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Background: International oncology societies recommend early palliative care. Specific models to integrate early palliative care efficiently into clinical practice are debated. The authors designed a study to look at the quantitative and qualitative outcomes of an early palliative care intervention in oncological care to decrease stress and improve quality of life., Aims: To compare a single structured early palliative care intervention added to a usual oncology care in terms of distress and health-related quality of life at baseline compared to 6 months after enrollment., Design: This multicenter randomized controlled trial (NCT01983956) enrolled adult patients with advanced cancer. Participants were either randomly assigned to usual oncology care alone or usual care plus a structured early palliative care intervention., Setting/participants: One hundred fifty adult patients with a variety of advanced cancer diagnoses were randomized. Seventy-four participants were in the intervention and 76 participants in the control group. The primary outcome was the change in patient distress assessed by the National Comprehensive Cancer Network distress thermometer at 6 months. Health-related quality of life, the secondary outcome, was assessed by the Functional Assessment of Cancer Therapy-General Questionnaire., Results: The results showed no significant effect of the early palliative care intervention neither on patient distress nor on health-related quality of life., Conclusion: The addition of an early intervention to usual care for patients with advanced cancer did not improve distress or quality of life. Thus, patients may need more intensive early palliative care with continuous professional support to identify and address their palliative needs early.

The European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) are publishing a new edition of the ESMO/ASCO Global Curriculum (GC) thanks to contribution of 64 ESMO-appointed and 32 ASCO-appointed authors. First published in 2004 and updated in 2010, the GC edition 2016 answers to the need for updated recommendations for the training of physicians in medical oncology by defining the standard to be fulfilled to qualify as medical oncologists. At times of internationalisation of healthcare and increased mobility of patients and physicians, the GC aims to provide state-of-the-art cancer care to all patients wherever they live. Recent progress in the field of cancer research has indeed resulted in diagnostic and therapeutic innovations such as targeted therapies as a standard therapeutic approach or personalised cancer medicine apart from the revival of immunotherapy, requiring specialised training for medical oncology trainees. Thus, several new chapters on technical contents such as molecular pathology, translational research or molecular imaging and on conceptual attitudes towards human principles like genetic counselling or survivorship have been integrated in the GC. The GC edition 2016 consists of 12 sections with 17 subsections, 44 chapters and 35 subchapters, respectively. Besides renewal in its contents, the GC underwent a principal formal change taking into consideration modern didactic principles. It is presented in a template-based format that subcategorises the detailed outcome requirements into learning objectives, awareness, knowledge and skills. Consecutive steps will be those of harmonising and implementing teaching and assessment strategies., Competing Interests: JBe received research support to Karolinska Institutet and University Hospital from Amgen, AstraZeneca, Bayer, Merck, Roche and Sanofi-Aventis. JBu received travel accommodations from Genentech/Roche. FC received a consultant honoraria in Astellas/Medivation, AstraZeneca, Celgene, Daiitchi-Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline (GSK), Merck-Scharp, Merus BV, Novartis, Pfizer, Pierre-Fabre, Roche, Sanofi, Teva. HC has worked in a consulting or advisory role in Amgen received speakers’ bureau in Baxalta, Celgene and received research funding from Celgene. PC received honoraria for consultancy/advisory role and/or for lectures from Bayer, Blueprint Medicines, Eisai, Eli Lilly, Glaxo SK, Merck SD, Merck Serono, Nektar Ther., Novartis, Pfizer, PharmaMar. AC received honoraria from MerckSerono, Roche, Amgen, Bayer, Lilly and speakers’ bureau from Roche and MerckSerono. RC received research funding from Genentech/Roche, Puma Biotechnology, Novartis and travel, accommodations, expenses from Novartis. LDP received fees as consultant or for lectures (no speakers’ bureau) from F. Hoffmann-La Roche, Pfizer, Bristol Meyer Squibb, AstraZeneca, Qiagen, Boehringer Ingelheim. All fees were paid to Institution. MDS received honoraria and consultation fees from Amgen, Astellas, Bayer, Celgene, Dendreon, Eisai Inc, ESSA, Ferring, GSK, Janssen Cilag, Merck, Novartis, Pfizer, Pierre Fabre Oncologie, Roche, Sanofi Aventis, Shionogi, Synthon, Takeda, Teva/OncoGenex; received research grant from Pierre Fabre Oncologie. EGEdV received research grants to the institute from Roche/Genentech, Amgen, Novartis, Pieris, Servier, is part of data monitoring committee in Biomarin and of advisory board in Synthon. CD received (un)restricted research grants donated to the research institute from Amgen, AstraZeneca, Bayer, Celgene, Eisai, Boehringer Ingelheim, Merck, MSD, Mundipharma, Novartis, Pfizer Corporation, PharmaMar, Pierre Fabre, Roche Austria, Sanofi-aventis, Takeda; received honoraria for consulting from AstraZeneca, Eli Lilly, Merck, Novartis Pharma, Roche Austria. DSD has worked in a consulting or advisory role for UpToDate and received research funding from Aeterna Zentaris (to Institution). LRD received research funding from GlaxoSmithKline (to Institution), Millennium (to Institution), Bristol-Myers Squibb (to Institution), Aeterna Zentaris (to Institution), Millenuim (to Institution) and has other relationship with Genentech. NES received honoraria from Roche, Novartis, MSD Oncology; received research funding from GlaxoSmithKline, Roche; received travel, accommodations, expenses from Novartis, Roche, Celgene. AE conduct research sponsored by Roche, GSK, Novartis, AstraZeneca, Celltrion, Apotex Inc. ME has stock and other ownership interests with Bristol-Myers Squibb, GE Healthcare, Nestle SA, Pfizer, CVS CAREMARK; has worked in a consulting or advisory role from Merck, Bristol-Myers Squibb, ALKERMES; received research funding from Altor BioScience, Bristol-Myers Squibb, Merck, Alkermes, Polynoma; received travel, accommodations, expenses from Myriad Genetics, Bristol-Myers Squibb, Merck. EF has worked as a consultant for Boehringer Ingelheim, Eli Lilly, Pfizer, Roche, BMS, MSD, Novartis; received speaker's bureau from Eli Lilly, BMS, Novartis. MFF has owned stock from