Ultrasound supports clinical decision-making in determining the Sanders' skeletal maturity score of the hand.

PURPOSE: The Sanders Scoring System has revolutionized the way we assess the remaining growth potential of the skeleton. However, because it involves radiation exposure, it must be used with caution in children. The purpose of the study was to evaluate whether the Sanders skeletal maturity score (SMS) could be accurately determined using ultrasound (U). METHODS: We took radiographs (R) of the hand and performed U of the thumb and index finger in 115 patients between six and 19 years of age who were undergoing treatment for scoliosis or limb deformities. Paediatric orthopaedic surgeons, a paediatrician, and a paediatric radiologist were evaluated the blinded images. Those classified images are based on the SMS and the Thumb Ossification Composite Index (TOCI). RESULTS: Intrarater reliability was high for SMS and slightly weaker for TOCI, but still significant. Interrater reliability was clear for R and weaker for U in both staging systems. Ultimately, SMS 3 and 7 achieved the highest percentage of concordance (P) of 71.7% and 66.0%, respectively, when U was performed. Combining the clinically relevant groups of SMS 3&4 and SMS 7&8 also significantly increased peak scores (SMS 3 and 4 P = 76.7%; SMS 7 and 8 P = 79.7%). The probabilities of peak scores were significantly weaker when the TOCI score was examined. CONCLUSION: Our study shows that U can be used effectively especially to measure stages 3 and 4 and stages 7 and 8 of SMS. The U method is easy to use and therefore may offer advantages in clinical practice without the need for radiation exposure.

Influence of platelet count at diagnosis and during the course of disease on prognosis in MDS patients.

Thrombocytopenia at diagnosis and platelet drop within the first 6 months have an adverse effect on prognosis of MDS patients. We therefore were interested in the association and impact on prognosis of morphologic findings of megakaryocytes and platelets with platelet count at diagnosis, bleeding complications, and the drop of platelets during the course of disease. This retrospective analysis was based on 334 MDS patients from the Duesseldorf MDS registry that were followed up for blood counts, bleeding, transfusion dependency, and AML evolution and correlated with morphology of the megakaryocytes and platelets. Thrombocytopenia was found more frequently in higher risk MDS and was associated with hypocellularity of the megakaryocytes in the bone marrow. Signs of bleeding were present at diagnosis in 14% and occurred during the disease in 48% of all MDS patients. Death due to bleeding was ranked third behind infections and AML. A decrement of platelets during the first 6 months was associated with an inferior overall survival of 21 vs. 49 months and with a higher cumulative 2-year AML rate of 22.2% vs. 8.3% (p = 0.001). In a multivariate analysis, besides bone marrow blasts and karyotype, decreasing platelets were also associated with an inferior outcome. Signs of bleeding are present in a relevant number of MDS patients and account for significant morbidity and mortality in MDS. We could demonstrate the prognostic importance of decreasing platelets during the course of disease in all MDS patients, identifying patients at higher risk for death or AML progression.

Prognostic impact of pretransplant measurable residual disease assessed by peripheral blood WT1-mRNA expression in patients with AML and MDS.

OBJECTIVE: As peripheral blood (PB) Wilm's Tumor 1 (WT1)-mRNA expression is established as MRD-marker during conventional AML chemotherapy, impact of pretransplant WT1 expression remains unclear. Therefore, we aimed to assess prognostic impact of pretransplant WT1 expression on post-transplant outcome in patients with AML/MDS. METHODS: In 64 AML/MDS patients, pretransplant WT1 expression was retrospectively analyzed using a standardized assay offering high sensitivity, specificity, and a validated cut-off. Patients were divided into three groups determined by pretransplant remission and WT1 expression. Post-transplant outcome of these groups was compared regarding cumulative incidence of relapse (CIR), relapse-free (RFS), and overall survival (OS). RESULTS: Pretransplant forty-six patients (72%) showed hematologic remission, including 21 (46%) MRD-negative and 25 (54%) MRD-positive patients indicated by WT1 expression, while 18 refractory patients (28%) showed active disease. Two-year estimates of post-transplant CIR, RFS, and OS were similar in MRD-positive (61%, 37%, 54%) and refractory patients (70%, 26%, 56%), but significantly inferior compared with MRD-negative patients (10%, 89%, 90%). After multivariable adjustment, pretransplant MRD negativity measured by WT1 expression retained its prognostic impact on CIR (P = .008), RFS (P = .005), and OS (P = .049). CONCLUSIONS: PB WT1 expression represents a useful method to estimate pretransplant MRD, which is highly predictable for post-transplant outcome and may help improving peri-transplant management in AML/MDS patients.

