Bruton's tyrosine kinase inhibitors in B-cell lymphoma: current experience and future perspectives.

INTRODUCTION: The Bruton tyrosine kinase (BTK) is a central hub in the B cell receptor (BCR) pathway and strongly influences B cell maturation, differentiation and proliferation. Not surprisingly, BTK plays an essential role in the pathogenesis of various B cell lymphomas. Inhibitors of BTK have broadened our therapeutic options in several B cell lymphomas and already are an integral element in the treatment of Mantle Cell Lymphoma (MCL), chronic lymphocytic leukemia (CLL) and Waldenström's marcoglobulinemia. Several second generation BTK inhibitors are in clinical development and might further improve tolerability and efficacy of therapy in advanced stage CLL and MCL. Areas covered: This review illustrates the mechanism of action of BTK inhibitors and provides a comprehensive summary of key clinical trials in the development of BTK inhibitors. Characteristics of second generation BTK-inhibitors are described. Expert opinion: With accumulation of clinical experience after drug approval, longer patient follow-up and larger numbers of treated patients, future development will focus on the identification of intelligent treatment combinations. Individual selection of patients with distinct biologically properties might guide treatment decisions. While BTK inhibitors are moving to earlier treatment lines, the incorporation of these drugs into a comprehensive therapeutic strategy is still difficult to date.

[Limitations of SMILE (Small Incision Lenticule Extraction)]. / Grenzen von SMILE (Small Incision Lenticule Extraction).

Background SMILE is a relatively new technique to correct moderate and high myopia. The limits of SMILE are yet unknown. Methods Literature research using PubMed until October 1, 2016. Results/Discussion Recently presented axial 2D-strain-stress measurements indicate that the biomechanical impairment of the cornea after SMILE and LASIK is comparable. The difference in elastic moduli is statistically not different. The visual rehabilitation after SMILE takes significantly longer (weeks) compared to LASIK (days). The refractive success rate of SMILE is still not as good as that of LASIK (88 % vs. 95 % within ± 0.5 D) but SMILE has caught up during the past years. The problem of reoperations is not yet solved. Conclusion More technical and clinical improvements are required to make SMILE comparable to LASIK regarding success rate and patient convenience. The biomechnical argument pro SMILE has turned out to be weak. To achieve the improvements a commercially competing femtosecond laser would be of advantage.

Effect of first-line treatment on second primary malignancies and Richter's transformation in patients with CLL.

This study aimed to assess the frequency of and the contributing factors for second primary malignancies (SPMs) and Richter's transformations (RTs) following first-line treatment of chronic lymphocytic leukemia within four phase II/III trials of the GCLLSG evaluating fludarabine (F) vs F+cyclophosphamide (FC), chlorambucil vs F, FC without or with rituximab, and bendamustine+R (BR). Among 1458 patients, 239 (16.4%) experienced either an SPM (N=191) or a RT (N=75). Solid tumors (N=115; 43.2% of all second neoplasias) appeared most frequently, followed by RTs (N=75; 28.2%). Patients showed a 1.23-fold increased risk of solid tumors in comparison to the age-matched general population from the German cancer registry. Age>65 (hazard ratio (HR) 2.1; P<0.001), male sex (HR 1.7; P=0.01), co-morbidities (HR 1.6; P=0.01) and number of subsequent treatments⩾1 (HR 12.1; P<0.001) showed an independent adverse prognostic impact on SPM-free survival. Serum thymidine kinase>10 U/l at trial enrollment (HR 3.9; P=0.02), non-response to first-line treatment (HR 3.6; P<0.001) and number of subsequent treatments⩾1 (HR 30.2; P<0.001) were independently associated with increased risk for RT.

Bioaccumulation and molecular effects of sediment-bound metals in zebrafish embryos.

