Kahook Dual-Blade Goniotomy with and without Phacoemulsification in Medically Uncontrolled Glaucoma.

Purpose: To evaluate the 2-year efficacy and safety of Kahook dual-blade (KDB) goniotomy in patients with medically uncontrolled glaucoma. Methods: This was a retrospective case-series study of 90 consecutive patients with primary open-angle glaucoma (POAG) or pseudoexfoliation glaucoma (PEXG) that underwent KDB goniotomy alone (KDB-alone group) or KDB goniotomy in combination with phacoemulsification (KDB-phaco group) during 2019-2020. All patients were uncontrolled on three or more medications. Surgical success was defined as an IOP reduction ≥20% and/or a reduction of one or more medications at 24 months. We also report IOP levels and number of medications from baseline to 24 months, as well as the need for further glaucoma interventions. Results: At 24 months, mean IOP had reduced from 24.8±8.3 to 15.0±5.3 mmHg in the KDB-alone group (P<0.001) and from 22.3±5.8 to 13.9±3.0 mmHg in the KDB-phaco group (P<0.001). Medications had reduced from 3.5±0.6 to 3.1±0.9 in the KDB-alone group (P=0.047) and from 3.3±0.5 to 2.3±1.1 in the KDB-phaco group (P<0.001). An IOP reduction ≥20% and/or a reduction with one or more medications was achieved by 47% of eyes in the KDB-alone group and by 76% of eyes in the KDB-phaco group. Eyes with PEXG and POAG responded equally well to the success criteria. During the 24-month follow-up, additional glaucoma surgery or transscleral photocoagulation was performed in 28% of eyes in the KDB-alone group and in 12% of eyes in the KDB-phaco group. Conclusion: In patients with medically uncontrolled glaucoma, KDB had a significant IOP-lowering effect after 24 months, but success rates were higher when KDB was performed in combination with cataract surgery compared to stand-alone treatment.

A Review on Pathogens and Necessary Diagnostic Work for Bleb-Related Infections (BRIs).

At the present time, as newer techniques and minimally invasive procedures gain popularity among anterior segment surgeons for regulating intraocular pressure, trabeculectomy still has a leading role in glaucoma surgery. Trabeculectomy retains a highly successful and safe profile; however, one of the major complications includes bleb-related infections (BRIs). To date, the most common pathogens remain Gram-positive cocci, but the list of pathogens that have been identified in the literature includes more than 100 microorganisms. Because antibiotic use is more widespread than ever before and our ability to identify pathogens has improved, the pathogen spectrum will broaden in the future and more pathogens causing BRIs will be described as atypical presentations. The scope of this review was to identify all pathogens that have been described to cause bleb-related infections to date, as well as focus on the risk factors, clinical presentation, and various available diagnostic tools used for an appropriate diagnostic workup.

Effectiveness of MicroShunt in Patients with Primary Open-Angle and Pseudoexfoliative Glaucoma: A Retrospective European Multicenter Study.

