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Background The treatment of acute myeloid leukemia of older, medically non-fit patients still poses a highly unmet clinical need, and only few large, prospective studies have been performed in this setting. Given the established activity of hypomethylating agents such as 5-aza-2'-deoxycytidine (decitabine) in myelodysplastic syndromes and acute myeloid leukemia with 20–30% bone marrow blasts, we investigated whether this drug is also active in patients with more than 30% blasts.Design and Methods To evaluate the efficacy and toxicity of decitabine in patients over 60 years old with untreated acute myeloid leukemia ineligible for induction chemotherapy, 227 patients (median age, 72 years), many with comorbidities, adverse cytogenetics and/or preceding myelodysplastic syndrome were treated with this hypomethylating agent. During the initial decitabine treatment (135 mg/m2 total dose infused intravenously over 72 hours every 6 weeks), a median of two cycles was administered (range, 1–4). All-trans retinoic acid was administered to 100 patients during course 2. Fifty-two patients who completed four cycles of treatment subsequently received a median of five maintenance courses (range, 1–19) with a lower dose of decitabine (20 mg/m2) infused over 1 hour on 3 consecutive days every 4–6 weeks.Results The complete and partial remission rate was 26%, 95% CI (20%, 32%), and an antileukemic effect was noted in 26% of patients. Response rates did not differ between patients with or without adverse cytogenetics; patients with monosomal karyotypes also responded. The median overall survival from the start of decitabine treatment was 5.5 months (range, 0–57.5+) and the 1-year survival rate was 28%, 95%CI (22%,34%). Toxicities were predominantly hematologic.Conclusions Decitabine is well tolerated by older, medically non-fit patients with acute myeloid leukemia; myelosuppression is the major toxicity. The response rate and overall survival were not adversely influenced by poor-risk cytogenetics or myelodysplastic syndrome. Because of these encouraging results, randomized studies evaluating single-agent decitabine versus conventional treatment are warranted. The study is registered with the German Clinical Trials Registry, number DRKS00000069.

Background Several genetic aberrations with prognostic impact in first-line therapy have been described in patients with acute myeloid leukemia and normal karyotype. However, little is known about the influence of these aberrations on outcome after relapse. This study aimed to identify clinical and molecular risk factors for patients with relapsed acute myeloid leukemia with normal karyotype.Design and Methods We analyzed 94 patients with acute myeloid leukemia and normal karyotype after first relapse for clinical and molecular risk factors for survival. All patients had received first-line treatment and follow-up within two prospective, multicenter trials. Leukemic blasts were analyzed at diagnosis for genetic aberrations in the FLT3, NPM1, CEBPA, WT1, IDH1 and IDH2 genes by polymerase chain reaction and/or direct sequencing.Results A second complete remission was achieved in 52% of patients who received re-induction therapy. The presence of an FLT3-internal tandem duplication, duration of first complete remission less than 6 months and age above the median of 47 years were associated with a significantly lower rate of second complete remission. The median survival after relapse was 11 months and the 6-year survival rate was 28%. In multivariate analysis, FLT3-internal tandem duplication and age above the median were the only independent negative prognostic factors for survival. The 6-year survival rate of patients with none of these factors was 56%, whereas it was significantly inferior in patients with one or both of these factors (15% and 6%, respectively). This was also true for patients who underwent allogeneic stem cell transplantation after relapse.Conclusions FLT3-internal tandem duplication and age are the major prognostic factors in patients with relapsed acute myeloid leukemia with a normal karyotype. Patients with at least one of these risk factors have a dismal outcome and might be considered for investigational treatment approaches after relapse. (ClinicalTrials.gov Identifier: NCT00209833)

Background and Objectives Trisomy 8 (+8) is among the commonest genetic aberrations seen in acute myeloid leukemia (AML). However, the prognostic significance of this aberration and the best consolidation strategy for patients with it are still not resolved. Additional prognostic indicators are needed to further classify these patients and determine their appropriate management.Design and Methods Individual patient data-based meta-analysis was performed on 131 patients (median age 50 (18–60) years) with +8 as a sole aberration or +8 with one additional aberration treated between 1993 and 2002 in eight prospective German AML treatment trials. All patients received state-of-the-art treatment including high-dose cytarabine with the option for autologous or allogeneic hematopoietic stem cell transplantation (HSCT).Results In total, the 131 patients had a 3-year overall survival (OS) of 29% and a 3-year relapse-free survival (RFS) of 32%. Independent prognostic factors contributing to shorter OS were age ≥45 years, extramedullary disease, and a percentage of +8 positive metaphases ≥80%. Combining these three prognostic variables established a hierarchical model for OS. The 3-year OS was 13% for the high-risk group, 36% for the intermediate-risk group, and 55% for the low-risk group (p

