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Objective: This study investigated the association between loss of MSH2/MSH6 versus loss of MLH1/PMS2 expression and overall survival and disease-free survival in patients with localized colorectal cancer., Background: The risk of developing colorectal cancer varies depending on the expression of mismatch repair proteins. However, it is unknown if the prognosis differs accordingly., Methods: In this retrospective study, we included a Danish cohort of patients who underwent surgery for colorectal cancer between 2009 and 2020. The Danish Colorectal Cancer Group database was used to identify patients, and patient-level data were extracted from six registries. Subsequently, patients with proficient mismatch repair status, with metastatic disease, who underwent emergency surgery, or who received neoadjuvant therapy were excluded. Patients were then propensity score matched in a 1:1 ratio., Results: A total of 3,625 patients with localized deficient mismatch repair colorectal cancer were included in the study. Patients had a median age of 75 years and a median follow-up of 4.3 years. Before matching, the MSH2/MSH6 versus MLH1/PMS2 groups differed in age, gender, and comorbidities. After matching, 556 patients were included and loss of MSH2/MSH6 was significantly associated with better overall survival (hazard ratio 0.60; 95% CI, 0.37-0.94); however, not disease-free survival (hazard ratio 0.84; 95% CI, 0.54-1.30)., Conclusions: In patients with localized deficient mismatch repair colorectal cancer who underwent surgery, a significant association was found between loss of MSH2/MSH6 versus loss of MLH1/PMS2 expression and overall survival. Thus, these patients may be a target for a differentiated follow-up strategy., Competing Interests: Conflicts of Interest: The authors declare no conflicts of interest., (Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: This study examined the association between deficient mismatch repair (dMMR) versus proficient MMR (pMMR) status and overall survival and disease-free survival in patients with localized colorectal cancer., Background: Several distinctions exist between patients with dMMR and pMMR colorectal cancer. However, the impact on prognosis is yet to be investigated in large-scale cohort studies., Methods: In this cohort study, we included patients who underwent curative-intent surgery for localized colorectal cancer between 2009 and 2020. Patients were identified in the Danish Colorectal Cancer Group database and patient-level data were extracted from 6 registry databases. After inclusion, patients with dMMR status were matched 1:1 to patients with pMMR status using an estimated propensity score., Results: After matching, 5994 patients were included. The patients had a median age of 74 years and a median follow-up of 4.1 years. There was no significant association between mismatch repair (MMR) status and overall survival (hazard ratio, 0.91; 95% confidence interval [CI], 0.81-1.03) or disease-free survival (hazard ratio, 0.89; 95% CI, 0.78-1.01). However, the restricted 5-year mean disease-free survival time, calculated due to violation of the proportional hazards assumption, showed a significant absolute difference of 0.13 years (95% CI, 0.03-0.23; P = 0.01) in favor of the dMMR group., Conclusions: No significant association with overall survival was found according to MMR status. dMMR status was, however, found to be associated with marginally improved disease-free survival compared to pMMR status in patients with localized colorectal cancer undergoing curative-intent surgery., Competing Interests: Disclosure: The authors declare that they have no conflicts of interest to disclose. This study was supported by the Innovative Medicines Initiative 2 Joint Undertaking (JU) (grant number: 806968), the Novo Nordisk Foundation with the project title “Personalized medicine infrastructure using the open-source OMOP common data model including an Electronic Health Record interface” (grant number: NNF21OC0069821), and the Danish Ministry of Higher Education and Science and the Region Zealand (grant number not provided)., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Importance: The timing of adjuvant chemotherapy after surgery for colorectal cancer and its association with long-term outcomes have been investigated in national cohort studies, with no consensus on the optimal time from surgery to adjuvant chemotherapy., Objective: To analyze the association between the timing of adjuvant chemotherapy after surgery for colorectal cancer and disease-free survival., Design, Setting, and Participants: This is a post hoc analysis of the phase 3 SCOT randomized clinical trial, from 244 centers in 6 countries, investigating the noninferiority of 3 vs 6 months of adjuvant chemotherapy. Patients with high-risk stage II or stage III nonmetastatic colorectal cancer who underwent curative-intended surgery were randomized to either 3 or 6 months of adjuvant chemotherapy consisting of fluoropyrimidine and oxaliplatin regimens. Those with complete information on the date of surgery, treatment type, and long-term follow-up were investigated for the primary and secondary end points. Data were analyzed from May 2022 to February 2024., Intervention: In the post hoc analysis, patients were grouped according to the start of adjuvant chemotherapy being less than 6 weeks vs greater than 6 weeks after surgery., Main Outcomes and Measures: The primary end point was disease-free survival. The secondary end points were adverse events in the total treatment period or the first cycle of adjuvant chemotherapy., Results: A total of 5719 patients (2251 [39.4%] female; mean [SD] age, 63.4 [9.3] years) were included in the primary analysis after data curation; among them, 914 were in the early-start group and 4805 were in the late-start group. Median (IQR) follow-up was 72.0 (47.3-88.1) months, with a median (IQR) of 56 (41-66) days from surgery to chemotherapy. Five-year disease-free survival was 78.0% (95% CI, 75.3%-80.8%) in the early-start group and 73.2% (95% CI, 72.0%-74.5%) in the late-start group. In an adjusted Cox regression analysis, the start of adjuvant chemotherapy greater than 6 weeks after surgery was associated with worse disease-free survival (hazard ratio, 1.24; 95% CI, 1.06-1.46; P = .01). In adjusted logistic regression models, there was no association with adverse events in the total treatment period (odds ratio, 0.82; 95% CI, 0.65-1.04; P = .09) or adverse events in the first cycle of treatment (odds ratio, 0.77; 95% CI, 0.56-1.09; P = .13)., Conclusions and Relevance: In this international population of patients with high-risk stage II and stage III colorectal cancer, starting adjuvant chemotherapy more than 6 weeks after surgery was associated with worse disease-free survival, with no difference in adverse events between the groups., Trial Registration: isrctn.org Identifier: ISRCTN59757862.