PURPOSE: To evaluate the effectiveness and safety of the Preserflo MicroShunt implant (Santen) in patients with primary open-angle glaucoma (POAG) and pseudoexfoliation glaucoma (PXG). DESIGN: Retrospective, open-label, multicenter study. PARTICIPANTS: Patients with insufficiently controlled primary POAG or PXG who underwent a standalone MicroShunt implantation procedure. METHODS: Consecutive patients with POAG and PXG who underwent surgery with the ab externo minimally invasive glaucoma surgery device Preserflo MicroShunt with mitomycin C. MAIN OUTCOME MEASURES: Primary end points were mean change in intraocular pressure (IOP) and number of hypotensive medications from baseline through month 12. Success was defined as an IOP of 18 mmHg or less and an IOP reduction of 20% or more, with (qualified) or without (complete) any hypotensive medication. RESULTS: Among the 130 patients who underwent MicroShunt implantation, 104 fulfilled the inclusion and exclusion criteria and were included in the analysis. Eighty-one eyes (77.9%) were diagnosed with POAG and 23 eyes (22.1%) were diagnosed with PXG. The mean age was 71.4 ± 12.6 years, and 45 patients (43.3%) were women. Mean IOP was lowered significantly from 25.1 ± 6.5 mmHg at baseline to 14.1 ± 3.4 mmHg at month 12 (P < 0.0001). At month 12, 27 eyes (26.0%) were categorized as complete successes and 61 eyes (58.7%) were categorized as qualified successes. The mean number of hypotensive medications was reduced significantly from 3.0 ± 1.0 medications at the preoperative visit to 0.77 ± 0.95 medication at month 12 (P < 0.001). Throughout the study, 19 eyes (18.3%) required needling and 14 eyes (13.5%) underwent surgical revision. Eight eyes (7.7%) showed hyphema and 5 eyes (4.8%) showed choroidal detachment. These were resolved with medical therapy without sequelae. Four patients underwent subsequent surgeries, and 2 patients underwent trabeculectomy (at months 3 and 6): One patient underwent transscleral cyclophotocoagulation at month 3 and 1 patient underwent MicroPulse cyclophotocoagulation at month 4. CONCLUSIONS: In this retrospective study, the MicroShunt effectively lowered IOP and the need for IOP-lowering medications.

Preserved Versus Preservative-Free Latanoprost for the Treatment of Glaucoma and Ocular Hypertension: A Post Hoc Pooled Analysis.

INTRODUCTION: To compare the tolerability and efficacy of a preservative-containing latanoprost (PCL) to a preservative-free formulation of latanoprost (PFL) in patients with open-angle glaucoma or ocular hypertension. METHODS: A pooled analysis was performed of data from five published studies. The primary outcome was tolerability as evaluated by the severity of hyperemia. The secondary objectives were patient tolerance based on a composite ocular surface disease (OSD) score arising from ocular signs and symptoms, patient and investigator satisfaction, and a comparison of IOP-lowering efficacy. RESULTS: There were three randomized controlled trials and two observational studies included in the analysis. Conjunctival hyperemia improved significantly in 25.6% (388) of patients switched to the PFL group versus 11.7% (117) of patients switched to the PCL group (p < 0.001). PFL was two times superior to PCL in reducing ocular hyperemia (odds ratio = 1.96; p < 0.001). The mean OSD composite score decreased by 32.2% in patients switched to the PFL group and 14.1% in the PCL group (p < 0.001). At 3 months, the mean IOP was similar between groups (p = 0.312). CONCLUSION: This post hoc pooled analysis confirmed the findings of the individual studies that PFL is as efficacious at reducing IOP as PCL but better tolerated. After switching to PFL, there was twice the improvement in the OSD composite score. PFL was twice as effective at reducing ocular hyperemia and other ocular signs. These findings suggest that PFL has features that may improve patient compliance, thereby potentially improving the IOP-lowering efficacy on a long-term basis.

Preservatives in eye drops for glaucoma can cause side effects such as stinging and eye redness. These side effects can cause some patients to reduce the frequency of the drops as prescribed or stop using the drops. One of the most common drops for glaucoma is latanoprost. This study evaluated whether a preservative-free latanoprost (PFL) is as effective as preservative-containing latanoprost (PCL) for reducing eye pressure and whether PFL is better tolerated in patients with glaucoma. The results of the study indicated that PFL was as effective as PCL for reducing eye pressure. The results also indicated PFL was much better at reducing the side effects related to PCL. For example PFL reduces eye redness up to twofold compared to PCL. By reducing the side effects associated with PCL patients may continue to take their glaucoma drops as directed and thereby reduce the risk of vision loss from glaucoma.

Kahook Dual Blade Goniotomy vs iStent inject: Long-Term Results in Patients with Open-Angle Glaucoma.

