Comparability of input parameters in the German Retina.net ROP registry and the EU-ROP registry - An exemplary comparison between 2011 and 2021.

PURPOSE: The German Retina.net ROP registry and its Europe-wide successor, the EU-ROP registry, collect data from patients treated for ROP. This analysis compares input parameters of these two registries to establish a procedure for joint analyses of different registry data using exemplary datasets from the two registries. METHODS: Exemplary datasets from the two databases over a 1-year period each (German Retina.net ROP Registry, 2011, 22 infants; EU-ROP Registry, 2021, 44 infants) were compared. The parameters documented in the two databases were aligned and analysed regarding demographic parameters, treatment modalities, complications within first 24 h and retreatments. RESULTS: The current analysis showed that data can be aligned for joint analyses with some adjustments within the data structure. The registry with more detailed data collection (EU-ROP) needs to be reduced regarding granularity in order to align the different registries, as the registry with lower granularity determines the level of analyses that can be performed in a comparative approach. In the exemplary datasets, we observed that the overall most common ROP severity in both registries was zone II, 3+ (2011: 70.5%; 2021: 65%), with decreasing numbers of clock hours showing preretinal neovascularisations (2011: 10-12 clock hours in 29% of cases, 2021: 4-6 clock hours in 38%). The most prevalent treatment method was laser coagulation in 2011 (75%) and anti-VEGF therapy in 2021 (86.1%). Within the anti-VEGF group, all patients were treated with bevacizumab in 2011 and with ranibizumab in 2021. Retreatment rates were comparable in 2011 and 2021. CONCLUSION: Data from two different ROP registries can be aligned and jointly analysed. The analysis reveals a paradigm shift in treatment modalities, from predominantly laser to anti-VEGF, and within the anti-VEGF group from bevacizumab to ranibizumab in Germany. In addition, there was a trend towards earlier treatment in 2021.

Necrotizing enterocolitis after intravitreal bevacizumab in an infant with Incontinentia Pigmenti - a case report.

BACKGROUND: Incontinentia Pigmenti is a rare disease affecting multiple organs. Fifty of patients show affection of the eye with retinopathy and possible amaurosis being the worst outcome. Treatment has commonly been panretinal laser coagulation but intravitreal application of bevacizumab as VEGF-inhibitor has shown to effectively suppress retinal neovascularization. CASE PRESENTATION: A six-week-old female infant with Incontinentia Pigmenti developed a foudroyant necrotizing enterocolitis shortly after intravitreal injection of bevazicumab due to a retinopathy with impending tractional detachment of the left eye. Since the onset of abdominal symptoms occurred immediately after the intravitreal application, a link between the two events seemed likely. Sequential analyses of the VEGF serum concentrations showed a massive suppression of endogenous VEGF with only a very slow recovery over weeks. Such a severe systemic adverse event has not been reported after intravitreal treatment with bevacizumab in an infant. CONCLUSION: This case report shows a relevant systemic uptake of bevacizumab after intravitreal application as suppressed VEGF levels show. There seems to be a connection between suppressed VEGF levels and the onset of necrotizing enterocolitis. Therefore, treatment with bevacizumab should be carefully considered and further research is needed to assess this drug's safety profile.

[Treated cases of retinopathy of prematurity in Germany : 5-year data from the Retina.net ROP registry]. / Behandelte Frühgeborenenretinopathie in Deutschland : 5-Jahres-Daten des Retina.net ROP-Registers.

BACKGROUND: Retinopathy of prematurity (ROP) is one of the main reasons for childhood blindness. The number of infants requiring treatment, however, is low for individual centers. The Retina.net ROP registry has been founded to allow a joint analysis of treatment patterns and courses post treatment. OBJECTIVE: This paper reports treatment patterns over 5 years. MATERIAL AND METHODS: All infants born between January 2011 and December 2015 who were entered into the treatment registry by one of the 12 participating centers were analyzed. RESULTS: The data of 150 infants (292 eyes) were analyzed and ROP 3+ in zone II was the most prevalent treatment indication. Gestational age and birth weight remained stable over the years. The treatment patterns, however, changed with anti-VEGF treatment (bevacizumab or ranibizumab) accounting for only 10% of treated eyes in 2011 but for 56% and 30% in 2014 and 2015, respectively. Almost all eyes with AP-ROP or zone I disease received anti-VEGF treatment. Zone II disease was predominantly treated with laser photocoagulation. Recurrences were more common and appeared later in the anti-VEGF group compared to the laser group (23%/interval 60 days vs. 17%/interval 23 days). Perioperative complications were evenly distributed across treatment groups. CONCLUSION: The data in this analysis represent about 10-15% of treated infants in Germany. The results provide evidence for an increasing use of anti-VEGF agents for ROP. The data reflect a selection bias for anti-VEGF treatment in eyes with a more aggressive disease. This needs to be considered when interpreting data such as disease recurrence rates. The risk for late recurrences after anti-VEGF treatment is of particular clinical significance.

