UV light-mediated corneal crosslinking as (lymph)angioregressive pretreatment to promote graft survival after subsequent high-risk corneal transplantation (CrossCornealVision): protocol for a multicenter, randomized controlled trial.

BACKGROUND: Good vision highly depends on the transparency of the cornea, which is the "windscreen" of the eye. In fact, corneal blindness due to transparency loss is the second most common cause of blindness worldwide, and corneal transplantation is the main cure. Importantly, the cornea is normally avascular but can secondarily be invaded by pathological (blood and lymphatic) vessels due to severe inflammation, and the survival prognosis of a corneal graft mainly depends on the preoperative vascular condition of the recipient's cornea. Whereas transplants placed into avascular recipient beds enjoy long-term survival rates of > 90%, survival rates significantly decrease in pathologically pre-vascularized, so-called high-risk recipients, which account for around 10% of all performed transplants in Germany and > 75% in lower and middle-income countries worldwide. METHODS: This parallel-grouped, open-randomized, multicenter, prospective controlled exploratory investigator-initiated trial (IIT) intends to improve graft survival by preconditioning pathologically vascularized recipient corneas by (lymph)angioregressive treatment before high-risk corneal transplantation. For this purpose, corneal crosslinking (CXL) will be used, which has been shown to potently regress corneal blood and lymphatic vessels. Prior to transplantation, patients will be randomized into 2 groups: (1) CXL (intervention) or (2) no pretreatment (control). CXL will be repeated once if insufficient reduction of corneal neovascularization should be observed. All patients (both groups) will then undergo corneal transplantation. In the intervention group, remaining blood vessels will be additionally regressed using fine needle diathermy (on the day of transplantation). Afterwards, the incidence of graft rejection episodes will be evaluated for 24 months (primary endpoint). Overall graft survival, as well as regression of corneal vessels and/or recurrence, among other factors, will be analyzed (secondary endpoints). DISCUSSION: Based on preclinical and early pilot clinical evidence, we want to test the novel concept of temporary (lymph)angioregressive pretreatment of high-risk eyes by CXL to promote subsequent corneal graft survival. So far, there is no evidence-based approach to reliably improve graft survival in the high-risk corneal transplantation setting available in clinical routine. If successful, this approach will be the first to promote graft survival in high-risk transplants. It will significantly improve vision and quality of life in patients suffering from corneal blindness. TRIAL REGISTRATION: ClinicalTrials.gov NCT05870566. Registered on 22 May 2023.

Influence of Descemet Membrane Endothelial Keratoplasty Graft Preparation Patterns on Postoperative Clinical Outcome.

PURPOSE: The aim of this study was to quantify preparation difficulties and complications during DMEK graft preparation and their influence on clinical outcome. METHODS: A retrospective evaluation of 214 consecutive DMEK surgeries from the prospective Cologne DMEK database was performed between July 2018 and December 2019. Preparation conditions (such as central and peripheral adherences, tissue fragility, and Descemet membrane splitting) were quantified and divided into 3 groups: easy, difficult, and very difficult preparation. At follow-up (3, 6, and 12 months after DMEK), best spectacle-corrected visual acuity, endothelial cell count (ECC), and rebubbling rates were evaluated and compared between groups. RESULTS: An easy preparation was possible in 41.6% of cases (group 1, n = 89), a difficult preparation of the DMEK graft occurred in 30.8% (group 2, n = 66), and a very difficult preparation occurred in 27.6% (group 3, n = 59). There was no difference between groups for best spectacle-corrected visual acuity at 3, 6, and 12 months ( P = 0.179, P = 0.325, and P = 0.682, respectively) or for ECC at 3 and 6 months ( P = 0.537 and P = 0.606, respectively). Only at 12 months, the ECC was slightly significant between groups ( P = 0.045). Regarding the rebubbling rate, there was no difference ( P = 0.585). 17.9% of eyes from group 1, 25.7% of eyes from group 2, and 23.7% of eyes from group 3 received at least 1 rebubbling. CONCLUSIONS: These data suggest that difficult preparation conditions do not lead to any worsening of visual acuity or rebubbling rate in the 1-year outcome after DMEK. The endothelial cell density at 12 months showed slightly poorer results in the cases of very difficult preparation.