PURPOSE: Efficacy and safety evaluation of Kahook Dual Blade (KDB) goniotomy vs iStent inject implantation. MATERIALS AND METHODS: Retrospective study in patients that underwent goniotomy with KDB or iStent inject implantation, stand-alone or combined with cataract surgery. Main outcome parameters were intraocular pressure (IOP), number of glaucoma medications, proportion of eyes achieving >20% IOP reduction and number of eyes with postoperative IOP <19 mmHg at last follow-up. RESULTS: A total of 29 patients (30 eyes) were included in the iStent inject group and 30 patients (32 eyes) in the KDB group. Mean follow-ups were 20.9±6.5 (KDB-alone) to 29.5±7.6 (phaco-iStent inject) months. Pre- and post-operative IOPs were 22.2±5.8 mmHg and 15.9±4.3 mmHg (P=0.004) in the KDB-alone, 24.2±6.8 mmHg and 16.2±6.7 mmHg (P=0.001) in the phaco-KDB, 20.6±5.4 mmHg and 20.9±6.8 mmHg (P=0.598) in the iStent inject-alone as well as 20.9±5.5 mmHg and 15.6±3.4 mmHg (P=0.003) in the phaco-iStent inject subgroups. No major complications occurred. CONCLUSION: All KDB and iStent subgroups except the stand-alone iStent inject subgroup showed a clinically significant IOP-lowering effect as a stand-alone procedure or combined with cataract surgery. Goniotomy with KDB in this setting seems to offer an advantageous IOP reduction compared to iStent inject.

XEN® Gel Stent: A Comprehensive Review on Its Use as a Treatment Option for Refractory Glaucoma.

The XEN Gel Microstent is a subconjunctival microinvasive glaucoma surgical device developed with the aim of improving the predictability and safety profile of bleb-forming glaucoma surgical procedures. The stent is a hydrophilic tube composed of a porcine gel cross-linked with glutaraldehyde with good stability and biocompatibility with minimal tissue reaction. This device has demonstrated promising outcomes with fewer risks compared to traditional surgeries. The aim of the review is to present early studies on different designs of the XEN Gel Stent, to summarize different surgical techniques of implantation and to analyze more comprehensively the results, complications and rates of needling of the commercially available device (Xen 45). The review will address separately special cases (PXG, UVG, ICE, congenital glaucoma) and describe small series and case reports.

European study of the efficacy of a cross-linked gel stent for the treatment of glaucoma.

PURPOSE: To investigate the efficacy and safety of a cross-linked gel stent (XEN45) with or without cataract surgery in the treatment of glaucoma patients. SETTING: Five university hospitals. DESIGN: Prospective multicenter clinical trial. METHODS: Patients with glaucoma inadequately controlled by treatment or poor compliance or intolerance to topical therapy were included. Patients were divided into those who had an implant only (Solo Group; phakic and pseudophakic patients) and those who had an implant combined with cataract surgery (Combo Group). Differences in mean intraocular pressure (IOP) and number of medications between the baseline preoperative visit and study end (12 months), and the rate of qualified and complete success, were evaluated. RESULTS: The Solo Group comprised 115 glaucoma patients (43 phakic and 72 pseudophakic) and the Combo Group comprised 56 patients. Compared with baseline, mean IOP (23.9 ± 7.6 to 15.5 ± 3.9) and number of medications (3.0 ± 1.1 to 0.5 ± 1.0) decreased significantly at 12-month follow-up (P < .001 for both). A >20% and >30% reduction in IOP from baseline was achieved by 72.3% and 52.6% of patients, respectively. IOP at 1 week postoperatively was a predictor of success, and the needling rate was inversely correlated with early postoperative IOP. The number of preoperative medications and patient age were not significantly associated with failure. CONCLUSIONS: Insertion of a cross-linked gel stent alone or combined with phacoemulsification might be effective and safe in the treatment of open-angle glaucoma, with a substantial reduction in IOP and number of medications.

