Inappropriate expression of EVI1 (ecotropic virus integration-1), in particular splice form EVI1-1D, through chromosome 3q26 lesions or other mechanisms has been implicated in the development of ...high-risk acute myeloid leukemia (AML). To validate the clinical relevance of EVI1-1D, as well as of the other EVI1 splice forms and the related MDS1/EVI1 (ME) gene, real-time quantitative polymerase chain reaction was performed in 534 untreated adults with de novo AML. EVI1-1D was highly expressed in 6% of cases (n = 32), whereas 7.8% were EVI1+ (n = 41) when all splice variants were taken into account. High EVI1 predicted a distinctly worse event-free survival (HR = 1.9; P = .002) and disease-free survival (HR = 2.1, P = .006) following multivariate analysis. Importantly, we distinguished a subset of EVI1+ cases that lacked expression of ME (EVI1+ME−; n = 17) from cases that were ME+ (EVI1+ME+; n = 24). The atypical EVI1+ME− expression pattern exhibited cytogenetically detectable chromosomal 3q26 breakpoints in 8 cases. Fluorescence in situ hybridization revealed 7 more EVI1+ME− cases that carried cryptic 3q26 breakpoints, which were not found in the EVI1+ME+ group. EVI1+ME− expression predicts an extremely poor prognosis distinguishable from the general EVI1+ AML patients (overall survival OS: P < .001 and event-free survival EFS: P = .002). We argue that EVI1/ME quantitative expression analysis should be implemented in the molecular diagnostic procedures of AML.
Objective: To establish the statistical relationship between offenses and crashes when the unit of analysis is the vehicle instead of the driver, to show the influence of the severity (e.g., minor ...speed offenses) on this relationship, and to research whether the form of this relationship is similar in different enforcement contexts.
Methods: An exploratory analysis was conducted using Dutch traffic offense and crash data. Crash data included all police-registered crashes involving motorized and registered vehicles in 2009; offense data included all non-criminal traffic offenses registered during 2005-2009 (mostly camera detected). Together these comprise an estimated 97 percent of all traffic offenses registered in this period. The analysis was done on a level of identified vehicles rather than persons. Vehicles involved in crashes were matched to vehicles involved in traffic offenses. The offense frequency distributions of registered crash involved vehicles and a random selection of vehicles was analyzed. Two comparisons were made: (1) privately owned vehicles versus company-owned vehicles and (2) vehicles for which only minor speed offenses were registered versus vehicles for which at least one major speed offense was registered.
Results: An increase in traffic offense frequency coincides with a stronger increase in relative crash involvement. This relationship was adequately described by a power function. The slightly more than linear increase in the crash risk for vehicles with only minor speed offenses suggests that minor speed offenses (<10 km/h over the limit) contributed slightly to crashes. This relationship was unlikely to be caused by increased distance traveled only. For vehicles with at least one or more major speed violation an approximately quadratic increase of crash risk with increasing speed offense frequency was found. A comparison of Dutch and Canadian data showed a much more progressive offense-crash relationship in the Dutch data.
Conclusion: The crash involvement of vehicles increased more than linearly with the number of minor traffic violations. Thus, automatic detection of minor offenses bears relevance to safety. The substantial increase in crash rates with speed offense frequency for vehicles with at least one major speed violation suggests that these vehicles represent a specific group with a significantly increased crash risk, especially in the case of many minor offenses. The more progressive relationship between offenses and crashes in The Netherlands when compared to Canada was hypothesized to result from the higher intensity camera enforcement levels and less severe consequences in the Dutch enforcement and adjudication system.
Supplemental materials are available for this article. Go to the publisher's online edition of Traffic Injury Prevention to view the supplemental file.