Transcorneal Electrical Stimulation Dose-Dependently Slows the Visual Field Loss in Retinitis Pigmentosa.

Purpose: To assess whether transcorneal electrical stimulation (TcES) current-dependently slows progressive loss of visual field area (VFA) in retinitis pigmentosa (RP). Methods: Data from 51 patients with RP who received monocular TcES treatment once weekly over 1 year in an interventional, randomized study have been analyzed a posteriori. Current amplitudes were 0.1 to 1.0 mA in the TcES-treated group (n = 31) and 0.0 mA in the sham group (n = 20). VFA was assessed in both eyes (semiautomatic kinetic perimetry, Goldmann targets V4e, III4e). Annual decline rate (ADR) of exponential loss and model-independent percentage reduction of VFA at treatment cessation were correlated to current amplitude. Results: For V4e, mean ADR was -4.1% in TcES-treated eyes, -6.4% in untreated fellow eyes, and -7.2% in placebo-treated eyes; mean VFA reduction in TcES-treated eyes was 64% less than in untreated fellow eyes (P = 0.013) and 72% less than in placebo-treated eyes (P = 0.103). Individual VFA reductions correlated with current amplitude (P = 0.043) and tended toward zero in patients who received 0.8 to 1.0 mA. For III4e, there was a marginally significant current-dependency of interocular difference in reduction (P = 0.11). ADR and VFA reduction did not significantly correlate with baseline VFA. Conclusions: Loss of VFA (V4e) in patients with RP was significantly reduced in treated eyes compared to untreated eyes by regular use of TcES in a dose-dependent manner. No dependence of effects on the initial extent of VFA loss was found. Translational Relevance: TcES provides potential for preservation of visual field in patients with RP.

Efficacy and safety of ruxolitinib in patients with newly-diagnosed polycythemia vera: futility analysis of the RuxoBEAT clinical trial of the GSG-MPN study group.

Patients (pts) with polycythemia vera (PV) suffer from pruritus, night sweats, and other symptoms, as well as from thromboembolic complications and progression to post-PV myelofibrosis. Ruxolitinib (RUX) is approved for second-line therapy in high-risk PV pts with hydroxyurea intolerance or resistance. The RuxoBEAT trial (NCT02577926, registered on October 1, 2015, at clinicaltrials.gov) is a multicenter, open-label, two-arm phase-IIb trial with a target population of 380 pts with PV or ET, randomized to receive RUX or best available therapy. This pre-specified futility analysis assesses the early clinical benefit and tolerability of RUX in previously untreated PV pts (6-week cytoreduction was allowed). Twenty-eight patients were randomly assigned to receive RUX. Compared to baseline, after 6 months of treatment, there was a significant reduction of median hematocrit (46 to 41%), the median number of phlebotomies per year (4.0 to 0), and median patient-reported pruritus scores (2 to 1), and a trend for reduced night sweat scores (1.5 to 0). JAK2V617F allele burden, as part of the scientific research program, also significantly decreased. One hundred nine adverse events (AEs) occurred in 24/28 patients (all grade 1 to 3), and no pt permanently discontinued treatment because of AEs. Thus, treatment with ruxolitinib in untreated PV pts is feasible, well-tolerated, and efficient regarding the above-mentioned endpoints.

Desiccating Stress Significantly Increases the Risk for Chronic Ocular Graft-versus-Host-Disease.

Desiccating stress (DS) is known to induce dry eye disease but has not been studied in the context of ocular graft-versus-host disease (oGVHD). Patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) are exposed to DS on transplantation wards, which are highly climate-regulated for hygienic purposes. Because oGVHD demonstrates features of dry eye disease, this retrospective study aimed to analyze DS as a risk factor for chronic oGVHD. A total of 444 patients undergoing allo-HSCT were investigated with a maximum follow-up of 5.8 years post-transplantation. Relative humidity (%rH) on the transplantation ward was monitored, and data were correlated with the occurrence, severity, and onset of chronic oGVHD, as well as the occurrence of acute skin GVHD. A logistic regression model was used to predict the development of oGVHD. One hundred three of 213 surviving patients developed oGVHD. oGVHD was significantly correlated with a lower %rH (r = .2; P = .03), and more patients (73%) developed oGVHD after transplantation under DS compared with patients after transplantation under high-humidity conditions (30%; P = .02). Reduced humidity increased the relative risk for oGVHD by 4% for each %rH, but it did not affect the severity or time of first diagnosis of oGVHD. In this study, we demonstrate that DS is an independent risk factor for oGVHD. Adjusting air humidity during allo-HSCT has the potential to serve as a preventive measure with clinical relevance.