Better tolerance of preservative-free latanoprost compared to preserved glaucoma eye drops: the 12-month real-life FREE study.

BACKGROUND: Lack of efficacy due to bad compliance caused by intolerance issues is the main reason for a change to a better tolerated ocular treatment, such as using preservative-free (PF) eye drops. AIM: To assess the efficacy and local tolerance after 12 months and patient satisfaction regarding local treatment tolerance and handling at inclusion and after 6 months of PF latanoprost compared to preserved glaucoma eye drops. METHODS: This was an international, prospective, and observational real-life study. Up to three visits, one at inclusion and two follow-up visits (one after 6 and one after 12 months) were planned. Efficacy, local tolerance, and patient satisfaction were the main evaluation criteria. RESULTS: Data from 721 patients were available for the statistical analysis. Overall, 64.8% (467/721) of patients switched treatment before inclusion: 62.2% in the preserved and 68.9% in the PF latanoprost group. IOP values were similar between PF latanoprost and preserved eye drops and remained stable at all visits. Ocular signs and symptoms improved after switching to PF latanoprost; the prevalence of conjunctival hyperemia was significantly lower (P=0.0015) at both follow-up visits. At follow-up visit 1, 49.5% of the patients who switched to PF latanoprost decreased or stopped the use of artificial tears. Satisfaction regarding tolerance in patients using PF latanoprost improved significantly after the switch from preserved eye drops to PF latanoprost (88.9% and 42.5%, respectively, P<0.0001). CONCLUSION: This first real-life study showed that PF latanoprost was as efficacious but better tolerated than preserved eye drops over a sustained period of 12 months, while providing a significantly higher patient satisfaction and potentially allowing improvement in the patient's daily life.

Needling With 5-Fluorouracil (5-FU) After XEN Gel Stent Implantation: 6-Month Outcomes.

PURPOSE: The purpose of this study was to evaluate frequency, safety, and efficacy of needling in patients that underwent XEN Gel Stent implantation. METHODS: Retrospective case review of 19 eyes of 57 consecutive patients (61 eyes) with primary open-angle glaucoma or pseudoexfoliative glaucoma that previously underwent implantation of XEN45 alone or in combination with cataract surgery followed by needling procedure with 5-FU. Success was defined at 2 IOP levels: ≤21 mm Hg and ≤15 mm Hg, with or without additional glaucoma medications. Treatment failure was defined as IOP>21 mm Hg or <5 mm Hg, need for additional glaucoma surgery or loss of light perception. RESULTS: Totally 19 of 61 eyes that underwent XEN gel implantation had subsequent needling and were included. Preneedling IOP was 26.2±9.5 and postneedling IOP at last follow-up 15.4±3.7 mm Hg (P=0.0001). Overall success rates of 17 (90%) and 13 eyes (69%) were observed at the ≤21 mm Hg and ≤15 mm Hg level, respectively. Preneedling and postneedling visual acuity and number of medications remained unchanged (P>0.05). Two eyes (10%) were categorized as treatment failures. No major complications occurred. Mean follow-up was 203.8±142.2 (range, 22 to 456) days. CONCLUSIONS: Needling revision following XEN gel stent implantation showed a good IOP-lowering effect without significant increase in number of antiglaucoma medications, decrease in visual acuity, nor any major complications. Further studies with long-term follow-up and a larger number of patients are needed to fully assess the safety and efficacy of this procedure.

Reversible Cystoid Macular Edema Following Uneventful Microinvasive Kahook Dual Blade Goniotomy in a Pseudophakic Patient: A Case Report.