Using fiducial-marker-based robotic respiratory tumor tracking, we treated perihilar cholangiocarcinoma patients in the STRONG trial with 15 daily fractions of 4 Gy. For each of the included ...patients, in-room diagnostic-quality repeat CTs (rCT) were acquired pre- and post-dose delivery in 6 treatment fractions to analyze inter- and intrafraction dose variations. Planning CTs (pCTs) and rCTs were acquired in expiration breath-hold. Analogous to treatment, spine and fiducials were used to register rCTs with pCTs. In each rCT, all OARs were contoured, and the target was rigidly copied from the pCT based on grey values. The rCTs acquired were used to calculate the doses to be delivered through the treatment-unit settings. On average, target doses in rCTs and pCTs were similar. However, due to target displacements relative to the fiducials in rCTs, 10% of the rCTs showed PTV coverage losses of >10%. Although target coverages had been planned below desired values in order to protect OARs, many pre-rCTs contained OAR constraint violations: 44.4% for the 6 major constraints. Most OAR dose differences between pre- and post-rCTs were not statistically significant. The dose deviations observed in repeat CTs represent opportunities for more advanced adaptive approaches to enhancing SBRT treatment quality.
This paper discusses the method used for an outlook on road safety in the Netherlands until 2020. The objectives of the outlook are to judge the feasibility of the Dutch road safety policy targets ...and to estimate the effects in 2020 of new measures. The outlook consists of baseline forecasts assuming the unchanged continuation of the effect of current road safety policy as a starting point, and the effect of new measures on top of that. We used four different mobility scenarios, derived from a comprehensive study about the macro-economic development of Dutch society until 2040. In the mobility scenario with the largest growth it appeared doubtful whether the policy targets of that time for the maximum number of fatalities in 2020 (580) can be achieved. An extensive inventory of new measures after 2010 produced five already intended new measures, the effects of which were estimated. The results show that the target of maximum 580 fatalities in 2020 can probably be met. The recently adjusted policy target of 500 fatalities in 2020 is also feasible if additional new measures are taken.
Mutations in splice factor (SF) genes occur more frequently in myelodysplastic syndromes (MDS) than in acute myeloid leukemias (AML). We sequenced complementary DNA from bone marrow of 47 refractory ...anemia with excess blasts (RAEB) patients, 29 AML cases with low marrow blast cell count, and 325 other AML patients and determined the presence of SF-hotspot mutations in SF3B1, U2AF35, and SRSF2. SF mutations were found in 10 RAEB, 12 AML cases with low marrow blast cell count, and 25 other AML cases. Our study provides evidence that SF-mutant RAEB and SF-mutant AML are clinically, cytologically, and molecularly highly similar. An integrated analysis of genomewide messenger RNA (mRNA) expression profiling and DNA-methylation profiling data revealed 2 unique patient clusters highly enriched for SF-mutant RAEB/AML. The combined genomewide mRNA expression profiling/DNA-methylation profiling signatures revealed 1 SF-mutant patient cluster with an erythroid signature. The other SF-mutant patient cluster was enriched for NRAS/KRAS mutations and showed an inferior survival. We conclude that SF-mutant RAEB/AML constitutes a related disorder overriding the artificial separation between AML and MDS, and that SF-mutant RAEB/AML is composed of 2 molecularly and clinically distinct subgroups. We conclude that SF-mutant disorders should be considered as myeloid malignancies that transcend the boundaries of AML and MDS.
•SF-mutant myeloid malignancies transcend the boundaries between AML and MDS.•Integrated analysis of gene expression and DNA-methylation profiles in leukemia uncovers novel subtypes.