Fibroblast activation protein-α, a stromal cell surface protease, shapes key features of cancer associated fibroblasts through proteome and degradome alterations.

Cancer associated fibroblasts (CAFs) constitute an abundant stromal component of most solid tumors. Fibroblast activation protein (FAP) α is a cell surface protease that is expressed by CAFs. We corroborate this expression profile by immunohistochemical analysis of colorectal cancer specimens. To better understand the tumor-contextual role of FAPα, we investigate how FAPα shapes functional and proteomic features of CAFs using loss- and gain-of function cellular model systems. FAPα activity has a strong impact on the secreted CAF proteome ("secretome"), including reduced levels of anti-angiogenic factors, elevated levels of transforming growth factor (TGF) ß, and an impact on matrix processing enzymes. Functionally, FAPα mildly induces sprout formation by human umbilical vein endothelial cells. Moreover, loss of FAPα leads to a more epithelial cellular phenotype and this effect was rescued by exogenous application of TGFß. In collagen contraction assays, FAPα induced a more contractile cellular phenotype. To characterize the proteolytic profile of FAPα, we investigated its specificity with proteome-derived peptide libraries and corroborated its preference for cleavage carboxy-terminal to proline residues. By "terminal amine labeling of substrates" (TAILS) we explored FAPα-dependent cleavage events. Although FAPα acts predominantly as an amino-dipeptidase, putative FAPα cleavage sites in collagens are present throughout the entire protein length. In contrast, putative FAPα cleavage sites in non-collagenous proteins cluster at the amino-terminus. The degradomic study highlights cell-contextual proteolysis by FAPα with distinct positional profiles. Generally, our findings link FAPα to key aspects of CAF biology and attribute an important role in tumor-stroma interaction to FAPα.

NF-κB-dependent DNA damage-signaling differentially regulates DNA double-strand break repair mechanisms in immature and mature human hematopoietic cells.

Hematopoietic stem and progenitor cells (HSPC), that is, the cell population giving rise not only to all mature hematopoietic lineages but also the presumed target for leukemic transformation, can transmit (adverse) genetic events, such as are acquired from chemotherapy or ionizing radiation. Data on the repair of DNA double-strand-breaks (DSB) and its accuracy in HSPC are scarce, in part contradictory, and mostly obtained in murine models. We explored the activity, quality and molecular components of DSB repair in human HSPC as compared with mature peripheral blood lymphocytes (PBL). To consider chemotherapy/radiation-induced compensatory proliferation, we established cycling HSPC cultures. Comparison of pathway-specific repair activities using reporter systems revealed that HSPC were severely compromised in non-homologous end joining and homologous recombination but not microhomology-mediated end joining. We observed a more pronounced radiation-induced accumulation of nuclear 53BP1 in HSPC relative to PBL, despite evidence for comparable DSB formation from cytogenetic analysis and γH2AX signal quantification, supporting differential pathway usage. Functional screening excluded a major influence of phosphatidylinositol-3-OH-kinase (ATM/ATR/DNA-PK)- and p53-signaling as well as chromatin remodeling. We identified diminished NF-κB signaling as the molecular component underlying the observed differences between HSPC and PBL, limiting the expression of DSB repair genes and bearing the risk of an inaccurate repair.

[VEGF inhibitors in vitreoretinal interventions]. / VEGF-Inhibitoren im Rahmen vitreoretinaler Eingriffe.

Vascular endothelial growth factor (VEGF) inhibitors are being used for an increasing number of indications. Beyond the classical use in exudative macular degeneration and macular edema, they are being used, for example off-label as additive treatment together with panretinal laser photocoagulation or in preparation for vitrectomy for ischemic retinopathy. In preparation for vitreoretinal surgery VEGF inhibitors are usually given prior to surgery. When given as an adjunct to laser treatment, VEGF inhibitors can be given either consecutively or parallel to laser photocoagulation. In most cases, however, anti-VEGF treatment does not render laser coagulation dispensable. The greatest danger with anti-VEGF treatment in the context of ischemic retinopathies lies in the fact that proliferative membranes are misjudged or overlooked. In these cases, anti-VEGF treatment can induce contraction of these membranes with induction of consecutive tractional retinal detachment. This review summarizes the current knowledge on VEGF inhibition as an adjunct to vitreoretinal surgery and also points out the gaps in the current knowledge and the need for further research.