Which Test Is the Best to Assess Visuo-Cognitive Impairment in Patients with Parkinson's Disease with Mild Cognitive Impairment and Dementia? A Systematic Review and Meta-Analysis.

BACKGROUND: Visuo-cognitive impairment is common in patients with Parkinson's disease with mild cognitive impairment (PD-MCI) and constitutes a prognostic factor for the conversion to Parkinson's disease dementia (PDD). However, systematic analyses on which neuropsychological tests are most suitable to assess visuo-cognition in PD-MCI and PDD and to differentiate these cognitive stages are lacking. OBJECTIVE: To review neuropsychological tests used to assess visuo-cognition including visuo-perceptual and visuo-spatial processing, visuo-constructive copying and drawing on command abilities; and to identify the visuo-cognitive subdomain as well as tests most suitable to discriminate between PD-MCI and PDD. METHODS: MEDLINE, PsycINFO, Web of Science Core Collection, and CENTRAL were systematically searched for relevant studies assessing visuo-cognitive outcomes in patients with PD-MCI and PDD. Risk of bias was assessed using a customized form based on well-established tools. Random-effect meta-analyses were conducted. RESULTS: 33 studies were included in the systematic review. Data of 19 studies were entered in meta-analyses. Considerable heterogeneity regarding applied tests, test versions, and scoring systems exists. Data indicate that visuo-constructive command tasks are the subdomain best suited to discriminate between PD-MCI and PDD. Furthermore, they indicate that the Rey-Osterrieth-Complex-Figure Test (ROCF), Corsi Block-Tapping Test, Judgment of Line Orientation (JLO), and Clock Drawing Test (CDT) are tests able to differentiate between the two stages. CONCLUSION: We provide suggestions for suitable visuo-cognitive tests (Corsi Block-Tapping Test, or JLO, ROCF, CDT) to improve diagnostic accuracy. Methodological challenges (e.g., heterogeneity of definitions, tests) are discussed and suggestions for future research are provided. REGISTRATION: https://www.crd.york.ac.uk/prospero/, ID: CRD42018088244.

Gender gap in deep brain stimulation for Parkinson's disease.

Previous studies have shown less access to deep brain stimulation (DBS) for Parkinson's disease (PD) in women compared to men raising concerns about a potential gender gap resulting from nonclinical factors or gender differences in clinical efficacy for postoperative quality of life (QoL), motor, and nonmotor symptoms (NMS) outcomes. This was a cross-sectional and a longitudinal, prospective, observational, controlled, quasi-experimental, international multicenter study. A total sample size of 505 consisted of 316 consecutively referred patients for DBS indication evaluation at the University Hospital Cologne (01/2015-09/2020) and 189 consecutively treated patients at DBS centers in the University Hospitals Cologne and Marburg, Salford's Royal Hospital Manchester, and King's College Hospital London. In the cross-sectional cohort, we examined gender proportions at referral, indication evaluations, and DBS surgery. In the longitudinal cohort, clinical assessments at preoperative baseline and 6-month follow-up after surgery included the PD Questionnaire-8, NMSScale, Scales for Outcomes in PD-motor scale, and levodopa-equivalent daily dose. Propensity score matching resulted in a pseudo-randomized sub-cohort balancing baseline demographic and clinical characteristics between women with PD and male controls. 316 patients were referred for DBS. 219 indication evaluations were positive (women n = 102, respectively n = 82). Women with PD were disproportionally underrepresented in referrals compared to the general PD population (relative risk [RR], 0.72; 95%CI, 0.56-0.91; P = 0.002), but more likely to be approved for DBS than men (RR, 1.17; 95%CI, 1.03-1.34; P = 0.029). Nonetheless, their total relative risk of undergoing DBS treatment was 0.74 (95%CI, 0.48-1.12) compared to men with PD. At baseline, women had longer disease duration and worse dyskinesia. Exploring QoL domains, women reported worse mobility and bodily discomfort. At follow-up, all main outcomes improved equally in both genders. Our study provides evidence of a gender gap in DBS for PD. Women and men with PD have distinct preoperative nonmotor and motor profiles. We advocate that more focus should be directed toward the implementation of gender equity as both genders benefit from DBS with equal clinical efficacy. This study provides Class II evidence of beneficial effects of DBS in women with PD compared to male controls.

