Integration of radiation oncology teaching in medical studies by German medical faculties due to the new licensing regulations : An overview and recommendations of the consortium academic radiation oncology of the German Society for Radiation Oncology (DEGRO).

The new Medical Licensing Regulations 2025 (Ärztliche Approbationsordnung, ÄApprO) will soon be passed by the Federal Council (Bundesrat) and will be implemented step by step by the individual faculties in the coming months. The further development of medical studies essentially involves an orientation from fact-based to competence-based learning and focuses on practical, longitudinal and interdisciplinary training. Radiation oncology and radiation therapy are important components of therapeutic oncology and are of great importance for public health, both clinically and epidemiologically, and therefore should be given appropriate attention in medical education. This report is based on a recent survey on the current state of radiation therapy teaching at university hospitals in Germany as well as the contents of the National Competence Based Learning Objectives Catalogue for Medicine 2.0 (Nationaler Kompetenzbasierter Lernzielkatalog Medizin 2.0, NKLM) and the closely related Subject Catalogue (Gegenstandskatalog, GK) of the Institute for Medical and Pharmaceutical Examination Questions (Institut für Medizinische und Pharmazeutische Prüfungsfragen, IMPP). The current recommendations of the German Society for Radiation Oncology (Deutsche Gesellschaft für Radioonkologie, DEGRO) regarding topics, scope and rationale for the establishment of radiation oncology teaching at the respective faculties are also included.

Thrombomodulin-dependent protein C activation is required for mitochondrial function and myelination in the central nervous system.

Essentials The role of protein C (PC) activation in experimental autoimmune encephalitis (EAE) is unknown. PC activation is required for mitochondrial function in the central nervous system. Impaired PC activation aggravates EAE, which can be compensated for by soluble thrombomodulin. Protection of myelin by activated PC or solulin is partially independent of immune-modulation. SUMMARY: Background Studies with human samples and in rodents established a function of coagulation proteases in neuro-inflammatory demyelinating diseases (e.g. in multiple sclerosis [MS] and experimental autoimmune encephalitis [EAE]). Surprisingly, approaches to increase activated protein C (aPC) plasma levels as well as antibody-mediated inhibition of PC/aPC ameliorated EAE in mice. Hence, the role of aPC generation in demyelinating diseases and potential mechanisms involved remain controversial. Furthermore, it is not known whether loss of aPC has pathological consequences at baseline (e.g. in the absence of disease). Objective To explore the role of thrombomodulin (TM)-dependent aPC generation at baseline and in immunological and non-immunological demyelinating disease models. Methods Myelination and reactive oxygen species (ROS) generation were evaluated in mice with genetically reduced TM-mediated protein C activation (TMPro/Pro ) and in wild-type (WT) mice under control conditions or following induction of EAE. Non-immunological demyelination was analyzed in the cuprizone-diet model. Results Impaired TM-dependent aPC generation already disturbs myelination and mitochondrial function at baseline. This basal phenotype is linked with increased mitochondrial ROS and aggravates EAE. Reducing mitochondrial ROS (p66Shc deficiency), restoring aPC plasma levels or injecting soluble TM (solulin) ameliorates EAE in TMPro/Pro mice. Soluble TM additionally conveyed protection in WT-EAE mice. Furthermore, soluble TM dampened demyelination in the cuprizone-diet model, demonstrating that its myelin-protective effect is partially independent of an immune-driven process. Conclusion These results uncover a novel physiological function of TM-dependent aPC generation within the CNS. Loss of TM-dependent aPC generation causes a neurological defect in healthy mice and aggravates EAE, which can be therapeutically corrected.

[Structure of pain management facilities in Germany : Classification of medical and psychological pain treatment services-Consensus of the Joint Commission of the Professional Societies and Organizations for Quality in Pain Medicine]. / Struktur der schmerzmedizinischen Versorgung in Deutschland : Klassifikation schmerzmedizinischer Einrichtungen - Konsens der Gemeinsamen Kommission der Fachgesellschaften und Verbände für Qualität in der Schmerzmedizin.

On behalf of the Medical/Psychological Pain Associations, Pain Patients Alliance and the Professional Association of Pain Physicians and Psychologists, the Joint Commission of Professional Societies and Organizations for Quality in Pain Medicine, working in close collaboration with the respective presidents, has developed verifiable structural and process-related criteria for the classification of medical and psychological pain treatment facilities in Germany. Based on the established system of graded care in Germany and on existing qualifications, these criteria also argue for the introduction of a basic qualification in pain medicine. In addition to the first-ever comprehensive description of psychological pain facilities, the criteria presented can be used to classify five different levels of pain facilities, from basic pain management facilities, to specialized institutions, to the Centre for Interdisciplinary Pain Medicine. The recommendations offer binding and verifiable criteria for quality assurance in pain medicine and improved pain treatment.