Lenalidomide has been proven to be effective but with a distinct and difficult to manage toxicity profile in the context of chronic lymphocytic leukemia, potentially hampering combination treatment ...with this drug. We conducted a phase 1-2 study to evaluate the efficacy and safety of six cycles of chlorambucil (7 mg/m
daily), rituximab (375 mg/m
cycle 1 and 500 mg/m
cycles 2-6) and individually-dosed lenalidomide (escalated from 2.5 mg to 10 mg) (induction-I) in first-line treatment of patients with chronic lymphocytic leukemia unfit for treatment with fludarabine, cyclophosphamide and rituximab. This was followed by 6 months of 10 mg lenalidomide monotherapy (induction-II). Of 53 evaluable patients in phase 2 of the study, 47 (89%) completed induction-I and 36 (68%) completed induction-II. In an intention-to-treat analysis, the overall response rate was 83%. The median progression-free survival was 49 months, after a median follow-up time of 27 months. The 2- and 3-year progression-free survival rates were 58% and 54%, respectively. The corresponding rates for overall survival were 98% and 95%. No tumor lysis syndrome was observed, while tumor flair reaction occurred in five patients (9%, 1 grade 3). The most common hematologic toxicity was grade 3-4 neutropenia, which occurred in 73% of the patients. In conclusion, addition of lenalidomide to a chemotherapy backbone followed by a fixed duration of lenalidomide monotherapy resulted in high remission rates and progression-free survival rates, which seem comparable to those observed with novel drug combinations including novel CD20 monoclonal antibodies or kinase inhibitors. Although lenalidomide-specific toxicity remains a concern, an individualized dose-escalation schedule is feasible and results in an acceptable toxicity profile.
.
Background
We recently reported results of the prospective, open‐label HOVON‐100 trial in 334 adult patients with acute lymphoblastic leukemia (ALL) randomized to first‐line treatment with or without ...clofarabine (CLO). No improvement of event‐free survival (EFS) was observed, while a higher proportion of patients receiving CLO obtained minimal residual disease (MRD) negativity.
Aim
In order to investigate the effects of CLO in more depth, two multi‐state models were developed to identify why CLO did not show a long‐term survival benefit despite more MRD‐negativity.
Methods
The first model evaluated the effect of CLO on going off‐protocol (not due to refractory disease/relapse, completion or death) as a proxy of severe treatment‐related toxicity, while the second model evaluated the effect of CLO on obtaining MRD negativity. The subsequent impact of these intermediate events on death or relapsed/refractory disease was assessed in both models.
Results
Overall, patients receiving CLO went off‐protocol more frequently than control patients (35/168 21% vs. 18/166 11%, p = 0.019; HR 2.00 1.13–3.52, p = 0.02), especially during maintenance (13/44 30% vs. 6/56 11%; HR 2.85 95%CI 1.08–7.50, p = 0.035). Going off‐protocol was, however, not associated with more relapse or death. Patients in the CLO arm showed a trend towards an increased rate of MRD‐negativity compared with control patients (HR MRD‐negativity: 1.35 0.95–1.91, p = 0.10), which did not translate into a significant survival benefit.
Conclusion
We conclude that the intermediate states, i.e., going off‐protocol and MRD‐negativity, were affected by adding CLO, but these transitions were not associated with subsequent survival estimates, suggesting relatively modest antileukemic activity in ALL.
We developed two multi‐state models to identify in more depth why clofarabine (CLO) did not show a long‐term survival benefit despite more MRD‐negativity, as recently reported in the HOVON‐100 trial. Patients receiving CLO went off‐protocol (indicated by the left figures) more frequently than control patients (HR 2.00 1.13–3.52, p = 0.02)—especially during maintenance (HR 2.85 95%CI 1.08–7.50, p = 0.035)—and showed a trend towards an increased rate of MRD‐negativity (indicated by the right figures) (HR 1.35 0.95–1.91, p = 0.10); however, neither transition significantly affected subsequent survival estimates. We conclude that the intermediate states, i.e., going off‐protocol and MRD‐negativity, were affected by adding CLO, but these transitions were not associated with subsequent survival estimates, suggesting relatively modest antileukemic activity in ALL.
