Explaining survival differences between two consecutive studies with allogeneic stem cell transplantation in patients with chronic myeloid leukemia

Purpose

In the two consecutive German studies III and IIIA on chronic myeloid leukemia, between 1995 and 2004, 781 patients were randomized to receive either allogeneic hematopoietic stem cell transplantation with a related donor or continued drug treatment. Despite comparable transplantation protocols and most centers participating in both studies, the post-transplant survival probabilities for patients transplanted in first chronic phase were significantly higher in study IIIA (144 patients) than in study III (113 patients). Prior to the decision on a combined analysis of both studies, reasons for this discrepancy had to be investigated.

Methods

The Cox proportional hazard cure model was used to identify prognostic factors for post-transplant survival.

Results

Donor–recipient matching for human leukocyte antigen, patient age, time between diagnosis and transplantation, and calendar time showed a significant influence on survival and/or the incidence of cure. Added as a further factor, affiliation to study IIIA had no significant impact any longer.

Conclusions

Discrepancies in influential prognostic factors explained the different post-transplant survival probabilities between the studies. The significance of calendar time suggests a lack of consistency of transplantation practice over time. Accordingly, the prerequisite for a common assessment of overall survival in the two randomized transplantation arms was not met. Moreover, our analyses provide an independent validation of established prognostic factors and their cutoffs. The statistical approach in investigating and modeling potential prognostic factors for survival sets an example for the examination of studies with unexpected outcome differences in concurrent treatment arms.     

Physical activity behaviour in children and adolescents before,during and after cancer treatment

Purpose

Childhood cancer survivors show reduced physical activity (PA) levels which may considerably impact child development, quality of life, social participation and sequelae such as functional and cardiovascular health. This study aims to evaluate different aspects of PA behaviour in patients with childhood cancer (PaC) before (bT), during (dT) and after (aT) cancer treatment.

Methods

In this cross-sectional, multicentre study, 114 PaC and 37 healthy controls between 4 and 20 years of age were enrolled. PA behaviour was assessed using an adapted questionnaire which included items asking about PA level, PA intensity and domains of PA.

Results

Patients reported lower PA levels and less minutes of PA at moderate-intensity dT than aT and bT (P?≤?0.05). Healthy controls reported higher PA levels than patients aT (P?≤?0.05). At school, 41.7% of PaC did not participate in physical education aT or bT. Lastly, 45.6% of PaC who were engaged in sport club activities bT did no more participate in sport club activities aT.

Conclusion

Patients reported different PA behaviours dT and aT than bT. Therefore, monitoring of PA should be considered to increase PA levels in PaC. Future studies also need to examine how PA behaviour can be influenced in a positive way in PaC.

     

Marginal and internal fit of heat pressed versus CAD/CAM fabricated all-ceramic onlays after exposure to thermo-mechanical fatigue

Objectives

The aim of the study was to evaluate the marginal and internal fit of heat-pressed and CAD/CAM fabricated all-ceramic onlays before and after luting as well as after thermo-mechanical fatigue.

Materials and methods

Seventy-two caries-free, extracted human mandibular molars were randomly divided into three groups (n = 24/group). All teeth received an onlay preparation with a mesio-occlusal–distal inlay cavity and an occlusal reduction of all cusps. Teeth were restored with heat-pressed IPS-e.max-Press* (IP, *Ivoclar-Vivadent) and Vita-PM9 (VP, Vita-Zahnfabrik) as well as CAD/CAM fabricated IPS-e.max-CAD* (IC, Cerec 3D/InLab/Sirona) all-ceramic materials. After cementation with a dual-polymerising resin cement (VariolinkII*), all restorations were subjected to mouth-motion fatigue (98 N, 1.2 million cycles; 5 °C/55 °C). Marginal fit discrepancies were examined on epoxy replicas before and after luting as well as after fatigue at 200× magnification. Internal fit was evaluated by multiple sectioning technique. For the statistical analysis, a linear model was fitted with accounting for repeated measurements.