Abstract The continuous changes in the business environment require transformation processes and innovation in organizational structures to maintain competitiveness. Innovation is required for future orientation and need an appropriate leadership style to be implemented in the company successfully. Various studies in the literature examine the topic of change models and the requirements for effective implementation of changes. Based on the constant change in the labor market, which is due to ongoing digitalization, the need for research of transformation, change-management and radical or disruptive innovation remains topical. A new challenge arises with a transformation in the entire company which affects all essential business processes. Because several levels are simultaneously affected by the transformation process, a more complex concept is required for the implementation than it could be found in the literature. There is a lack of empirical research in general for innovation-driven transformation processes and a missing connection to the implementation of radical or disruptive innovation in company. The aim of this paper is to investigate the need for new research in change theory. The focus is on the importance of innovation leadership for a radical or disruptive innovation change process, what is to be classified under a comprehensive transformation process in the company. In addition, the need for an innovation transformation model is established.

Background: Eastern and South-Eastern Asian countries have witnessed a marked decline in old age mortality in recent decades. Yet no studies have investigated the trends and patterns in old age morality and cause-of-death in the region. Objective: We reviewed the trends and patterns of old age mortality and cause-of-death for countries in the region. Methods: We examined data on old age mortality in terms of life expectancy at age 65 and age-specific death rates from the 2012 Revision of the World Population Prospects for 14 countries in the region (China, Hong Kong, Democratic People's Republic of Korea, Indonesia, Japan, Lao People's Democratic Republic, Myanmar, Malaysia, Mongolia, Philippines, Republic of Korea, Singapore, Thailand, and Viet Nam) and data on cause-of-death from the WHO for five countries (China, Hong Kong, Japan, Republic of Korea, and Singapore) from 1980 to 2010. Results: While mortality transitions in these populations took place in different times, and at different levels of socioeconomic development and living environment, changes in their age patterns and sex differentials in mortality showed certain similarities: women witnessed a similar decline to men in spite of their lower mortality, and young elders had a larger decline than the oldest-old. In all five countries examined for cause-of-death, most of the increases in life expectancy at age 65 in both men and women were attributable to declines in mortality from stroke and heart disease. GDP per capita, educational level, and urbanization explained much of the variations in life expectancy and cause-specific mortality, indicating critical contributions of these basic socioeconomic development indicators to the mortality decline over time in the region. Conclusions: These findings shed light on the relationship between epidemiological transition, changing age patterns of mortality, and improving life expectancy in these populations.

Purpose: To assess the efficacy of a second-line regimen of oxaliplatin and folinic acid-modulated fluorouracil in patients with advanced pancreatic cancer who have experienced progression while receiving gemcitabine monotherapy., Patients and Methods: A randomized, open-label, phase III study was conducted in 16 institutions throughout Germany. Recruitment ran from January 2004 until May 2007, and the last follow-up concluded in December 2012. Overall, 168 patients age 18 years or older who experienced disease progression during first-line gemcitabine therapy were randomly assigned to folinic acid and fluorouracil (FF) or oxaliplatin and FF (OFF). Patients were stratified according to the presence of metastases, duration of first-line therapy, and Karnofsky performance status., Results: Median follow-up was 54.1 months, and 160 patients were eligible for the primary analysis. The median overall survival in the OFF group (5.9 months; 95% CI, 4.1 to 7.4) versus the FF group (3.3 months; 95% CI, 2.7 to 4.0) was significantly improved (hazard ratio [HR], 0.66; 95% CI, 0.48 to 0.91; log-rank P = .010). Time to progression with OFF (2.9 months; 95% CI, 2.4 to 3.2) versus FF (2.0 months; 95% CI, 1.6 to 2.3) was significantly extended also (HR, 0.68; 95% CI, 0.50 to 0.94; log-rank P = .019). Rates of adverse events were similar between treatment arms, with the exception of grades 1 to 2 neurotoxicity, which were reported in 29 patients (38.2%) and six patients (7.1%) in the OFF and FF groups, respectively (P < .001)., Conclusion: Second-line OFF significantly extended the duration of overall survival when compared with FF alone in patients with advanced gemcitabine-refractory pancreatic cancer., (© 2014 by American Society of Clinical Oncology.)