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Purpose: To correlate inflammatory and proangiogenic key cytokines from undiluted vitreous of treatment-naïve central retinal vein occlusion (CRVO) patients with SD-OCT parameters.
Methods: Thirty-five patients (age 71.1 years, 24 phakic, 30 nonischemic) underwent intravitreal combination therapy, including a single-site 23-gauge core vitrectomy. Twenty-eight samples from patients with idiopathic, non-uveitis floaterectomy served as controls. Interleukin 6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and vascular endothelial growth factor (VEGF-A) levels were correlated with the visual acuity (logMar), category of CRVO (ischemic or nonischemic) and morphologic parameters, such as central macular thickness-CMT, thickness of neurosensory retina-TNeuro, extent of serous retinal detachment-SRT and disintegrity of the IS/OS and others.
Results: The mean IL-6 was 64.7pg/ml (SD ± 115.8), MCP-1 1015.7 ( ± 970.1), and VEGF-A 278.4 ( ± 512.8), which was significantly higher than the control IL-6 6.2 ± 3.4pg/ml (P=0.06), MCP-1 253.2 ± 73.5 (P<0.0000001) and VEGF-A 7.0 ± 4.9 (P<0.0006). All cytokines correlated highly with one another (correlation coefficient r=0.82 for IL-6 and MCP-1; r=0.68 for Il-6 and VEGF-A; r=0.64 for MCP-1 and VEGF-A). IL-6 correlated significantly with CMT, TRT, SRT, dIS/OS, and dELM. MCP-1 correlated significantly with SRT, dIS/OS, and dELM. VEGF-A correlated not with changes in SD-OCT, while it had a trend to be higher in the ischemic versus the nonischemic CRVO group (P=0.09).
Conclusions: The inflammatory cytokines were more often correlated with morphologic changes assessed by SD-OCT, whereas VEGF-A did not correlate with CRVO-associated changes in SD-OCT. VEGF inhibition alone may not be sufficient in decreasing the inflammatory response in CRVO therapy.
The creation of entirely synthetically derived bone substitute materials which are as effective as autologous bone grafts is desirable. Osteogenesis involves the concerted action of several proteins within a signaling cascade. Hedgehog proteins act upstream of this cascade, inducing the expression of various bone morphogenetic proteins (BMPs) and promoting physiological bone healing. Therefore, the hypothesis that hedgehog signaling in bone defects improves bone healing more than BMP signaling alone was tested. Recombinant N-terminal sonic hedgehog protein (N-SHh), BMP-2 or a combination of the two was added to β-tricalcium phosphate (β-TCP) and 5-mm femoral midshaft defects in nude rats were filled with these composites. The defects were stabilized with mini-plates. After eight weeks, the animals were sacrificed and the femora were explanted. The radiological evaluation was followed by a three-point bending test and histological examination. BMP-2/β-TCP composites showed a trend of increased stiffness compared with the controls (β-TCP without protein). N-SHh/β-TCP composites had lower stiffness compared with the control group and the N-SHh/BMP-2/β-TCP composites also had lower average stiffness compared with the controls (all not significant). Histomorphometry, however, revealed abundant cartilage and bone core formation in the N-SHh-composite groups. The sum of the new cartilage and bone was highest in the combination group N-SHh/BMP-2 (not significant). The addition of N-SHh to bone substitute materials appears to delay bone healing at the applied concentration and observation time but also showed a trend for higher amounts of ossifying cartilage.
We present the case of an aphasic 77-year-old stroke patient with left distal M1 occlusion who received rt-PA for thrombolysis while on oral anticoagulant treatment with dabigatran (150 mg b.i.d.). Coagulation parameters were normal (thrombin time 20 s, aPTT 20 s, INR 1.08) and the patient improved from an NIHSS of 15 to 5 within 24 h with sonographic evidence of M1 recanalization. She did not develop intracranial bleeding complications but showed unusually large diffuse skin ecchymoses. In our report, we give an overview of all reported cases of thrombolysis under dabigatran anticoagulation and discuss the questions of medication adherence under novel oral anticoagulants (NOA) and the safety of NOA in terms of secondary intracerebral hemorrhage after stroke.
Background: The incidence of pulmonary failure in trauma patients is considered to be influenced by several factors such as liver injury. We intended to assess the association of various potential predictors of pulmonary failure following thoracic trauma and liver injury.
Methods: Records of 12,585 trauma patients documented in the TraumaRegister DGU® of the German Trauma Society were analyzed regarding the potential impact of concomitant liver injury on the incidence of pulmonary failure using uni- and multivariate analyses. Pulmonary failure was defined as pulmonary failure of ≥ 3 SOFA-score points for at least two days. Patients were subdivided according to their injury pattern into four groups: group 1: AIS thorax < 3; AIS liver < 3; group 2: AIS thorax ≥ 3; AIS liver < 3; group 3: AIS thorax < 3; AIS liver ≥ 3 and group 4: AIS thorax ≥ 3; AIS liver ≥ 3.
