Long-term success of complex recurrent rectovaginal fistula repair.

Rectovaginal fistulas (RVF) are the cause of major affliction to the affected patient and are a foremost challenge for the attending surgeon. Traditional techniques for treatment of RVF are quite extensive and particularly invasive. A more local procedure, with an acceptable success rate, would be the ideal first approach in treatment of this particular ailment. The aim of the current study is to show the step-by-step technique to correct a complex recurrent RVF (rRVF) using a biomesh implant. A 61-year-old female, who had undergone a prior vaginal hysterectomy, presented with a complex recurrent RVF. A third attempt to repair the RVF was conducted by a surgical team with the utilization of a biomesh, which resulted in no further recurrence of symptoms or RVF for up to 4 years. Complex rRVF repair by the placement of the biomesh allows for a secure and sustainable closure with potentially better prognosis for the patients.

Radiologist Agreement for Mammographic Recall by Case Difficulty and Finding Type.

PURPOSE: The aim of this study was to assess agreement of mammographic interpretations by community radiologists with consensus interpretations of an expert radiology panel to inform approaches that improve mammographic performance. METHODS: From 6 mammographic registries, 119 community-based radiologists were recruited to assess 1 of 4 randomly assigned test sets of 109 screening mammograms with comparison studies for no recall or recall, giving the most significant finding type (mass, calcifications, asymmetric density, or architectural distortion) and location. The mean proportion of agreement with an expert radiology panel was calculated by cancer status, finding type, and difficulty level of identifying the finding at the patient, breast, and lesion level. Concordance in finding type between study radiologists and the expert panel was also examined. For each finding type, the proportion of unnecessary recalls, defined as study radiologist recalls that were not expert panel recalls, was determined. RESULTS: Recall agreement was 100% for masses and for examinations with obvious findings in both cancer and noncancer cases. Among cancer cases, recall agreement was lower for lesions that were subtle (50%) or asymmetric (60%). Subtle noncancer findings and benign calcifications showed 33% agreement for recall. Agreement for finding responsible for recall was low, especially for architectural distortions (43%) and asymmetric densities (40%). Most unnecessary recalls (51%) were asymmetric densities. CONCLUSIONS: Agreement in mammographic interpretation was low for asymmetric densities and architectural distortions. Training focused on these interpretations could improve the accuracy of mammography and reduce unnecessary recalls.

Randomized clinical trial of dexketoprofen/tramadol 25 mg/75 mg in moderate-to-severe pain after total hip arthroplasty.

BACKGROUND: The aim was to evaluate the analgesic efficacy and safety of the dexketoprofen/tramadol 25 mg/75 mg fixed-dose combination vs dexketoprofen (25 mg) and tramadol (100 mg) in moderate-to-severe acute pain after total hip arthroplasty. METHODS: This was a randomized, double-blind, parallel-group study in patients experiencing pain of at least moderate intensity on the day after surgery, compared with placebo at first administration to validate the pain model. The study drug was administered orally every 8 h throughout a 5 day period. Rescue medication, metamizole 500 mg, was available during the treatment period. The evaluation of efficacy was based on patient assessments of pain intensity and pain relief. The primary end point was the mean sum of the pain intensity difference values throughout the first 8 h (SPID8). RESULTS: Overall, 641 patients, mean age 62 (range 29-80) yr, were analysed; mean (sd) values of SPID8 were 247 (157) for dexketoprofen/tramadol, 209 (155) for dexketoprofen, 205 (146) for tramadol, and 151 (159) for placebo. The primary analysis confirmed the superiority of the combination over dexketoprofen 25 mg (P=0.019; 95% confidence interval 6.4-73) and tramadol 100 mg (P=0.012; 95% confidence interval 9.5-76). The single components were superior to placebo (P<0.05), confirming model sensitivity. Most secondary analyses supported the superiority of the combination. The incidence of adverse drug reactions was low and similar among active treatment groups. CONCLUSION: The efficacy results confirmed the superiority of dexketoprofen/tramadol over its single components, even at higher doses (tramadol), with a safety profile fully in line with that previously known for these agents in monotherapy. CLINICAL TRIAL REGISTRATION: EudraCT 2012-004548-31 (https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-004548-31);ClinicalTrials.gov NCT01902134 (https://www.clinicaltrials.gov/ct2/show/NCT01902134?term=NCT01902134&rank=1).

