thus, the protective effect of PLZF/ZBTB16 can be attributed to interference with transcriptional regulation by GC.
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microRNA-34a expression correlates with MDM2 SNP309 polymorphism and treatment-free survival in chronic lymphocytic leukemia.
Blood
PUBLISHED: 01-20-2010
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In chronic lymphocytic leukemia (B-CLL), aberrations along the p53 axis lead to decreased overall survival and therapy resistance. Recent studies identified microRNA-34a (miR-34a) as a major downstream target of p53. We monitored the expression of miR-34a during disease development in a murine B-CLL model. miR-34a was up-regulated more than 20-fold during the leukemic but not during the preleukemic phase. In the human system, B-CLL cells also had 4.6-fold higher miR-34a expression compared with B cells of healthy controls. In B-CLL cells of patients with p53 aberrations, miR-34a expression was consistently low. The broad distribution of miR-34a levels in p53 wild-type patients prompted us to study the correlation between single nucleotide polymorphism 309 (SNP309) in the intronic promoter of MDM2 and miR-34a expression. B-CLL cells of patients with the SNP309 GG genotype had significantly lower miR-34a expression levels compared with patients with the TT genotype (P = .002). Low miR-34a levels were able to predict shorter time to treatment (P = .003) and were associated with an abbreviated lymphocyte doubling time. Further, overexpression of miR-34a in primary B-CLL cells induced apoptosis. These findings suggest miR-34a as a possible therapeutic avenue and a sensitive indicator of the activity of the p53 axis in B-CLL.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.