Dear Editor,
Patients receiving anticancer therapy usually suffer from side effects, such as loss of hair, epithelial barrier defects, and myelosuppression, which, however, are usually reversible ...when the therapy is discontinued. Although this clinical experience suggests that adult stem cells may survive such therapeutic interventions, the underlying molecular regulatory mechanisms are poorly understood. Such regulatory mechanisms also seem to protect adult stem cells from acquiring mutations, which could lead to additional tumorigenesis.
Summary 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 ( I2 0%, p=0·87 for mortality during the active study period, and I2 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).
Highlights • Src inhibition results in autophagy activation in NSCLC cell lines. • Combining Src with autophagy inhibition results in significant cell death. • Induction of ULK1 upon Scr inhibition ...allows for autophagy activation. • Src inhibition causes induction of the ULK1 targeting microRNA-106a. • Expression of the “oncogenic” miR-106a sensitizes NSCLC cells to Src inhibition.
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.
We report the results of a prospective, randomized phase 3 trial evaluating autologous peripheral blood stem cell transplantation (ASCT) versus intensive consolidation chemotherapy in newly diagnosed ...AML patients in complete remission (CR1). Patients with AML (16-60 years) in CR1 after 2 cycles of intensive chemotherapy and not eligible for allogeneic SCT were randomized between intensive chemotherapy with etoposide and mitoxantrone or ASCT ater high-dose cyclophosphamide and busulfan. Of patients randomized (chemotherapy, n = 259; ASCT, n = 258), more than 90% received their assigned treatment. The 2 groups were comparable with regard to prognostic factors. The ASCT group showed a markedly reduced relapse rate (58% vs 70%, P = .02) and better relapse-free survival at 5 years (38% vs 29%, P = .065, hazard ratio = 0.82; 95% confidence interval, 0.66-1.1) with nonrelapse mortality of 4% versus 1% in the chemotherapy arm (P = .02). Overall survival was similar (44% vs 41% at 5 years, P = .86) because of more opportunities for salvage with second-line chemotherapy and stem cell transplantation in patients relapsing on the chemotherapy arm. This large study shows a relapse advantage for ASCT as postremission therapy but similar survival because more relapsing patients on the chemotherapy arm were salvaged with a late transplantation for relapse. This trial is registered at www.trialregister.nl as #NTR230 and #NTR291.
Interferons (IFNs) are cytokines that possess potent anti-viral and immunoregulatory activities. In contrast, their potential
role(s) in anti-bacterial defense and neutrophil activation mechanisms is ...less well explored. By comparing gene expression
patterns between immature and mature human neutrophils, we obtained evidence that intracellular proteases and other anti-bacterial
proteins are produced at earlier stages of maturation, whereas the genes for receptors and signaling molecules required for
the release of these effector molecules are preferentially induced during terminal differentiation. For instance, mature neutrophils
strongly expressed genes that increase their responses to type I and type II IFNs. Interestingly, granulocyte/macrophage colony-stimulating
factor was identified as a repressor of IFN signaling components and consequently of IFN-responsive genes. Both IFN-α and
IFN-γ induced strong tyrosine phosphorylation of STAT1 in mature but not in immature neutrophils. Functional in vitro studies suggested that IFNs act as priming factors on mature neutrophils, allowing the formation of extracellular traps upon
subsequent stimulation with complement factor 5a (C5a). In contrast, both IFN-α and IFN-γ had only little capacity to prime
immature cells in this system. Moreover, both IFNs did not have significant anti-proliferative effects on immature neutrophils.
These data contribute to our understanding regarding changes of gene expression during neutrophil differentiation and IFN-mediated
anti-bacterial defense mechanisms.
Purpose: The recognition of a number of leukemia-specific cytogenetic abnormalities and their role as independent prognostic factors
have provided considerable insights into leukemia pathogenesis and ...have paved the way to adopt risk-adapted treatment. However,
∼50% of newly diagnosed acute myeloid leukemia (AML) have a normal karyotype. There has therefore been much interest in identifying
molecular markers that could help to improve the prognostic stratification of patients with normal-karyotype AML.
Experimental Design: Consecutive untreated AML patients ( n = 67) from a single institution all with normal karyotype were analyzed for the presence of mutations in the myeloid transcription
factor gene CEBPA (for CCAAT/enhancer binding protein-α), for internal tandem duplications (ITD) of the tyrosine kinase receptor gene FLT3 (for fms -like tyrosine kinase 3), and for expression of the BAALC gene (for brain and acute leukemia, cytoplasmic).
Results: 17.9% of normal-karyotype AML had mutations in the CEBPA gene, and 28.4% had FLT3 -ITD; 65.7% (44 of 67) had high BAALC expression and 34.3% (23 of 67) had low BAALC expression. Patients with CEBPA mutations had a very favorable course of their disease. Median disease-free survival (DFS) and overall survival (OS) were
33.5 and 45.5 months, respectively, compared with 10 (e.g., 12 months in patients without CEBPA mutations; P = 0.0017; P = 0.0007). AML patients with FLT3 -ITD had significantly shorter median DFS ( P = 0.0328) and OS ( P = 0.0148) than patients without FLT3 -ITD. High BAALC expression predicted for a shorter DFS ( P = 0.0152) and OS ( P = 0.0210) compared with AML with low BAALC expression; 53.7% of normal-karyotype AML had neither FLT3 -ITD nor CEBPA mutations. We found that high BAALC expression in normal-karyotype AML with neither FLT3 -ITD nor CEBPA mutations (18 of 67) indicates adverse prognosis for both DFS and OS ( P = 0.0001; e.g., P = 0.0001) compared with the group with low BAALC expression and absent FLT3 -ITD and CEBPA mutations (18 of 67). Thus, BAALC expression represents a novel prognostic marker particularly for normal-karyotype AML patients with neither FLT3 -ITD nor CEBPA mutations.
Conclusions: Assessment of CEBPA mutations, FLT3 -ITD, and BAALC expression permits to split normal-karyotype AML into clinically distinct subgroups.
Survivin has received great attention due to its expression in many human tumors and its potential as a therapeutic target in cancer. Survivin expression has been described to be cell cycle-dependent ...and restricted to the G2-M checkpoint, where it inhibits apoptosis in proliferating cells. In agreement with this current view, we found that survivin expression was high in immature neutrophils, which proliferate during differentiation. In contrast with immature cells, mature neutrophils contained only little or no survivin protein. Strikingly, these cells reexpressed survivin upon granulocyte/macrophage colony-stimulating factor (CSF) or granulocyte CSF stimulation in vitro and under inflammatory conditions in vivo. Moreover, survivin-deficient mature neutrophils were unable to increase their lifespan after survival factor exposure. Together, our findings demonstrate the following: (a) overexpression of survivin occurs in primary, even terminally differentiated cells and is not restricted to proliferating cells; and (b) survivin acts as an inhibitor of apoptosis protein in a cell cycle-independent manner. Therefore, survivin plays distinct and independent roles in the maintenance of the G2-M checkpoint and in apoptosis control, and its overexpression is not restricted to proliferating cells. These data provide new insights into the regulation and function of survivin and have important implications for the pathogenesis, diagnosis, and treatment of inflammatory diseases and cancer.
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