Hemispheric differences in the duration of focal onset seizures.

OBJECTIVE: To assess hemispheric differences in the duration of focal onset seizures and its association with clinical and demographic factors. METHODS: A retrospective analysis was performed on adult patients with drug-resistant unifocal epilepsy, who underwent intracranial EEG recording between 01/2006 and 06/2016. Seizure duration was determined based on the subdural and/or stereo-EEG (sEEG) recordings. Hemispheric differences in seizure duration were statistically evaluated with regard to clinical and demographic data. RESULTS: In total, 69 patients and 654 focal onset seizures were included. The duration of seizures with left-hemispheric onset (n = 297) was by trend longer (91.88 ± 93.92 s) than of right-hemispheric seizures (n = 357; 71.03 ± 68.53 s; p = .193). Significant hemispheric differences in seizures duration were found in temporal lobe seizures (n = 225; p = .013), especially those with automotor manifestation (n = 156; p = .045). A prolonged duration was also found for left-hemispheric onset seizures with secondary generalized commencing during waking state (n = 225; p = .034), but not during sleep. A similar hemispheric difference in seizure duration was found in female patients (p = .040), but not in men. CONCLUSIONS: Hemispheric differences in seizure duration were revealed with significantly longer durations in case of left-hemispheric seizure onset. The observed differences in seizure duration might result from brain asymmetry and add new aspects to the understanding of seizure propagation and termination.

Who seizes longest? Impact of clinical and demographic factors.

OBJECTIVE: To investigate the impact of clinical and demographic parameters on the duration of focal onset seizures with and without secondary generalization using precise duration measurements from intracranial electroencephalographic (iEEG) recordings. METHODS: Patients with unifocal epilepsy syndromes and iEEG recording were retrospectively identified from the database of the local epilepsy center (2006-2016). Seizure duration was defined as time difference of iEEG seizure pattern onset and cessation. The seizure semiology was classified based on video recordings. Clinical and demographic data were extracted from patient reports. RESULTS: In total, 69 adults were included, and 654 focal onset seizures were analyzed. Focal to bilateral tonic-clonic seizures (FBTCSs; 98/654) were significantly longer than focal seizures (FSs) without generalization (FS-BTCs; 556/654, P < .001), and most FSs (545/654, 83.3%) terminated within 2 minutes. The duration of FSs was prolonged with increasing age of the patients (P = .003) and was significantly shortened (P < .001) by evolution into an FBTCS. FBTCSs with lateralizing semiologies like version (P = .015) and sign of four (P = .043) were associated with longer bilateral tonic-clonic manifestations. Furthermore, FBTCSs with preceding aura, frontal origin, or onset during sleep were by trend shorter. Age (P < .001) and disease duration (P = .028) were essential for prediction of FS-BTC duration, whereas the vigilance state (P = .085) was the main prediction factor for the duration of FBTCSs. SIGNIFICANCE: The identified modifiers of seizure duration are of great relevance for clinical risk evaluation, especially in the aging epilepsy patient suffering from temporal lobe epilepsy with secondary generalized seizures.

Infections after kidney transplantation: A comparison of mTOR-Is and CNIs as basic immunosuppressants. A systematic review and meta-analysis.