Short-term uvb-irradiation leads to putative limbal stem cell damage and niche cell-mediated upregulation of macrophage recruiting cytokines.

Ultraviolet light B (UVB)-irradiation is linked to various ocular pathologies such as limbal stem cell defects in pterygium. Despite the large circumstantial evidence linking UVB irradiation and limbal epithelial stem cell damage, the precise molecular responses of limbal stem cells to UVB irradiation are unclear. Here the effect of UVB irradiation on the putative stem cell phenotype, limbal niche cells and the subsequent effects on corneal (lymph)angiogenic privilege were investigated. Primary human limbal epithelial stem cells and fibroblasts were irradiated with 0.02 J/cm(2) of UVB, a low dose corresponding to 3 min of solar irradiation. UVB irradiation caused significant reduction of limbal epithelial and limbal fibroblast proliferation for 24 h, but apoptosis of limbal epithelial stem cells only. Moreover, UVB induced stem-like character loss of limbal epithelial cells, as their colony forming efficiency and putative stem cell marker expression significantly decreased. Interestingly, limbal epithelial cells co-cultured with UVB-irradiated limbal fibroblasts also exhibited loss of stem cell character and decrease of colony forming efficiency. Conditioned media from limbal epithelial cells inhibited lymphatic endothelial cell proliferation and tube network complexity; however this effect diminished following UVB irradiation. In contrast, pro-inflammatory and macrophage-recruiting cytokines such as TNFα, IFNγ and MCP1 were significantly upregulated following cell irradiation of limbal fibroblasts. These data demonstrate the key role of the limbal stem cell niche in response to UVB and subsequent (lymph)angiogenic and inflammatory events. These data suggest that the known pro(lymph)angiogenic effect of UVB irradiation in pterygium is not linked to a direct up-regulation of pro-angiogenic cytokines, but rather to indirect macrophage-recruiting cytokines being upregulated after UVB irradiation.

PDGFRß(+) cells in human and experimental neuro-vascular dysplasia and seizures.

INTRODUCTION: Neuro-vascular rearrangement occurs in brain disorders, including epilepsy. Platelet-derived growth factor receptor beta (PDGFRß) is used as a marker of perivascular pericytes. Whether PDGFRß(+) cell reorganization occurs in regions of neuro-vascular dysplasia associated with seizures is unknown. METHODS: We used brain specimens derived from epileptic subjects affected by intractable seizures associated with focal cortical dysplasia (FCD) or temporal lobe epilepsy with hippocampal sclerosis (TLE-HS). Tissues from cryptogenic epilepsy, non-sclerotic hippocampi or peritumoral were used for comparison. An in vivo rat model of neuro-vascular dysplasia was obtained by pre-natal exposure to methyl-axozy methanoic acid (MAM). Status epilepticus (SE) was induced in adult MAM rats by intraperitoneal pilocarpine. MAM tissues were also used to establish organotypic hippocampal cultures (OHC) to further assess pericytes positioning at the dysplastic microvasculature. PDGFRß and its colocalization with RECA-1 or CD34 were used to segregate perivascular pericytes. PDGFRß and NG2 or IBA1 colocalization were performed. Rat cortices and hippocampi were used for PDGFRß western blot analysis. RESULTS: Human FCD displayed the highest perivascular PDGFRß immunoreactivity, indicating pericytes, and presence of ramified PDGFRß(+) cells in the parenchyma and proximal to microvessels. Tissues deriving from human cryptogenic epilepsy displayed a similar pattern of immunoreactivity, although to a lesser extent compared to FCD. In TLE-HS, CD34 vascular proliferation was paralleled by increased perivascular PDGFRß(+) pericytes, as compared to non-HS. Parenchymal PDGFRß immunoreactivity co-localized with NG2 but was distinct from IBA1(+) microglia. In MAM rats, we found pericyte-vascular changes in regions characterized by neuronal heterotopias. PDGFRß immunoreactivity was differentially distributed in the heterotopic and adjacent normal CA1 region. The use of MAM OHC revealed microvascular-pericyte dysplasia at the capillary tree lining the dentate gyrus (DG) molecular layer as compared to control OHC. Severe SE induced PDGFRß(+) immunoreactivity mostly in the CA1 region of MAM rats. CONCLUSION: Our descriptive study points to microvascular-pericyte changes in the epileptic pathology. The possible link between PDGFRß(+) cells, neuro-vascular dysplasia and remodeling during seizures is discussed.