Novartis. PKG research funding from Abbvie (to Institution) and Onyx (to Institution). AG has worked in a consulting or advisory role for Genentech/Roche (to Institution), Bayer (to Institution), Sanofi (to Institution), Bristol-Myers Squibb (to Institution), Lilly (to Institution), Boston Biomedical (to Institution), Amgen (to Institution); received research funding from Genentech/Roche (to Institution), Bayer (to Institution), Pfizer (to Institution), Eisai (to Institution), Sanofi (to Institution), Lilly (to Institution), Boston Biomedical (to Institution); received travel, accommodations, expenses from Genentech/Roche, Bayer, Bristol-Myers Squibb, Boston Biomedical, Amgen. SMH has stock and other ownership interests with Liquid Biotech, USA; has patents, royalties, other intellectual property with Liquid Biotech, USA. JH received advisory board and speaker fee from Tesaro and honorarium from SOBI. DVJ has worked in a consulting or advisory role for Bayer. UK received honoraria from Amgen, BMS, GSK, Glycotope, MerckSerono, Merck/MSD, Pfizer; received research support from Pfizer, MerckSerono, Innate, Sirtec. RK conduct research supported by Roche; a member of speaker's bureau of Roche, Meda, Novartis. SK received research funding from Novartis (to Institution), Merck (to Institution), Threshold Pharmaceuticals (to Institution), Gilead Sciences (to Institution), Bayer/Onyx (to Institution); received travel, accommodation, expenses from Novartis. C-HK received honoraria from Merck/Darmstadt, Amgen. MK is on speakers’ bureau for Astellas Pharma, Genentech/Roche, Sanofi, Lilly, Bayer; received research funding from Genentech/Roche (to Institution) and Merck Serono (to Institution). H-JL has received honoraria from Merck Serono, Roche, Celgene, Bayer, Boehringer Ingelheim; has served in a consulting or advisory role for Merck Serono, Roche, Bayer; received travel, accommodations, expenses from Merck Serono, Bayer, Roche. LL has served as a consultant/advisory for EISAI, BMS, MSD, Merck-Serono, Boehringer Ingelheim, DEBIOPHARM, SOBI, Novartis, AstraZeneca, Bayer and Roche; received research funds to institute for clinical studies from EISAI, MSD, Merck-Serono, Boehringer Ingelheim, Novartis, AstraZeneca and Roche; received travel coverage for medical meetings from Merck-Serono, DEBIOPHARM, SOBI, Bayer. PJL received research funding from Novartis (to Institution), Celgene (to Institution), ImClone Systems (to Institution), Taiho Pharmaceutical (to Institution); has patents, royalties, other intellectual property US PPA/61/499,988 Gene Expression Analysis of Thymic Neoplasms Inventors Sunil Badve, Yesim Gokmen-Polar, Patrick Loehrer (to Institution). RIL has served in consulting or advisory role for Roche, Novartis, Janssen; received speakers’ bureau from Roche, Novartis, Janssen. MJM received research funding from Astex Pharmaceuticals (to Institution). TN has ownership interest with Bioclassifier LLC; has role for invention of PAM50 breast cancer assay, which has been licensed to NanoString technologies and being marketed as Prosigna; has served as a consultant for NanoString. KÖ received speaker bureau from Novartis, Ipsen. PÖ received consulting fees, honoraria, travel grants or lecturing fees from Amgen, Bayer, Baxalta, Celgene, EliLilly, Merck, Nordic Drugs, Prime Oncology, Sanofi Oncology. AP received honoraria and consultancy fee from Amgen, Novartis, Bristol-Myers Squibb, Genmab A/S, Celgene, Janssen-Cilag, Millennium Pharmaceuticals, Onyx Pharmaceuticals, Sanofi Aventis. MR received honoraria from AstraZeneca; has served in a consulting or advisory role for Bayer, Pfizer, McKesson; received research funding from AstraZeneca (to Institution), AbbVie (to Institution), Myriad Genetics (to Institution), Biomarin (to Institution); received travel, accommodations, expenses from AstraZeneca, Biomarin. LS has served in a consulting or advisory role for bioTheranostics. MS conduct research sponsored by AstraZeneca, Bayer, Eisai, Exelixis, Genzyme. H-JS is an advisor for Roche, Bayer. LS has served in leadership for Eviti; has served in a consulting or advisory role for Merck; has patents, royalties, other intellectual property; as Co-Editor-in-Chief of UpToDate, Oncology. JS is an employee of Genentech; received honoraria, speakers’ bureau, travel, accommodations, expenses from Genentech. CNS received honoraria or research grant from Novartis, GSK, Pfizer, Merck, Lilly, BMS, Astellas, Bayer, Janssen, Sanofi. FS received unrestricted industry grants for clinical research from Celgene, Fresenius, Helsinn; FS participates in Novartis-lead clinical trials and received punctual advisorship (boards, expert meetings) from Acacia, ACRAF, Amgen, Baxter, Celgene, Danone, Fresenius, GlaxoSmithKline, Grünenthal, Helsinn, ISIS Global, Millennium/Takeda, Mundipharma, Novartis, Novelpharm, Nycomed, Obexia, Otsuka, Ono, Pharm-Olam, Pfizer, Psioxus, PrIME, Santhera, Sunstone, Teva, Vifor. RS received honoraria or consulting fee (paid to institution) from Roche, Merck KGaA/EMD-Serono, MSD/Merck & Co, Pfizer, Ipsen Pharma, Novartis. JT has worked in a consultant/advisory role for Amgen, Bayer, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Symphogen, Taiho and Takeda. EV has stock and other ownership interests with McKesson; has worked in a consulting or advisory role for Abbvie, AstraZeneca, Boehringer Ingelheim, Celgene, Clovis Oncology, GeneCentric, Genentech, Merck, Synta, VentiRx, Eisai, Lilly, Transgene; received speakers’ bureau for Amgen; received research funding from Abbvie (to Institution), Bristol-Myers Squibb (to Institution), Gen Vec Inc, (to Institution), Sanofi (to Institution), Monsanto (to Institution), Cyclacel (to Institution); received travel, accommodations, expenses from Amgen. JSW has stock and other ownership interests with Altor BioScience, Celldex, cCam Biotherapeutics; received honoraria from Bristol-Myers Squibb, Merck, Genentech, Abbvie, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Eisai, Altor BioScience, Lion Biotechnologies, Amgen, Roche, Ichor Medical Systems, Celldex, cCam Biotherapeutics, Pieris; has worked in a consulting or advisory role for Celldex, Ichor Medical Systems, cCam Biotherapeutics, Lion Biotechnologies, Pieris, Altor BioScience, Bristol-Myers Squibb, Merck, Genentech, Roche, Amgen, AstraZeneca, GlaxoSmithKline, Daiichi Sankyo, Abbvie, Eisai; received research funding from Bristol-Myers Squibb (to Institution), Merck (to Institution), GlaxoSmithKline (to Institution), Genentech (to Institution), Astellas Pharma (to Institution), Incyte (to Institution), Roche (to Institution), Novartis (to Institution); received travel, accommodations, expenses from Bristol-Myers Squibb, GlaxoSmithKline, Daiichi Sankyo, Pieris, cCam Biotherapeutics, Lion Biotechnologies, Roche, Celldex, Amgen, Merck, AstraZeneca, Genentech.