BACKGROUND: Side effects of the immunosuppressive therapy after solid organ transplantation are well known. Recently, significant benefits were shown for mTOR-Is with respect to certain viral infections in comparison with CNIs. However, reported total incidences of infections under mTOR-Is vs CNIs are usually not different. This raises the question to additional differences between these immunosuppressants regarding development and incidence of infections. METHODS: The current literature was searched for prospective randomized controlled trials in renal transplantation. There were 954 trials screened of which 19 could be included (9861 pts.). The 1-year incidence of infections, patient and graft survival were assessed in meta-analyses. RESULTS: Meta-analysis on 1-year incidence of infections showed a significant benefit of an mTOR-I based therapy when combined with a CNI vs CNI-based therapy alone (OR 0.76). There was no difference between mTOR-I w/o CNI and CNI therapy (OR 0.97). For pneumonia, a significant disadvantage was seen only for mTOR-I monotherapy compared to CNI's (OR 2.09). The incidence of CMV infections was significantly reduced under mTOR-I therapy (combination with CNI: OR 0.30; mTOR w/o CNI: OR: 0.46). There was no significant difference between mTOR-I and CNI therapy with respect to patient survival (mTOR-I w/o CNI vs CNI: OR 1.22; mTOR-I with CNI vs CNI: OR 0.86). Graft survival was negatively affected by mTOR-I monotherapy (OR 1.52) but not when combined with a CNI (OR 0.97). CONCLUSION: Following renal transplantation the incidence of infections is lower when mTOR-Is are combined with a CNI compared to a standard CNI therapy. Pneumonia occurs more often under mTOR-I w/o CNI.

Estimating the distribution of heterogeneous treatment effects from treatment responses and from a predictive biomarker in a parallel-group RCT: A structural model approach.

When the objective is to administer the best of two treatments to an individual, it is necessary to know his or her individual treatment effects (ITEs) and the correlation between the potential responses (PRs) Yi1 and Yi0 under treatments 1 and 0. Data that are generated in a parallel-group design RCT does not allow the ITE to be determined because only two samples from the marginal distributions of these PRs are observed and not the corresponding joint distribution. This is due to the "fundamental problem of causal inference." Here, we present a counterfactual approach for estimating the joint distribution of two normally distributed responses to two treatments. This joint distribution of the PRs Yi1 and Yi0 can be estimated by assuming a bivariate normal distribution for the PRs and by using a normally distributed baseline biomarker Zi functionally related to the sum Yi1+Yi0 . Such a functional relationship is plausible since a biomarker Zi and the sum Yi1+Yi0 encode for the same information in an RCT, namely the variation between subjects. The estimation of the joint trivariate distribution is subjected to some constraints. These constraints can be framed in the context of linear regressions with regard to the proportions of variances in the responses explained and with regard to the residual variation. This presents new insights on the presence of treatment-biomarker interactions. We applied our approach to example data on exercise and heart rate and extended the approach to survival data.

Comparison between Upfront Transplantation and different Pretransplant Cytoreductive Treatment Approaches in Patients with High-Risk Myelodysplastic Syndrome and Secondary Acute Myelogenous Leukemia.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for patients with advanced myelodysplastic syndrome (MDS) and secondary acute myelogenous leukemia (sAML), but in the absence of prospective trials the impact of pretransplant cytoreduction is controversially discussed. We retrospectively analyzed the outcome of 165 patients with MDS and excess blasts (n = 126, 76%) and sAML (n = 39, 24%) according to a pretransplant strategy. Sixty-seven patients (41%) were directly transplanted (upfront group), whereas 98 patients (59%) had received pretransplant cytoreductive treatment (induction chemotherapy [CTX], n = 64; hypomethylating agents [HMAs], n = 34) resulting in a significantly higher complete remission rate in the CTX group (59% versus HMA 18%, P < .0001). Estimated rates of 5-year overall survival (OS) and relapse-free survival (RFS) for the entire group were 54% and 39%, respectively. The 5-year OS rates of the upfront, CTX, and HMA groups were 61%, 50%, and 45%, respectively (P = .116), whereas RFS rates were 38%, 41%, and 38% (P = .926). Cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM) did not differ between treatment groups. In the upfront group no difference regarding OS and RFS was seen with respect to pretransplant blast count (>10% versus <10%). In multivariate analyses type of pretransplant strategy did not have an effect on OS, RFS, CIR, and NRM, whereas cytogenetics (OS, RFS, CIR), reduced-intensity conditioning (OS, RFS, CIR), and an unrelated donor (RFS, CIR) were identified as negative predictors. When compared with the upfront group, 5-year OS was significantly lower in patients with CTX-refractory disease (34% versus 64%, P = .0346) and by clear trend in HMA nonresponders (42% versus 61%, P = .073), whereas RFS did not differ significantly. In further support of the concept, that pretransplant therapy may favor the selection of resistant clones, patients in the upfront group had a higher likelihood to respond to HMAs as salvage therapy for relapse in comparison with pretreated patients (complete remission, 58% versus 10%; P = .0005) and a higher 2-year OS rate after relapse (59% versus 19%, P = .0001). These data suggest that an upfront transplant strategy is at least not inferior to pretransplant cytoreduction and may be augmented by HMAs + donor lymphocyte infusion salvage therapy in case of relapse after allo-HSCT.