Meibography and meibomian gland measurements in ocular graft-versus-host disease.

Meibomian gland loss in ocular GvHD was described as a mechanism contributing to dry eye and severe damage to the ocular surface. Infrared images of upper eyelid meibomian glands from 86 ocular GvHD patients, from 10 patients after allogeneic stem cell transplantation (aSCT) without ocular GvHD, from 32 patients prior to aSCT and from 30 healthy controls were analyzed retrospectively and evaluated using two grading schemes. The upper meibomian gland area (uMGA) was calculated and set in relation to the total tarsal area of the lid. Results demonstrate that meibomian gland loss is significantly increased in patients with ocular GvHD as well as in patients prior to aSCT in comparison with controls (P between 0.05 and <0.001). Patients after aSCT without ocular GvHD had no significant difference in uMGA in comparison with controls. This study suggests that meibomian gland loss in GvHD patients is likely to be a multifactorial process that also occurs prior to aSCT, possibly due to underlying diseases and/or secondary to chemotherapy or irradiation. In addition, the question has to be addressed whether meibomian gland loss could serve as a predictor for the development of ocular GvHD. Overall, infrared meibography should be included in routine examination of patients undergoing aSCT and during follow-up.

[Recommendations of the updated LONTS guidelines. Long-term opioid therapy for chronic noncancer pain]. / Empfehlungen der aktualisierten Leitlinie LONTS. Langzeitanwendung von Opioiden bei chronischen nicht-tumorbedingten Schmerzen.

BACKGROUND: The regular update of the German S3 guidelines on long-term opioid therapy for chronic noncancer pain (CNCP), the"LONTS" (AWMF registration number 145/003), began in November 2013. METHODS: The guidelines were developed by 26 scientific societies and two patient self-help organisations under the coordination of the Deutsche Schmerzgesellschaft (German Pain Society). A systematic literature search in the Cochrane Central Register of Controlled Trials (CENTRAL), Medline and Scopus databases (up until October 2013) was performed. Levels of evidence were assigned according to the classification system of the Oxford Centre for Evidence-Based Medicine. The strength of the recommendations was established by multistep formal procedures, in order to reach a consensus according to German Association of the Medical Scientific Societies ("Arbeitsgemeinschaft der Wissenschaftlich Medizinischen Fachgesellschaften", AWMF) regulations. The guidelines were reviewed by the Drug Commission of the German Medical Association, the Austrian Pain Society and the Swiss Association for the Study of Pain. RESULTS: Opioids are one drug-based treatment option for short- (4-12 weeks), intermediate- (13-25 weeks) and long-term (≥ 26 weeks) therapy of chronic osteoarthritis, diabetic polyneuropathy, postherpetic neuralgia and low back pain. Contraindications are primary headaches, as well as functional somatic syndromes and mental disorders with the (cardinal) symptom pain. For all other clinical presentations, a short- and long-term therapy with opioid-containing analgesics should be evaluated on an individual basis. Long-term therapy with opioid-containing analgesics is associated with relevant risks (sexual disorders, increased mortality). CONCLUSION: Responsible application of opioid-containing analgesics requires consideration of possible indications and contraindications, as well as regular assessment of efficacy and adverse effects. Neither an uncritical increase in opioid application, nor the global rejection of opioid-containing analgesics is justified in patients with CNCP.

[Decellularized collagen matrix from tilapia fish scales for corneal reconstruction (BioCornea)]. / Dezellularisierte Kollagenmatrix aus der Schuppe des Tilapia-Fisches als Hornhautersatz ("BioCornea").