Results: Overall, 2643 (21%) developed pulmonary failure, 12% (n= 642) in group 1, 26% (n= 697) in group 2, 16% (n= 30) in group 3, and 36% (n= 188) in group 4. Factors independently associated with pulmonary failure included relevant lung injury, pre-existing medical conditions (PMC), sex, transfusion of more than 10 units of packed red blood cells (PRBC), Glasgow Coma Scale (GCS) ≤ 8, and the ISS. However, liver injury was not associated with an increased risk of pulmonary failure following severe trauma in our setting.
Conclusions: Specific factors, but not liver injury, were associated with an increased risk of pulmonary failure following trauma. Trauma surgeons should be aware of these factors for optimized intensive care treatment.
In previous work we have documented the nuclear translocation of endothelial NOS (eNOS) and its participation in combinatorial complexes with Estrogen Receptor Beta (ERβ) and Hypoxia Inducible Factors (HIFs) that determine localized chromatin remodeling in response to estrogen (E2) and hypoxia stimuli, resulting in transcriptional regulation of genes associated with adverse prognosis in prostate cancer (PCa). To explore the role of nuclear eNOS in the acquisition of aggressive phenotype in PCa, we performed ChIP-Sequencing on chromatin-associated eNOS from cells from a primary tumor with poor outcome and from metastatic LNCaP cells. We found that: 1. the eNOS-bound regions (peaks) are widely distributed across the genome encompassing multiple transcription factors binding sites, including Estrogen Response Elements. 2. E2 increased the number of peaks, indicating hormone-dependent eNOS re-localization. 3. Peak distribution was similar with/without E2 with ≈ 55% of them in extragenic DNA regions and an intriguing involvement of the 5′ domain of several miRs deregulated in PCa. Numerous potentially novel eNOS-targeted genes have been identified suggesting that eNOS participates in the regulation of large gene sets. The parallel finding of downregulation of a cluster of miRs, including miR-34a, in PCa cells associated with poor outcome led us to unveil a molecular link between eNOS and SIRT1, an epigenetic regulator of aging and tumorigenicity, negatively regulated by miR-34a and in turn activating eNOS. E2 potentiates miR-34a downregulation thus enhancing SIRT1 expression, depicting a novel eNOS/SIRT1 interplay fine-tuned by E2-activated ER signaling, and suggesting that eNOS may play an important role in aggressive PCa.
Introduction: Vasospastic brain infarction is a devastating complication of aneurysmal subarachnoid hemorrhage (SAH). Using a probe for invasive monitoring of brain tissue oxygenation or blood flow is highly focal and may miss the site of cerebral vasospasm (CVS). Probe placement is based on the assumption that the spasm will occur either at the dependent vessel territory of the parent artery of the ruptured aneurysm or at the artery exposed to the focal thick blood clot. We investigated the likelihood of a focal monitoring sensor being placed in vasospasm or infarction territory on a hypothetical basis.
Methods: From our database we retrospectively selected consecutive SAH patients with angiographically proven (day 7–14) severe CVS (narrowing of vessel lumen >50%). Depending on the aneurysm location we applied a standard protocol of probe placement to detect the most probable site of severe CVS or infarction. We analyzed whether the placement was congruent with existing CVS/infarction.
Results: We analyzed 100 patients after SAH caused by aneurysms located in the following locations: MCA (n = 14), ICA (n = 30), A1CA (n = 4), AcoA or A2CA (n = 33), and VBA (n = 19). Sensor location corresponded with CVS territory in 93% of MCA, 87% of ICA, 76% of AcoA or A2CA, but only 50% of A1CA and 42% of VBA aneurysms. The focal probe was located inside the infarction territory in 95% of ICA, 89% of MCA, 78% of ACoA or A2CA, 50% of A1CA and 23% of VBA aneurysms.
Conclusion: The probability that a single focal probe will be situated in the territory of severe CVS and infarction varies. It seems to be reasonably accurate for MCA and ICA aneurysms, but not for ACA or VBA aneurysms.
Im Rahmen des Vortrags wird zunächst ein Überblick über die aktuell angewandten Linsensysteme in der (refraktiven) Kataraktchirurgie sowie im Rahmen des RLA gesprochen. Hierzu zählen die monofokalen sphärischen Standardlinsen, aber auch asphärische, torische und multifokale Implantate.
Speziell wird auf die Ergebnisse einer Studie zu einem neuen multifokalen-torischen Implantat eingegangen. Der Schwerpunkt des Vortrages liegt dann weiterhin auf den trifokalen Korrektionsmöglichkeiten. Zum einen wird die sog. binokulare Trifokalität, bei der zwei multifokale Intraokularlinsen unterschiedlicher Addition implantiert werden, besprochen. Durch die Anpassung jeweils eines Auges an den Intermediär- bzw. Nahbereich soll so bei verringerten optischen Phänomenen ein deutliches Sehen in drei Hauptdistanzen ermöglicht werden. Weiterhin befasst sich der Vortrag aber auch mit den neuen echten trifokalen Optiksystemen, welche ebenfalls deutliches Sehen in verschiedenen Entfernungen gewährleisten können.