The RNA binding proteins RBM binding motif protein 38 (RBM38) and DEAD END 1 (DND1) selectively stabilize mRNAs by attenuating RNAse activity or protecting them from micro(mi)RNA-mediated cleavage. Furthermore, both proteins can efficiently stabilize the mRNA of the cell cycle inhibitor p21(CIP1). Since acute myeloid leukemia (AML) differentiation requires cell cycle arrest and RBM38 as well as DND1 have antiproliferative functions, we hypothesized that decreased RBM38 and DND1 expression may contribute to the differentiation block seen in this disease. We first quantified RBM38 and DND1 mRNA expression in clinical AML patient samples and CD34(+) progenitor cells and mature granulocytes from healthy donors. We found significantly lower RBM38 and DND1 mRNA levels in AML blasts and CD34(+) progenitor cells as compared to mature neutrophils from healthy donors. Furthermore, the lowest expression of both RBM38 and DND1 mRNA correlated with t(8;21). In addition, neutrophil differentiation of CD34(+) cells in vitro with G-CSF (granulocyte colony stimulating factor) resulted in a significant increase of RBM38 and DND1 mRNA levels. Similarly, neutrophil differentiation of NB4 acute promyelocytic leukemia (APL) cells was associated with a significant induction of RBM38 and DND1 expression. To address the function of RBM38 and DND1 in neutrophil differentiation, we generated two independent NB4RBM38 as well as DND1 knockdown cell lines. Inhibition of both RBM38 and DND1 mRNA significantly attenuated NB4 differentiation and resulted in decreased p21(CIP1) mRNA expression. Our results clearly indicate that expression of the RNA binding proteins RBM38 and DND1 is repressed in primary AML patients, that neutrophil differentiation is dependent on increased expression of both proteins, and that these proteins have a critical role in regulating p21(CIP1) expression during APL differentiation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Modern oncology has much to offer, and the prognosis of cancer patients has undoubtedly improved over the last few decades. Nevertheless, medical and economic toxicities of modern cancer medicine demand that our many tools are viewed with a critical eye. Screening mammography and PSA screening for the detection of early breast, or prostate cancer, resp., are widely used. However, reduction of mortality from these disorders through early detection and treatment is quantitatively modest, whereas overdiagnosis of low-risk cancers and non-malignant conditions with these two methods is frequent. Cancer drug therapy increasingly uses predictive bio-markers to select patients (and their tumors) particularly likely to benefit from new drugs. Nevertheless palliative systemic treatment in oncology suffers from over-use of drugs with at times considerable toxicity and cost but little patient gain. It is still common practice to validate new cancer drugs in clinical trials using progression-free survival as a primary endpoint. PFS is easily measurable but often inadequate to discover true clinical benefit (i. e. prolonged overall survival and/or improved lasting quality of life). Licensing agencies such as the FDA or Swissmedic as well as clinical trialists are therefore challenged to review their criteria for the validation of new cancer drugs. Follow-up of cancer patients after treatment is widely practiced, often with "subscription series" for CT- or PET-scans and repetitive lab tests including tumor markers. Early detection of asymptomatic cancer relapse with these methods, however, is only warranted, if early re-treatment is proven to prolong survival, as cancer treatment in asymptomatic patients produces toxicity and costs that can only be justified if chances for long-term benefits are bettered.

The PU.1 transcription factor is essential for myeloid development. We investigated if the microtubule-associated protein 1S (MAP1S) is a novel PU.1 target with a link to autophagy, a cellular recycling pathway. Comparable to PU.1, MAP1S expression was significantly repressed in primary AML blasts as compared to mature neutrophils. Accordingly, MAP1S expression was induced during neutrophil differentiation of CD34(+) progenitor and APL cells. Moreover, PU.1 bound to the MAP1S promoter and induced MAP1S expression during APL differentiation. Inhibiting MAP1S resulted in aberrant neutrophil differentiation and autophagy. Taken together, our findings implicate the PU.1-regulated MAP1S gene in neutrophil differentiation and autophagy control., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Inhibitors of apoptosis (IAPs) were intensively investigated in the context of cancer where they promote tumor growth and chemoresistence. Overexpression of the IAP BIRC6 is associated with unfavorable clinical features and negatively impacts relapse-free survival in childhood acute myeloid leukemia (AML). Currently, BIRC6 levels in adult primary AML have not been compared to the expression in normal myeloid cells. Thus, we compared for the first time BIRC6 levels in adult primary AML patient samples to normal myeloid cells and studied its regulation and function during neutrophil differentiation., Findings: We found significantly lower BIRC6 levels in particular AML subtypes as compared to granulocytes from healthy donors. The lowest BIRC6 expression was found in CD34+ progenitor cells. Moreover, BIRC6 expression significantly increased during neutrophil differentiation of AML cell lines and knocking down BIRC6 in NB4 acute promyelocytic leukemia (APL) cells significantly impaired neutrophil differentiation, but not cell viability., Conclusion: Together, we found an association of low BIRC6 levels with an immature myeloid phenotype and describe a function for BIRC6 in neutrophil differentiation of APL cells.