Predicting the bioavailability and effects of metals in sediments is of major concern in context with sediment risk assessment. This study aimed to investigate the bioavailability and molecular effects of metals spiked into riverine sediments to zebrafish (Danio rerio) embryos. Embryos were exposed to a natural and an artificial sediment spiked with cadmium (Cd), copper (Cu), nickel (Ni) and zinc (Zn) individually or as a mixture at concentrations ranging from 150 to 3000 mg/kg dry weight (dw) over 48 h, and uptake of metals was determined. Furthermore, transcript abundances of the metallothioneins MT1 and MT2, the metal-responsive element-binding transcription factor (MTF) and the genes sod1, hsp70 and hsp90α1 were measured as indicators of metal-induced or general cellular stress. D. rerio embryos accumulated metals from sediments at concentrations up to 100 times greater than those spiked to the sediment with the greatest bioaccumulation factor (BAF) for Cu from artificial sediment (275.4 ± 41.9 (SD)). Embryos accumulated greater concentrations of all metals from artificial than from natural sediment, and accumulation was greater when embryos were exposed to individual metals than when they were exposed to the mixture. Exposure of embryos to Zn or the mixture exhibited up to 30-fold greater transcript abundances of MT1, MT2 and hsp70 compared to controls which is related to significant uptake of Zn from the sediment. Further changes in transcript abundances could not be related to a significant uptake of metals from sediments. These studies reveal that metals from spiked sediments are bioavailable to D. rerio embryos directly exposed to sediments and that the induction of specific genes can be used as biomarkers for the exposure of early life stages of zebrafish to metal-contaminated sediments.

[Pupil centroid shift: Marketing tool or essential clinical parameter?]. / Verschiebung des Pupillenzentroids : Marketing oder klinisch relevanter Parameter?

BACKGROUND: Pupil centroid shift (PCS) is an easily measured parameter which is rarely taken into consideration when planning surgery. PURPOSE: The aim of this study was to determine the physiological range of PCS and to evaluate its role in refractive and cataract surgery. METHODS: The pupil center was measured in 103 eyes of 103 patients using the newest PCS module of the Allegro Topolyzer Vario (Version 1.76r58, Wavelight-Alcon, Erlangen, Germany) and the difference between a mesopic and a photopic environment was determined as PCSm. Additionally, these measurements were linearly extrapolated to pupil diameters of 2 mm and 7 mm (photopic-scotopic, PCSe). The statistical analysis included correlations between various demographic and topographic parameters and PCS. RESULTS: The average (± standard deviation) PCSm was 0.12 ± 0.08 mm with a range of 0.02-0.53 mm, with 2 eyes out of 95 (2%) having a PCSm of more than 0.4 mm. The extrapolated PCSe was 0.24 ± 0.16 mm and ranged from 0.03 to 0.78 mm, with 14 eyes out of 95 (15%) having a PCSe of more than 0.4 mm. Of the 95 eyes 3 (3%) showed a PCSe of more than 0.7 mm. There was no correlation between PCS with any of the demographic parameters tested. CONCLUSION: Up to 15% of the patients showed a PCS of more than 0.4 mm which requires a decision of the (refractive) ophthalmic surgeon as to whether the optical zone should be centered on the photopic or mesopic/scotopic pupil center. In the 3% of patients with a PCSe value greater than 0.7 mm, the implantation of multifocal intraocular lens (IOL) is not recommended.

[Innovations in refractive laser surgery 2014]. / Innovationen in der refraktiven Laserchirurgie 2014.

BACKGROUND: Within less than 30 years refractive laser surgery has been developed from an experimental technique to one of the most frequently applied procedures in ophthalmology worldwide. RESULTS: Regarding the success rate of refractive results, myopia correction has reached a level (95% within ± 0.5 D) that is comparable to manifest refraction so that there is not much room for improvement. The most recently developed technique is femtosecond laser lenticule extraction which was introduced in 2007 in Germany. Early clinical results were very promising but the awaited bilateral comparative studies are still lacking. Although new laser types that will be able to provide improved profiles are on the horizon, the problem of reoperations has not yet been solved. Topography-guided ablation is notoriously plagued by undercorrection so that topography-guided treatment is planned as a two step-procedure. The reason for the undercorrection is the leveling effect of the epithelium. PERSPECTIVES: The evolution of refractive surgery has slowed down during the last years, however, some important innovations are at the advent.