Outcomes of deep anterior lamellar keratoplasty and penetrating keratoplasty in keratoconic eyes with and without previous hydrops.

PURPOSE: The study aims to compare outcomes after deep anterior lamellar keratoplasty (DALK) and penetrating keratoplasty (PK) in keratoconic eyes with or without previous hydrops. METHODS: Retrospective analysis of 211 eyes who received PK (group 1, n = 74 [history of hydrops: n = 33]) or DALK (group 2, n = 137 [history of hydrops: n = 9]) from 2012 to 2019 at the Department of Ophthalmology, University of Cologne, Germany. Analysis included best spectacle-corrected visual acuity (BSCVA), complications, immune reactions, graft survival and keratometry, and subgroup analyses for subjects with or without previous hydrops. RESULTS: Follow-up was 34.0 ± 23.6 months in group 1 and 30.7 ± 22.5 months in group 2. No significant difference was found in the course of BSCVA between groups 1 and 2 (p = 0.182) and in postoperative BSCVA between eyes with and without previous hydrops, regardless of the surgical method (p = 0.768). Endothelial immune reactions occurred exclusively in group 1 and did not occur more frequently in eyes with previous hydrops (p = 0.377). A higher risk of complications for eyes with previous hydrops was observed (p = 0.022). There was no difference in astigmatism and maximum keratometry (Kmax) preoperatively and postoperatively between eyes with and without history of hydrops. CONCLUSION: The prognosis for visual outcome after keratoplasty including visual acuity, astigmatism, and Kmax for keratoconic eyes with previous hydrops is as good as for keratoconic eyes without previous hydrops, irrespective of the surgical method. However, eyes after hydrops seem to have an increased risk of complications.

Comparison of Pre-Endoscopic C-WATCH Score with Established Risk Assessment Tools in Patients with Upper Gastrointestinal Bleeding.

INTRODUCTION: Use of risk scores for early assessment of patients with upper gastrointestinal bleeding (UGIB) is recommended by various guidelines. We compared Cologne-WATCH (C-WATCH) score with Glasgow-Blatchford score (GBS), Rockall score (RS), and pre-endoscopic RS (p-RS). METHODS: Patients with UGIB between January and December 2017 were retrospectively analyzed for 30-day mortality and composite endpoints risk of complications and need for intervention using areas under the receiver-operating characteristics curve (AUROC). Subgroup analysis was conducted for patients with UGIB on admission and in-hospital UGIB. RESULTS: A total of 252 patients were identified (67.5% men, mean age 63.8 ± 14.9 years). In-hospital UGIB occurred in 49.6%. AUROCs for 30-day mortality, risk of complications, and need for intervention (not applicable to RS) were 0.684 (95% confidence interval [CI]: 0.606-0.763), 0.665 (95% CI: 0.594-0.735), and 0.694 (95% CI: 0.612-0.775) for C-WATCH score, 0.724 (95% CI: 0.653-0.796) and 0.751 (95% CI: 0.687-0.815) for RS, 0.652 (95% CI: 0.57-0.735), 0.653 (95% CI: 0.579-0.727), and 0.673 (95% CI: 0.602-0.745) for p-RS and 0.652 (95% CI: 0.572-0.732), 0.663 (95% CI: 0.592-0.734), and 0.752 (95% CI: 0.683-0.821) for GBS. RS outperformed pre-endoscopic scores in predicting risk of complications, while there were no significant differences between pre-endoscopic scores except GBS outperforming p-RS in predicting need for intervention. The subgroup analysis obtained similar results. Positive predictive values for patients with estimated low risk for all three endpoints (C-WATCH score ≤1, RS ≤2, p-RS <1, and GBS ≤1) were 89%, 69%, 78%, and 92%. CONCLUSION: C-WATCH score performed similar to the established pre-endoscopic risk scores in patients with UGIB regarding relevant patient-related endpoints with no significant differences between both the subgroups.

