Maria Eveslage

German Multicenter Study Investigating 177Lu-PSMA-617 Radioligand Therapy in Advanced Prostate Cancer Patients

177Lu-labeled PSMA-617 is a promising new therapeutic agent for radioligand therapy (RLT) of patients with metastatic castration-resistant prostate cancer (mCRPC). Initiated by the German Society of Nuclear Medicine, a retrospective multicenter data analysis was started in 2015 to evaluate efficacy and safety of 177Lu-PSMA-617 in a large cohort of patients. Methods: One hundred forty-five patients (median age, 73 y; range, 43–88 y) with mCRPC were treated with 177Lu-PSMA-617 in 12 therapy centers between February 2014 and July 2015 with 1–4 therapy cycles and an activity range of 2–8 GBq per cycle. Toxicity was categorized by the common toxicity criteria for adverse events (version 4.0) on the basis of serial blood tests and the attending physician’s report. The primary endpoint for efficacy was biochemical response as defined by a prostate-specific antigen decline ≥ 50% from baseline to at least 2 wk after the start of RLT. Results: A total of 248 therapy cycles were performed in 145 patients. Data for biochemical response in 99 patients as well as data for physician-reported and laboratory-based toxicity in 145 and 121 patients, respectively, were available. The median follow-up was 16 wk (range, 2–30 wk). Nineteen patients died during the observation period. Grade 3–4 hematotoxicity occurred in 18 patients: 10%, 4%, and 3% of the patients experienced anemia, thrombocytopenia, and leukopenia, respectively. Xerostomia occurred in 8%. The overall biochemical response rate was 45% after all therapy cycles, whereas 40% of patients already responded after a single cycle. Elevated alkaline phosphatase and the presence of visceral metastases were negative predictors and the total number of therapy cycles positive predictors of biochemical response. Conclusion: The present retrospective multicenter study of 177Lu-PSMA-617 RLT demonstrates favorable safety and high efficacy exceeding those of other third-line systemic therapies in mCRPC patients. Future phase II/III studies are warranted to elucidate the survival benefit of this new therapy in patients with mCRPC.

Accelerated (18 mW/cm²) Corneal Collagen Cross-Linking for Progressive Keratoconus.

Purpose: The aim of this study was to determine the efficacy of accelerated riboflavin–ultraviolet A–induced corneal collagen cross-linking (CXL) (irradiance of 18 mW/cm2 for 5 minutes). Methods: In this study, we retrospectively reviewed the charts and anterior segment data of patients after accelerated CXL. Visual, topographic, pachymetry, and densitometry data were extracted and analyzed before surgery and at follow-up (minimum 12 months) after treatment. Results: A total of 28 eyes of 20 patients (mean age, 28.1 ± 8.1 years) were included in this study. The mean follow-up time was 21.7 ± 7.2 months (range, 12–34 months). No statistically significant changes were found in the mean corrected distance visual acuity, corneal astigmatism, Kmean, Kflat, Ksteep, corneal pachymetry (at the apex and at the thinnest point), and corneal densitometry at follow-up. A significant reduction of Kmax, index of surface variance, index of vertical asymmetry, and Km of the posterior corneal surface (KmB) was observed (Kmax: P = 0.018; index of surface variance: P = 0.016; index of vertical asymmetry: P = 0.038; KmB: P = 0.008). No complications were reported during the postoperative follow-up period in this study. Conclusions: Based on a mean follow-up time of 21.7 months, accelerated CXL (18 mW/cm; 5 minutes) is effective in stopping the progression of keratoconus without raising any safety concerns. Improvement in Kmax and stabilization of corrected distance visual acuity were noted after treatment. However, prospective studies with longer follow-up using different accelerated CXL settings are needed to validate these findings.