[Complications of corneal cross-linking]. / Komplikationen der Vernetzung der Hornhaut.

BACKGROUND: More than 10 years after the clinical introduction of corneal cross-linking (CXL) the indications and contraindications are still not yet defined. Fundamental for such a list is the incidence of complications. METHODS: A PubMed search for complications of corneal crosslinking published up to March 2013 was carried out. RESULTS: The published complication rates ranged from 1 % to 10 % depending on the stage of keratoconus. Early postoperative complications were transient stromal haze, sterile infiltrates, endothelium decompensation, delayed epithelial healing and infectious keratitis. Stromal opacity can be a delayed postoperative event. CONCLUSIONS: Complications after corneal cross-linking treatment for keratoconus are rare but the management of these complications may need keratoplasty.

Investigating the significance of dissolved organic contaminants in aquatic environments: coupling passive sampling with in vitro bioassays.

We investigated the feasibility of coupling passive sampling and in vitro bioassay techniques for both chemical and ecotoxicological assessment of complex mixtures of organic contaminants in water. Silicone rubber passive sampling devices (SR-PSDs) were deployed for 8-9 weeks in four streams and an estuary of an agricultural catchment in North East (NE) Scotland. Extracts from the SR-PSDs were analysed for freely dissolved hydrophobic organic contaminants (HOCs) and screened for wide range of pesticides. The total concentrations of dissolved PAHs (∑PAH(40), parent and branched) in the water column of the catchment varied from 38 to 69 ng L(-1), whilst PCBs (∑PCB(32)) ranged 0.02-0.06 ng L(-1). A number and level of pesticides and acid/urea herbicides of varying hydrophobicity (logK(OW)s ~2.25 to ~5.31) were also detected in the SR extracts, indicating their occurrence in the catchment. The acute toxicity and EROD induction potentials of SR extracts from the study sites were evaluated with rainbow trout liver (Oncorhynchus mykiss; RTL-W1) cell line. Acute cytotoxicity was not observed in cells following 48 h exposure to the SR extracts using neutral red uptake assay as endpoint. But, on a sublethal level, for every site, statistically significant EROD activity was observed to some degree following 72 h exposure to extracts, indicating the presence of compounds with dioxin-like effect that are bioavailable to aquatic organisms in the water bodies of the catchment. Importantly, only a small fraction of the EROD induction could be attributed to the PAHs and PCBs that were determined. This preliminary study demonstrates that the coupling of silicone rubber passive sampling techniques with in vitro bioassays is feasible and offers a cost effective early warning signal on water quality deterioration.

[Bone marrow histology from the clinical point of view]. / Knochenmarkhistologie aus klinischer Sicht.

Bone marrow diagnostics is an essential tool in routine hematological clinical practice. Not only conventional cytological and histological approaches but also more modern techniques, such as immunohistochemistry, cytogenetics and molecular diagnostics are used. The molecular basis of more and more hematological disorders is being discovered and makes its way not only into routine diagnostics but also into daily clinical practice. Recurrent genomic aberrations associated with the individual patient prognosis are well characterized and are being applied in differential therapeutic decisions. In addition, understanding deregulated biochemical pathways have led to the development of targeted therapeutic approaches. This review outlines the value of bone marrow diagnostics in hematological diseases with a focus on the currently emerging molecular diagnostic possibilities.

Variability of sediment-contact tests in freshwater sediments with low-level anthropogenic contamination--determination of toxicity thresholds.

