[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.

[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.

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.

[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.

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.

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.

[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.

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.

Determination of excimer laser ablation rate of the human cornea using in vivo Scheimpflug videography.

PURPOSE: To determine in vivo the amount of human corneal tissue removed by each excimer laser pulse, the so-called ablation rate, during photorefractive keratectomy (PRK). There is confusion in the literature because the experimentally determined ablation rate of 0.4 to 0.5 microns per pulse differs from the nominal ablation rate of 0.23 to 0.3 microns per pulse, which is the value used in clinical procedures. METHODS: Eleven eyes of 11 patients were treated with PRK for correction of myopia. The corneal curvature was determined by Scheimpflug videography before and immediately after surgery. Starting from this curvature change, the authors calculated the real ablation rate. RESULTS: The real ablation rate is coincident with the nominal ablation rate and differs significantly from the ablation rate derived from deep keratectomy experiments. CONCLUSIONS: The outer layers of the cornea show significantly different ablation behavior than the deeper stroma. This information has clinical relevance for the predictability of intrastromal excimer laser procedures.

Gas chromatographic and mass spectroscopic analysis of excimer and erbium: yttrium aluminum garnet laser-ablated human cornea.

The photoablative products from human cadaver corneas treated with lasers were investigated using gas chromatography and mass spectroscopy. The photoablations were done separately with an excimer laser (193 nm) and with an erbium: yttrium aluminum garnet (Er:YAG) laser (2.94 microns). More than 20 different types of molecules with a molecular weight of 40-400 mass units could be identified, most of which were found to be alkanes. The comparison of the two types of laser ablations showed larger fragments and fewer types of molecules present after excimer laser treatment than after Er:YAG photoablation.

Repeated excimer laser treatment after photorefractive keratectomy.

Scarring or undercorrection occurs in a small percentage of patients after myopic photorefractive keratectomy. Scarring occurred in 1.8% of 298 patients with a baseline myopia of 6.0 diopters or less, increasing to 8.8% in those with corrections of more than 6.0 D. Undercorrection of more than 1 D occurred in 2.7% of the eyes with a baseline myopia of up to -6.0 D. A much greater incidence of undercorrection (30% to 40%) was found after corrections of more than 6.0 D. Thirty eyes in 30 patients were reoperated because of scarring (11 eyes) and/or undercorrection (27 eyes) and were observed for 6 to 18 months (average, 7.8 months). Only one of the eyes has shown mild scar formation after this second laser treatment. Sixty-three percent of these patients had a manifest refraction between -1.0 D and +1.0 D six months after reoperation. Repeated phototablation seems to be a valuable technique for treatment of undercorrection and/or scarring after photorefractive keratectomy.

Ocular optical aberrations after photorefractive keratectomy for myopia and myopic astigmatism.

OBJECTIVES: To study the effects of photorefractive keratectomy on ocular optical aberrations and to establish correlations with glare vision and low-contrast vision. METHODS: Preoperative ocular aberroscopy of 15 eyes undergoing photorefractive keratectomy was compared with aberroscopy at 3 months postoperatively by means of a newly developed automated aberroscope of the Tscherning type. The correlation of the wavefront errors with best spectacle-corrected visual acuity, low-contrast visual acuity, and visual acuity under glare conditions was analyzed. RESULTS: In any individual treated, the total wavefront error increased. On average, the total wavefront error increased by a factor of 17.65; this increase was highly statistically significant (P = .001). Also, the correlation with best-corrected visual acuity, low-contrast visual acuity, and glare visual acuity was statistically significant (P = .02, P = .001, and P = .03, respectively). The increase in ocular aberrations was significantly related with the virtual pupil size. CONCLUSIONS: Photorefractive keratectomy increases the ocular aberrations, impairing the visual performance of the eyes treated. In detail, scotopic visual measures such as low-contrast visual acuity and glare visual acuity suffer most from the myopia correction. Aberroscopy-guided photorefractive keratectomy may avoid such effects.

Excimer laser photorefractive keratectomy.

Excimer laser photorefractive keratectomy has been used for the correction of myopia, hyperopia and astigmatism. This laser removes tissue through a process termed photoablative decomposition, in which incident photon energy is sufficient to break molecular bonds. Selective removal of tissue across the anterior corneal surface results in a change in anterior corneal curvature. The surgical outcome may be influenced also by interindividual variability in wound healing and pharmacologic interventions. The nature of the excimer laser-tissue interaction, and clinical outcomes of predictability, stability and complications of surgery for myopia are discussed in detail.

Excimer laser keratectomy for correction of astigmatism.

We treated 13 eyes (12 patients) with excimer laser surgery for correction of astigmatism using linear corneal T-excisions. All eyes were followed up for a minimum of three months. We used a newly developed delivery system and special contact masks to deliver the 193-nm excimer light. Astigmatic corrections of up to 4.16 diopters were obtained. The actual corrections corresponded well with the intended values as predicted by a biomechanical theory. The refractive change over time was different than that observed after knife incisions, suggesting different repair mechanisms. An epithelial plug filling the whole T-excision persisted for over one year in all eyes.