Introduction: MicroRNAs are small, noncoding RNAs that suppress gene expression by binding to the 3' untranslated region (UTR) and thereby repress translation or decrease messenger RNA stability. Inhibitor of differentiation 1 (ID1) is a putative stem-cell gene involved in invasion and angiogenesis. We previously showed that ID1 is regulated by Src kinases, overexpressed in human lung adenocarcinoma, and targeted by Src-dependent microRNAs. The current study focused on the association between miR-381 and ID1 in lung adenocarcinoma., Methods: An ID1 3'UTR-luciferase reporter assay was used to determine whether miR-381 directly targets ID1. Human lung cancer cell lines were stably transduced with a precursor of miR-381 to evaluate its role on ID1 expression and to investigate changes in cell migration and invasion. The Src tyrosine kinase inhibitors saracatinib and dasatinib were used to repress ID1 expression. MiR-381 expression was measured in 18 human lung adenocarcinomas and corresponding normal lung tissue by quantitative reverse-transcription polymerase chain reaction., Results: ID1 is a direct target of miR-381 as shown by 3'UTR luciferase reporter assays. MiR-381 expression was negatively correlated with ID1 expression in lung cancer cell lines. Ectopic expression of miR-381 reduced ID1 mRNA and protein levels, and significantly decreased cell migration and invasion. Furthermore, miR-381 was significantly downregulated in human lung adenocarcinomas, and low miR-381 expression levels correlated with poor prognosis., Conclusion: These results suggest that downregulation of miR-381 and thus induction of its target ID1 may contribute to the metastatic potential of lung adenocarcinomas. Further studies to explore potential therapeutic strategies, including Src inhibitors, are ongoing.

The transcription factor PU.1 is a master regulator of myeloid differentiation and function. On the other hand, only scarce information is available on PU.1-regulated genes involved in cell survival. We now identified the glycolytic enzyme hexokinase 3 (HK3), a gene with cytoprotective functions, as transcriptional target of PU.1. Interestingly, HK3 expression is highly associated with the myeloid lineage and was significantly decreased in acute myeloid leukemia patients compared with normal granulocytes. Moreover, HK3 expression was significantly lower in acute promyelocytic leukemia (APL) compared with non-APL patient samples. In line with the observations in primary APL patient samples, we observed significantly higher HK3 expression during neutrophil differentiation of APL cell lines. Moreover, knocking down PU.1 impaired HK3 induction during neutrophil differentiation. In vivo binding of PU.1 and PML-RARA to the HK3 promoter was found, and PML-RARA attenuated PU.1 activation of the HK3 promoter. Next, inhibiting HK3 in APL cell lines resulted in significantly reduced neutrophil differentiation and viability compared with control cells. Our findings strongly suggest that HK3 is: (1) directly activated by PU.1, (2) repressed by PML-RARA, and (3) functionally involved in neutrophil differentiation and cell viability of APL cells.

Background: We assessed adherence to the European Society of Medical Oncology (ESMO)/Multinational Association of Supportive Care in Cancer recommendations for prophylaxis of chemotherapy-induced nausea and vomiting (CINV) at our institution., Patients and Methods: The charts of 299 patients starting a new chemotherapy between November 2008 and April 2009 were reviewed. Baseline characteristics and prophylaxis of CINV during the first cycle were recorded, and adherence to ESMO recommendations was determined. Chi-square tests and logistic regression were used to test for predictors of adherence., Results: Prophylaxis of acute CINV was not adherent in 39% of the patients: 39 of 54 patients with low emetogenic chemotherapy had a serotonin antagonist, and 24 of 100 with moderately emetogenic therapy had a neurokinin antagonist. Nevertheless, 71% of the patients treated with highly emetogenic therapy received the guideline-specified prescription. Prophylaxis of delayed CINV was not adherent in 89% of the patients: 101 of 125 patients with highly or moderately emetogenic single-day chemotherapy received a serotonin antagonist. Male gender (odds ratio (OR) 0.484, 95% confidence interval (CI) 0.291-0.806; P = 0.005) and hematologic neoplasia (OR 2.151, 95% CI 1.19-3.887; P = 0.011) were independent predictors of non-adherence. Age (OR 0.981, 95% CI 0.964-0.998; P = 0.029) and inpatient treatment (OR 0.457, 95% CI 0.25-0.836; P = 0.011) indicated a lower risk of non-adherence., Conclusion: Contrary to older studies reporting frequent omissions of corticosteroids, the current study demonstrated significant overuse of serotonin antagonists for prophylaxis of delayed CINV.

The in vitro production of recombinant protein molecules has fostered a tremendous interest in their clinical application for treatment and support of cancer patients. Therapeutic proteins include monoclonal antibodies, interferons, and haematopoietic growth factors. Clinically established monoclonal antibodies include rituximab (targeting CD20-positive B-cell lymphomas), trastuzumab (active in HER-2 breast and gastric cancer), and bevacizumab (blocking tumor-induced angiogenesis through blockade of vascular-endothelial growth factor and its receptor). Interferons have lost much of their initial appeal, since equally or more effective treatments with more pleasant side effects have become available, for example in chronic myelogenous leukaemia or hairy cell leukaemia. The value of recombinant growth factors, notably granulocyte colony stimulating factor (G-CSF) and erythropoietin is rather in the field of supportive care than in targeted anti-cancer therapy. Adequately powered clinical phase III trials are essential to estimate the true therapeutic impact of these expensive compounds, with appropriate selection of clinically relevant endpoints and sufficient follow-up. Monoclonal antibodies, interferons, and growth factors must also, and increasingly so, be subjected to close scrutiny by appropriate cost-effectiveness analyses to ensure that their use results in good value for money. With these caveats and under the condition of their judicious clinical use, recombinant proteins have greatly enriched the therapeutic armamentarium in clinical oncology, and their importance is likely to grow even further.

The known participation of Kruppel-like transcription factors (KLF) in cellular differentiation prompted us to investigate their expression in acute myeloid leukemia (AML) blast cells that are typically blocked in their differentiation. We determined the expression patterns of KLFs with a putative role in myeloid differentiation in a large cohort of primary AML patient samples, CD34+ progenitor cells and granulocytes from healthy donors. We found that KLF2, KLF3, KLF5 and KLF6 are significantly lower expressed in AML blast and CD34+ progenitor cells as compared to normal granulocytes. Moreover, we found markedly increased KLF levels in acute promyelocytic leukemia patients who received oral ATRA. Accordingly, we observed a strong induction of KLF5/6 upon ATRA-treatment in NB4 and HT93 APL but not in ATRA-resistant NB4-R cells. Lastly, knocking down KLF5 or KLF6 in NB4 cells significantly attenuated neutrophil differentiation. In conclusion, we found a significant repression of KLF transcription factors in primary AML samples as compared to mature neutrophils and further show that KLF5 and KLF6 are functionally involved in neutrophil differentiation of APL cells., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