Purpose: The COVID-19 pandemic profoundly affected healthcare systems and patients. There is a need to comprehend the collateral effects of the pandemic on non-communicable diseases. We examined the impact of the pandemic on short-term survival for common solid tumours, including breast, colorectal, head and neck, liver, lung, oesophageal, pancreatic, prostate, and stomach cancer in the UK., Methods: This was a population-based cohort study of electronic health records from the UK primary care Clinical Practice Research Datalink GOLD database. In sum, 12,259,744 eligible patients aged ≥18 years with ≥1 year's history identified from January 2000 to December 2022 were included. We estimated age-standardised incidence and short-term (one- and two-year) survival for several common cancers from 2000 to 2019 (in five-year strata) and compared these to 2020-2022 using the Kaplan-Meier method., Results: Incidence decreased for most cancers in 2020 and recovered to different extents in 2021-2022. Short-term survival improved for most cancers between 2000 and 2019, but then declined, albeit minimally, for those diagnosed in 2020-2022. This was most pronounced for colorectal cancer, with one-year survival falling from 78.8% (95% CI 78%-79.6%) in 2015-2019 to 77% (95% CI 75.6-78.3%) for those diagnosed in 2020-2022., Conclusion: Short-term survival for many cancers was impacted, albeit minimally, by the pandemic in the UK, with reductions in survivorship from colorectal cancer equivalent to returning to the mortality seen in the first decade of the 2000s. While data on longer-term survival are needed to fully comprehend the impact of COVID-19 on cancer care, our findings illustrate the need for an urgent and substantial commitment from the UK National Health Service to address the existing backlog in cancer screening and diagnostic procedures to improve cancer care and mortality., Competing Interests: NB reports personal fees from Sleep Universal, Roche and Theramex, outside the submitted work. DPA receives funding from the UK National Institute for Health and Care Research (NIHR) in the form of a senior research fellowship. DPA’s group received partial support from the Oxford NIHR Biomedical Research Centre. DPA’s department has received grant/s from Amgen, Chiesi-Taylor, Lilly, Janssen, Novartis, and UCB Biopharma. His research group has received consultancy fees from AstraZeneca and UCB Biopharma. Amgen, Astellas, Janssen, Synapse Management Partners, and UCB Biopharma have funded or supported training programmes organised by DPA’s department. ÀRS reports honoraria for presentations, lectures, speakers, support for attending meetings and travel from Janssen, Astellas, and Bayer and support for attending meetings and travel from Ipsen outside the submitted work. FX-A-J is funded by Fundación Cientifica AECC (LABAE18025AVIL) and Plan Estatal de I+D+I of the Instituto de Salud Carlos III (FIS PI15/02047 and FIS PI18/0844). DN reports grants from OPTIMA and EHDEN. All other authors declare no conflicts of interest in this work., (© 2024 Barclay et al.)

Aim: This study aimed to evaluate the association of age and postoperative morbidity on 5-year overall survival (OS) after elective surgery for colorectal cancer., Method: Patients undergoing elective, curatively intended surgery for colorectal cancer Union for International Cancer Control Stages I-III between January 2014 and December 2019 were selected from four Danish nationwide healthcare databases. Patients were divided into four groups: group I 65-69 years old; group II 70-74 years old; group III 75-79 years old; and group IV ≥80 years old. Propensity score matching was used to reduce potential confounding bias. The primary outcome was the association of age and postoperative morbidity with 5-year OS. The secondary outcome was conditional survival, given that the patient had already survived the first 90 days after surgery., Results: After propensity score matching with a 1:1 ratio, group II contained 2221 patients; group III 952 patients; and group IV 320 patients. There was no significant difference in 5-year OS between group I (reference) and groups II and III (P = 0.4 and P = 0.9, respectively). Patients with severe postoperative complications within 30 days after surgery had a significantly decreased OS (P < 0.01); however, when patients who died within the first 90 days were excluded from the analysis, the differences in 5-year OS were less pronounced across all age groups., Conclusion: Postoperative morbidity, and not patient age, was associated with a lower 5-year OS. Long-term survival for patients who experience a complication is similar to patients who did not have a complication when conditioning on 90 days of survival., (© 2024 The Authors. Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

Purpose: To develop prediction models for short-term mortality risk assessment following colorectal cancer surgery., Methods: Data was harmonized from four Danish observational health databases into the Observational Medical Outcomes Partnership Common Data Model. With a data-driven approach using the Least Absolute Shrinkage and Selection Operator logistic regression on preoperative data, we developed 30-day, 90-day, and 1-year mortality prediction models. We assessed discriminative performance using the area under the receiver operating characteristic and precision-recall curve and calibration using calibration slope, intercept, and calibration-in-the-large. We additionally assessed model performance in subgroups of curative, palliative, elective, and emergency surgery., Results: A total of 57,521 patients were included in the study population, 51.1% male and with a median age of 72 years. The model showed good discrimination with an area under the receiver operating characteristic curve of 0.88, 0.878, and 0.861 for 30-day, 90-day, and 1-year mortality, respectively, and a calibration-in-the-large of 1.01, 0.99, and 0.99. The overall incidence of mortality were 4.48% for 30-day mortality, 6.64% for 90-day mortality, and 12.8% for 1-year mortality, respectively. Subgroup analysis showed no improvement of discrimination or calibration when separating the cohort into cohorts of elective surgery, emergency surgery, curative surgery, and palliative surgery., Conclusion: We were able to train prediction models for the risk of short-term mortality on a data set of four combined national health databases with good discrimination and calibration. We found that one cohort including all operated patients resulted in better performing models than cohorts based on several subgroups., (© 2024. The Author(s).)