Lipids, obesity and gallbladder disease in women: insights from genetic studies using the cardiovascular gene-centric 50K SNP array.

Gallbladder disease (GBD) has an overall prevalence of 10-40% depending on factors such as age, gender, population, obesity and diabetes, and represents a major economic burden. Although gallstones are composed of cholesterol by-products and are associated with obesity, presumed causal pathways remain unproven, although BMI reduction is typically recommended. We performed genetic studies to discover candidate genes and define pathways involved in GBD. We genotyped 15,241 women of European ancestry from three cohorts, including 3216 with GBD, using the Human cardiovascular disease (HumanCVD) BeadChip containing up to ~ 53,000 single-nucleotide polymorphisms (SNPs). Effect sizes with P-values for development of GBD were generated. We identify two new loci associated with GBD, GCKR rs1260326:T>C (P = 5.88 × 10(-7), ß = -0.146) and TTC39B rs686030:C>A (P = 6.95 x 10(-7), ß = 0.271) and detect four independent SNP effects in ABCG8 rs4953023:G>A (P=7.41 × 10(-47), ß = 0.734), ABCG8 rs4299376:G(>)T (P = 2.40 × 10(-18), ß = 0.278), ABCG5 rs6544718:T>C (P = 2.08 × 10(-14), ß = 0.044) and ABCG5 rs6720173:G>C (P = 3.81 × 10(-12), ß(=)0.262) in conditional analyses taking genotypes of rs4953023:G>A as a covariate. We also delineate the risk effects among many genotypes known to influence lipids. These data, from the largest GBD genetic study to date, show that specific, mainly hepatocyte-centred, components of lipid metabolism are important to GBD risk in women. We discuss the potential pharmaceutical implications of our findings.

Clinical experiences with cartilage repair techniques: outcomes, indications, contraindications and rehabilitation.

Untreated articular cartilage defects may lead to chronic joint degeneration and functional disability. In the past decade, several cartilage repair techniques have emerged for the treatment of cartilage lesions. Among these techniques, mosaicplasty was introduced by the senior author into the clinical practice in 1992. This article does not intend to give a review or a comparison of currently existing surgical techniques which aim to repair symptomatic focal defects; however, it focuses on the procedures used in the everyday practice in the authors' institute, namely microfracture, mosaicplasty, autologous chondrocyte implantation (ACI), osteochondral allograft transplantation and biodegradable osteochondral scaffolds. It gives a brief summary of these well-described techniques, summarizes the authors' clinical experience and available data on the clinical outcome, and the rehabilitation protocol following different procedures, with a special emphasis on mosaicplasty.

Vascular endothelial growth factor levels in tears of patients with retinal vein occlusion.

PURPOSE: We measured vascular endothelial growth factor (VEGF) levels in tear fluid and serum in patients with retinal vein occlusion (RVO). PATIENTS AND METHODS: Eight patients with RVO due to secondary macular oedema were examined. VEGF levels were measured by enzyme-linked immunosorbent assay. All patients had a full ophthalmic examination (visual acuity, slit lamp biomicroscopy, perimetry, and fluorescein angiography). Central retinal thickness (CRT) was examined using optical coherence tomography (OCT). Tear and serum samples were collected and examinations were performed at diagnosis and 1 and 4 weeks later. RESULTS: VEGF levels in the tears of RVO eyes were significantly higher than in fellow eyes at diagnosis and after both 1 and 4 weeks (paired t test, p1 = 0.01, p2 = 0.02, p3 = 0.006). We found a weak but significant positive correlation between VEGF levels in tear fluid and serum of patients with RVO (r = 0.21), while this correlation tended to be stronger between the fellow eyes and serum levels (r = 0.33). CONCLUSION: To the best of our knowledge, we are the first to report an increased level of VEGF in the tear fluid of patients with RVO. Alterations of VEGF levels in tears may be useful for determining stages of RVO. This non-invasive and objective method may also be helpful for estimating the severity of macular oedema and efficacy of treatment.