C-type lectin domain family 5, member A (CLEC5A), also known as myeloid DNAX activation protein 12 (DAP12)-associating lectin-1 (MDL-1), is a cell surface receptor strongly associated with the activation and differentiation of myeloid cells. CLEC5A associates with its adaptor protein DAP12 to activate a signaling cascade resulting in activation of downstream kinases in inflammatory responses. Currently, little is known about the transcriptional regulation of CLEC5A. We identified CLEC5A as one of the most highly induced genes in a microarray gene profiling experiment of PU.1 restored myeloid PU.1-null cells. We further report that CLEC5A expression is significantly reduced in several myeloid differentiation models upon PU.1 inhibition during monocyte/macrophage or granulocyte differentiation. In addition, CLEC5A mRNA expression was significantly lower in primary acute myeloid leukemia (AML) patient samples than in macrophages and granulocytes from healthy donors. Moreover, we found activation of a CLEC5A promoter reporter by PU.1 as well as in vivo binding of PU.1 to the CLEC5A promoter. Our findings indicate that CLEC5A expression in monocyte/macrophage and granulocytes is regulated by PU.1., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

The chromosomal region 17p13.3 is frequently deleted or epigenetically silenced in a variety of human cancers. It includes the hypermethylated in cancer 1 (HIC1) gene placed telomerically to the p53 tumour suppressor gene. HIC1 encodes a transcriptional repressor, and its targets identified to date are genes involved in proliferation, tumour growth and angiogenesis. In addition, HIC1 functionally cooperates with p53 to suppress cancer development. Frequent allelic loss at position 17p13.1 in human cancers often points to mutations of the tumour suppressor p53. However, in a variety of cancer types, allelic loss of the short arm of chromosome 17 may hit regions distal to p53 and, interestingly, without leading to p53 mutations. Furthermore, the neighbouring region 17p13.3 often shows loss of heterozygosity or DNA hypermethylation in various types of solid tumours and leukaemias. In line with this concept, Wales et al. described a new potential tumour suppressor in this region and named it hypermethylated in cancer 1 (HIC1). Further, it was shown that in the majority of cases hypermethylation of this chromosomal region leads to epigenetic inactivation of HIC1. A role for HIC1 in tumour development is further supported by a mouse model, since various spontaneous, age- and gender-specific malignant tumours occur in heterozygous Hic1+/- knockout mice. Furthermore, exogenously delivered HIC1 leads to a significant decrease in clonogenic survival in cancer cell lines. This review highlights the role of HIC1 inactivation in solid tumours and particularly in leukaemia development.

The literature on malignant lymphomas has grown to an extent which is hardly palatable for general practitioners and non-lymphoma aficionados. Nevertheless some lymphomas exhibit typical clinical and radiological features which permit to suspect the correct histopathological diagnosis even before a pathology report becomes available. The present article points out such "case vignettes" of particular types of malignant lymphoma.

Acute promyelocytic leukaemia (APL) patients are successfully treated with all-trans retinoic acid (ATRA). However, concurrent chemotherapy is still necessary and less toxic therapeutic approaches are needed. Earlier studies suggested that in haematopoietic neoplasms, the green tea polyphenol epigallocatechin-3-gallate (EGCG) induces cell death without adversely affecting healthy cells. We aimed at deciphering the molecular mechanism of EGCG-induced cell death in acute myeloid leukaemia (AML). A significant increase of death-associated protein kinase 2 (DAPK2) levels was found in AML cells upon EGCG treatment paralleled by increased cell death that was significantly reduced upon silencing of DAPK2. Moreover, combined ATRA and EGCG treatment resulted in cooperative DAPK2 induction and potentiated differentiation. EGCG toxicity of primary AML blasts correlated with 67 kDa laminin receptor (67LR) expression. Pretreatment of AML cells with ATRA, causing downregulation of 67LR, rendered these cells resistant to EGCG-mediated cell death. In summary, it was found that (i) DAPK2 is essential for EGCG-induced cell death in AML cells, (ii) ATRA and EGCG cotreatment significantly boosted neutrophil differentiation, and 67LR expression correlates with susceptibility of AML cells to EGCG. We thus suggest that EGCG, by selectively targeting leukaemic cells, may improve differentiation therapies for APL and chemotherapy for other AML subtypes.

The current therapeutic strategy in breast cancer is to identify a target, such as estrogen receptor (ER) status, for tailoring treatments. We investigated the patterns of recurrence with respect to ER status for patients treated in two randomized trials with 25 years' median follow-up. In the ER-negative subpopulations most breast cancer events occurred within the first 5-7 years after randomization, while in the ER-positive subpopulations breast cancer events were spread through 10 years. In the ER-positive subpopulation, 1 year endocrine treatment alone significantly prolonged disease-free survival (DFS) with no additional benefit observed by adding 1 year of chemotherapy. In the small ER-negative subpopulation chemo-endocrine therapy had a significantly better DFS than endocrine alone or no treatment. Despite small numbers of patients, "old-fashioned" treatments, and competing causes of treatment failure, the value of ER status as a target for response to adjuvant treatment is evident through prolonged follow-up.

To compare the efficacy of chemoendocrine treatment with that of endocrine treatment (ET) alone for postmenopausal women with highly endocrine responsive breast cancer. In the International Breast Cancer Study Group (IBCSG) Trials VII and 12-93, postmenopausal women with node-positive, estrogen receptor (ER)-positive or ER-negative, operable breast cancer were randomized to receive either chemotherapy or endocrine therapy or combined chemoendocrine treatment. Results were analyzed overall in the cohort of 893 patients with endocrine-responsive disease, and according to prospectively defined categories of ER, age and nodal status. STEPP analyses assessed chemotherapy effect. The median follow-up was 13 years. Adding chemotherapy reduced the relative risk of a disease-free survival event by 19% (P = 0.02) compared with ET alone. STEPP analyses showed little effect of chemotherapy for tumors with high levels of ER expression (P = 0.07), or for the cohort with one positive node (P = 0.03). Chemotherapy significantly improves disease-free survival for postmenopausal women with endocrine-responsive breast cancer, but the magnitude of the effect is substantially attenuated if ER levels are high.