[Transcorneal electrostimulation in retinitis pigmentosa : Protocol of a multicentric prospective, randomized, controlled and double-masked trial on behalf of the Joint Federal Committee (G-BA pilot regulation)]. / Transkorneale Elektrostimulation bei Retinitis pigmentosa : Prüfplan einer multizentrischen, prospektiven, randomisierten, kontrollierten und doppelblinden Studie im Auftrag des Gemeinsamen Bundesausschusses (G-BA-Erprobungsrichtlinie).

The focus of this large multicenter trial commissioned by the Joint Federal Committee (Gemeinsamer Bundesausschuss, G­BA) is to determine a benefit of transcorneal electrical stimulation for retinitis pigmentosa (RP) patients. The main criterion for benefit is the kinetic visual field and whether the deterioration progresses more slowly in the study eyes compared to the sham-stimulated fellow eyes over a treatment period of 3 years.

The Cologne rebubbling study: a reappraisal of 624 rebubblings after Descemet membrane endothelial keratoplasty.

BACKGROUND/AIMS: To analyse graft detachments prior to rebubbling, the influence of rebubbling on the postoperative outcome after Descemet membrane endothelial keratoplasty (DMEK) and the need for rebubbling on the contralateral eye. METHODS: In this retrospective cohort study, out of 1541 DMEKs, optical coherence tomography scans and clinical records of 499 eyes undergoing rebubbling after DMEK at the University Hospital of Cologne, Cologne, Germany, were examined. Main Outcome measures were (a) number, localisation and size of graft detachments; (b) influence of rebubbling/s on postoperative outcome after 12 months; and (c) rebubbling risk of the contralateral eye after DMEK. RESULTS: Mean number of detachment areas was 2.02±0.9. Mean lateral diameter of all detachments was 4534.76±1920.83 µm. Mean axial diameter was 382.53±282.02 µm. Detachments were equally distributed over all regions of the cornea. Best spectacle corrected visual acuity ( BSCVA) after 12 months was 0.197±0.23 logarithm of the minimum angle of resolution, endothelial cell density (ECD) was 1575.21±397.71 cells/mm2 and mean central corneal thickness (CCT) was 566.37±68.11 µm. BSCVA, CCT, ECD or endothelial cell loss of all rebubbled patients were not influenced by the number of rebubblings or the time between DMEK and rebubbling. Of the rebubbled patients, which received a DMEK subsequently on the other eye, 193 (58.8%) also received a rebubbling, which was significantly higher, when compared to the overall rebubbling rate of 32.3% (p=0.000). CONCLUSIONS: The overall number of rebubblings has no influence on the postoperative outcome after DMEK, if a rebubbling becomes necessary. Patients who received a rebubbling on one eye have an elevated risk for a rebubbling on the fellow eye.

Hemoadsorption: effective in reducing circulating fragments of the endothelial glycocalyx during cardiopulmonary bypass in patients undergoing on-pump cardiac surgery?

BACKGROUND: The vascular endothelial glycocalyx is susceptible to ischemia and hypoxia. Released soluble components of the endothelial glycocalyx (EG) have been identified as potential damage associated molecular patterns (DAMPs) able to enhance an ongoing inflammatory response. Shedding of the EG has been associated with released atrial-natriuretic peptide (ANP) during cardiac surgery procedures. A novel hemoadsorption technique (CytoSorb®) has been shown to effectively remove molecules up to 55 kDa unspecifically from circulation. It is not known whether ANP or glycocalyx components can be removed successfully by this technique. METHODS: In 15 patients undergoing on-pump cardiac surgery, the hemoadsorption device was integrated in the cardiopulmonary bypass (CPB) circuit. Pre- and post-adsorber concentrations of ANP, heparan sulphate (HEP), syndecan-1 (SYN) and hyaluronan (HYA) were measured at 10 (T1), 30 (T2), and 60 (T3) minutes after aortic cross-clamping and complete CPB. RESULTS: Hemoadsorption significantly reduced mean HEP concentrations (-157.5 [333.4] ng/mL; P<0.001) post adsorber. For ANP and SYN no statistically significant changes were detected whereas mean [SD] HYA concentrations even increased significantly (+21.6 [43.0] ng/mL; P<0.001) post adsorber. CONCLUSIONS: In this study representing a real-life scenario, we could demonstrate that the novel hemoadsorption device (CytoSorb®) was able to effectively adsorb HEP from the circulation if integrated in a CPB circuit. However, blood concentrations of HYA, SYN, and ANP could not be reduced during CPB in our investigation.