Anticoagulation with rivaroxaban for livedoid vasculopathy (RILIVA): a multicentre, single-arm, open-label, phase 2a, proof-of-concept trial

BACKGROUND Livedoid vasculopathy is a thrombotic skin disease characterised by recurrent occlusion of the cutaneous microcirculation in lower extremities, which results in skin infarctions with painful ulcerations and irreversible scar formation. Rivaroxaban is a direct factor Xa inhibitor that prevents thrombus formation. We investigated whether rivaroxaban is effective for the treatment of livedoid vasculopathy. METHODS We did this single-arm, open-label, multicenter, phase 2a, proof-of concept trial at three university hospitals in Germany. Patients with livedoid vasculopathy and a minimum pain score of 40 on the visual analogue scale were eligible to participate. Patients received oral rivaroxaban tablets for 12 weeks at an initial dose of 10 mg twice per day, which was reduced to once per day if a reduction of pain by 50% on the visual analogue scale was achieved. Subcutaneous enoxaparin at 1 mg per kg bodyweight once or twice per day was allowed as a backup treatment in case of insufficient efficacy and increased pain. The primary endpoint was change in pain on the visual analogue scale from baseline to 12 weeks. Efficacy was assessed in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study drug. This trial is registered with the EU Clinical Trials Register, EudraCT number 2012-000108-13-DE, and is closed to new participants. FINDINGS Between Dec 28, 2012, and April 24, 2014, 36 patients were screened, 28 patients were recruited for the study, and 25 patients received treatment. During treatment, five patients dropped out of the study because of withdrawal of consent (one patient), lack of compliance (one patient), violation of inclusion criteria (two patients), and a serious adverse event (one patient). Median pain on the visual analogue scale decreased from 65·0 (IQR 52·0-78·0) at baseline to 6·0 (1·0-14·0) after 12 weeks of treatment (p<0·0001). Six of the 20 patients required additional treatment with enoxaparin. Eight treatment-related adverse events were recorded in six (24%) of the 25 patients: five cases of menorrhagia including one classified as both menorrhagia and dysmenorrhoea, one case of dyspnoea, and one case of gingival bleeding. The only serious adverse reaction to rivaroxaban during the study was one case of menorrhagia in a patient with concomitant endometriosis, which resulted in study discontinuation. INTERPRETATION Rivaroxaban seems to effectively reduce pain in livedoid vasculopathy. Therefore we suggest that rivaroxaban with enoxaparin as a backup treatment is a suitable treatment option for patients with livedoid vasculopathy. FUNDING Deutsche Forschungsgemeinschaft and Bayer Vital.

Saccharomyces boulardii to Prevent Antibiotic-Associated Diarrhea: A Randomized, Double-Masked, Placebo-Controlled Trial

Antibiotic-associated diarrhea is an important clinical problem, associated with morbidity, mortality and healthcare costs. Our randomized, placebo controlled multicenter trial do not support the efficacy of Saccharomyces boulardii in the prevention of antibiotic-associated diarrhea.

Changes in Corneal Transparency After Cross-linking for Progressive Keratoconus: Long-term Follow-up.

PURPOSE To determine long-term changes in corneal transparency after riboflavin-ultraviolet A-induced corneal collagen cross-linking (CXL). METHODS Charts and anterior segment data of patients after CXL for progressive keratoconus were retrospectively reviewed. Patients were examined using the Scheimpflug-based Pentacam corneal densitometry module (Oculus Optikgeräte, Wetzlar, Germany) before CXL and at five postoperative follow-up visits: 1 to 3, 3 to 6, 6 to 12, 12 to 24, and 24 to 36 months. RESULTS Forty-two eyes of 28 patients (mean age: 27.9 ± 8.6 years) were included. Total corneal light backscatter was higher 1 to 3 months after CXL than before CXL (P < .001). There were significant differences, especially in the anterior (P < .001) and central (P < .001) layer at total diameter and posterior layer (P = .014) and the three central annuli at total corneal thickness (0 to 2 mm: P < .001; 2 to 6 mm: P < .001; 6 to 10 mm: P = .002). Total corneal light backscatter at total corneal thickness and total diameter faded over time following CXL. The backscatter was significantly lower 24 to 36 months after CXL than before CXL (P < .001). CONCLUSIONS Corneal densitometry peaks in the first months after CXL and returns to preoperative values approximately 1 year after CXL. Two years after CXL, corneal densitometry reaches values obtained for healthy, untreated corneas, thus achieving an improvement in corneal clarity over untreated keratoconic corneas.