Cathepsin proteases promote angiogenic sprouting and laser-induced choroidal neovascularisation in mice.

Cysteine cathepsins are a family of proteases involved in intracellular protein turnover and extracellular matrix degradation. Cathepsin B (Ctsb) and cathepsin Z (Ctsz) promote tumorigenesis and Ctsb is a known modulator of tumor angiogenesis. We therefore investigated the angiomodulatory function of these cathepsins in vitro as well as in a mouse model of laser-induced choroidal neovascularization (laser-CNV). Ctsb(-/-), Ctsz(-/-), Ctsb/Ctsz double-knockout (Ctsb/z DKO), and wild type (WT) mice underwent argon laser treatment to induce choroidal neovascularization (CNV). The neovascularized area was quantified individually for each lesion at 14 days after laser coagulation. In vitro the effects of cathepsin inhibitors on angiogenesis were analysed by endothelial cell (EC) spheroid sprouting and EC invadosome assays. Retinas from cathepsin KO mice did not show gross morphological abnormalities. In the laser CNV model, however, Ctsb/z DKO mice displayed a significantly reduced neovascularized area compared to WT (0.027 mm(2) vs. 0.052 mm(2); p = 0.012), while single knockouts did not differ significantly from WT. In line, VEGF-induced EC spheroid sprouting and invadosome formation were not significantly altered by a specific cathepsin B inhibitor alone, but significantly suppressed when more than one cathepsin was inhibited. Our results demonstrate that laser-CNV formation is significantly reduced in Ctsb/z DKO mice. In line, EC sprouting and invadosome formation are blunted when more than one cathepsin is inhibited in vitro. These results reveal an angiomodulatory potential of cathepsins with partial functional redundancies between different cathepsin family members.

[Pathogenesis of retinopathy of prematurity]. / Pathogenese der Frühgeborenenretinopathie.

Retinopathy of prematurity (ROP) is a complex disease with a multifactorial pathogenetic cascade that is still only partially understood. Important pathogenetic factors are gestational age at birth and birth weight. Potent postnatal factors are exposure to supplemental oxygen, slow weight gain and expression of angiogenic growth factors. Some of these crucial aspects of ROP pathogenesis will be discussed in this article and put into clinical context. With the introduction of intravitreal anti-VEGF (vascular endothelial growth factor) treatment into ROP therapy, the pathomechanistic role of VEGF in ROP deserves a special focus. Apart from VEGF, other factors will be discussed that may precede VEGF upregulation and thus may represent targets for an earlier and potentially protective intervention. Among these insulin-like growth factor 1 (IGF-1) appears to be most prominent. Finally, factors such as postnatal weight gain will be discussed in light of their potential role as screening parameters and their ability to predict ROP severity.

[Retinopathy of prematurity - pathophysiologic mechanisms and new treatment options]. / Frühgeborenenretinopathie - Pathophysiologische Grundlagen und aktuelle Behandlungsoptionen.

Retinopathy of prematurity (ROP), like other angioproliferative retinal disorders, has witnessed the advent of anti-VEGF therapy in clinical practice. The first report from the BEAT-ROP study published in 2011 represents the first comparison of anti-VEGF therapy versus conventional laser treatment in a randomised controlled trial. This review article investigates these novel aspects of ROP therapy from a pathophysiological angle and delineates the stages of ROP in which anti-VEGF treatment appears as a reasonable option. Furthermore, the novel chances of anti-VEGF therapy are being weighed against some still unanswered questions and novel study concepts are being presented.

An international opinion research survey of the etiology, diagnosis, therapy and outcome of Kienböck's disease (KD).

OBJECTIVES: Every fourth publication on Kienböck's disease (KD) is based for the most part on rather divergent expert opinion. We therefore surveyed expert opinion on KD in three European countries: (1) for the suspected aetiologies; (2) routinely used diagnostic tools; (3) recommended treatment and (4) expected outcome. METHODS: A questionnaire consisting of 16 questions was handed out at the national meetings for surgery of the hand in Germany (DE), France (FR) in 2009 and in the United Kingdom (UK) in 2010. RESULTS: Among the 126 surgeons who participated in the survey, 82 had a national diploma for surgery of the hand. None of the most commonly discussed etiopathological hypotheses were estimated as being very likely. Hand/arm vibration exposure was considered less likely among respondents in France and the UK than among respondents in Germany. Treatment recommendations are very heterogeneous for stage IIIB according to Lichtman. CONCLUSIONS: Expert opinions on diagnostic criteria, the pathogenesis and the choice of treatment are not consistent and may vary from one country to another.