Developmental outcome of extremely preterm infants is improved after less invasive surfactant application: Developmental outcome after LISA.

AIM: The aim of this study was to evaluate neurocognitive outcome at 24 months of corrected age after less invasive surfactant application (LISA) in preterm infants born at 23-26 weeks of gestational age. METHODS: Surviving participants of a LISA trial conducted in 13 German level III neonatal intensive care units were reviewed for assessment of developmental outcome, hearing and vision problems, growth and rehospitalisation days. Maternal depression, breastfeeding rates and socio-economic factors were evaluated as potentially confounding factors. RESULTS: In total, 156/182 infants took part in the study, 78 had received surfactant via LISA and 78 via endotracheal intubation. 22% of LISA infants compared to 42% of intubated infants had a psychomotor development index (PDI) <70 (0.012). A significant difference in mental development index (MDI) was observed in the stratum of more mature infants (25 and 26 weeks of GA). For this group, MDI < 70 was observed in 4% of LISA infants vs 21% of intubated infants (P = 0.008). CONCLUSION: At 24 months of age, the LISA-treated infants scored less often PDI < 70 and had similar results in MDI. Infants born at 25 and 26 weeks treated with LISA had lower rates of severe disability. LISA is safe and may be superior.

Deep brain stimulation and sensorimotor gating in tourette syndrome and obsessive-compulsive disorder.

Recent translational data suggest that deep brain stimulation (DBS) of the cortico-striato-thalamo-cortical (CSTC) loops improves sensorimotor gating in psychiatric disorders that show deficient prepulse inhibition (PPI), a robust operational measure of sensorimotor gating. To our knowledge we are the first to investigate this effect in patients with Tourette syndrome (TS). We measured PPI of the acoustic startle reflex in patients with TS (N = 10) or Obsessive-Compulsive Disorder (OCD) (N = 8) treated with DBS of the centromedian and ventro-oral internal thalamic nucleus and the anterior limb of internal capsule-nucleus accumbens area respectively, and aged- and gender-matched healthy controls (HC). PPI of the DBS groups was measured in randomized order in the ON and OFF stimulation condition. Statistical analysis revealed no significant difference in PPI (%) of patients with TS between ON (M = 20.5, SD = 14.9) and OFF (M = 25.2, SD = 29.7) condition. There were significantly reduced PPI levels in patients with TS in the ON condition compared to HC (M = 49.2, SD = 10.7), but no significant difference in PPI between TS in the OFF condition and HC. Furthermore, we found no significant stimulation or group effect for OCD and HC (OCD ON: M = 57.0, SD = 8.3; OCD OFF: 67.8, SD = 19.6; HC: M = 63.0, SD = 24.3). Our study has a number of limitations. Sample sizes are small due to the restricted patient collective. The study was not controlled for use of psychoactive medication or nicotine. Furthermore, we were not able to assess presurgical PPI measurements. In conclusion, we were able to show that PPI is impaired in patients with TS. This finding is in line with recent translational work. With respect to the OCD cohort we were not able to replicate our previously published data. A disability in sensorimotor gating plays a pivotal role in many psychiatric disorders therefore more research should be conducted to disentangle the potential and limitations of modulating sensorimotor gating via brain stimulation techniques.

Risk factors for endothelial cell loss after Descemet membrane endothelial keratoplasty (DMEK).