Introduction: One of the considerations when investigating neoadjuvant interventions is the prolonging of time from diagnosis to curative surgery (i.e. the treatment interval [TI]). The aim of this study was to investigate the association between the length of TI and overall survival and disease-free survival in patients with deficient mismatch repair (dMMR) colon cancer., Materials and Methods: This retrospective propensity score-adjusted study included all patients of ≥18 years of age undergoing elective curative surgery for stage I-III, dMMR colon cancer. Data were extracted from four Danish patient databases. Outcomes were investigated in groups with TIs of ≤14 days versus >14 days. Propensity scores were computed using all demographics, diagnoses and measurements. Matching was done in a 1:1 ratio., Results: A total of 4130 patients were included in the study with a mean age of 73.8 years and a median follow-up time of 43.9 months. After matching, 2794 patients were included in the analysis of overall survival. No significant difference in overall survival was seen between patients with TIs of ≤14 days versus >14 days (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.81-1.17; p = 0.78). In the analysis of disease-free survival, 1798 patients were included after matching. This showed no significant difference between patients with TIs of ≤14 days versus >14 days (HR, 0.85; 95% CI, 0.69-1.06; p = 0.14)., Conclusion: No associations were found between TI and overall survival and disease-free survival in patients with stage I-III, dMMR colon cancer undergoing elective curative surgery., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest. This is also stated in the “author form” which is signed by all the authors as well as in the manuscript., (Copyright © 2023 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background and study aims  Colorectal cancer is one of the most common malignancies, with approximately 20 % of patients having metastatic disease. Local symptoms from the tumor remain a common issue and affect quality of life. Electroporation is a method to permeabilize cell membranes with high-voltage pulses, allowing increased passage of otherwise poorly permeating substances such as calcium. The aim of this study was to determine the safety of calcium electroporation for advanced colorectal cancer. Patients and methods  Six patients with inoperable rectal and sigmoid colon cancer were included, all presenting with local symptoms. Patients were offered endoscopic calcium electroporation and were followed up with endoscopy and computed tomography/magnetic resonance scans. Biopsies and blood samples were collected at baseline and at follow-up, 4, 8, and 12 weeks after treatment. Biopsies were examined for histological changes and immunohistochemically with CD3/CD8 and PD-L1. In addition, blood samples were examined for circulating cell-free DNA (cfDNA). Results  A total of 10 procedures were performed and no serious adverse events occurred. Prior to inclusion, patients reported local symptoms, such as bleeding (N = 3), pain (N = 2), and stenosis (N = 5). Five of six patients reported symptom relief. In one patient, also receiving systemic chemotherapy, clinical complete response of primary tumor was seen. Immunohistochemistry found no significant changes in CD3 /CD8 levels or cfDNA levels after treatment. Conclusions  This first study of calcium electroporation for colorectal tumors shows that calcium electroporation is a safe and feasible treatment modality for colorectal cancer. It can be performed as an outpatient treatment and may potentially be of great value for fragile patients with limited treatment options., Competing Interests: Competing interests The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Increasing evidence indicates that disruption of circadian rhythms may be directly linked to cancer. Here we report that the expression levels of the core clock genes Per1 and Per3 measured by droplet digital polymerase chain reaction are significantly decreased in tumour tissue from 16 patients undergoing colorectal cancer surgery compared to paired normal mucosa. No differences were observed in the expression of Per2, Bmal1, and Clock. In conclusion, abnormal expression levels of the clock genes Per1 and Per3 in CRC tissue may be related to tumourigenesis and may provide future diagnostic and prognostic information.

Purpose: Ocular hypotony secondary to proliferative vitreoretinopathy-related retinal detachment, trauma or inflammation is difficult to treat. Besides endotamponades such as silicone oil, vitreous implants such as iris diaphragms or balloons have been developed to stabilize the eye and to prevent phthisis of the globe. Vitreous implants tested thus far exhibit a seam at the attachment site of the hemispheres, or micropores. This manuscript reports the development of a seamless silicone balloon implant without micropores, which can be filled with silicone oil and surface-modified to improve its biocompatibility. Developed for intraocular placement in the management of chronic hypotony and phthisis prevention, it may also be suitable for tamponading retinal detachments., Methods: Silicone was used as the basic structure for the fabrication of a seamless balloon-shaped intraocular implant, which was coated by employing a six-arm star-shaped (sP) macromer of a copolymer of 80 % ethylene oxide (EO) and 20 % propylene oxide (PO) with conjugated functional terminal isocyanate groups, NCO-sP(EO-stat-PO), with and without heparin. Three variants of implants, which differ in their surfaces, were manufactured: uncoated silicone, NCO-sP (EO-stat-PO) coated silicone and heparin-NCO-sP (EO-stat-PO) coated silicone implants. To exert a tamponade effect, the implant was filled with silicone oil and its properties were studied., Results: Seamless thin balloon implants made of silicone, which are considered biocompatible and intrinsically resistant to biological attacks in vivo, could be fabricated in different sizes. The silicone oil-filled implant can mimic the mechanism of buoyant force and high surface tension of silicone oil, which is the only long-term vitreous substitute currently available. The silicone oil-filled implant can also mimic the natural vitreous body by occupying the entire posterior segment., Conclusions: The intraocular silicone implant as an alternative long-term treatment of chronic ocular hypotony might offer a new option for clinical ophthalmological practice. In vivo studies need to be performed to collect more data on the implant's long-term mechanical and optical properties, as well as long-term biocompatibility.