Corneal Densitometry, Central Corneal Thickness, and Corneal Central-to-Peripheral Thickness Ratio in Patients With Fuchs Endothelial Dystrophy.

Purpose: The aim of the study was to quantify Scheimpflug corneal densitometry in patients with Fuchs endothelial dystrophy (FED). Methods: In this study, we retrospectively reviewed the charts and anterior segment data of 49 patients with FED before posterior lamellar keratoplasty and 51 healthy controls. The patients were examined using the Scheimpflug-based Oculus Pentacam. Central corneal thickness (CCT), ring-averaged (on a circle of 2, 2.4–10 mm diameter) noncentral corneal thickness, and densitometry data in different corneal layers and in different annuli were extracted and analyzed. Results: The total corneal light backscatter at total corneal thickness (CT) and at total diameter was significantly higher in the FED group when compared with the control group (FED group: 28.8 ± 6.7; control group: 24.3 ± 4.1; P < 0.001). When the corneal surface was divided into concentric annular zones at total CT, the differences were significant only in the 2 central annuli (P < 0.001). The total corneal light backscatter at total CT in the central 0–2 mm annulus correlated moderately with the central corneal thickness (Pearsons correlation = 0.55, P < 0.001). Conclusions: Corneal light backscatter in the central cornea was greater in patients with FED than in normal subjects. Corneal densitometry enables us to evaluate the optical quality of the cornea in different corneal layers and in different annuli. It is a useful, objective method that, in combination with central corneal thickness and corneal central-to-peripheral thickness ratio, can help to quantify FED severity.

Changes in Corneal Densitometry in Patients with Fuchs Endothelial Dystrophy after Endothelial Keratoplasty

ABSTRACT Purpose: The aim of the study was to quantify corneal densitometry in patients with Fuchs endothelial dystrophy (FED) after endothelial keratoplasty. Materials and methods: We retrospectively reviewed the charts and anterior segment data of patients with FED before and after endothelial keratoplasty. Patients were examined using the Scheimpflug-based Oculus Pentacam corneal densitometry module. Densitometry parameters in different corneal layers and in different annuli were extracted and analyzed. Results: 27 eyes of 27 patients after endothelial keratoplasty (11 DSAEK, 16 DMEK) were included. After endothelial keratoplasty the total corneal light backscatter at total corneal thickness in the central cornea (0–2 mm annulus) was significantly lower than before (DSAEK: p = 0.026, DMEK: p = 0.001). In the entire group the total corneal light backscatter at total corneal thickness and at total diameter before surgery correlated with the postoperative values (Pearson correlation = 0.49, p = 0.01). The strongest correlation was found in the central layer in the DMEK group (Pearson correlation = 0.79, p < 0.001). Conclusions: Corneal densitometry is a useful, objective method for quantification of the outcome of posterior lamellar keratoplasty irrespective of visual acuity. There is a significant correlation between preoperative and postoperative corneal light backscatter values after endothelial keratoplasty, especially in the case of the DMEK procedure.