Imatinib dose reduction in major molecular response of chronic myeloid leukemia: results from the German Chronic Myeloid Leukemia-Study IV.

Standard first-line therapy of chronic myeloid leukemia is treatment with imatinib. In the randomized German Chronic Myeloid Leukemia-Study IV, more potent BCR-ABL inhibition with 800 mg ('high-dose') imatinib accelerated achievement of a deep molecular remission. However, whether and when a de-escalation of the dose intensity under high-dose imatinib can be safely performed without increasing the risk of losing deep molecular response is unknown. To gain insights into this clinically relevant question, we analyzed the outcome of imatinib dose reductions from 800 mg to 400 mg daily in the Chronic Myeloid Leukemia-Study IV. Of the 422 patients that were randomized to the 800 mg arm, 68 reduced imatinib to 400 mg after they had achieved at least a stable major molecular response. Of these 68 patients, 61 (90%) maintained major molecular remission on imatinib at 400 mg. Five of the seven patients who lost major molecular remission on the imatinib standard dose regained major molecular remission while still on 400 mg imatinib. Only two of 68 patients had to switch to more potent kinase inhibition to regain major molecular remission. Importantly, the lengths of the intervals between imatinib high-dose treatment before and after achieving major molecular remission were associated with the probabilities of maintaining major molecular remission with the standard dose of imatinib. Taken together, the data support the view that a deep molecular remission achieved with high-dose imatinib can be safely maintained with standard dose in most patients. Study protocol registered at clinicaltrials.gov 00055874.

Differences in treatment and monitoring of chronic myeloid leukemia with regard to age, but not sex: Results from a population-based study.

There are established guidelines for treatment and monitoring of chronic myeloid leukemia (CML) but little is known about routine care. Data on ICD-10 codes as well as prescribed medications were available for 10.5 million patients in the statutory health insurance system in Bavaria for the years 2010 to 2016. Also, data on the molecular and cytogenetic monitoring were integrated. A total of 1714 adult patients with CML were observed. Only 50.8% received more than 67.5 daily doses per quarter year (target: 91.5) while 18.2% did not receive any tyrosine kinase inhibitor (TKI). The median number of daily doses was at least 80 doses per quarter year for all age groups in men, but decreased to 62 doses in elderly women. With this exception, no differences between men and women were observed. The percentage of patients without any TKI increased with age. The median number of molecular examinations was 3.54 independent of age and sex. Even in a highly developed country, still a considerable number of patients with CML seem to not receive adequate treatment, whereas molecular monitoring can be considered satisfactory.

Prognosis of patients with chronic myeloid leukemia presenting in advanced phase is defined mainly by blast count, but also by age, chromosomal aberrations and hemoglobin.