The treatment of colon cancer has undergone a rapid development with improved surgical and medical regimes and the introduction of targeted treatments. This review offers insight into the current available tailored treatment of colon cancer, and some of the new tailored treatment possibilities with focus on preoperative-, surgical- and post-operative treatment are presented.

Background: A common haplotype in the gene for the regulator of the alternative pathway of complement activation factor H has been linked to individual predisposition to age- related macular degeneration (AMD)., Methods: In this study, retinal pigment epithelial (RPE) cells, i.e. immortalized ARPE-19 as well as primary human RPE cells, were investigated for expression of factor H and FHL-1 by immunohistochemistry and in situ hybridization analysis., Results: Factor H and the alternative spliced product FHL-1 are expressed in RPE cells, i.e. in immortalized ARPE-19 and primary human RPE cells. Factor H and FHL-1 expression was induced in a dose-dependent manner in ARPE-19 cells upon treatment with the inflammatory marker interleukin-6 (IL-6). In situ hybridization experiments confirmed an elevated expression rate of the factor H gene in IL-6-treated ARPE-19 cells. AMD is characterized by complement-associated inflammatory processes in the retina. Thus, local synthesis of complement regulators affects the protection of retinal cells and may be involved in the pathogenesis at the RPE-choroid interface.

Background: To assess the prevalence of thrombophilia in patients with central (CRVO) and branch retinal vein occlusion (BRVO)., Methods: In 139 patients with CRVO (n = 88) and BRVO (n = 51) and in 40 healthy controls factor VIII, fibrinogen, antithrombin III, protein C, protein S, activated protein C resistance, anticardiolipin antibodies (ACA), homocysteine, factor V Leiden, prothrombin G20210A and methylene tetrahydrofolate reductase (MTHFR) C677T mutation were assessed retrospectively., Results: Elevated factor VIII activity and the homozygous MTHFR C677T mutation were significantly more often found in CRVO and BRVO cases compared to controls. Age-, gender- and C-reactive protein-adjusted logistic regression analysis did not show a significant additive effect of elevated factor VIII activity on the risk of developing CRVO/BRVO. Elevated fibrinogen levels and ACA were significantly more often found in CRVO than amongst controls. No significant differences were found concerning the remaining variables., Conclusions: We suggest elevated fibrinogen levels, ACA and the homozygous MTHFR C677T mutation as potential risk factors for CRVO/BRVO., (© 2014 S. Karger AG, Basel.)

Objective: Changes in fundus autofluorescence (AF) are observed in various retinal disorders. Lipofuscin accumulation within the retinal pigment epithelium (RPE) is a source of fundus AF (FAF); however, the causes of short-term increases in FAF observed in inflammatory conditions or after laser treatment are unknown. Here, we describe an RPE cell culture model that is useful for investigations of FAF., Methods: ARPE-19 cells were cultured in 2-well chamber slides. Cells were exposed to isolated rabbit photoreceptor outer segments (POS) to mimic in vivo phagocytic activity. The AF of RPE cells exposed to POS was measured before and after focal coagulation of the cultures. AF was measured over a period of 4 weeks. Cell lysates were examined by two-dimensional (2D) gel electrophoresis and mass spectrometry analysis., Results: The exposure of ARPE cells to POS did not lead to increased AF; however, after coagulation, cells exposed to POS showed a statistically significant increase in AF (p < 0.05). 2D electrophoresis of the cell lysates revealed changes in 3 proteins. One of these proteins, identified by mass spectrometry as ezrin-radixin-moesin-binding phosphoprotein 50, was reduced in the coagulated cell population., Conclusions: We have established an in vitro model of RPE cells in culture that can be used to evaluate the development of AF and changes in cellular proteins that accompany laser photocoagulation., (Copyright © 2012 S. Karger AG, Basel.)

Background: Implantation of silicone materials like iris diaphragms into the eye can be complicated by cell migration and attachment. We studied polydimethylsiloxane (PDMS) foils coated with isocyanate terminated, star-shaped poly(ethylene glycol-stat-propylene glycol) (NCO-sP(EO-stat-PO)) equipped with heparin towards the inhibition of cell attachment without influencing cell viability., Methods: Mouse fibroblasts L929 were cultured and seeded onto sterilized pieces of either uncoated NCO-sP(EO-stat-PO) or heparin-NCO-sP(EO-stat-PO) loaded foils. Polyvinylchloride (PVC) foils served as the positive control and biomembranes as the negative control. The cultured cells were examined after 24 h for cell viability and adhesion by fluorescence microscopy; morphological cell changes were documented after hemalaun staining. Cell density was measured and quantification of cell proliferation was assessed by a BrdU test; quantification of cell activity was analyzed by a WST-1 test., Results: The fibroblasts' cell viability was excellent on all tested foils except the toxic PVC foil. NCO-sP(EO-stat-PO) coating provided significantly reduced cell activity. On heparin-loaded coatings, cells were viable and less dense but showed almost the same cell proliferation and cell activity as on the negative control. NCO-sP(EO-stat-PO) coated, heparin loaded foils proved high biocompatibility and reduced cell adhesion., Conclusions: Both NCO-sP(EO-stat-PO)-coated foils with and without heparin seemed to be a viable implantation material for less cell migration, attachment, and reduced implant complications. Conclusive we give a recommendation for further studies on the intraocular implantation in particular for the NCO-sP(EO-stat-PO)-coated foils.