BACKGROUND: The worldwide need for donor corneal tissue clearly exceeds the availability of transplantable human tissue; therefore, recent efforts aim to identify and characterize alternative tissues, such as decellularized collagen scaffolds. OBJECTIVES: The transparent fish scales of tilapia (Oreochromis mossambicus) were analyzed as a potential alternative for corneal reconstruction ("BioCornea"). MATERIAL AND METHODS: The article gives a review of the literature and own preliminary results. After decellularization the tissue characteristics of the fish scales, the repopulation with corneal epithelium and stromal cells, immunogenicity, the feasibility of corneal transplantation and the angiogenic properties were analyzed in vitro and in various animal models. RESULTS: The fish scales mainly consist of collagen type I and show an architecture that is similar to the human cornea. Corneal epithelium and stromal cells are able to grow over and into the scaffold. It is possible to transplant fish scales in various animal models without severe inflammatory responses. Furthermore, in mice, less blood and lymphatic vessels grow into the xenograft when compared to conventional allogenic transplants. CONCLUSION: Preliminary results with decellularized tilapia fish scales as an alternative for corneal reconstruction ("BioCornea") are promising.

Death of p53-defective cells triggered by forced mitotic entry in the presence of DNA damage is not uniquely dependent on Caspase-2 or the PIDDosome.

Much effort has been put in the discovery of ways to selectively kill p53-deficient tumor cells and targeting cell cycle checkpoint pathways has revealed promising candidates. Studies in zebrafish and human cell lines suggested that the DNA damage response kinase, checkpoint kinase 1 (Chk1), not only regulates onset of mitosis but also cell death in response to DNA damage in the absence of p53. This effect reportedly relies on ataxia telangiectasia mutated (ATM)-dependent and PIDDosome-mediated activation of Caspase-2. However, we show that genetic ablation of PIDDosome components in mice does not affect cell death in response to γ-irradiation. Furthermore, Chk1 inhibition largely failed to sensitize normal and malignant cells from p53(-/-) mice toward DNA damaging agents, and p53 status did not affect the death-inducing activity of DNA damage after Chk1 inhibition in human cancer cells. These observations argue against cross-species conservation of a Chk1-controlled cell survival pathway demanding further investigation of the molecular machinery responsible for cell death elicited by forced mitotic entry in the presence of DNA damage in different cell types and model organisms.

Two-step retrograde closed stenting: a novel method for treating canalicular lacerations in Chinese patients.

PURPOSE: To evaluate the efficacy of two-step retrograde closed stenting for treating canalicular laceration. methods: Forty-eight consecutive canalicular laceration cases (48 eyes) were randomised and divided into two groups: a one-step group and a two-step group. In the two-step group (23 cases), the first step was performed in the outpatient department and included identifying the medial cut end of the canaliculus and probing under a slit-lamp microscope, followed by a retrograde canalicular stenting assisted by a memory titanium stylet. The second step was canalicular anastomosis, which was performed in the operating room. In the one-step group (25 cases), all of the surgical procedures were performed when preoperative preparations were simultaneously available. RESULTS: The time elapsed from the doctor visit to the treatment was 4.3 ± 2.4 h in the two-step group and 18.8 ± 6.3 h in the one-step group (P<0.01). The canalicular medial cut ends were found in all cases, but 8.6 ± 3.5 min was needed in the two-step group, and 51.4 ± 24.2 min was needed in the one-step group (P<0.01). The numerical rating scale for pain during surgery was 1.8 ± 1.2 in the two-step group and 5.4 ± 2.2 in the one-step group (P<0.01). One case (2.63%) in the two-step group and nine cases (36%) in the one-step group required other assisted methods to locate the medial cut end (P=0.007). Twenty-one cases (91.3%) in the two-step group and 20 cases (80%) in the one-step group achieved patent lacrimal drainage systems during a 12-month follow-up (P=0.528). CONCLUSIONS: The two-step canalicular anastomosis method allows an early search for the medial cut end of the canaliculus and improves the chances of finding it; it is also a quicker, less invasive method for treating canalicular lacerations.

[Anti(lymph)angiogenic preconditioning prior to keratoplasty]. / Antiangiogene Präkonditionierung vor Keratoplastik.

PURPOSE: The aim of this study is to describe novel therapeutic concepts to promote graft survival in high-risk keratoplasty by targeting (lymph)angiogenesis in the transplant context. METHODS: A PubMed literature search and our own clinical and experimental data are evaluated. RESULTS: There are three options for anti(lymph)angiogenic preconditioning: a) primary prevention of neovascularisation during the disease process, b) secondary prevention by regressing established blood vessels prior to transplantation and (c) tertiary prevention through inhibition of post-keratoplasty neovascularisation. CONCLUSION: Modern topical anti(lymph)angiogenic therapies seem to be able to reduce the risk of graft rejection especially in high-risk keratoplasty.

[Immune reactions after DMEK, DSAEK and DALK]. / Immunreaktionen nach DMEK, DSAEK und DALK.