Chronic myeloid leukemia (CML) is usually diagnosed in chronic phase, yet there is a small percentage of patients that is diagnosed in accelerated phase or blast crisis. Due to this rarity, little is known about the prognosis of these patients. Our aim was to identify prognostic factors for this cohort. We identified 283 patients in the EUTOS population-based and out-study registries that were diagnosed in advanced phase. Nearly all patients were treated with tyrosine kinase inhibitors. Median survival in this heterogeneous cohort was 8.2 years. When comparing patients with more than 30% blasts to those with 20-29% blasts, the hazard ratio (HR) was 1.32 (95%-confidence interval (CI): [0.7-2.6]). Patients with 20-29% blasts had a significantly higher risk than patients with less than 20% blasts (HR: 2.24, 95%-CI: [1.2-4.0], P = .008). We found that the blast count was the most important prognostic factor; however, age, hemoglobin, basophils and other chromosomal aberrations should be considered as well. The ELTS score was able to define two groups (high risk vs non-high risk) with an HR of 3.01 (95%-CI: [1.81-5.00], P < .001). Regarding the contrasting definitions of blast crisis, our data clearly supported the 20% cut-off over the 30% cut-off in this cohort. Based on our results, we conclude that a one-phase rather than a two-phase categorization of de novo advanced phase CML patients is appropriate.

Analysis of cause of death: Competing risks or progressive illness-death model?

The analysis of cause of death is increasingly becoming a topic in oncology. It is usually distinguished between disease-related and disease-unrelated death. A frequently used approach is to define death as disease-related when a progression to advanced phases has occurred before, otherwise as disease-unrelated. The data are often analyzed as competing risks, while a progressive illness-death model might in fact describe the situation more precisely. In this study, we investigated under which circumstances this misspecification leads to biased estimations of the state occupation probabilities. We simulated data according to the progressive illness-death model in various settings, analyzed them with a competing risks model and with a progressive illness-death model and compared them to the true state occupation probabilities. Censoring was either added independently of the status or based on the patients' status. The simulations showed that the censoring mechanism was decisive for the bias while neither the progression hazard nor the Markov property was important. Further, we found a slightly increased standard deviation for the competing risk estimator when censoring was independent of the patients' status. For illustration, both methods were applied to two practical examples of chronic myeloid leukemia (CML): one randomized controlled trial and one registry data set. While in the first case both estimators yielded almost identical results, in the latter case, visible differences were found between both methods.

Higher retransplantation rate following extended right split-liver transplantation: An analysis from the eurotransplant liver follow-up registry.

Split-liver transplantation has been perceived as an important strategy to increase the supply of liver grafts by creating 2 transplants from 1 allograft. The Eurotransplant Liver Allocation System (ELAS) envisages that the extended right lobes (ERLs) after splitting (usually in the pediatric center) are almost exclusively shipped to a second center. Whether the ELAS policy impacts the graft and patient survival of extended right lobe transplantation (ERLT) in comparison to whole liver transplantation (WLT) recipients remains unclear. Data on all liver transplantations performed between 2007 and 2013 were retrieved from the Eurotransplant Liver Follow-up Registry (n = 5351). Of these, 5013 (269 ERL, 4744 whole liver) could be included. The impact of the transplant type on patient and graft survival was evaluated using univariate and multivariate proportional hazard models adjusting for demographics of donors and recipients. Cold ischemia times were significantly prolonged for ERLTs (P < 0.001). Patient survival was not different between ERLT and WLT. In the univariate analysis, ERLT had a significantly higher risk for retransplantation (P = 0.02). For WLT, the risk for death gradually and significantly increased with laboratory Model for End-Stage Liver Disease (MELD) scores of >20. For ERLT, this effect was seen already with laboratory MELD scores of >14. These results mandate a discussion on how to refine the splitting policy to avoid excess retransplant rates in ERL recipients and to further improve transplant outcomes of these otherwise optimal donor organs. Liver Transplantation 24 26-34 2018 AASLD.

CCL1 is a major regulatory T cell attracting factor in human breast cancer.