Background: Heat shock proteins are acute phase proteins that are upregulated in inflammation or following thermal stress. We analyzed the presence of the heat shock protein 70 (Hsp 70) in choroidal neovascular (CNV) membranes secondary to AMD after treatment with verteporphin photodynamic therapy (PDT) or transpupillary thermo therapy (TTT) to determine whether treatment correlated with the presence of Hsp70., Results: CNV membranes were removed by pars plana vitrectomy (ppV) and subretinal extraction. The membranes were analysed by light microscopy and the presence of Hsp 70 was examined using histochemistry. HeLa Cells served as controls.Of the 14 membranes analysed 11 were Hsp70 positive and 3 negative. In the no pre-treatment group of 8 membranes 6 were Hsp70 positive and 2 negative; in the PTD group all 4 membranes were positive and in the TTT group 1 membrane was positive and 1 membrane was negative for Hsp70., Conclusion: Hsp70 is present in the most CNV membranes secondary to AMD. Pre-treatment of the membrane with PTD or TTT does not appear to influence the expression of Hsp70.

Background: Age-related macular degeneration (AMD) is a prevalent cause of blindness in Western societies. Variants in the genes encoding complement factor H (CFH), complement component 3 (C3) and age-related maculopathy susceptibility 2 (ARMS2) have repeatedly been shown to confer significant risks for AMD; however, their role in disease progression and thus their potential relevance for interventional therapeutic approaches remains unknown., Methodology/principal Findings: Here, we analyzed association between variants in CFH, C3 and ARMS2 and disease progression of geographic atrophy (GA) due to AMD. A quantitative phenotype of disease progression was computed based on longitudinal observations by fundus autofluorescence imaging. In a subset of 99 cases with pure bilateral GA, variants in CFH (Y402H), C3 (R102G), and ARMS2 (A69S) are associated with disease (P = 1.6x10(-9), 3.2x10(-3), and P = 2.6x10(-12), respectively) when compared to 612 unrelated healthy control individuals. In cases, median progression rate of GA over a mean follow-up period of 3.0 years was 1.61 mm(2)/year with high concordance between fellow eyes. No association between the progression rate and any of the genetic risk variants at the three loci was observed (P>0.13)., Conclusions/significance: This study confirms that variants at CFH, C3, and ARMS2 confer significant risks for GA due to AMD. In contrast, our data indicate no association of these variants with disease progression which may have important implications for future treatment strategies. Other, as yet unknown susceptibilities may influence disease progression.

Purpose: To evaluate pigment epithelium detachment (PED) secondary to exudative age-related macular degeneration (AMD) treated with intravitreal injection of bevacizumab with regard to incidence of retinal pigment epithelium tears (RIPs)., Design: Retrospective, interventional case series., Methods: Institutional study of 31 eyes with PED in exudative AMD receiving intravitreal bevacizumab. Main outcome measures were Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity, PED vascularization and size measured by angiography and optical coherence tomography (OCT) imaging, and incidence of RIP., Results: Vision improved in six eyes and remained stable in 22 eyes (follow-up, 12.3 +/- 10.3 weeks). Twenty-eight eyes showed a vascularized PED. Four eyes (12.9%) experienced an RIP without vision loss. All RIP cases were vascularized in more than 50% of total lesion size., Conclusions: In short-term follow-up, the risk for RIP after bevacizumab injection in eyes with PED seems to be moderately, but not statistically significantly, increased in PED lesions vascularized more than 50%.

Background: In multifocal flicker stimulation, each step of the M-sequence consists of four consecutive flashes with a frequency of 30 Hz. The resulting amplitudes can be calculated by means of a discrete fourier transformation (DFT). With this method, amplitudes can be calculated without having to localise peaks and troughs and set cursors. The purpose of this study is to compare the re-test stability of this method to conventional mfERG stimulation., Methods: We examined 27 healthy subjects using a RETI-scan device (Roland Consult, Wiesbaden). We used 61 hexagons within a 30 deg. visual field. We compared the classic first order kernel (FOK) stimulation with the multifocal 30 Hz Flicker (mfFlicker-ERG) stimulation. Repeatability was calculated using coefficients of variation., Results: Both methods had coefficients of 15% for the sum P1-amplitude and the DFT results, respectively. The amplitudes calculated by flicker and DFT were approximately 25% smaller than the FOK amplitudes., Conclusions: This study showed no difference of re-test repeatability between the mfFlicker-ERG and the conventional first order kernel method. Since the mfFlicker-ERG method does not require a definition of peaks and troughs in order to calculate the amplitudes, we believe that a common source of error is eradicated, especially when dealing with distorted or atypical curves.