This study aimed to identify the risk factors for endothelial cell density (ECD) loss after Descemet membrane endothelial keratoplasty (DMEK) and analyse whether donor tissues from cold versus organ culture differ in terms of ECD loss after DMEK. Consecutive DMEK cases from a prospective database for Fuchs' endothelial corneal dystrophy were retrospectively analysed between 2011 and 2016 at the University of Cologne, and the possible risk factors for ECD loss, including patient-related factors, type of tamponade (air or 20% sulphur hexafluoride gas), type of surgery (triple DMEK or DMEK alone), re-bubbling, immune rejection, and donor-related factors were determined. Eight hundred and forty-one eyes were selected. There was no significant difference in the best-corrected visual acuity (logarithm of the minimal angle of resolution) and corneal thickness (P = 0.540 and P = 0.667) between groups. Immune reactions were more common in cold cultures (P = 0.019), but ECD loss (1 year after DMEK) was greater in organ cultures (38.3 ± 0.8%) than in cold cultures (34.7 ± 1.4%) (P = 0.022). Only re-bubbling was significantly associated with ECD loss (P < 0.001). Re-bubbling was found to be a key factor for ECD loss at 1 year after DMEK.

Sorafenib and everolimus in patients with advanced solid tumors and KRAS-mutated NSCLC: A phase I trial with early pharmacodynamic FDG-PET assessment.

BACKGROUND: Treatment of patients with solid tumors and KRAS mutations remains disappointing. One option is the combined inhibition of pathways involved in RAF-MEK-ERK and PI3K-AKT-mTOR. METHODS: Patients with relapsed solid tumors were treated with escalating doses of everolimus (E) 2.5-10.0 mg/d in a 14-day run-in phase followed by combination therapy with sorafenib (S) 800 mg/d from day 15. KRAS mutational status was assessed retrospectively in the escalation phase. Extension phase included KRAS-mutated non-small-cell lung cancer (NSCLC) only. Pharmacokinetic analyses were accompanied by pharmacodynamics assessment of E by FDG-PET. Efficacy was assessed by CT scans every 6 weeks of combination. RESULTS: Of 31 evaluable patients, 15 had KRAS mutation, 4 patients were negative for KRAS mutation, and the KRAS status remained unknown in 12 patients. Dose-limiting toxicity (DLT) was not reached. The maximum tolerated dose (MTD) was defined as 7.5 mg/d E + 800 mg/d S due to toxicities at previous dose level (10 mg/d E + 800 mg/d S) including leucopenia/thrombopenia III° and pneumonia III° occurring after the DLT interval. The metabolic response rate in FDG-PET was 17% on day 5 and 20% on day 14. No patient reached partial response in CT scan. Median progression free survival (PFS) and overall survival (OS) were 3.25 and 5.85 months, respectively. CONCLUSIONS: Treatment of patients with relapsed solid tumors with 7.5 mg/d E and 800 mg/d S is safe and feasible. Early metabolic response in FDG-PET was not confirmed in CT scan several weeks later. The combination of S and E is obviously not sufficient to induce durable responses in patients with KRAS-mutant solid tumors.

A prospective, controlled study of non-motor effects of subthalamic stimulation in Parkinson's disease: results at the 36-month follow-up.

OBJECTIVE: To examine 36-month effects of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) on non-motor symptoms (NMS) compared with standard-of-care medical treatment (MED) in Parkinson's disease (PD). METHODS: Here we report the 36-month follow-up of a prospective, observational, controlled, international multicentre study of the NILS cohort. Assessments included NMSScale (NMSS), PDQuestionnaire-8 (PDQ-8), Scales for Outcomes in PD (SCOPA)-motor examination, -activities of daily living, and -complications, and levodopa equivalent daily dose (LEDD). Propensity score matching resulted in a pseudo-randomised sub-cohort balancing baseline demographic and clinical characteristics between the STN-DBS and MED groups. Within-group longitudinal outcome changes were analysed using Wilcoxon signed-rank and between-group differences of change scores with Mann-Whitney U test. Strength of clinical responses was quantified with Cohen's effect size. In addition, bivariate correlations of change scores were explored. RESULTS: Propensity score matching applied on the cohort of 151 patients (STN-DBS n=67, MED n=84) resulted in a well-balanced sub-cohort including 38 patients per group. After 36 months, STN-DBS significantly improved NMSS, PDQ-8, SCOPA-motor examination and -complications and reduced LEDD. Significant between-group differences, all favouring STN-DBS, were found for NMSS, SCOPA-motor complications, LEDD (large effects), motor examination and PDQ-8 (moderate effects). Furthermore, significant differences were found for the sleep/fatigue, urinary (large effects) and miscellaneous NMSS domains (moderate effects). NMSS total and PDQ-8 change scores correlated significantly. CONCLUSIONS: This study provides Class IIb evidence for beneficial effects of STN-DBS on NMS at 36-month follow-up which also correlated with quality of life improvements. This highlights the importance of NMS for DBS outcomes assessments.