Nerve stretch injury induced pain pattern and changes in sensory ganglia in a clinically relevant model of limb-lengthening in rabbits.

We used a model of tibial lengthening in rabbits to study the postoperative pain pattern during limb-lengthening and morphological changes in the dorsal root ganglia (DRG), including alteration of substance P (SP) expression. Four groups of animals (naive; OG: osteotomized only group; SDG/FDG: slow/fast distraction groups, with 1 mm/3 mm lengthening a day, respectively) were used. Signs of increasing postoperative pain were detected until the 10(th) postoperative day in OG/SDG/FDG, then they decreased in OG but remained higher in SDG/FDG until the distraction finished, suggesting that the pain response is based mainly on surgical trauma until the 10(th) day, while the lengthening extended its duration and increased its intensity. The only morphological change observed in the DRGs was the presence of large vacuoles in some large neurons of OG/SDG/FDG. Cell size analysis of the S1 DRGs showed no cell loss in any of the three groups; a significant increase in the number of SP-positive large DRG cells in the OG; and a significant decrease in the number of SP-immunoreactive small DRG neurons in the SDG/FDG. Faster and larger distraction resulted in more severe signs of pain sensation, and further reduced the number of SP-positive small cells, compared to slow distraction.

Reported mammographic density: film-screen versus digital acquisition.

PURPOSE: To test the hypothesis that American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) categories for breast density reported by radiologists are lower when digital mammography is used than those reported when film-screen (FS) mammography is used. MATERIALS AND METHODS: This study was institutional review board approved and HIPAA compliant. Demographic data, risk factors, and BI-RADS breast density categories were collected from five mammography registries that were part of the Breast Cancer Surveillance Consortium. Active, passive, or waiver of consent was obtained for all participants. Women aged 40 years and older who underwent at least two screening mammographic examinations less than 36 months apart between January 1, 2000, and December 31, 2009, were included. Women with prior breast cancer, augmentation, or use of agents known to affect density were excluded. The main sample included 89 639 women with both FS and digital mammograms. The comparison group included 259 046 women with two FS mammograms and 87 066 women with two digital mammograms. BI-RADS density was cross-tabulated according to the order in which the two types of mammogram were acquired and by the first versus second interpretation. RESULTS: Regardless of acquisition method, the percentage of women with a change in density from one reading to the next was similar. Breast density was lower in 19.8% of the women who underwent FS before digital mammography and 17.1% of those who underwent digital before FS mammography. Similarly, lower density classifications were reported on the basis of the second mammographic examination regardless of acquisition method (15.8%-19.8%). The percentage of agreement between density readings was similar regardless of mammographic types paired (67.3%-71.0%). CONCLUSION: The study results showed no difference in reported BI-RADS breast density categories according to acquisition method. Reported BI-RADS density categories may be useful in the development of breast cancer risk models in which FS, digital, or both acquisition methods are used.

Radiologist agreement for mammographic recall by case difficulty and finding type.