Purpose: To analyze the occurrence of near infrared (NIR) fluorescence in relation to NIR reflectance, blue-light-excited autofluorescence, angiograms, and funduscopy., Methods: Observational consecutive case series in patients with macular diseases. Imaging was performed with a confocal scanning laser ophthalmoscope for NIR reflectance, blue-light-excited autofluorescence, NIR fluorescence, and fluorescein and indocyanine green (ICG) angiograms. In cases in which NIR fluorescence was observed, five to nine images were averaged. The leakage of the scanning laser ophthalmoscope was analyzed., Results: In the 291 eyes analyzed, NIR fluorescence was observed in 51 and was graded weak in 27 with wet age-related macular degeneration (AMD, 10 cases), dry AMD with pigment clumping (n=7), chronic central serous choroidopathy (CSC; n=5), choroidal nevi (n=2), subretinal hemorrhages (n=2), and chloroquine maculopathy (n=1). Strong NIR fluorescence was found in 24 eyes, with wet AMD (n=14), subretinal hemorrhages (n=8), and choroidal nevi (n=2). Except for four eyes, we observed a strong correlation of NIR fluorescence and increased NIR reflectance at identical fundus location (92.2%). NIR fluorescence corresponded with increased blue-light-excited autofluorescence in 21 of 31 patients with AMD and in 4 of 5 patients with chronic CSC, but in none of the 4 patients with nevi. Funduscopy showed that structures with NIR fluorescence were pigmented or consisted of degraded blood. Barrier filter leakage of the imaging system was 6.2x10(-6)., Conclusions: The high correlation of NIR fluorescence and reflectance indicated that part of the observed NIR fluorescence is pseudofluorescence, whereas gray-scale analysis indicated that both NIR autofluorescence and pseudofluorescence contribute to the NIR fluorescence images. Quantification of leakage of the imaging system indicated a significant part of the observed NIR fluorescence is NIR autofluorescence. As NIR fluorescence derives from pigmented lesions, melanin is a possible source if NIR reflectance is also increased. Comparison with blue-light-excited autofluorescence showed differences between AMD and patients with nevi. NIR autofluorescence was also detected in single cases of maculopathy without corresponding NIR reflectance.

Aim: To describe and classify patterns of abnormal fundus autofluorescence (FAF) in the junctional zone of geographic atrophy (GA) in patients with age related macular degeneration., Methods: Digital FAF images were recorded in 164 eyes of 107 patients using a confocal scanning laser ophthalmoscope (cSLO; excitation 488 nm, detection above 500 nm) as part of a prospective multicentre natural history study (FAM Study). FAF images were obtained in accordance with a standardised protocol for digital image acquisition and generation of mean images after automated alignment., Results: Image quality was sufficient for classification of FAF patterns in 149 eyes (90.9%) with lens opacities being the most common reason for insufficient image quality. Abnormal FAF outside GA in 149 eyes was classified into four patterns: focal (12.1%), banded (12.8%), patchy (2.0%), and diffuse (57.0%), whereby 12.1% had normal background FAF in the junctional zone. In 4% there was no predominant pattern. The diffuse pattern was subdivided into four groups including reticular (4.7%), branching (27.5%), fine granular (18.1%), and fine granular with peripheral punctate spots (6.7%)., Conclusions: Different phenotypic patterns of abnormal FAF in the junctional zone of GA can be identified with cSLO FAF imaging. These distinct patterns may reflect heterogeneity at a cellular and molecular level in contrast with a non-specific ageing process. A refined phenotypic classification may be helpful to identify prognostic determinants for the spread of atrophy and visual loss, for identification of genetic risk factors as well as for the design of future interventional trials.

Purpose: To report the practicability and efficacy of autologous iris pigment epithelium (IPE) translocation in exudative age-related macular degeneration (ARMD) over 1 year., Methods: The consecutive interventional case series included 56 patients with exudative ARMD. During vitrectomy the submacular neovascular membrane (CNV) was removed and IPE cells, harvested from a peripheral iridectomy, were injected into the submacular space. Included were patients with subfoveal occult CNV (11 eyes), classic CNV (10 eyes), mixed CNV (17 eyes), CNV with a pigment epithelial detachment (13 eyes) or CNV with a hemorrhage (5 eyes). Outcome measures were visual acuity, foveal fixation, size of CNV and rate of recurrence based on fluorescence angiographic imaging., Results: All patients underwent successful surgical removal of the CNV with consecutive subretinal IPE injection. Visual acuity was better than 20/100 in 19 patients preoperatively and in 18 patients postoperatively. A visual acuity of 20/100 or less was found in 37 patients preoperatively and in 38 patients postoperatively. Mean preoperative visual acuity (1.0+/-0.3 logMAR units) did not change significantly after 1 year (1.0+/-0.3 logMAR units). Ten eyes (18%) developed a recurrence. Fixation within the surgically denuded area could be demonstrated in 25 eyes (45%)., Conclusions: Autologous IPE translocation for ARMD over one year can preserve foveal function on a low level, but cannot improve visual acuity. IPE translocation is technically feasible with a low rate of complications. Continued research seems justified to improve functional outcome.

Background: Macular hole surgery including vitrectomy and peeling of epiretinal membranes and the internal limiting membrane (ILM) has become a standard procedure in retinal surgery. Poor visualization of the ILM is an obstacle for successful surgery. Recently, indocyanine green (ICG) has been reported to be a helpful intraocular substance in identifying these membranes., Patients and Methods: Eighteen eyes with macular holes stages 2-4 were included. Intraoperatively, the ILM was stained with three drops of 1:9-diluted ICG. After 1 min incubation, the vitreous cavity was rinsed with Ringer's lactate solution, and the ILM was peeled. Autologous thrombocytes were applied to the macular hole and the eye was endotamponaded with 20% SF-6 gas. Preoperatively, 6 weeks postoperatively, and in 3-month intervals thereafter, visual acuity, fundus photographs, scanning laser ophthalmoscope imaging, and Humphrey 24-2 static perimetry was performed., Results: Intraoperatively, the ILM could be nicely visualized by ICG, which allowed easier and less traumatic peeling. At 6 weeks follow-up, visual acuity had improved in 14 of 18 patients, and the macular hole was closed 6 weeks after surgery. Scanning laser imaging revealed a strong signal. During prolonged follow-up, visual acuity declined due to cataract formation., Conclusion: ICG as an intraocular tool for staining of the ILM is helpful in macular hole surgery. We observed no negative effects on retinal function, but patients should be followed.