PURPOSE: The aim of this study is to describe incidence, diagnosis and therapy for endothelial immune reactions after modern lamellar corneal transplantat surgery (DMEK, DSAEK, DALK). METHODS: A PubMed-based literature review and our own clinical and experimental data are evaluated. RESULTS: There is no longer an endothelial immune reaction after DALK for keratoconus. DMEK significantly reduces the risk for endothelial immune reactions after surgery for Fuchs dystrophy. CONCLUSIONS: Modern lamellar corneal transplant techniques such as DALK and DMEK have nearly abolished the risk for endothelial immune reactions in the avascular recipient bed.

Loss of PIDD limits NF-κB activation and cytokine production but not cell survival or transformation after DNA damage.

Activation of NF-κB (nuclear factor of kappa light chain gene enhancer in B cells) in response to DNA damage is considered to contribute to repair of genetic lesions, increased cell survival and cytokine release. The molecular mechanisms orchestrating this cytoplasmic event involve core components of the nuclear DNA damage response machinery, including ATM-kinase (ataxia telangiectasia mutated kinase) and PARP-1 (poly (ADP-ribose) polymerase 1). The physiological consequences of defective NF-κB activation in this context, however, remain poorly investigated. Here we report on the role of the 'p53-induced protein with a death domain', PIDD, which appears rate limiting in this process, as is PARP-1. Despite impaired NF-κB activation, DNA damage did not increase cell death or reduce clonal survival of various cell types lacking PIDD, such as mouse embryonic fibroblasts or stem and progenitor cells of the hematopoietic system. Furthermore, lymphomagenesis induced by γ-irradiation (IR) was unaffected by deficiency for PIDD or PARP-1, indicating that loss of DNA damage-triggered NF-κB signalling does not affect IR-driven tumorigenesis. However, loss of either gene compromised cytokine release after acute IR injury. Hence, we propose that NF-κB's most notable function after DNA damage in primary cells is related to the release of cytokines, thereby contributing to sterile inflammation.

PIDDosome-independent tumor suppression by Caspase-2.

The PIDDosome, a multiprotein complex constituted of the 'p53-induced protein with a death domain (PIDD), 'receptor-interacting protein (RIP)-associated ICH-1/CED-3 homologous protein with a death domain' (RAIDD) and pro-Caspase-2 has been defined as an activating platform for this apoptosis-related protease. PIDD has been implicated in p53-mediated cell death in response to DNA damage but also in DNA repair and nuclear factor kappa-light-chain enhancer (NF-κB) activation upon genotoxic stress, together with RIP-1 kinase and Nemo/IKKγ. As all these cellular responses are critical for tumor suppression and deregulated expression of individual PIDDosome components has been noted in human cancer, we investigated their role in oncogenesis induced by DNA damage or oncogenic stress in gene-ablated mice. We observed that Pidd or Caspase-2 failed to suppress lymphoma formation triggered by γ-irradiation or 3-methylcholanthrene-driven fibrosarcoma development. In contrast, Caspase-2 showed tumor suppressive capacity in response to aberrant c-Myc expression, which did not rely on PIDD, the BH3-only protein Bid (BH3 interacting domain death agonist) or the death receptor ligand Trail (TNF-related apoptosis-inducing ligand), but associated with reduced rates of p53 loss and increased extranodal dissemination of tumor cells. In contrast, Pidd deficiency associated with abnormal M-phase progression and delayed disease onset, indicating that both proteins are differentially engaged upon oncogenic stress triggered by c-Myc, leading to opposing effects on tumor-free survival.

P53-induced protein with a death domain (PIDD): master of puppets?

P53-induced protein with a death domain (PIDD) has been described as primary p53 target gene, induced upon DNA damage. More than 10 years after its discovery, its physiological role in the DNA damage response remains enigmatic, as it seems to be able to execute life-death decisions in vitro, yet genetic ablation in mice failed to reveal an obvious phenotype. Nonetheless, evidence is accumulating that it contributes to the fine-tuning of the DNA-damage response by orchestrating critical processes such as caspase activation or nuclear factor κB translocation and can also exert additional nuclear functions, for example, the modulation of translesion synthesis. In this review, we aim to integrate these observations and propose possible unexplored functions of PIDD.

[Antiangiogenic therapy at the ocular surface: when, what and why?]. / Antiangiogene Therapie am vorderen Augenabschnitt: Wann? Was? Wofür?