Erbium:YAG laser photoablation of human cornea.

PURPOSE: To determine whether the healing response of the human cornea after photoablation with a midinfrared solid-state laser was more pronounced than after excimer laser keratectomies because of the increased thermal damage in adjacent tissue. METHODS: We treated five blind human eyes with an erbium:YAG (Er:YAG) laser prototype and followed up the patients for nine months. RESULTS: Regarding epithelial healing and corneal clarity, the patients had a healing response very similar to that of excimer laser. Further clinical and experimental studies are necessary to estimate healing and regression.

Erbium: yttrium-aluminum-garnet laser induced vapor bubbles as a function of the quartz fiber tip geometry.

BACKGROUND: The use of modern erbium: yttrium-aluminum-garnet (YAG) laser systems in opthalmic microsurgery requires a precise knowledge of the size and dynamics of the laser induced vapor bubbles. The aim of this work was to clarify the possibilities of controlling the vapor bubble shape and size by using an optimized fiber tip geometry for various ophthalmic applications with the erbium: YAG laser. METHODS: The mid-infrared radiation of free-running erbium: YAG laser was coupled optically into means of different low OH(-) quartz fiber tips to investigate the vapor bubble formation in water by high-speed photography. The core diameter of four fiber tips ranged from 200 up to 940 microm. Fourteen fiber tips were polished at an angle graduated from 10 degrees to 70 degrees over the full core diameter (seven fiber tips) and over the half core diameter (seven fiber tips). Three fiber tips were produced to have a curvature at the distal end with curvature radii of 160, 230, and 420 microm. RESULTS: The shape as well as the size of erbium: YAG laser induced vapor bubbles can be controlled systematically by using adequate fiber tip geometries. In detail, the used different angles and curvatures demonstrate that the propagation direction of the vapor bubbles can be estimated by optical modeling considering Snell's law and the Fresnel laws at a quartz-air boundary. Beside this, the size of a vapor bubble can be predetermined by choosing ideal fiber tip geometries to reduce or increase the radiant exposure at the distal end of the quartz fiber tip. CONCLUSIONS: The good possibility of controlling the shape and size of vapor bubbles offers a wider range of new applications, especially in ophthalmic microsurgery such as erbium YAG laser vitrectomy.

Ocular optical aberrometer for clinical use.

Higher-order optical errors of the human eye are often responsible for reduced visual acuity in spite of an optimal spherical or cylindrical refraction. These optical aberrations are of natural origin or can result from operations in the eye that involve optical structures. The ocular aberrometer presented is based on Tscherning's aberroscope. A collimated laser beam (532 nm, 10 mW) illuminates a mask with a regular matrix of holes which forms a bundle of thin parallel rays of 0.3 mm diameter. These rays are focused by a lens in front of the eye so that their intraocular focus point is located a certain distance in front of the retina, generating a corresponding pattern of light spots on it. According to the existing ocular optical errors, this spot pattern is more or less distorted in comparison to the mask matrix. For a 6 mm pupil diameter 68 retinal spots are plottable for assessment of the optical aberrations. The retinal spot pattern is imaged onto the sensor of a low-light charge coupled device video camera by indirect ophthalmoscopy. Deviations of all spots from their ideal regular positions are measured by means of a PC, and from these values the intraocular wave front aberration is computed in the form of the sum of Zernike polynomials up to sixth order.

Clear lens extraction in the 19th century--an early demonstration of premature dissemination.

Clear lens extraction for correction of high myopia is a concept known since at least 1800, but was performed only occasionally because of the hazards of cataract operation in general in the era before aseptic surgery. After the invention of sterilization, in 1889 a rush for myopia correction by clear lens extraction was started by Fukala in Austria/Germany and Vacher in France. It took 10 years until a retrospective comparison of operated and non-operated eyes revealed the high complication rate after clear lens extraction. After 1900, the "myopia operation" was increasingly abandoned and eventually disappeared.

Influence of corneal curvature on calculation of ablation patterns used in photorefractive laser surgery.

PURPOSE: The aim of this work was to clarify the influence of the effective illumination area and possible reflection losses that occur during laser-tissue interaction on the modeling of profiles for customized corneal ablation, such as wavefront-guided treatments. METHODS: The changes of the ablation depth per laser pulse due to the projection of a laser spot onto the corneal front surface and reflection losses at the air-tissue interface were calculated. RESULTS: Moving with a scanning-spot from the center of the cornea toward the limbus resulted in an increase of the effective illumination area and reflection losses, which led to a decrease in the ablation depth per laser pulse. The decrease of the ablation depth was strongly related to the initial radiant exposure and the corneal curvature radius. CONCLUSIONS: The corneal front surface must be taken into consideration for ablation profile calculations, especially in customized treatments, due to the strong dependence of the ablation depth on the corneal curvature.