Background: Erythropoiesis-stimulating agents reduce anaemia in patients with cancer and could improve their quality of life, but these drugs might increase mortality. We therefore did a meta-analysis of randomised controlled trials in which these drugs plus red blood cell transfusions were compared with transfusion alone for prophylaxis or treatment of anaemia in patients with cancer., Methods: Data for patients treated with epoetin alfa, epoetin beta, or darbepoetin alfa were obtained and analysed by independent statisticians using fixed-effects and random-effects meta-analysis. Analyses were by intention to treat. Primary endpoints were mortality during the active study period and overall survival during the longest available follow-up, irrespective of anticancer treatment, and in patients given chemotherapy. Tests for interactions were used to identify differences in effects of erythropoiesis-stimulating agents on mortality across prespecified subgroups., Findings: Data from a total of 13 933 patients with cancer in 53 trials were analysed. 1530 patients died during the active study period and 4993 overall. Erythropoiesis-stimulating agents increased mortality during the active study period (combined hazard ratio [cHR] 1.17, 95% CI 1.06-1.30) and worsened overall survival (1.06, 1.00-1.12), with little heterogeneity between trials (I(2) 0%, p=0.87 for mortality during the active study period, and I(2) 7.1%, p=0.33 for overall survival). 10 441 patients on chemotherapy were enrolled in 38 trials. The cHR for mortality during the active study period was 1.10 (0.98-1.24), and 1.04 (0.97-1.11) for overall survival. There was little evidence for a difference between trials of patients given different anticancer treatments (p for interaction=0.42)., Interpretation: Treatment with erythropoiesis-stimulating agents in patients with cancer increased mortality during active study periods and worsened overall survival. The increased risk of death associated with treatment with these drugs should be balanced against their benefits., Funding: German Federal Ministry of Education and Research, Medical Faculty of University of Cologne, and Oncosuisse (Switzerland).

A hallmark of acute myeloid leukaemia (AML) is a block in differentiation caused by deregulated gene expression. The tumour suppressor Hypermethylated In Cancer 1 (HIC1) is a transcriptional repressor, which is epigenetically silenced in solid cancers. HIC1 mRNA expression was found to be low in 128 patient samples of AML and CD34+ progenitor cells when compared with terminally differentiated granulocytes. HIC1 mRNA was induced in a patient with t(15;17)-positive acute promyelocytic leukaemia receiving all-trans retinoic acid (ATRA) therapy. We therefore investigated whether HIC1 plays a role in granulocytic differentiation and whether loss of function of this gene might contribute to the differentiation block in AML. We evaluated HIC1 mRNA levels in HL-60 and U-937 cells upon ATRA-induced differentiation and in CD34+ progenitor cells after granulocyte colony-stimulating factor-induced differentiation. In both models of granulocytic differentiation, we observed significant HIC1 induction. When HIC1 mRNA was suppressed in HL-60 cells using stably expressed short hairpin RNA targeting HIC1, granulocytic differentiation was altered as assessed by CD11b expression. Bisulphite sequencing of GC-rich regions (CpG islands) in the HIC1 promoter provided evidence that the observed suppression in HL-60 cells was not because of promoter hypermethylation. Our findings indicate a role for the tumour suppressor gene HIC1 in granulocytic differentiation. Low expression of HIC1 may very well contribute to pathogenic events in leukaemogenesis.

Purpose: We evaluated the long-term outcome after 1 cycle of adjuvant modified bleomycin, etoposide and cisplatin chemotherapy in patients who underwent orchiectomy for high risk clinical stage I nonseminomatous germ cell tumor of the testis., Materials and Methods: Between 1995 and 1999 a consecutive series of 44 patients underwent orchiectomy for clinical stage I nonseminomatous germ cell tumor of the testis, followed by a single postoperative cycle of adjuvant modified bleomycin, etoposide and cisplatin for vascular or lymphatic tumor invasion, and/or a predominance (50% or greater) of embryonal carcinoma., Results: Four of the 44 patients were excluded from analysis. Of the patients 35 had no evidence of disease at a median followup of 99 months (range 60 to 134). One patient with progression after 13 months showed complete remission after 3 cycles of salvage bleomycin, etoposide and cisplatin chemotherapy but he died of pneumonia 4 weeks after the third course. Two patients underwent orchiectomy for contralateral testis cancer at 18 and 42 months, respectively, followed by an additional 3 cycles of adjuvant chemotherapy. They remained relapse-free for 4 and 92 months, respectively. The former patient was lost to followup after 4 months. Two other patients were disease-free at 10 and 31 months, respectively, and were lost to followup thereafter. Late side effects were tinnitus in 3 patients and involuntary childlessness in 3, of whom 2 had cryptorchidism of the contralateral testis. Nine patients fathered children., Conclusions: One cycle of bleomycin, etoposide and cisplatin effectively decreases the risk of relapse in patients with high risk stage I nonseminomatous germ cell tumor of the testis. It has minimal side effects and can be a valuable alternative to retroperitoneal lymph node dissection.

Clinical resistance to chemotherapy in acute myeloid leukemia (AML) is associated with the expression of the multidrug resistance (MDR) proteins P-glycoprotein, encoded by the MDR1/ABCB1 gene, multidrug resistant-related protein (MRP/ABCC1), the lung resistance-related protein (LRP), or major vault protein (MVP), and the breast cancer resistance protein (BCRP/ABCG2). The clinical value of MDR1, MRP1, LRP/MVP, and BCRP messenger RNA (mRNA) expression was prospectively studied in 154 newly diagnosed AML patients >or=60 years who were treated in a multicenter, randomized phase 3 trial. Expression of MDR1 and BCRP showed a negative whereas MRP1 and LRP showed a positive correlation with high white blood cell count (respectively, p < 0.05, p < 0.001, p < 0.001 and p < 0.001). Higher BCRP mRNA was associated with secondary AML (p < 0.05). MDR1 and BCRP mRNA were highly significantly associated (p < 0.001), as were MRP1 and LRP mRNA (p < 0.001) expression. Univariate regression analyses revealed that CD34 expression, increasing MDR1 mRNA as well as MDR1/BCRP coexpression, were associated with a lower complete response (CR) rate and with worse event-free survival and overall survival. When adjusted for other prognostic actors, only CD34-related MDR1/BCRP coexpression remained significantly associated with a lower CR rate (p = 0.03), thereby identifying a clinically resistant subgroup of elderly AML patients.