[Pharmacological treatment for retinopathy of prematurity]. / Pharmakologische Therapie der Frühgeborenenretinopathie.

Mandatory screening performed by an experience ophthalmologist remains the most important pillar in the management of retinopathy of prematurity (ROP). The current gold standard for treatment of proliferative ROP is still panretinal laser photocoagulation, depending on severity, in combination with vitreoretinal surgery if necessary. The first case series of off-label intravitreal anti-VEGF treatment are encouraging. In addition to intravitreal anti-VEGF therapy, other treatment concepts such as supplementation with IGF-1 or omega-3 fatty acids also represent interesting pharmacological approaches to the management of ROP. However, larger controlled trials are required to validate the benefits and safety of these systemic treatment approaches.

Diagnostic accuracy of fused positron emission tomography/magnetic resonance mammography: initial results.

OBJECTIVES: The aim of this study was to evaluate the diagnostic accuracy of fused fluoro-deoxy-D-glucose positron emission tomography/magnetic resonance mammography (FDG-PET/MRM) in breast cancer patients and to compare FDG-PET/MRM with MRM. METHODS: 27 breast cancer patients (mean age 58.9±9.9 years) underwent MRM and prone FDG-PET. Images were fused software-based to FDG-PET/MRM images. Histopathology served as the reference standard to define the following parameters for both MRM and FDG-PET/MRM: sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy for the detection of breast cancer lesions. Furthermore, the number of patients with correctly determined lesion focality was assessed. Differences between both modalities were assessed by McNemars test (p<0.05). The number of patients in whom FDG-PET/MRM would have changed the surgical approach was determined. RESULTS: 58 breast lesions were evaluated. The sensitivity, specificity, PPV, NPV and accuracy were 93%, 60%, 87%, 75% and 85% for MRM, respectively. For FDG-PET/MRM they were 88%, 73%, 90%, 69% and 92%, respectively. FDG-PET/MRM was as accurate for lesion detection (p = 1) and determination of the lesions' focality (p = 0.7722) as MRM. In only 1 patient FDG-PET/MRM would have changed the surgical treatment. CONCLUSION: FDG-PET/MRM is as accurate as MRM for the evaluation of local breast cancer. FDG-PET/MRM defines the tumours' focality as accurately as MRM and may have an impact on the surgical treatment in only a small portion of patients. Based on these results, FDG-PET/MRM cannot be recommended as an adjunct or alternative to MRM.

[Intravitreal drug therapy for retinal vein occlusion--pathophysiological mechanisms and routinely used drugs]. / Intravitreale Medikamenteneingabe bei retinalem Venenverschluss--pathophysiologische Mechanismen und angewandte Substanzen.

The novel therapeutic principle of intravitreal drug therapy for retinal vein occlusion has become an integrated constituent of clinical practice over the last years. The two substance classes that have been evaluated in large randomised clinical trials so far are corticosteroids and inhibitors of vascular endothelial growth factor (VEGF). The reported treatment success of these intravitreally administered substances has lead not only to a paradigm shift in clinical care but has also advanced our understanding of the underlying pathophysiological principles of retinal vein occlusions. In this review the different substances are discussed, their mechanisms of action are analysed and the results of the large clinical trials available to date are critically evaluated. Furthermore, an approach to integrate these novel treatment options into the existing treatment regimes for retinal vein occlusions is suggested.

Computer-aided quantification of retinal neovascularization.

Rodent models of retinal angiogenesis play a pivotal role in angiogenesis research. These models are a window to developmental angiogenesis, to pathological retinopathy, and are also in vivo tools for anti-angiogenic drug screening in cancer and ophthalmic research. The mouse model of oxygen-induced retinopathy (OIR) has emerged as one of the leading in vivo models for these purposes. Many of the animal studies that laid the foundation for the recent breakthrough of anti-angiogenic treatments into clinical practice were performed in the OIR model. However, readouts from the OIR model have been time-consuming and can vary depending on user experience. Here, we present a computer-aided quantification method that is characterized by (i) significantly improved efficiency, (ii) high correlation with the established hand-measurement protocols, and (iii) high intra- and inter-individual reproducibility of results. This method greatly facilitates quantification of retinal angiogenesis while at the same time increasing lab-to-lab reproducibility of one of the most widely used in vivo models in angiogenesis research.

[Evaluation of an internet-based e-learning ophthalmology module for medical students]. / Evaluation eines internetbasierten E-Learnings für den Studentenunterricht im Fach Augenheilkunde.