PURPOSE: The aim of this study was to assess agreement of mammographic interpretations by community radiologists with consensus interpretations of an expert radiology panel to inform approaches that improve mammographic performance. METHODS: From 6 mammographic registries, 119 community-based radiologists were recruited to assess 1 of 4 randomly assigned test sets of 109 screening mammograms with comparison studies for no recall or recall, giving the most significant finding type (mass, calcifications, asymmetric density, or architectural distortion) and location. The mean proportion of agreement with an expert radiology panel was calculated by cancer status, finding type, and difficulty level of identifying the finding at the patient, breast, and lesion level. Concordance in finding type between study radiologists and the expert panel was also examined. For each finding type, the proportion of unnecessary recalls, defined as study radiologist recalls that were not expert panel recalls, was determined. RESULTS: Recall agreement was 100% for masses and for examinations with obvious findings in both cancer and noncancer cases. Among cancer cases, recall agreement was lower for lesions that were subtle (50%) or asymmetric (60%). Subtle noncancer findings and benign calcifications showed 33% agreement for recall. Agreement for finding responsible for recall was low, especially for architectural distortions (43%) and asymmetric densities (40%). Most unnecessary recalls (51%) were asymmetric densities. CONCLUSIONS: Agreement in mammographic interpretation was low for asymmetric densities and architectural distortions. Training focused on these interpretations could improve the accuracy of mammography and reduce unnecessary recalls.

[Acanthamoeba keratitis in patients with contact lens wear in the Department of Ophthalmology in Debrecen]. / Akanthamöbenkeratitis bei Kontaktlinsenträgern in der Patientenpopulation der Augenklinik Debrecen.

BACKGROUND: With increasing numbers of contact lens wearers, Acanthamoeba infections are also more frequent all over the world and also in Hungary. Despite improved diagnostic and therapeutic possibilities it can still cause serious visual loss. In this study the symptoms, signs, diagnostics and treatment options for Acanthamoeba keratitis (AK) in patients treated in our department are presented and compared to the literature. PATIENTS AND METHODS: Between 2001 and 2006 a total of 11 patients were treated in our department for Acanthamoeba keratitis. RESULTS: The mean age of the patients was 30 years and the 8 female and 3 male patients were all contact lens wearers. In six cases the right eye was affected and in five cases the left eye. Poor and improper contact lens hygiene was the cause of infection in all cases and 82% of the infections occurred in the summer period between June and September. In addition to long-term conservative treatment, perforating keratoplasty was performed in six cases. After the therapy the best visual acuity was 0.6, but 4 of the patients had a serious visual loss. Follow-up time ranged from 6 months to 5 years. CONCLUSIONS: Early diagnosis and long-term suitable local therapy are necessary for effective recovery. If the patient wears contact lens and there is severe pain with ring infiltration in the cornea, Acanthamoeba infection should be considered and suitable therapy should be given. Immediately performed perforating keratoplasty does not lead to visual improvement. Prevention by informing the patients about adequate hygiene and use of the cleaning solutions is one of the most important tasks of contact lens specialists.

Hepatitis C virus presumably associated bilateral consecutive anterior ischemic optic neuropathy.

PURPOSE: To report a case of bilateral nonarteritic anterior ischemic optic neuropathy (NAION) in a hepatitis C (HCV) infected patient and demonstrate the relationship between HCV and the development of NAION. METHODS: Case report. RESULTS: A 43-year-old woman with chronic HCV infection and long-term euthyroid autoimmune thyroiditis suddenly lost vision in her right eye, and 6 months later in her left eye, due to NAION. Slightly elevated levels of aminotransferases suggested liver infection activity. Anti-HCV antibody was detected; the genotype of the virus was 1b and the viral RNA level was 1.8 x 106 IU/mL. Liver biopsy proved chronic active hepatitis (Ishak score grading: 7, staging: 2). Except for the elevated levels of antithyroid antibodies and a weak antinuclear factor, the detailed laboratory examinations (thrombophilia, cryoglobulin, anticardiolipin antibodies, co-infections) revealed no other abnormalities; a causative relationship between the underlying chronic hepatitis C and bilateral NAION therefore seems probable. The patient was treated with pegylated interferon and ribavirin for 1 year and a sustained viral remission could be achieved. Her vision has neither improved nor deteriorated further. CONCLUSIONS: This appears to be the first reported case of bilateral NAION presumably caused by HCV infection.