Microarray gene expression profiles of fresh clinical samples of chronic myeloid leukaemia in chronic phase, acute promyelocytic leukaemia and acute monocytic leukaemia were compared with profiles from cell lines representing the corresponding types of leukaemia (K562, NB4, HL60). In a hierarchical clustering analysis, all clinical samples clustered separately from the cell lines, regardless of leukaemic subtype. Gene ontology analysis showed that cell lines chiefly overexpressed genes related to macromolecular metabolism, whereas in clinical samples genes related to the immune response were abundantly expressed. These findings must be taken into consideration when conclusions from cell line-based studies are extrapolated to patients.

Tightly regulated expression of the transcription factor PU.1 is crucial for normal hematopoiesis. PU.1 knockdown mice develop acute myeloid leukemia (AML), and PU.1 mutations have been observed in some populations of patients with AML. Here we found that conditional expression of promyelocytic leukemia-retinoic acid receptor alpha (PML-RARA), the protein encoded by the t(15;17) translocation found in acute promyelocytic leukemia (APL), suppressed PU.1 expression, while treatment of APL cell lines and primary cells with all-trans retinoic acid (ATRA) restored PU.1 expression and induced neutrophil differentiation. ATRA-induced activation was mediated by a region in the PU.1 promoter to which CEBPB and OCT-1 binding were induced. Finally, conditional expression of PU.1 in human APL cells was sufficient to trigger neutrophil differentiation, whereas reduction of PU.1 by small interfering RNA (siRNA) blocked ATRA-induced neutrophil differentiation. This is the first report to show that PU.1 is suppressed in acute promyelocytic leukemia, and that ATRA restores PU.1 expression in cells harboring t(15;17).

To determine whether MDR1 reversal by the addition of the P-glycoprotein (P-gp) inhibitor PSC-833 to standard induction chemotherapy would improve event-free survival (EFS), 419 untreated patients with acute myeloid leukemia (AML) aged 60 years and older were randomized to receive 2 induction cycles of daunorubicin and cytarabine with or without PSC-833. Patients in complete remission were then given 1 consolidation cycle without PSC-833. Neither complete response (CR) rate (54% versus 48%; P = .22), 5-year EFS (7% versus 8%; P = .53), disease-free survival (DFS; 13% versus 17%; P = .06) nor overall survival (OS; 10% in both arms; P = .52) were significantly improved in the PSC-833 arm. An integrated P-gp score (IPS) was determined based on P-gp function and P-gp expression in AML cells obtained prior to treatment. A higher IPS was associated with a significantly lower CR rate and worse EFS and OS. There was no significant interaction between IPS and treatment arm with respect to CR rate and survival, indicating also a lack of benefit of PSC-833 in P-gp-positive patients. The role of strategies aimed at inhibitory P-gp and other drug-resistance mechanisms continues to be defined in the treatment of patients with AML.

Purpose: We sought to determine retrospectively whether extracapsular spread (ECS) might identify a subgroup that could benefit from radiotherapy after mastectomy, especially patients with 1 to 3 positive lymph nodes (LN1-3+)., Patients and Methods: We randomized 1,475 premenopausal women with node-positive breast cancer to three, six, or nine courses of "classical" CMF (cyclophosphamide, methotrexate, and fluorouracil). After a review of all pathology forms, 933 patients (63%) had information on the presence or absence of ECS. ECS was present in 49.5%. The median follow-up was 10 years., Results: In univariate analyses, ECS was associated with worse disease-free survival (DFS) and overall survival (OS). In multivariate analyses adjusting for tumor size, vessel invasion, surgery type, and age group, ECS remained significant (DFS: hazard ratio, 1.61; 95% CI, 1.34 to 1.93; P < .0001; OS: 1.67; 95% CI, 1.34 to 2.08; P < .0001). However, ECS was not significant when the number of positive nodes was added. The locoregional failure rate +/- distant failure (LRF +/- distant failure) within 10 years was estimated at 19% (+/- 2%) without ECS, versus 27% (+/- 2%) with ECS. The difference was statistically significant in univariate analyses, but not after adjusting for the number of positive nodes. No independent effect of ECS on DFS, OS, or LRF could be confirmed within the subgroup of 382 patients with LN1-3+ treated with mastectomy without radiotherapy., Conclusion: Our results do not support an independent prognostic value of ECS, nor its use as an indication for irradiation in premenopausal patients with LN1-3+ treated with classical CMF. However, we could not examine whether extensive ECS is of prognostic importance.

The pericentric inversion of chromosome 16, inv(16)(p13q22), is associated with acute myeloid leukemia (AML) subtype M4Eo that is characterized by the presence of myelomonocytic blasts and atypical eosinophils. This rearrangement fuses the CBFB and MYH11 genes, with the latter encoding the smooth muscle myosin heavy chain (SMMHC). The myeloid transcription factor CCAAT/enhancer-binding protein alpha (CEBPA) is crucial for normal granulopoiesis. Alterations of structure and expression of CEBPA have been implicated in particular subtypes of AML. Here, we found that conditional expression of core-binding factor beta (CBFB)-SMMHC in U937 cells suppresses CEBPA protein expression and binding activity. However, CEBPA mRNA levels remained unchanged. No differences were detected in CEBPA mRNA levels in patients with inv(16) AML-M4Eo (n = 12) compared to patients with AML with a normal karyotype and M4 subtype (n = 6), whereas CEBPA protein and binding activity were significantly reduced in patients with CBFB-SMMHC. Furthermore, calreticulin, an inhibitor of CEBPA translation, was induced on mRNA and protein level in CBFB-SMMHC patients with AML and after expression of CBFB-SMMHC in the U937-cell system. Inhibition of calreticulin by siRNA restored CEBPA levels. Our results suggest that modulation of CEBPA by calreticulin represents a novel mechanism involved in the differentiation block in CBFB-SMMHC AML.