BACKGROUND: In 2006, the University Eye Hospital Freiburg (Germany) introduced an Internet-based e-learning module as part of the ophthalmology training for medical students. METHODS: In the e-learning module, the students encounter the same cases as discussed during lectures and seminars. The case presentation is based on an interactive question-and-answer game. Content, format, usability, and effectiveness of the e-learning module were evaluated by the students over two terms. RESULTS: Of 307 students, 272 used the e-learning module. On average, 94% of the content was processed per student. More than 75% stated that they had fun working with the e-learning module. Students with frequent e-learning use tended to achieve higher marks in their final ophthalmology exams. CONCLUSION: E-learning represents a sensible addendum to the established ophthalmology training for medical students. It is comparably easy to integrate into the curriculum and is well accepted by medical students.

Rapamycin reduces VEGF expression in retinal pigment epithelium (RPE) and inhibits RPE-induced sprouting angiogenesis in vitro.

Anti-VEGF treatment has become accepted first-line treatment for choroidal neovascularisation (CNV) in age-related macular degeneration. However, VEGF-inhibition does not always lead to sustained CNV-reduction. In this study, the effect of rapamycin was superior to VEGF-inhibition in a co-culture assay of endothelial cells (ECs) and retinal pigment epithelium (RPE). Rapamycin reduced EC sprouting in groups that did not respond to anti-VEGF treatment. Rapamycin did not induce EC apoptosis, but reduced both VEGF-production in RPE and the responsiveness of ECs to stimulation. Rapamycin might therefore be a therapeutic option for CNV patients that do not respond sufficiently to the established anti-VEGF treatments.

Renal accumulation of [111In]DOTATOC in rats: influence of inhibitors of the organic ion transport and diuretics.

AIM: Radiation exposure to the kidney limits therapy with radiometal labelled DOTATOC. This study evaluates the organic anion and cation transport (inhibitors: probenecid and cimetidine/dexamethasone) as well as diuresis (furosemide and mannitol) regarding renal uptake of [(111)In]DOTATOC. METHODS: One hundred eight male Fisher rats were injected with [(111)In]DOTATOC via the tail vein. Prior to activity injection a total of 84 rats underwent injection with probenecid vs. sodium chloride 0.9% (48 rats), cimetidine vs. dexamethasone vs. sodium chloride 0.9% (18 rats), and furosemide vs. mannitol vs. sodium chloride 0.9% (18 rats). Rats were sacrificed at predetermined time points up to 48 h after activity injection. Kidneys, adrenal glands, pancreas, spleen, blood, liver, and muscle were harvested and injected activity per gram tissue was determined. Autoradiographic images of the kidneys were acquired in a total of 24 rats. RESULTS: Probenecid led to a reduction in renal uptake by up to 30% while not significantly changing the activity accumulation in the other organs investigated. This reduction was attributable to the renal cortex (ratio cortex/medulla 1.72 vs. 1.99; p = 0.006). Cimetidine and dexamethasone had no effect in any of the organs. Furosemide led to a 44% increase in renal activity accumulation attributable to enhanced renal medullary uptake (ratio cortex/medulla 1.44 versus 1.69; p = 0.006). Mannitol had no effect on renal activity uptake. CONCLUSION: Inhibition of the organic anion transport by probenecid may help reduce renal uptake regarding therapy with radiometal labelled DOTATOC. The enhancing effect of furosemide may be unfavourable for therapy. The results must be confirmed by human studies.

[Nuclear medical diagnostics for liver tumors]. / Nuklearmedizinische Diagnostik von Lebertumoren.

Standard nuclear medical procedures, such as functional, blood-pool and colloid scintigraphy, play a minor role in the routine workup of liver tumors. However, these techniques are capable of assessing specific organ functions and frequently allow the diagnosis of unclear liver lesions. The sensitivity of scintigraphic procedures can be increased using tomographic imaging (SPECT), the specificity with the introduction of hybrid scanners such as SPECT/CT. Whole body positron emission tomography with 18F-fluoro-deoxy-glucose (FDG) in combination with CT scanning (PET/CT) represents one of the most sensitive imaging modalities for the detection of hepatic metastases and extrahepatic tumor manifestations. For the staging and follow-up of colorectal cancer, FDG-PET/CT represents a standard imaging modality. Metastases from neuroendocrine tumors can be detected using PET and specific tracers such as [68Ga]DOTATOC and [18F]DOPA. Molecular imaging with PET allows the quantification of metabolic processes which can be used for the assessment of an early response to treatment.