BACKGROUND: Regulatory T cells (Treg) suppress cytotoxic T cell anti-tumoral immune responses and thereby promote tumor progression. Prevention of intratumoral Treg accumulation by inhibition of their migration to the tumor microenvironment is a promising therapeutic strategy. The aim of this study was to identify the role of the two major Treg-attracting chemokines CCL1 and CCL22 in human breast cancer. METHODS: One hundred ninety-nine tissue samples of patients with invasive breast cancer were stained for CCL1 and CCL22 by immunohistochemistry. Chemokine expression and tumor infiltration by regulatory T cells, determined by expression of the transcription factor FoxP3, were quantified and their correlation to clinical features was statistically analyzed. RESULTS: Both CCL1 and CCL22 were expressed in most breast cancer tissues. CCL1 was significantly over-expressed in invasive breast cancer as compared to normal breast tissue. CCL1, but surprisingly not CCL22, showed a significant correlation with the number of tumor-infiltrating FoxP3+ Treg (p< 0.001). High numbers of intratumoral CCL1 expressing cells were related to high grade tumors (G4) and a positive estrogen receptor (ER) status whereas high CCL22 expression was generally seen in lower grade tumors. The median survival of 88 patients with high intratumoral CCL1 expression was 37 months compared to 50 months for the 87 patients with low CCL1 levels, this trend was however not statistically significant. CONCLUSIONS: We found a high expression of CCL1 in human breast cancer. CCL1 significantly correlated with the infiltration of immunosuppressive FoxP3+ Treg, that are known to negatively affect survival. Thus, CCL1 may serve as prognostic marker and novel therapeutic target in breast cancer.

GSK3α/ß: A Novel Therapeutic Target for Neuroendocrine Tumors.

INTRODUCTION: Glycogen synthase kinase 3α/ß (GSK3α/ß) is a serine/threonine kinase that plays a critical role in cancer. AIMS: In this study, we evaluated the effects of the specific GSK3α/ß inhibitor AR-A014418 in vitro to gain novel insights into GSK3α/ß signaling in neuroendocrine tumors (NETs). MATERIALS AND METHODS: Human NET cell lines (BON1, QGP1, H727, and GOT1) were treated with different concentrations of AR-A014418 alone and in combination with lovastatin, everolimus, 5-fluorouracil (5-FU), and γ-irradiation. RESULTS: AR-A014418 significantly dose- and time-dependently decreased cell viability in all 4 NET cell lines through inhibition of epithelial growth factor receptor and mTORC1/p70S6K signaling, as well as cyclin D3 downregulation and induction of pChk1. In all cell lines tested, FACS analysis showed an AR-A014418-induced increase in the sub-G1 phase, reflecting cell death. Apoptosis induction was observed in H727, GOT1 and QGP1 cells, but not in BON1 cells. Furthermore, significant antimigratory effects upon GSK3α/ß inhibition were found and were associated with ß-catenin downregulation in all cell lines tested. Compensatory upregulation of pAkt and pERK in response to GSK3α/ß inhibition was prevented by combining AR-A014418 with the ERK and Akt inhibitor lovastatin. Accordingly, the lovastatin/AR-A014418 combination was synergistic in BON1 and QGP1 cells. Moreover, AR-A014418 displayed promising chemosensitizing effects on 5-FU in QGP1 and slight radiosensitizing properties in BON1 and QGP1 cells. CONCLUSION: Our data provide new insights into the role of GSK3α/ß in NETs and suggest that GSK3α/ß inhibition could be a novel therapeutic option in NETs, especially in combination with lovastatin or 5-FU, depending on tumor entity.

Cytogenetic clonal evolution in myelodysplastic syndromes is associated with inferior prognosis.

BACKGROUND: The karyotype of bone marrow cells at the time of diagnosis is a strong prognostic parameter for overall survival as well as acute myeloid leukemia (AML) progression in patients with myelodysplastic syndromes (MDS). However, to the authors' knowledge, few data exist regarding the prognostic impact of cytogenetic clonal evolution during the course of MDS. METHODS: The authors evaluated follow-up karyotype analyses in 549 patients from the Dusseldorf MDS Registry. RESULTS: Clonal evolution was detectable in 24% of the entire cohort and in 18% of 294 patients receiving best supportive care. The authors noted a clear adverse effect of clonal evolution on the risk of leukemic transformation (hazard ratio, 2.233; P = .036) and overall survival (hazard ratio, 3.677; P<.001). The authors also analyzed the prognostic influence of subclones detectable at the time of diagnosis. Again, such a finding was associated with a significantly shorter overall survival and a higher 5-year-probability of acute myeloid leukemia progression (30% vs 22%). CONCLUSIONS: The results of the current study support the belief that follow-up karyotype analyses should be performed, especially in patients with lower-risk and intermediate-risk MDS, to identify those patients who are at higher risk of disease progression and therefore might benefit from earlier or more intensive treatment. Cancer 2017;123:4608-4616. © 2017 American Cancer Society.