Freshwater sediments with low levels of anthropogenic contamination and a broad range of geochemical properties were investigated using various sediment-contact tests in order to study the natural variability and to define toxicity thresholds for the various toxicity endpoints. Tests were performed with bacteria (Arthrobacter globiformis), yeast (Saccharomyces cerevisiae), nematodes (Caenorhabditis elegans), oligochaetes (Lumbriculus variegatus), higher plants (Myriophyllum aquaticum), and the eggs of zebrafish (Danio rerio). The variability in the response of some of the contact tests could be explained by particle size distribution and organic content. Only for two native sediments could a pollution effect not be excluded. Based on the minimal detectable difference (MDD) and the maximal tolerable inhibition (MTI), toxicity thresholds (% inhibition compared to the control) were derived for each toxicity parameter: >20% for plant growth and fish-egg survival, >25% for nematode growth and oligochaete reproduction, >50% for nematode reproduction and >60% for bacterial enzyme activity.

[Therapeutic cross-linking of the cornea using riboflavin/UVA]. / Therapeutische Quervernetzung der Hornhaut mittels UVA und Riboflavin.

BACKGROUND: The method of cross-linking of the cornea using riboflavin and ultraviolet light (UV) has recently entered the phase of clinical evaluation. The purpose of this paper is to review the current knowledge about corneal cross-linking. METHODS: A literature research (medline) using the key words "cross-linking" and "cornea" revealed 99 citations. Thirty-four of the 99 articles dealt with the topic and were used for this review. Some of our own as yet unpublished data were also included. RESULTS: In a first phase (until 2003) different methods of cross-linking were experimentally compared regarding efficacy and safety. As the most promising compromise the use of UVA (370 nm) and riboflavin as a photomediator was tested in pilot studies on human eyes with progressive keratoconus. In 2003, the first results of such pilot studies were published. Surprisingly, not only a halt in progression was found but in more than half of the eyes treated a regression towards a more regular cornea took place. So far, no complications have been reported. Keratocytes are killed up to 320 microns deep in the stroma and the endothelium appears unaffected. Nine cases of therapy-refractory corneal melting were treated by means of UVA/riboflavin cross-linking and in 8 of the 9 cases the melting process was stopped. CONCLUSIONS: In the current situation, we can state only that UVA/riboflavin cross-linking of the keratoconus cornea leads in the majority of the cases to a halt of the progression and complications seem to be rare. There are not yet enough data available to establish a list of indications and contraindications. A potential clinical acceptance of the procedure requires the results of prospective controlled studies that are currently underway.

[Reoperations after LASIK]. / Reoperationen nach LASIK.

BACKGROUND: Repeat operations after refractive surgery have increased in frequency during the past 10 years. The spectrum of the indications for repeat LASIK may have changed. METHODS: All cases of repeat operations after refractive surgery performed between May 1, 2004 and April 30, 2005 at the Institute of Refractive and Ophthalmic Surgery (IROC) were retrospectively investigated regarding indication for repeat surgery and visual and refractive results. The 1-month results were used to estimate the refractive and visual success rate. RESULTS: Of the 76 reoperations, 69 were performed as re-lifts, 3 eyes had new lamellae cut, and 3 cases needed keratoplasties. The reoperations took place 7.5 +/- 13 months after the primary operation (range 0.5 to 60 months). The most frequent indication was residual astigmatism of 0.5 D and more. Visual loss of more than 1 decimal line did not occur and unaided visual acuity increased from 0.64 to 1.05. No complications were reported, however, 3 eyes needed additional enhancement. CONCLUSIONS: Reoperations after LASIK performed as re-lifts appear to be effective and reasonably safe when using the technique described and respecting a residual stromal thickness of 280 microns.

[Ablation profiles in corneal laser surgery. Current and future concepts]. / Ablationsprofile in der kornealen refraktiven Laserchirurgie. Gegenwärtige und zukünftige Konzepte.

The predictability and quality of results in corneal refractive laser surgery are determined by a number of factors. Here, the calculation and choice of the ablation profile represent central elements. Our growing knowledge about the physical and optical properties of the eye in recent years has led to the development of different strategies in the generation of ablation profiles. This review describes the currently used ablation profiles with their advantages and disadvantages and provides an outlook on future methods for the calculation of ablation profiles.