A comparison of accommodation amplitudes in pseudophakic eyes measured with three different methods.

PURPOSE: To compare the accommodative amplitudes with three different methods in pseudophakic eyes with different types of intraocular lenses (IOLs). METHODS: Fifty-one pseudophakic eyes of 44 patients (age: 72.02+/-8.53 years) were studied. One of two different types of IOL were implanted (N=30, three-piece Alcon Acrysof MA60AC and N=21, one-piece Alcon Acrysof SA60AT) in-the-bag after standard phacoemulsification. The time of the examinations was 13.85+/-7.35 months postoperatively. We measured the amplitude of accommodation with three different methods: (1) subjective minus-lenses-to-blur method; (2) a new optical device (ACMaster, Carl Zeiss, Jena, Germany) using partial coherence interference (PCI) technique under physiological stimulus; and (3) objective anterior chamber depth measuring with a standard A-scan ultrasonic device (Ultrascan Imaging System, Alcon Laboratories, Forth Worth, TX, USA) before and after pharmacological relaxation of ciliary muscle. RESULTS: We measured -0.83+/-0.63 D amplitude of accommodation with subjective minus-lenses-to-blur method. The IOL position did not change significantly during physiological accommodation effort measured with PCI method (-0.026+/-0.134 mm). The change in the IOLs position between near fixating and after ciliary muscle relaxation was -0.18+/-0.28 mm measured with ultrasound. There were no significant differences between values of one-piece and three-piece IOL groups. CONCLUSION: The amplitude of accommodation measured by subjective and objective methods are different and are not comparable with each other. We did not observe any difference between values of examined two types of IOLs.

[Experiences with the Introduction of Diagnosis Related Groups (DRG) in the Hungarian Ophthalmology]. / Erfahrungen der Umsetzung von Diagnosis Related Groups (DRG) in der ungarischen Augenheilkunde.

OBJECTIVE: The aim of our investigation is to analyse the effect of the introduction of the DRG (Diagnosis Related Groups) principle on the financing of ophthalmology care including the analysis of market share of ophthalmology. DATA AND METHODS: Data of the study derive from the financial database of the Hungarian National Health Insurance Fund Administration (OEP) containing the monthly activity reports of health care providers. The financing of acute hospital care in Hungary is based on a case-mix system called Homogeneous Disease Groups (Homogén Betegségcsoportok, HBCS). The analysis covers the period between 1995 and 2003. We used the following indicators in order to analyse the market share of ophthalmology: financial cases (patients), DRG costweights and nursing days (length of stay). RESULTS: From the DRG costweights - serving as a base value for financing - the market share of ophthalmology was 3.3 - 3.5 % in 1995 - 1996, but decreased to 2.6 - 2.7 % in 1997 - 1998, and after a gradual increase since 1999 it went up to 3.4 % in 2002 - 2003. The market share of ophthalmology from financial cases (patients) increased from 3.1 - 3.2 % in 1995 - 1996 to 3.8 - 3.9 % in 2002 - 2003. From the total number of nursing days ophthalmology had a market share of 2.4 - 2.6 % in 1995 - 1996, which showed a further decrease to 2.2 - 2.3 % in 2002 - 2003. The average length of stay in ophthalmology decreased from 8 days (1995) to 4 days (2003). CONCLUSION: The frequent changes of the Hungarian DRG system had a significant effect on the financing of Hungarian ophthalmology care. The continuous changes in the regulation of financing and reimbursement represent a big challenge for ophthalmology.

Cell proliferation and apoptosis in stromal corneal dystrophies.