PURPOSE: The purpose of this study is to present a case of cystoid macular edema (CME) as a potential complication following uncomplicated stand-alone Kahook Dual Blade (KDB) goniotomy in a patient with pseudoexfoliative glaucoma. METHODS: A 71-year-old woman who developed CME following KDB goniotomy subsequently treated with topical nonsteroidal anti-inflammatory (NSAID) therapy. RESULTS: The CME successfully regressed following a standard course of topical NSAID therapy. CONCLUSIONS: This case report describes the first case of CME following uneventful stand-alone KDB goniotomy and highlights the importance of postoperative topical NSAID therapy with regard to both prophylaxis and treatment.

JARID1B protein expression and prognostic implications in uveal melanoma.

PURPOSE: It has been suggested recently that stem cell marker expression of jumonji AT-rich interactive domain 1B (JARID1B) is required for continuous tumor growth and maintenance in human cutaneous melanoma cells. The aim of this study is to determine whether JARID1B is also expressed in uveal melanoma (UM) and whether JARID1B marks an expanded cancer stem cell pool in poor prognosis UM. Based on the available data, this is the first time JARID1B expression in UM has been studied. METHODS: A total of 121 consecutive patients diagnosed with UM and who underwent enucleation were included in the study. Immunohistochemical staining with JARID1B antibodies was performed and immunoreactivity was assessed. Correlations of JARID1B expression with established clinicopathological parameters and overall survival (OS) were evaluated in univariate and multivariate analyses. RESULTS: JARID1B positive expression, as defined by >0% staining, was present in 55% of UMs and invariably in ciliary body epithelium. The correlation between JARID1B negative expression and JARID1B expression >5% inside the tumor tissue and OS was borderline statistically significant based on LogRank test at 5% significance level (P = 0.06). There were significantly more JARID1B positive cells in tumors with extrascleral extension than in tumors with no or minimal intrascleral invasion (P < 0.01, Mann-Whitney test). CONCLUSIONS: This study demonstrates that JARID1B is expressed by UM cells. Despite that JARID1B was highly expressed in UM, a statistically significant association (P < 0.05) between JARID1B expression and OS could not be obtained. However, a P-value of 0.06 could suggest that high JARID1B expression is correlated with lower survival; thus, a follow up study with a greater patient sample is recommended. In addition, samples of tumors characterized by high invasiveness showed a higher JARID1B expression. Furthermore, this study substantiates the presence of progenitor cells in the ciliary body epithelium.

Nuclear HER3 is associated with favorable overall survival in uveal melanoma.

HER3 is a member of the epidermal growth factor receptor (EGFR) family and is expressed in several types of cancer. Both the cytoplasmic and nuclear appearances of the receptor have been reported. Here, we investigate the expression and subcellular distribution of HER3 in uveal melanoma (UM) cells and tissues and its potential impact on clinical outcome of patients. Paraffin-embedded samples from 128 consecutive UM patients, enucleated without alternative treatment on UM diagnosis, were evaluated for HER3 using immunohistochemistry. Immunoreactivity was scored for frequency, intensity of positive cells, and subcellular distribution. The results were correlated with the established clinicopathological parameters using univariate and multivariate statistical analyses. HER3 expression was shown in 70% of the cases (89/128). This contrasts with the other EGFR family receptors (EGFR, HER2 and HER4) that are infrequently expressed in UM. Surprisingly, HER3 was found to be localized solely in the cell nuclei in 56 cases. The remaining 33 HER3 positive cases showed diffuse distribution (cytoplasmic ± nuclear). Nuclear HER3 was independently correlated with a more favorable overall survival (p = 0.043 and hazard ratio = 0.618) compared to cases with diffuse and/or no HER3. Nuclear localization of HER3 was also confirmed in fresh UM material and in UM cell lines. In conclusion, HER3 is frequently localized solely in the cell nuclei in UM and as such it predicts a more favorable overall survival.

Intratumoral forkhead box P3-positive regulatory T cells predict poor survival in cyclooxygenase-2-positive uveal melanoma.