There are numerous indications for local antiangiogenic therapy at the ocular surface. These include vision-limiting corneal neovascularization, corneal blood and lymphatic vessels endangering corneal graft survival and tumor-associated lymphangiogenesis. A literature review in PubMed and own clinical and experimental data form the basis for a discussion of the indications, current therapeutic options and potential side-effects of local antiangiogenic therapy at the ocular surface.

Tumour-associated lymphangiogenesis in conjunctival malignant melanoma.

BACKGROUND: To evaluate whether tumour-associated lymphangiogenesis, that is the formation of new lymphatic vessels (LVs) induced by a tumour, occurs in and around conjunctival malignant melanoma (MM). METHODS: Clinical files and conjunctival specimens of 20 patients with histologically diagnosed conjunctival MM were analysed. Sections were stained with LYVE-1 and podoplanin antibodies as specific lymphatic endothelial markers and Ki67 as proliferation marker. The tumour area and the area covered by LV (LVA), LV number (LVN) and LV density (LVD) were measured within the tumour and in the peritumoural area in digital images of the specimen. The LV results were correlated with the histopathological characteristics, tumour location, recurrence rate, mitomycin C therapy and presence of metastases. RESULTS: LVs were detected in all specimens within the tumour and peritumourally. Significantly more Ki67(+) proliferating lymphatic endothelial cells were detected in the tumour and in the peritumoural tissue up to 300 microm compared with the surrounding normal conjunctiva (>300 microm distance). There was a slightly positive correlation between the tumour size and the LVN and LVA in the 50 microm zone adjacent to the tumour. We did not find any significant correlations between LVs and histopathological and clinical characteristics (location, shape, relapses, metastases), possibly due to the small sample sizes. Non-limbal tumours with involvement of tarsus or fornix showed a tendency towards a higher LVD compared with limbal tumours. CONCLUSION: Conjunctival MMs display tumour-associated LV within and around the tumour. The MM seems to induce lymphangiogenesis not only in the tumour, but also in its proximity.

[Topical inhibition of angiogenesis at the cornea. Safety and efficacy]. / Topische antiangiogene Therapie an der Hornhaut. Sicherheit und Effektivität.

BACKGROUND: The efficacy and safety of novel topical inhibitors of corneal neovascularisation will be discussed. METHODS: A literature review after a PUBMED search and own clinical and experimental results are presented. RESULTS: The off-label use of Avastin eye drops and GS101 eye drops against insulin receptor substrate (IRS)-1, which have been tested in phase II trial, both seem to be relatively efficient and safe ways to inhibit progressive corneal neovascularisation. Other VEGF antagonists, such as ranibizumab and pegaptanib eye drops also inhibit corneal neovascularisation. CONCLUSIONS: Avastin and GS101 eye drops are the first specific angiogenesis inhibitors for topical inhibition of corneal angiogenesis available for clinical use.

Transient postoperative vascular endothelial growth factor (VEGF)-neutralisation improves graft survival in corneas with partly regressed inflammatory neovascularisation.

BACKGROUND: High-risk keratoplasties are usually performed after an uninflamed and quiescent interval in corneas with partly regressed blood and lymphatic vessels. We analysed whether the inhibition of post-keratoplasty revascularisation in mice with partly regressed corneal vessels ("intermediate-risk") improves graft survival. METHODS: Three interrupted stromal sutures (11-0) in corneas of Balb/c mice (6-8 weeks old) were placed for 6 weeks. Six months after suture removal, penetrating keratoplasty was performed with C57BL/6 donors. The treatment group received a vascular endothelial growth factor-A specific cytokine trap (VEGF Trap) intraperitoneally at days 0, 4, 7 and 14 after keratoplasty (25 mg/kg per mouse; controls received equal amounts of Fc protein). Pathological haemangiogenesis and lymphangiogenesis prior to as well as 3 days or 8 weeks after keratoplasty and graft survival were analysed. RESULTS: Three days after keratoplasty corneal revascularisation was sufficiently reduced by VEGF Trap (haem-vascularised areas 42.7% reduction; lymph-vascularised areas 54.7% reduction). Survival proportions 8 weeks after keratoplasty were 36% in the treatment group compared with 9% in the control group (n = 11; p<0.05). At that time no differences in haemangiogenesis or lymphangiogenesis were observed between the two groups. CONCLUSION: Early transient postoperative induction of haemangiogenesis and lymphangiogenesis and reformation of regressed corneal blood and lymphatic vessels are important for transplant rejections after "intermediate-risk" corneal transplantation.