The aim of our study was to evaluate corneal cell proliferation and apoptosis in cases of granular, macular and lattice dystrophy, and to provide evidence which may help to clarify whether apoptosis is a pathogenic factor in any of these dystrophies. The study group comprised 39 eyes (from 33 patients) which had undergone penetrating keratoplasty (PK) for stromal dystrophies: these comprised 12 eyes (from 9 patients, 55.5% males) with granular dystrophy, 13 eyes (12 patients, 33.3% males) with macular dystrophy, and 14 eyes (13 patients, 61.5% males) with lattice type I dystrophy. A further 4 corneal buttons from enucleated eyes of 4 patients with choroideal melanoma served as controls. Immunocytochemical analysis of Ki67 (DNAcon Kit, DakoCytomation A/S, Glostrup, Denmark) was used for evaluation of cell proliferation. Apoptosis was detected by use of the TUNEL (terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick-end labelling) assay method (Apoptag reagent, Q-Biogene, Strasbourg, France). Statistical comparisons were made using the Mann-Whitney test. No Ki67-positive cells were detected in the study-group or control corneas. In control corneas no apoptotic activity was found. In the study group the mean (normalised) apoptotic keratocyte number was 1.1+/-1.7 in granular dystrophy and 0.5+/-1.1 in lattice type I dystrophy (p = 0.36, 0.63 respectively). Compared to the controls, the difference was statistically significant only for macular dystrophy (1.6+/-1.2; p = 0.01). Keratocyte apoptosis seems to be a concomitant or pathogenic factor in macular dystrophy. However, the pathways that are triggered to result in increased apoptotic cell death remain to be clarified.

Comparison of divide and conquer and phaco-chop techniques during fluid-based phaco-emulsification.

PURPOSE: To determine whether, similar to ultrasound phaco-emulsification, applied energy and surgery time decrease using phaco-chop nucleus fragmentation method compared to divide and conquer technique using the fluid-based system. METHODS: This prospective, comparative, randomized clinical study included patients with cataract who were randomly assigned to use either standard divide and conquer technique (25 eyes of 25 patients, Group 1) or Nagahara phaco-chop maneuver (25 eyes of 25 patients, Group 2) during fluid-based phaco-emulsification. Surgical parameters were recorded and patients were examined 1 day, 10 days, and 1 month after surgery. Statistical analyses were performed using the paired test of Wilcoxon. RESULTS: Fluid-based time, mean fluid-based magnitude, effective fluid-based time, and the number of pulses were significantly less using phaco-chop technique compared to divide and conquer method (p<0.001). Surgery time was similar using the two nucleofractis techniques (p=0.97). Visual acuities showed no statistical differences between the two groups (p>0.05). CONCLUSIONS: Nuclear fragmentation can be performed with Nagahara phaco-chop technique using the fluid-based system as well. The applied fluid-based energy decreases compared to divide and conquer method. However, surgery time is not reduced due to the difficulties reaching the full occlusion necessary to hold the nucleus during the chop maneuver.

Corneal endothelial function after phacoemulsification using the fluid-based system compared to conventional ultrasound technique.

AIM: To quantitatively assess corneal endothelial changes after phacoemulsification with the fluid-based system compared to conventional ultrasound technique. METHODS: This prospective, randomized clinical study included patients with cataract who were randomly assigned either to have phacoemulsification with the fluid-based system (30 eyes of 30 patients--Group 1) or with traditional ultrasound (30 eyes of 30 patients--Group 2). Patients who were available at each follow-up visit (25 eyes in both groups) were enrolled in the statistical analysis. Endothelial function was evaluated by measuring central corneal thickness, central endothelial cell density (ECD), mean cell size, and coefficient of variation in cell size preoperatively, 10 days, 1 and 3 months, and 1 year after surgery. Statistical analyses were performed using two-way repeated measure ANOVA. RESULTS: An acute, reversible increase of central corneal thickness (CCT) was found 10 days after surgery, which was similar in both groups (P=0.35). ECD decreased, whereas mean cell size increased significantly immediately after surgery. However, the impairments were finished after 1 month. The alterations were similar in both groups (ECD: P=0.99; mean cell size: P=0.85). The coefficient of variation in cell size remained stable after surgery (P=0.08), and significant difference was not found between groups (P=0.99). The endothelial cell loss (ECL) was 6.5+/-8.4% in Group 1 and 6.5+/-11.7% in Group 2 (P=0.69). CONCLUSIONS: Corneal endothelial changes were similar using the fluid-based system compared to the traditional ultrasound technique. The fluid-based method proved to be as safe as conventional ultrasound in cataract surgery.