BACKGROUND: Forkhead box P3 (FOXP3)-positive regulatory T cells (Tregs) are key mediators of peripheral tolerance and suppress efficient antitumor responses. Prostaglandin E(2) (PGE(2)) produced by inducible cyclooxygenase-2 (COX-2) can lead to Treg induction. COX-2 expression has been linked to tumorigenesis and growth in various malignancies. The objective of the current study was to investigate whether Tregs infiltrate uveal melanomas (UMs) and whether their prevalence is linked to COX-2 expression and the prediction of overall survival (OS). METHODS: One hundred patients who underwent enucleation after they were diagnosed with UM were included in the study. Immunohistochemical staining with monoclonal anti-FOXP3, anti-CD4, and anti-COX-2 antibodies was performed, and immunoreactivity was assessed. Correlations of COX-2 expression with the presence of Tregs, established clinicopathologic parameters, and OS were evaluated in univariate and multivariate analyses. RESULTS: High expression of COX-2 was predictive of shortened OS. FOXP3-positive Tregs were detectable in 24% of UMs and were restricted to malignant tissue. The extent of COX-2 expression was associated significantly with Treg prevalence (P = .004) and Treg intratumoral localization (P = .005). Intratumoral Tregs (but not the prevalence of Tregs) were independent marker for worse OS with a hazard ratio of 5.36 in patients with COX-2-positive tumors. CONCLUSIONS: The current results demonstrated that high COX-2 expression is associated with OS and Treg prevalence in UM. These findings are in line with the observations that COX-2/PGE(2) induces Tregs and that Tregs may alter antitumor responses, resulting in a negative effect on the clinical disease course. Intratumoral Tregs are an independent prognostic marker for COX-2-positive UM, and these results put COX-2 inhibitors and Treg depletion into the spotlight of potential novel treatment modalities for patients with UM.

Expression and prognostic significance of iNOS in uveal melanoma.

Uveal melanoma (UM) is the most common primary intraocular tumor in adults. Disease metastasis occurs in half of the patients and is uniformly fatal despite systemic therapy. Inducible nitric oxide synthase (iNOS) is associated with disease progression in various malignancies including cutaneous melanoma. In this retrospective cohort, we examined the prognostic value of iNOS in UM by performing immunohistochemistry on paraffin-embedded sections of primary tumors (90 patients) and matched primary and metastatic hepatic tumors (19 patients) with complete histopathological and clinical data. We show that iNOS is expressed in UM (57% of the patients) and high iNOS levels significantly (p = 0.04; hazard ratio (HR) = 2.3) predict disease-specific survival (DSS) as assessed by Kaplan-Meier analysis and univariate Cox's proportional hazards regression model. Furthermore, high iNOS expression in the UM primary tissue was significantly associated with metastatic disease and vice versa. Expression of iNOS in hepatic metastases significantly (p = 0.02) predicted a shortened survival as assessed by Kaplan-Meier analysis. However, iNOS did not appear to be a significant (p = 0.16; HR = 1.9) factor in the multivariate Cox's regression analysis performed together with the clinical parameters tumor diameter, tumor cell type, and tumor location in which only tumor diameter predicted DSS. In conclusion, iNOS predicts DSS in UM and may play a role in disease progression but it is not an independent prognostic factor.

Receptors for the liver synthesized growth factors IGF-1 and HGF/SF in uveal melanoma: intercorrelation and prognostic implications.