IntroductionThe locoregional failure (LRF) rate in human papilloma virus (HPV)-negative oropharyngeal squamous cell carcinoma (OPSCC) remains disappointingly high and toxicity is substantial. ...Response prediction prior to or early during treatment would provide opportunities for personalised treatment. Currently, there are no accurate predictive models available for correct OPSCC patient selection. Apparently, the pivotal driving forces that determine how a OPSCC responds to treatment, have yet to be elucidated. Therefore, the holistiC early respOnse assessMent for oroPharyngeaL cancer paTiEnts study focuses on a holistic approach to gain insight in novel potential prognostic biomarkers, acquired before and early during treatment, to predict response to treatment in HPV-negative patients with OPSCC.Methods and analysisThis single-centre prospective observational study investigates 60 HPV-negative patients with OPSCC scheduled for primary radiotherapy (RT) with cisplatin or cetuximab, according to current clinical practice. A holistic approach will be used that aims to map the macroscopic (with Intra Voxel Incoherent Motion Diffusion Kurtosis Imaging (IVIM-DKI); before, during, and 3 months after RT), microscopic (with biopsies of the primary tumour acquired before treatment and irradiated ex vivo to assess radiosensitivity), and molecular landscape (with circulating tumour DNA (ctDNA) analysed before, during and 3 months after treatment). The main end point is locoregional control (LRC) 2 years after treatment. The primary objective is to determine whether a relative change in the mean of the diffusion coefficient D (an IVIM-DKI parameter) in the primary tumour early during treatment, improves the performance of a predictive model consisting of tumour volume only, for 2 years LRC after treatment. The secondary objectives investigate the potential of other IVIM-DKI parameters, ex vivo sensitivity characteristics, ctDNA, and combinations thereof as potential novel prognostic markers.Ethics and disseminationThe study was approved by the Medical Ethical Committee of Erasmus Medical Center. The main results of the trial will be presented in international meetings and medical journals.Trial registration numberNL8458.
Treatment results of AML in elderly patients are unsatisfactory. We hypothesized that addition of tosedostat, an aminopeptidase inhibitor, to intensive chemotherapy may improve outcome in this ...population. After establishing a safe dose in a run-in phase of the study in 22 patients, 231 eligible patients with AML above 65 years of age (median 70, range 66-81) were randomly assigned in this open label randomized Phase II study to receive standard chemotherapy (3+7) with or without tosedostat at the selected daily dose of 120 mg (
= 116), days 1-21. In the second cycle, patients received cytarabine 1000 mg/m
twice daily on days 1-6 with or without tosedostat. CR/CRi rates in the 2 arms were not significantly different (69% (95% C.I. 60-77%) vs 64% (55-73%), respectively). At 24 months, event-free survival (EFS) was 20% for the standard arm versus 12% for the tosedostat arm (Cox-p = 0.01) and overall survival (OS) 33% vs 18% respectively (
= 0.006). Infectious complications accounted for an increased early death rate in the tosedostat arm. Atrial fibrillation was more common in the tosedostat arm as well. The results of the present study show that the addition of tosedostat to standard chemotherapy does negatively affect the therapeutic outcome of elderly AML patients.
Background: In unresectable pCCA, the standard of care is palliative chemotherapy. We investigated the feasibility and safety of adding stereotactic body radiation therapy (SBRT) after chemotherapy. ...Methods: Patients with unresectable pCCA, stage T1-T4N0-N1M0, ECOG 0-1, having finished 6–8 cycles of cisplatin and gemcitabine without disease progression were eligible. SBRT was planned in 15 fractions of 3.0–4.5 Gy. The primary endpoints were feasibility (defined as completing SBRT as planned) and toxicity, evaluated within 3 months after SBRT (CTCAE v4.03). A conventional “3 + 3” design was used, corresponding to a sample size of 6 patients. Dose-limiting toxicity (DLT) was defined as grade ≥ 4 hepatobiliary or grade ≥ 3 gastrointestinal toxicity. The secondary endpoints, measured from the start of radiotherapy, were local control, progression-free survival, overall survival, and quality of life (QoL). ClinicalTrials.gov identifier: NCT03307538. Results: Six patients were enrolled between November 2017 and March 2020. SBRT was delivered as planned. All patients were treated with 60Gy (15 × 4.0Gy). No SBRT-related DLT was observed. The most common grade ≥ 3 toxicity was cholangitis (n = 5). The median follow-up was 14 months. The 12-month local control rate was 80%. We observed no substantial changes in QoL. Conclusion: In patients with unresectable pCCA with stable disease after palliative chemotherapy, adding SBRT is feasible and safe. The observed local control merits an additional evaluation of effectiveness.
PDF