The efficacy and safety of timolol maleate versus brinzolamide each given twice daily added to travoprost in patients with ocular hypertension or primary open-angle glaucoma.

PURPOSE: To compare the efficacy and safety of timolol maleate 0.5% versus brinzolamide 1% when added to travoprost 0.004% in patients with ocular hypertension or primary open-angle glaucoma. DESIGN: A prospective, double-masked, randomized, active-controlled, parallel comparison. METHODS: Qualified patients at Visit 1 were placed on travoprost dosed every evening for 4 weeks and then were randomized at baseline (Visit 2) to the addition of timolol maleate or brinzolamide each given twice daily. Patients returned to clinic at Week 4 (Visit 3) for a safety visit and Week 12 (Visit 4) for an efficacy visit. At Visits 2 and 4 the intraocular pressure (IOP) was measured at 08:00, 12:00, and 16:00 hours. RESULTS: Ninety-seven patients on brinzolamide had a baseline diurnal IOP of 21.5+/-2.2 mmHg and 95 on timolol maleate had 21.3+/-2.5 mmHg, each added to travoprost. The diurnal mean IOP at Week 12 was 18.1+/-2.7 mmHg for brinzolamide and 18.1+/-3.0 mmHg for timolol maleate (p=0.96). There was no statistical difference found between treatment groups in the absolute level of pressure, or in the reduction in IOP from baseline, at each time point or for the diurnal curve (p>0.05). There was no significant difference for any adverse event between groups (p>0.05), with the most common side effect being conjunctival hyperemia in 15/97 (16%) brinzolamide and 6/95 (6%) timolol treated patients (p=0.06). CONCLUSIONS: This study showed that brinzolamide provides similar safety and efficacy compared to timolol maleate when added to travoprost.

Antiproliferative effect of 4-thiouridylate on OCM-1 uveal melanoma cells.

PURPOSE: Brachytherapy is a well-established, effective treatment for uveal melanoma with a failure rate of 15%. The fatal consequence of unsuccessful treatments offers reason for improvement of the method. The authors propose using an apoptosis inducing agent locally, concomitantly with the well-established therapy, to sensitize the tumor cells. The authors propose a new nontoxic moderately active apoptosis inducing agent, 4-thio-uridylate (s4UMP), for this purpose. METHODS: OCM-1 uveal melanoma cells were treated with various concentrations of s4UMP and its effect was monitored by measuring the cell viability (MTT assay). The following apoptosis detecting methods were performed to reveal the mechanism of decreased cell viability: light microscopy, DNA fragmentation assay, determination of caspase 9 activity, and FACS analysis. RESULTS: The viability of uveal melanoma cells was decreased by 32%, 40%, and 9% after 24, 48, and 72 hours of treatment with 10 microg/mL (30 microM) s4UMP. The effect was not dose dependent; it rather followed a saturation-type inhibition and the cells at lower drug concentration recovered after 72 hours. Characteristic apoptotic cell morphology and DNA fragmentation was detected in treated cells. The caspase-9 was activated upon treatment showing maximal activity at 48 hours suggesting the induction of apoptosis. The annexin binding activity further verified the apoptogenic activity of s4UMP. CONCLUSIONS: Uveal melanoma, more than other solid tumors, is resistant to most of the chemotherapeutic protocols as indicated by the high mortality rate of metastatic disease. The authors showed that s4UMP, a naturally occurring nucleotide, could induce apoptosis in uveal melanoma cells, suggesting a potential supplementary therapeutic application of the compound.