Oxytocin in survivors of childhood-onset craniopharyngioma

Quality of survival of childhood-onset craniopharyngioma patients is frequently impaired by hypothalamic involvement or surgical lesions sequelae such as obesity and neuropsychological deficits. Oxytocin, a peptide hormone produced in the hypothalamus and secreted by posterior pituitary gland, plays a major role in regulation of behavior and body composition. In a cross-sectional study, oxytocin saliva concentrations were analyzed in 34 long-term craniopharyngioma survivors with and without hypothalamic involvement or treatment-related damage, recruited in the German Childhood Craniopharyngioma Registry, and in 73 healthy controls, attending the Craniopharyngioma Support Group Meeting 2014. Oxytocin was measured in saliva of craniopharyngioma patients and controls before and after standardized breakfast and associations with gender, body mass index, hypothalamic involvement, diabetes insipidus, and irradiation were analyzed. Patients with preoperative hypothalamic involvement showed similar oxytocin levels compared to patients without hypothalamic involvement and controls. However, patients with surgical hypothalamic lesions grade 1 (anterior hypothalamic area) presented with lower levels (p = 0.017) of oxytocin under fasting condition compared to patients with surgical lesion of posterior hypothalamic areas (grade 2) and patients without hypothalamic lesions (grade 0). Craniopharyngioma patients’ changes in oxytocin levels before and after breakfast correlated (p = 0.02) with their body mass index. Craniopharyngioma patients continue to secrete oxytocin, especially when anterior hypothalamic areas are not involved or damaged, but oxytocin shows less variation due to nutrition. Oxytocin supplementation should be explored as a therapeutic option in craniopharyngioma patients with hypothalamic obesity and/or behavioral pathologies due to lesions of specific anterior hypothalamic areas. Clinical trial number: KRANIOPHARYNGEOM 2000/2007(NCT00258453; NCT01272622).

Quality of life and growth after childhood craniopharyngioma: results of the multinational trial KRANIOPHARYNGEOM 2007

ContextQuality of life (QoL) after childhood-onset craniopharyngioma (CP) is frequently impaired due to tumor and/or treatment-related factors such as endocrine deficits and hypothalamic involvement/lesions.Patients and methodsIn a multinational trial, we prospectively analyzed parental and self-assessment of CP patient QoL at 3 months, 1 and 3 years after CP diagnosis related to growth hormone (GH) substitution. 47 of 194 CP recruited between 2007 and 2015 in KRANIOPHARYNGEOM 2007 were analyzed for QoL 1 and 3 years after CP diagnosis. QoL was assessed by Pediatric Quality of Life (PEDQOL) questionnaire and PEDQOL scores of parental and self-assessed QoL during 3 years follow-up after CP diagnosis were analyzed.ResultsParents estimated QoL of their children worse than patients did themselves. GH substitution had no relevant effect on short-term weight and height development. CP patients GH-treated at 3 years follow-up presented at baseline (1 year after diagnosis, before GH substitution) with reduced self-assessed QoL when compared with GH non-treated CP. QoL stabilized during 1–3 years of follow-up in GH-treated patients, whereas non GH-treated patients experienced decreases in autonomy (p = 0.03), cognition (p = 0.01), and physical function (p = 0.04).ConclusionsParents assess QoL in CP survivors worse than their children. GH substitution should be considered as a therapeutic option to ameliorate imminent impairments of QoL after CP.

GDF15 and Hepcidin as Prognostic Factors in Patients with Prostate Cancer

Background: Prostate Cancer (PCa) is a frequent malignancy worldwide. Prognosis of prostate cancer (PCa) is diverse with 80% not life-threatening even if untreated. In contrast, 20% are aggressive with short course of the disease. Hence the need for prognostic markers to predict aggressiveness, patients’ outcome, and efficacy of treatment is increasing. Methods: We retrospectively analyzed serum and demographic data from 38 PCa-patients. Serum growth differentiation factor 15 (GDF15), hepcidin and interleukin-6 (IL-6) were measured. Results: Serum GDF15 levels were higher in metastatic castration-resistant PCa patients with rapid disease progression than in metastatic PCa patients with slow disease progression. There was a trend to higher serum hepcidin - but not IL-6 - serum levels in patients with rapid disease progression than in slow disease progression. Prostate-specific antigen (PSA) correlated with serum GDF15 and hepcidin levels. Serum GDF15 levels correlated with serum hepcidin levels. The height of serum GDF15 and hepcidin levels correlated with survival of patients in months. Increase of 25 ng/ml serum hepcidin predicted an increase in mortality by 10%. Conclusion: In conclusion, the current manuscript supports the use of serum GDF15 and serum hepcidin measurements as prognostic markers in PCa.