Background: Central retinal artery occlusion causes severe loss of vision. Treatment trials include massage of the globe, paracentesis, antiglaucomatous eye drops, haemodilution or lysis therapy, which in individual cases did improve the visual outcome, although in general the prognosis remains poor. In this study we applied hyperbaric oxygenation treatment additionally to haemodilution to overcome retinal ischaemia until spontaneous recanalisation of the central retinal artery occurs., Patients and Methods: Patients with central retinal artery occlusion and onset of symptoms up to 12 h were included. Following initial ocular massage and application of antiglaucomatous eyedrops, hyperbaric oxygenation treatment was performed twice daily for up to three days., Results: 21 patients could be included. The time lag between onset of symptoms and admission was between 4 and 12 h. Initial visual acuity ranged from light perception to 0.08. On discharge 19 patients reported on a subjective visual improvement which could be confirmed in 13 patients. In 9 patients an initial increase of visual acuity under hyperbaric oxygenation treatment could be observed which however was again reduced by at least one line on discharge. No patient experienced vision loss below admission vision., Conclusions: Hyperbaric oxygenation treatment seems to improve the visual outcome in central retinal artery occlusion. Major parameters for visual prognosis are the time lag from the onset of symptoms to the beginning of hyperbaric oxygenation treatment and the time lag until retinal reperfusion begins. Hyperbaric oxygenation treatment can compensate retinal ischaemia; however, the lack of glucose and accumulation of toxic metabolites is not addressed. A combination of hyperbaric oxygenation treatment with administration of glutamate antagonists or intravitreal glucose application might further improve the visual outcome.

Background: Macular hole surgery including vitrectomy and peeling of epiretinal membranes and the internal limiting membrane (ILM) has become a standard procedure in retinal surgery. Poor visualization of epiretinal membranes and the ILM is an obstacle to successful surgery. Recently, indocyanine green (ICG) has been reported to be a helpful intraocular substance in identifying these membranes., Methods: In a case of stage IV macular hole, epiretinal membranes and ILM were intraoperatively stained with three drops of 1:9 diluted ICG. After 1 min incubation the vitreous cavity was rinsed with Ringer's lactate solution, and the membranes were peeled. Autologous thrombocytes were applied to the macular hole, and the eye was endotamponaded with 20% SF6 gas. Six weeks postoperatively, visual acuity was measured and fundus photographs and autofluorescence images, as well as a multifocal ERG, were obtained., Results: Intraoperatively, the ILM could be nicely visualized by ICG, which allowed immediate peeling. Six weeks after surgery, the visual acuity had improved from 0.1 to 0.7 and the macular hole was closed. Autofluorescence imaging at 795 nm revealed a strong signal. Multifocal ERG recording showed regular amplitudes., Conclusion: ICG as an intraocular tool for staining of the ILM is helpful in macular hole surgery. We did not observe any negative effect on retinal function; however, we were surprised to identify traces of ICG in retinal fluorescein angiography images 6 weeks postoperatively.

Background: This prospective, non-controlled pilot study investigates the practicability of IPE translocation and functional outcome in ARMD patients. Removal of submacular choroidal neovascularization (CNV) in age-related macular degeneration (ARMD) is usually associated with RPE damage and poor visual prognosis. Homologous RPE transplants fail to preserve macular function, possibly due to immune rejection. Instead of homologous RPE, we suggest translocating autologous iris pigment epithelium (IPE), building on earlier evidence from animal and in vitro investigations that IPE can substitute RPE functions in the experimental animal. Immunological cell rejection is avoided., Methods: Four eyes with well-defined and eight eyes with ill-defined subfoveal CNV were submitted to operation and followed up for a minimum of 6 months. IPE cells were harvested from a peripheral iridectomy. A vitrectomy was performed. Submacular membranes were removed, and isolated IPE cells were injected into the subretinal space. Examinations included ETDRS visual acuity, fluorescein angiography, and SLO microperimetry., Results: All patients underwent successful surgical removal of CNV and subretinal IPE injection. Compared to preoperative visual acuity (20/400-20/100) no significant change was observed after 6 months (20/320-16/80). A change of more than two ETDRS chart lines was defined as significant. One eye with preoperative ill-defined CNV developed a recurrence, leading to reduced visual acuity. In all patients, postoperative fluorescence angiography revealed early hyperfluorescence (window defect) in the surgically denuded area. Central fixation was demonstrated in 50% of eyes., Conclusions: Preliminary data suggests that IPE translocation in submacular surgery for ARMD can preserve but not improve preoperative visual acuity over 6 months. Functional results are promising compared to submacular membrane extraction alone and RPE transplantation. Continued research on improvement of IPE translocation seems justified.

Purpose: We analyzed indocyanine green (ICG) angiograms in a patient with presumed ocular histoplasmosis syndrome (POHS) complaining about "seeing spots" and decreased visual acuity in order to identify the pathologic process., Patients and Methods: A 30-year-old caucasian man with clinical signs of POHS who had previously undergone laser photocoagulation for secondary choroidal neovascularization developed visual disturbances primarily in his temporal visual field. We performed fundus photography, fluorescein angiography and ICG angiography before, during and after the episode of visual disturbance. ICG angiographic findings were correlated to fundus photographs and fluorescein angiograms., Results: Fundus examination, fluorescein angiograms and early-phase ICG angiograms were unremarkable at all time points. However, during the phase of visual disturbance, late-phase ICG angiographic study revealed hypofluorescent lesions in the area representing the visual disturbances. At 1 week follow-up, these hypofluorescent lesions were reduced in size and number; at 6 months follow-up they had completely resolved., Conclusions: Late-phase ICG angiographic study can provide additional information in inflammatory retinal disease by virtue of identifying areas of choroidal alterations while standard diagnostic examination remain unremarkable.