Effect of Iris Color on the Outcome of Descemet Membrane Endothelial Keratoplasty.

PURPOSE: To explore the impact of iris color on the outcome of Descemet membrane endothelial keratoplasty (DMEK). METHODS: Consecutive cases of Fuchs endothelial dystrophy after DMEK were retrospectively analyzed from the prospective Cologne DMEK database between 2011 and 2017 at the University of Cologne, Germany. Iris pictures were graded by color into blue, green, or brown and compared regarding outcome parameters including best-corrected visual acuity (converted to logarithm of the minimal angle of resolution), central corneal thickness, endothelial cell density (ECD), each at preoperative (baseline) and postoperative 12 months, rebubbling rates, cystoid macular edema (CME), and immune rejections after surgery. RESULTS: One thousand one hundred six eyes of 814 patients were included in this study that consisted of 354 blue eyes, 418 green eyes, and 244 brown eyes. There was no significant correlation between iris color and any parameter (best corrected visual acuity; P = 0.064 at preoperatively, P = 0.959 at 12 months) (ECD; P = 0.158 preoperatively, P = 0.859 at 12 months) (central corneal thickness; P = 0.148 preoperatively, P = 0.252 at 12 months). The loss of ECD at 12 months after surgery was 37.2% ± 1.0% in blue eyes, 37.2% ± 0.9% in green eyes, and 37.2% ± 1.2% in brown eyes (P = 0.999). Immune rejections were 1.7%, 2.9%, and 0.8% (P = 0.168) in blue, green, and brown eyes, respectively. Rebubbling rates and CME incidence were similar in each group (P = 0.129, and P = 0.552 respectively). CONCLUSIONS: The iris color has no significant impact on the outcome after DMEK. Thus, DMEK can be applied effectively, regardless of the iris color.

Long Term Follow-up Data and Health-Related Quality of Life in Frontline Therapy of Fit Patients Treated With FCR Versus BR (CLL10 Trial of the GCLLSG).

Fludarabine, cyclophosphamide and rituximab (FCR) was compared to bendamustine and rituximab (BR) in an international, randomized, open label, phase 3 trial in 561 previously untreated, fit patients with chronic lymphocytic leukemia (CLL) without del (17p). Primary endpoint was progression free survival (PFS). The final primary endpoint analysis after 37.1 months median follow up failed to show the non-inferiority of BR as compared with FCR. With extended median follow up of 58.2 months, median PFS was 42.3 months in BR-treated patients versus 57.6 months for FCR-treated patients (Hazard Ratio [HR] 1.593; 95% CI 1.271-1.996; p < 0.0001). For patients > 65 years, median PFS was 48.5 months with BR versus 57.9 months with FCR without reaching statistical significance (HR 1.352; 95% CI 0.912-2.006; p = 0.134). Median OS was not reached for both arms with 5-year OS rates of 80.1% vs 80.9%, respectively (HR 1.108; 95% CI 0.755-1.627; p = 0.599). No statistically significant difference was found in the time to secondary malignancy between the 2 groups (at 5 years, 86.6% free from secondary malignancies in the BR group vs 83.8% in the FCR group [HR 0.801; 95% CI 0.507-1.267; p = 0.344]). In patients >65 years secondary neoplasia occurred more frequently after FCR treatment [28 of 86 (32.6%) patients] as compared with BR [18 of 107 (16.8%) patients; p = 0.011]. Health-related quality of life was similar in both treatments. Despite the improved PFS for FCR, OS did not differ. These results also suggest an increase in secondary neoplasia associated with FCR in elderly fit CLL patients.