Smokers with chronic myeloid leukemia are at a higher risk of disease progression and premature death.

BACKGROUND: Smoking is suspected to not only be a risk factor for chronic myeloid leukemia but an adverse prognostic factor for the disease as well. The objective of the current study was to investigate the impact of smoking on survival and progression to advanced phases of disease. METHODS: Based on the data of the German CML Study IV, the authors analyzed the effect of smoking using a multivariate Cox model with the addition of the European Treatment and Outcome Study (EUTOS) long-term survival score variables of age, spleen size, thrombocytes, and peripheral blasts as well as sex, comorbidities, and type of treatment center. RESULTS: The 8-year survival probability was 87% for a nonsmoking patient and 83% for a patient who smoked. The authors noted a 2.08-times higher risk of death for smokers in comparison with nonsmokers and a 2.11-times higher cause-specific hazard of disease progression. An interaction between smoking and age was found in the model for survival. No significant difference with regard to molecular response was observed. CONCLUSIONS: Even when considering differences in socioeconomic status and lifestyle between patients who smoke and nonsmokers, the current analysis demonstrated that smoking also might affect disease biology. The results of the current study indicate that patients with chronic myeloid leukemia, in particular those aged <60 years, should be encouraged to quit smoking. Cancer 2017;123:2467-71. © 2017 American Cancer Society.

Impact of comorbidities on overall survival in patients with chronic myeloid leukemia: results of the randomized CML study IV.

We studied the influence of comorbidities on remission rate and overall survival (OS) in patients with chronic myeloid leukemia (CML). Participants of the CML Study IV, a randomized 5-arm trial designed to optimize imatinib therapy, were analyzed for comorbidities at diagnosis using the Charlson Comorbidity Index (CCI); 511 indexed comorbidities were reported in 1519 CML patients. Age was an additional risk factor in 863 patients. Resulting CCI scores were as follows: CCI 2, n = 589; CCI 3 or 4, n = 599; CCI 5 or 6, n = 229; and CCI ≥ 7, n = 102. No differences in cumulative incidences of accelerated phase, blast crisis, or remission rates were observed between patients in the different CCI groups. Higher CCI was significantly associated with lower OS probabilities. The 8-year OS probabilities were 93.6%, 89.4%, 77.6%, and 46.4% for patients with CCI 2, 3 to 4, 5 to 6, and ≥7, respectively. In multivariate analysis, CCI was the most powerful predictor of OS, which was still valid after removal of its age-related components. Comorbidities have no impact on treatment success but do have a negative effect on OS, indicating that survival of patients with CML is determined more by comorbidities than by CML itself. OS may therefore be inappropriate as an outcome measure for specific CML treatments. The trial was registered at www.clinicaltrials.gov as #NCT00055874.

The impact of health care settings on survival time of patients with chronic myeloid leukemia.

With the introduction of tyrosine kinase inhibitors, the treatment of chronic myeloid leukemia (CML) patients has migrated extensively to municipal hospitals (MHs) and office-based physicians (OBPs). Thus, we wanted to check whether the health care setting has an impact on outcome. Based on 1491 patients of the German CML Study IV, we compared the outcomes of patients from teaching hospitals (THs) with those from MHs and OBPs. Adjusting for age, European Treatment and Outcome Study (EUTOS) score, Karnofsky performance status, year of diagnosis, and experience with CML, a significant survival advantage for TH patients (hazard ratio: 0.632 respectively 0.609) was found. In particular, when treated in THs, patients with blast crisis showed a superior outcome (2-year survival rate: 47.7% vs 22.3% vs 25.0%). Because the impact of the health care setting on the outcome of CML patients has not been reported before, these findings need confirmation by other study groups. This trial was registered at www.clinicaltrials.gov as #NCT00055874.