Results

Adhesive cementation of onlays resulted in significantly increased marginal gap values in all groups, whereas thermo-mechanical fatigue had no effect. Marginal gap values of all test groups were equal after fatigue exposure. Internal discrepancies of CAD/CAM fabricated restorations were significantly higher than both press manufactured onlays.

Conclusions

Mean marginal gap values of the investigated onlays before and after luting as well as after fatigue were within the clinically acceptable range. Marginal fit was not affected by the investigated heat-press versus CAD/CAM fabrication technique. Press fabrication resulted in a superior internal fit of onlays as compared to the CAD/CAM technique.

Clinical relevance

Clinical requirements of 100 μm for marginal fit were fulfilled by the heat-press as well as by the CAD/CAM fabricated all-ceramic onlays. Superior internal fit was observed with the heat-press manufacturing method. The impact of present findings on the clinical long-term behaviour of differently fabricated all-ceramic onlays warrants further investigation.     

The role of biocatalysis in the asymmetric synthesis of alkaloids – an update

Alkaloids are a group of natural products with interesting pharmacological properties and a long history of medicinal application. Their complex molecular structures have fascinated chemists for decades, and their total synthesis still poses a considerable challenge. In a previous review, we have illustrated how biocatalysis can make valuable contributions to the asymmetric synthesis of alkaloids. The chemo-enzymatic strategies discussed therein have been further explored and improved in recent years, and advances in amine biocatalysis have vastly expanded the opportunities for incorporating enzymes into synthetic routes towards these important natural products. The present review summarises modern developments in chemo-enzymatic alkaloid synthesis since 2013, in which the biocatalytic transformations continue to take an increasingly ‘central’ role.

This review article discusses developments in the chemo-enzymatic synthesis of alkaloids since 2013, showcasing how modern methods of organic synthesis and biocatalysis are combined to establish novel routes towards these important natural products.     

Effects of ketamine and midazolam on resting state connectivity and comparison with ENIGMA connectivity deficit patterns in schizophrenia

Subanesthetic administration of ketamine is a pharmacological model to elicit positive and negative symptoms of psychosis in healthy volunteers. We used resting‐state pharmacological functional MRI (rsPhfMRI) to identify cerebral networks affected by ketamine and compared them to the functional connectivity (FC) in schizophrenia. Ketamine can produce sedation and we contrasted its effects with the effects of the anxiolytic drug midazolam. Thirty healthy male volunteers (age = 19–37 years) underwent a randomized, three‐way, cross‐over study consisting of three imaging sessions, with 48 hr between sessions. A session consisted of a control period followed by infusion of placebo or ketamine or midazolam. The ENIGMA rsfMRI pipeline was used to derive two long‐distance (seed‐based and dual‐regression) and one local (regional homogeneity, ReHo) FC measures. Ketamine induced significant reductions in the connectivity of the salience network (Cohen's d: 1.13 ± 0.28, p = 4.0 × 10^?3), auditory network (d: 0.67 ± 0.26, p = .04) and default mode network (DMN, d: 0.63 ± 0.26, p = .05). Midazolam significantly reduced connectivity in the DMN (d: 0.77 ± 0.27, p = .03). The effect sizes for ketamine for resting networks showed a positive correlation (r = .59, p = .07) with the effect sizes for schizophrenia‐related deficits derived from ENIGMA's study of 261 patients and 327 controls. Effect sizes for midazolam were not correlated with the schizophrenia pattern (r = ?.17, p = .65). The subtraction of ketamine and midazolam patterns showed a significant positive correlation with the pattern of schizophrenia deficits (r = .68, p = .03). RsPhfMRI reliably detected the shared and divergent pharmacological actions of ketamine and midazolam on cerebral networks. The pattern of disconnectivity produced by ketamine was positively correlated with the pattern of connectivity deficits observed in schizophrenia, suggesting a brain functional basis for previously poorly understood effects of the drug.