Im dritten Teil des Vortrages werden aktuelle Langzeitergebnisse aus einer FDA Studie zur Evaluation einer kammerwinkelgestützten phaken Intraokularlinse, mit speziellem Augenmerk auf den cornealen Endothelzellverlust, sowie eine neuartige sulcusgestütze phake Intraokularlinse mit zentralem Loch zur Glaukomvermeidung vorgestellt.
Introduction: Recent data suggest that benefit from trastuzumab and chemotherapy might be related to expression of HER2 and estrogen receptor (ESR1). Therefore, we investigated HER2 and ESR1 mRNA levels in core biopsies of HER2-positive breast carcinomas from patients treated within the neoadjuvant GeparQuattro trial.
Methods: HER2 levels were centrally analyzed by immunohistochemistry (IHC), silver in-situ hybridization (SISH) and qRT-PCR in 217 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) core biopsies. All tumors had been HER2-positive by local pathology and had been treated with neoadjuvant trastuzumab/ chemotherapy in GeparQuattro.
Results: Only 73% of the tumors (158 of 217) were centrally HER2-positive (cHER2-positive) by IHC/SISH, with cHER2-positive tumors showing a significantly higher pCR rate (46.8% vs. 20.3%, p<0.0005). HER2 status by qRT-PCR showed a concordance of 88.5% with the central IHC/SISH status, with a low pCR rate in those tumors that were HER2-negative by mRNA analysis (21.1% vs. 49.6%, p<0.0005). The level of HER2 mRNA expression was linked to response rate in ESR1-positive tumors, but not in ESR1-negative tumors. HER2 mRNA expression was significantly associated with pCR in the HER2-positive/ESR1-positive tumors (p=0.004), but not in HER2-positive/ESR1-negative tumors.
Conclusions: Only patients with cHER2-positive tumors - irrespective of the method used - have an increased pCR rate with trastuzumab plus chemotherapy. In patients with cHER2-negative tumors the pCR rate is comparable to the pCR rate in the non-trastuzumab treated HER-negative population. Response to trastuzumab is correlated to HER2 mRNA levels only in ESR1-positive tumors. This study adds further evidence to the different biology of both subsets within the HER2-positive group.
Background: Critical organ shortage results in the utilization of extended donor criteria (EDC) liver grafts. These marginal liver grafts are prone to increased ischemia reperfusion injury (IRI) which may contribute to deteriorated graft function and survival. Experimental data have shown that the calcineurin inhibitor tacrolimus exerts protective effects on hepatic IRI when applied intravenously or directly as a hepatic rinse. Therefore, the aim of the present study is to examine the effects of an ex vivo tacrolimus perfusion on IRI in transplantation of EDC liver grafts.
Methods/Design: The TOP-Study (tacrolimus organ perfusion) is a randomized multicenter trial comparing the ex vivo tacrolimus perfusion of marginal liver grafts with placebo. We hypothesize that a tacrolimus rinse reduces IRI, potentially improving organ survival following transplantation of EDC livers. The study includes livers with two or more EDC, according to Eurotransplant International Foundation’s definition of EDC livers. Prior to implantation, livers randomized to the treatment group are rinsed with tacrolimus at a concentration of 20 ng/ml in 1000 ml Custodiol solution and in the placebo group with Custodiol alone. The primary endpoint is the maximum serum alanine transamninase (ALT) level within the first 48 hours after surgery; however, the study design also includes a 1-year observation period following transplantation. The TOP-Study is an investigator-initiated trial sponsored by the University of Munich Hospital. Seven other German transplant centers are participating (Berlin, Frankfurt, Heidelberg, Mainz, Münster, Regensburg, Tübingen) and aim to include a total of 86 patients.
Discussion: Tacrolimus organ perfusion represents a promising strategy to reduce hepatic IRI following the transplantation of marginal liver grafts. This treatment may help to improve the function of EDC grafts and therefore safely expand the donor pool in light of critical organ shortage.
Trial register: EudraCT number: 2010-021333-31, ClinicalTrials.gov identifier: NCT01564095
Background: Castleman’s disease is a rare lymphoproliferative disorder. It typically presents as mediastinal masses and causes a wide range of clinical symptoms. Histologically, Castleman’s disease is classified as either a hyalinic vascular or plasma cell variant. The prognosis mainly depends on the histological type and broadly varies. We herein report our sonographic findings in a patient with Castleman’s disease, including gray-scale ultrasonography, color Doppler ultrasonography, and sonoelastography ultrasonography, which have not been previously reported in the literature. These findings allowed for a preoperative diagnosis and avoidance of overly aggressive therapy.
Case presentation: A 28-year-old European female patient with unicentric Castleman’s disease of hyalinic vascular type (HV) restricted to the axilla was referred to us because of a 4-month history of a painless, solitary mass located in the left axilla. The patient’s medical history was unremarkable.
Conclusion: Castleman’s disease is a pathologic entity of unknown etiology and pathogenesis. In this case report of unicentric HV-type CD, we demonstrate that typical sonographic findings can lead to a preoperative diagnosis of Castleman’s disease. Core needle biopsy usually allows for a final diagnosis and helps to avoid unnecessary operations and overtreatment.