[Nomograms for the improvement of refractive outcomes]. / Verbesserung der refraktiven Ergebnisse durch Nomogramme.

BACKGROUND: Nomograms are efficient tools to improve the predictability of refractive procedures by using statistical methods to analyze pre- and postoperative refractive data. The purpose of this work was to analyze the clinical relevance and limitations of nomograms in a case series. METHODS: Computer simulations based on the known unpredictability for refractive outcomes were performed for three different distribution functions of the preoperative refractions. In addition, the clinical applicability was investigated in three different cohorts that underwent laser in situ keratomileusis (LASIK). RESULTS: The use of individual nomograms significantly improves the predictability of the refractive outcome. However, theoretical investigation demonstrates that a homogeneous data distribution within cohorts is a key factor for predictable nomogram calculations. Outliers within the cohorts are not integrated into the nomogram calculation due to the mathematical model used. CONCLUSIONS: Nomograms are helpful for improving refractive outcomes. However, they are currently limited to approximately 90% within +/-0.5 D.

Dependence of wave front refraction on pupil size due to the presence of higher order aberrations.

PURPOSE: Propagation of light through the optical pathway within the eye can lead to a deformation of the wave front that might affect objective but also subjective refraction depending on pupil size. The aim of this study was to investigate the change in wave front refraction that is calculated on the basis of second order Zernike polynomials when varying the pupil size from 6 mm to 3 mm. The change was correlated with the amount of fourth and sixth order spherical aberration and fourth and sixth order astigmatism. METHODS: Wave front aberrations were measured in 130 eyes by means of a Tscherning wave front sensor at a pupil size of 6 mm. Wave front aberrations in terms of Zernike coefficients up to sixth order were approximated for 6 mm and 3 mm pupil size. The wave front refraction was calculated based on the second order Zernike coefficients for both pupil diameters. Resulting differences in wave front refraction (sphere or cylinder) due to the change in pupil size were correlated with the initial higher order aberrations determined for the 6.0 mm pupil by means of a linear regression (Spearman rank correlation coefficient). RESULTS: The correlation between the change in sphere and cylinder on one hand and the spherical aberration and higher order astigmatism on the other hand was found to be highly significant (p<0.001), with a correlation coefficient of R = 0.96 for sphere and R = 0.85 for cylinder. CONCLUSIONS: Calculating the wave front refraction on the basis of second order Zernike polynomials is plagued with the influence of the higher order aberration preexisting in the individual eye. This is one reason why this method does not represent precisely enough subjective refraction. Other methods that calculate the refraction based on wave front measurement independent from the pupil size should be established in the ophthalmic community.

[Asphericity of the cornea and astigmatism]. / Asphärizität der Hornhaut und Astigmatismus.

BACKGROUND: Regarding astigmatism of the cornea, curvature as well as asphericity depend on the meridional axis. Their functional dependence and relation to the quality of the retinal image are still unclear. METHODS: The astigmatic eye was modelled using a biconoid anterior corneal surface by means of a commercially available optical designer programme (Zemax EE, Zemax). The influence of asphericity and astigmatism on the quality of the retinal image was determined by means of ray tracing. Thirty eyes with astigmatism of up to 5.3 D underwent corneal topography (Keratograph C, Oculus) which allowed a numerical evaluation of the cylindric power as well as the asphericity in the main meridians. RESULTS: The quality of the retinal image of an eye with corneal astigmatism can be improved by a factor of 2.28 if the asphericity is optimised. Correction of the central astigmatism only (without considering asphericity) yields only a rather marginal improvement. The average difference of the asphericity in the main meridians is close to zero, however, the individual difference ranges from - 0.372 to + 0.444 which is definitely clinically relevant. CONCLUSIONS: Anisotropic asphericity of the cornea may significantly enhance or compensate central corneal astigmatism. Clinically manifest astigmatism is an individually variable combination of asphericity and curvature difference in the two main meridians and is dependent on the pupil size. Laser correction of corneal astigmatism must take meridional asphericity into account.