Purpose: Cancer presenting at the medial site of the breast may have a worse prognosis compared with tumors located in external quadrants. For medial tumors, axillary lymph node staging may not accurately reflect the metastatic potential of the disease., Patients and Methods: Eight-thousand four-hundred twenty-two patients randomly assigned to International Breast Cancer Study Group clinical trials between 1978 and 1999 were classified as medial site (1,622; 19%) or lateral, central, and other sites (6,800; 81%). Median follow-up was 11 years., Results: A statistically significant difference was observed for patients with medial tumors versus those with nonmedial tumors in disease-free survival (DFS; 10-year DFS, 46% v 48%; HR, 1.10; 95% CI, 1.02 to 1.18; P = .01) and overall survival (10-year OS 59% v 61%; HR, 1.09; 1.01 to 1.19; P = .04). This difference increased after adjustment for other prognostic factors (HR, 1.22; 95% CI, 1.13 to 1.32 for DFS; and HR, 1.24; 95% CI, 1.14 to 1.35 for OS; both P = .0001). The risk of relapse for patients with medial presentation was largest for the node-negative cohort and for patients with tumors larger than 2 cm. In the subgroup of 2,931 patients with negative axillary lymph nodes, 10-year DFS was 61% v 67%, and OS was 73% v 80% for medial versus nonmedial sites, respectively (HR 1.33; 95% CI, 1.15 to 1.54; P = .0001 for DFS; and HR 1.40; 95% CI, 1.17 to 1.67; P = .0003 for OS)., Conclusion: Tumor site has a significant prognostic utility, especially for axillary lymph node-negative disease, that should be considered in therapeutic algorithms. New staging procedures such as biopsy of the sentinel internal mammary nodes or novel imaging methods should be further studied in patients with medial tumors.

Purpose: To evaluate the effect of single-agent rituximab given at the standard or a prolonged schedule in patients with newly diagnosed, or refractory or relapsed mantle cell lymphoma (MCL)., Patients and Methods: After induction treatment with the standard schedule (375 mg/m2 weekly x 4), patients who were responding or who had stable disease at week 12 from the start of treatment were randomly assigned to no further treatment (arm A) or prolonged rituximab administration (375 mg/m2) every 8 weeks for four times (arm B)., Results: The trial enrolled 104 patients. After induction, clinical response was 27% with 2% complete responses. Among patients with detectable t(11;14)-positive cells in blood and bone marrow at baseline, four of 20, and one of 14, respectively, became polymerase chain-reaction-negative after induction. Anemia was the only adverse predictor of response in the multivariate analysis. After a median follow-up of 29 months, response rate and duration of response were not significantly different between the two schedules in 61 randomly assigned patients. Median event-free survival (EFS) was 6 months in arm A versus 12 months in arm B; the difference was not significant (P = .1). Prolonged treatment seemed to improve EFS in the subgroup of pretreated patients (5 months in arm A v 11 months in arm B; P = .04). Thirteen percent of patients in arm A and 9% in arm B presented with grade 3 to 4 hematologic toxicity., Conclusion: Single-agent rituximab is active in MCL, but the addition of four single doses at 8-week intervals does not seem to significantly improve response rate, duration of response, or EFS after treatment with the standard schedule.

The potential benefits of extended rituximab treatment have been investigated in a randomized trial comparing the standard schedule with prolonged treatment in 202 patients with newly diagnosed or refractory/relapsed follicular lymphoma (FL). All patients received standard treatment (rituximab 375 mg/m(2) weekly x 4). In 185 evaluable patients, the overall response rate was 67% in chemotherapy-naive patients and 46% in pretreated cases (P <.01). Patients responding or with stable disease at week 12 (n = 151) were randomized to no further treatment or prolonged rituximab administration (375 mg/m(2) every 2 months for 4 times). At a median follow-up of 35 months, the median event-free survival (EFS) was 12 months in the no further treatment versus 23 months in the prolonged treatment arm (P =.02), the difference being particularly notable in chemotherapy-naive patients (19 vs 36 months; P =.009) and in patients responding to induction treatment (16 vs 36 months; P =.004). The number of t(14;18)-positive cells in peripheral blood (P =.0035) and in bone marrow (P =.0052) at baseline was predictive for clinical response. Circulating normal B lymphocytes and immunoglobulin M (IgM) plasma levels decreased for a significantly longer time after prolonged treatment, but the incidence of adverse events was not increased. In patients with FL, the administration of 4 additional doses of rituximab at 8-week intervals significantly improves the EFS.

Purpose: Increasing numbers of older women are affected by early breast cancer, because of prolonged life expectancy and the increasing incidence of breast cancer with age. The role of adjuvant therapy for this population is still a matter of debate. We reviewed the long-term outcome of a mature trial comparing endocrine treatment versus no adjuvant therapy in older women with node-positive breast cancer., Patients and Methods: From 1978 to 1981, 349 women 66 to 80 years of age with pathologically involved lymph nodes after total mastectomy and axillary clearance were randomly assigned to receive 12 months of adjuvant tamoxifen plus low-dose prednisone (p+T) or no adjuvant therapy. Three hundred twenty patients were eligible., Results: At 21 years' median follow-up, 1 year of p+T significantly prolonged disease-free survival (DFS; P =.003) and overall survival (P =.05; 15-year DFS, 10% +/- 3% v 19% +/- 3%; hazard ratio, 0.71; 95% CI, 0.58 to 0.86). When comparing competing causes of failure (breast cancer recurrence and deaths before breast cancer recurrence), p+T was far superior in controlling breast cancer recurrence (P =.0003), but the improvement was seen mainly in soft tissue sites. Conversely, patients in the p+T group were more likely to die before a breast cancer recurrence (P =.03)., Conclusion: This trial demonstrates that significant treatment benefits continue to be observed in older patients treated for 1 year with p+T. Despite issues relating to competing causes of failure, older breast cancer patients can benefit from treatment and should be considered for trials of adjuvant systemic therapy.

Purpose: To compare patients treated in or outside clinical protocols, using de novo acute myeloid leukemia (AML) as a model disorder., Patients and Methods: We retrospectively compared the characteristics of all patients with de novo AML diagnosed in the referral area of our university hospital between 1985 and 1994., Results: Of a total of 170 AML patients, 45% were included in a phase III trial for the treatment of AML and 55% were treated outside a protocol. Another 45 patients were registered only at diagnosis but were treated elsewhere. Nonstudy patients differed significantly from patients included in clinical trials with respect to age and performance status at clinical presentation, comorbidity, and type of AML. The great majority of patients excluded from trial participation showed distinct exclusion criteria, such as advanced age and severe comorbidity. Study patients were treated significantly more often with curative intent and achieved better response and survival. Patients treated in an equivalent manner but outside a protocol showed no significant difference in survival compared with patients enrolled onto a trial., Conclusion: Study patients were not representative for the entire population of patients with AML; many patients were excluded from phase III trial participation for failure to meet stringent entry criteria. Therefore, results of phase III studies may not be extrapolated to all AML patients but should only be applied to patients who do not differ in substantial characteristics from the study population.