PURPOSE: Uveal melanoma disseminates preferentially to the liver. The mechanism for this homing is largely unknown, but growth factors synthesized in the liver may be involved. The present study was undertaken to investigate the possible relationship between cell surface receptors for two such growth factors: the c-Met proto-oncogene, which constitutes the receptor for hepatocyte growth factor/scatter factor (HGF/SF), and the insulin-like growth factor 1 receptor (IGF-1R). Their role as a prognostic factor was also clarified. METHODS: Paraffin-embedded tumor specimens from 132 patients with primary uveal melanoma were analyzed by using well-established specific antibodies against c-Met and IGF-1R. The intercorrelation of receptor expression and association with melanoma-related survival of patients were determined by univariate and multivariate analyses. RESULTS: Whereas the expression of both IGF-1R and c-Met was significantly associated with melanoma-specific mortality by univariate analysis (p = 0.004 and p = 0.007, respectively) only IGF-1R showed independent prognostic value by multivariate analysis, p = 0.004. The prognostic value of IGF-1R was stronger than such currently used prognostic parameters as tumor cell type and tumor diameter (p = 0.021 and p = 0.026, respectively). The expression patterns of the two growth factors receptors were weakly intercorrelated. CONCLUSIONS: In conclusion, the data suggest that the receptors for IGF-1 and HGF/SF may play a role in the spread of uveal melanoma and its affinity to the liver. The strong correlation between IGF-1R expression and melanoma-specific mortality points to the use of IGF-1R as a prognostic tool [Economou MA, All-Ericsson C, Bykov V, Girnita L, Bartolazzi A, Larsson O & Seregard S (2005): Receptors for the liver synthesized growth factors IGF-1 and HGF/SF in uveal melanoma: intercorrelation and prognostic implications.

The insulin-like growth factor-I receptor inhibitor picropodophyllin causes tumor regression and attenuates mechanisms involved in invasion of uveal melanoma cells.

PURPOSE: Uveal melanoma has a high mortality rate due to a high incidence of metastasis (up to 50%) which preferentially occurs in the liver. Conventional chemotherapy being the only therapeutic option today against metastatic uveal melanoma, has not proved to be effective. Therefore, new molecular targets important for malignant phenotype of uveal melanoma have to be found to design efficient pharmacologic agents. EXPERIMENTAL DESIGN: We previously reported data indicating that the insulin-like growth factor-1 receptor (IGF-IR) is a metastasis predictor as well as a therapeutic target for uveal melanoma. In the present study, we made use of the cyclolignan picropodophyllin (PPP), which is an inhibitor of the IGF-IR. RESULT: We showed that PPP efficiently block growth and viability of uveal melanoma cells in cultures and causes tumor regression in xenografted mice. In addition, treatment with PPP inhibited several mechanism involved in metastasis, including tumor cells adhesion to extracellular matrix proteins, activity and expression of matrix metalloproteinase 2, and cell migration as well as invasion through basement membranes and endothelial cell layer. Furthermore, PPP significantly delayed established of uveal melanoma tumor and drastically reduced the incidence of liver metastasis in mice. CONCLUSIONS: Our data suggest that IGR-IR is crucial for growth and survival as well as invasion and metastasis of uveal melanoma cells. Targeting this receptor may therefore comprise a strategy to treat ongoing disease (today incurable) as well as a strategy to prevent development of metastases in patients with primary disease.

Oral picropodophyllin (PPP) is well tolerated in vivo and inhibits IGF-1R expression and growth of uveal melanoma.

PURPOSE: The cyclolignan picropodophyllin (PPP) efficiently blocks the activity of insulin-like growth factor-1 receptor (IGF-1R) and inhibits growth of uveal melanoma cells in vitro and in vivo. In this study, we aimed to investigate the efficiency of orally administered PPP on growth of uveal melanoma xenografts. Further, we focused on the effect of PPP on vascular endothelial growth factor (VEGF) in vivo and evaluated its effects in combination with other established anti-tumor agents in vitro. METHODS: Four different uveal melanoma cell lines (OCM-1, OCM-3, OCM-8, 92-1) were treated with PPP alone and in combination with imatinib mesylate, cisplatin, 5-FU and doxorubicin. Cell viability was determined by XTT assay. SCID mice xenografted with uveal melanoma cells were used to determine anti-tumor efficacy of oral PPP in vivo. Tumor samples obtained from the in vivo experiments were analyzed for VEGF and IGF-1R expression by western blotting. RESULTS: PPP was found to be superior to the other anti-tumor agents in killing uveal melanoma cells. Oral PPP inhibited uveal melanoma growth in vivo and was well tolerated by the animals. PPP decreased VEGF expression in the tumors. CONCLUSIONS: Oral PPP is well tolerated in vivo and caused total growth inhibition of uveal melanoma xenografts as well as it decreased the levels of VEGF in the tumors.