Aims: To determine whether indocyanine green (ICG) guided laser photocoagulation of occult choroidal neovascularisations (OCNV) is beneficial for patients with occult choroidal neovascularisation secondary to age related macular degeneration (AMD)., Methods: A prospective pilot study was performed in 21 eyes with OCNV secondary to AMD that could be identified extrafoveolarly or juxtafoveolarly in an early ICG angiographic study. Laser photocoagulation was applied to the neovascular membrane identified in the early ICG angiographic study., Results: Visual acuity ranged from 20/400 to 20/20 (logMAR 0.54 (SD 0.29) before and hand movements and 20/30 (logMAR 0.81 (0.69)) at the last follow up after laser photocoagulation. During the follow up (30 (13) months) vision improved in four eyes (two lines), in seven eyes the initial visual acuity could be stabilised (two lines), in five eyes vision dropped moderately (three to five lines), and in five eyes vision decreased severely (six or more lines). Recurrences (seven patients) or persistent CNV (six patients) was observed in 13 patients., Conclusion: This preliminary study of ICG guided laser photocoagulation of occult extrafoveal and juxtafoveal choroidal neovascularisations suggests that this technique may improve the visual prognosis of these patients. Further prospective controlled studies are necessary to confirm these data.

Background: Occult choroidal neovascularisation secondary to age-related macular degeneration cause severe visual loss due to exsudation, hemorrhage and fibrovascular scarring. So far, no efficient treatment of this condition could be established. Recently, some publications described an improved prognosis after low-dose radiation therapy of the neovascular membranes., Patients and Methods: Patients with occult choroidal neovascularisation as defined by the Macular Photocoagulation Study were inclosed in our study. Irradiation with Photons (10 to 12 MeV) in fractions of 5 x 2 Gy were administered. At three-month follow-up intervals visual acuity a complete ophthalmological examination including visual acuity, fluorescein- and ICG-angiography as well as fundus photography was performed., Results: In our study 64 patients (74 +/- 7 years) with occult CNV secondary to AMD were included. Follow-up was between 3 and 39 months (14.5 +/- 10). Compared to studies who investigated the natural history of this disease, the visual acuity measured in our study did not differ significantly from the natural course., Conclusions: Our results do not support the general use of radiation therapy in patients with occult choroidal neovascularisation secondary to AMD. However, the controlled multicenter studies might provide a better basis for a general recommendations.

Background: At present no satisfying treatment for subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) is available. Visual results after successful surgical removal of subfoveal CNV are disappointing. This has been explained by a primary dysfunction of the retinal pigment epithelium (RPE) in the macular region and the surgical trauma to the RPE in patients with AMD. Therefore, Machemer and Steinhorst developed a technique for macular translocation after surgical removal of subfoveal CNV. We report our first experiences with this technique in patients with subfoveal CNV secondary to AMD., Methods: Seven patients aged between 71 and 83 years with subfoveal CNV were included in the study. Visual acuity of the fellow eyes was below 20/400. All patients underwent pars plana vitrectomy. Retinal detachment was produced by subretinal infusion of balanced salt solution and a 360 degrees retinotomy at the base of the vitreous was performed. After removal of the CNV, retinal rotation and reattachment, the retina bordering the retinotomy was coagulated with endolaser photocoagulation. Silicone oil was used as temporary tamponade., Results: In all patients the subfoveal CNV was removed and the macula was translocated by a 15 degrees-45 degrees rotation onto functional RPE. The mean duration of follow-up was 11 +/- 3 months. Initial visual acuity ranged from 20/80 to hand movements. Final visual acuity was 20/100 to 20/400. Initially all patients complained of tilted vision. During follow-up the rotation of the image regressed and was well tolerated by all patients. Complications included the development of retinal detachment in three patients after silicone oil removal, development of a macula pucker, and a significant increase of lens opacity in the phakic eyes., Conclusion: In our series rapid improvement of visual function was observed in one patient only, even if the macula appeared ophthalmoscopically and angiographically normal. Vitreoretinal complications occurred frequently during follow-up.

Purpose: The authors sought to determine the effect of genistein, a naturally occurring protein tyrosine kinase inhibitor, in a model of ischemia-reperfusion injury in the rat retina., Methods: Ischemia-reperfusion injury was induced by temporary optic nerve ligation. A dose of 0.034 mg, 0.34 mg, and 3.4 mg of genistein or dimethyl sulfoxide (DMSO) alone was injected intraperitoneally 1 hour before the ligation of the optic nerve and just after the start of reperfusion. After 48 hours of reperfusion, the effect of genistein on overall protein tyrosine phosphorylation in the retina was studied using Western blot analysis. After 168 hours, the effect of increasing doses of genistein on retinal degeneration was examined by quantitative morphometric analysis of histologic sections of the retina., Results: The authors found that tyrosine phosphorylation was increased after 48 hours of reperfusion in the ischemia-reperfusion-injured eyes treated with DMSO alone. A severe inner retinal degeneration was observed in the animals treated with DMSO alone after 168 hours of reperfusion. The treatment with 3.4 mg genistein inhibited the increase in tyrosine phosphorylation and protected the eyes significantly from the induced ischemic retinal degeneration by morphometric analysis of the mean thickness of the inner limiting membrane to the outer limiting membrane, the inner plexiform layer, and the inner nuclear layer (P < 0.02). Treatments with lower amounts of genistein (0.034 mg and 0.34 mg) did not show a significant protection of retinal degeneration after the injury., Conclusions: Systemic administration of high dose of genistein, a dietary-derived isoflavone, can ameliorate an ischemia-reperfusion-induced retinal degeneration. Genistein may be useful to prevent neuronal degeneration in the inner retina as a result of ischemic injury.