Inhibition of VEGF secretion and experimental choroidal neovascularization by picropodophyllin (PPP), an inhibitor of the insulin-like growth factor-1 receptor.

INTRODUCTION: Choroidal neovascularization (CNV) is a debilitating complication of age-related macular degeneration (AMD) and a leading cause of vision loss. Along with other angiogenic factors like vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF-1) and its receptor, IGF-1R, have been implicated in CNV. PURPOSE: We have previously shown that the cyclolignan picropodophyllin (PPP) efficiently blocks the insulin-like growth factor-1 receptor (IGF-1R) activity and causes cell death in uveal melanoma cell lines and in an in-vivo model. In this study we investigated the effect of PPP on VEGF expression both in vitro and in vivo and whether this effect has anti-angiogenic consequences in a murine CNV model. MATERIALS AND METHODS: C57BL/6J mice with laser-induced CNVs were treated with PPP. Effects on CNV area were assayed by image analysis. VEGF levels in choroids and retinal pigment epithelial cells (APRE-19) were measured by Western blot or ELISA. Transcriptional activation of the VEGF promoter was determined by luciferase reporter gene assay. RESULTS: Mice treated with PPP, administered intraperitoneally or orally, showed 22-32% (p = 0.002) decrease in CNV area. Furthermore, VEGF levels in the choroids were significantly reduced. In cultured APRE-19 cells, IGF-1 was shown to increase VEGF secretion. This increase was completely blocked by PPP. We could confirm that PPP reduced the level of transcriptional activity of VEGF promoter. CONCLUSIONS: PPP reduces IGF-1 dependent VEGF expression and CNV in vivo. Accordingly, IGF-1R inhibitors may be useful tools in the therapy of conditions associated with CNV including neovascular AMD.

Oral picropodophyllin (PPP) is well tolerated in vivo and inhibits IGF-1R expression and growth of uveal melanoma.

PURPOSE: The cyclolignan picropodophyllin (PPP) efficiently blocks the activity of insulinlike growth factor-1 receptor (IGF-1R) and inhibits the growth of uveal melanoma cells in vitro and in vivo. In this study, the authors investigated the efficiency of orally administered PPP on the growth of uveal melanoma xenografts. In addition, they focused on the effect of PPP on vascular endothelial growth factor (VEGF) in vivo and evaluated its effects in combination with other established antitumor agents in vitro. METHODS: Four different uveal melanoma cell lines (OCM-1, OCM-3, OCM-8, 92-1) were treated with PPP alone and in combination with imatinib mesylate, cisplatin, 5-fluorouracil, and doxorubicin. Cell viability was determined by XTT assay. SCID mice that underwent xenografting with uveal melanoma cells were used to determine antitumor efficacy of oral PPP in vivo. Five mice were used per group. Tumor samples obtained from the in vivo experiments were analyzed for VEGF and IGF-1R expression by Western blotting. RESULTS: PPP was found to be superior to the other antitumor agents in killing uveal melanoma cells in all four cell lines (IC50 < 0.05 microM). Oral PPP inhibited uveal melanoma growth in vivo in OCM-3 (P = 0.03) and OCM-8 (P = 0.01) xenografts and was well tolerated by the animals. PPP decreased VEGF expression in the OCM-1 (P = 0.006) and OCM-8 (P = 0.01) tumors. CONCLUSIONS: Oral PPP was well tolerated in vivo, caused total growth inhibition of uveal melanoma xenografts, and decreased VEGF levels in the tumors.