Irreversible Electroporation of Human Primary Uveal Melanoma in Enucleated Eyes

PubMed Central

Mandel, Yossi; Laufer, Shlomi; Belkin, Michael; Rubinsky, Boris; Pe'er, Jacob; Frenkel, Shahar

2013-01-01

Uveal melanoma (UM) is the most common primary intraocular tumor in adults and is characterized by high rates of metastatic disease. Although brachytherapy is the most common globe-sparing treatment option for small- and medium-sized tumors, the treatment is associated with severe adverse reactions and does not lead to increased survival rates as compared to enucleation. The use of irreversible electroporation (IRE) for tumor ablation has potential advantages in the treatment of tumors in complex organs such as the eye. Following previous theoretical work, herein we evaluate the use of IRE for uveal tumor ablation in human ex vivo eye model. Enucleated eyes of patients with uveal melanoma were treated with short electric pulses (50–100 µs, 1000–2000 V/cm) using a customized electrode design. Tumor bioimpedance was measured before and after treatment and was followed by histopathological evaluation. We found that IRE caused tumor ablation characterized by cell membrane disruption while sparing the non-cellular sclera. Membrane disruption and loss of cellular capacitance were also associated with significant reduction in total tumor impedance and loss of impedance frequency dependence. The effect was more pronounced near the pulsing electrodes and was dependent on time from treatment to fixation. Future studies should further evaluate the potential of IRE as an alternative method of uveal melanoma treatment. PMID:24039721

Laparoscopic management of liver metastases from uveal melanoma.

PubMed

Akyuz, Muhammet; Yazici, Pınar; Dural, Cem; Yigitbas, Hakan; Okoh, Alexis; Bucak, Emre; McNamara, Michael; Singh, Arun; Berber, Eren

2016-06-01

Although uveal melanoma is a rare disease, its metastasis to the liver is associated with a poor survival. The aim of this study is to analyze the survival after surgical treatment of uveal melanoma metastases to the liver. Within 15 years, 44 patients with uveal melanoma metastases to the liver were managed at a single center. Medical records were reviewed to identify patients who underwent surgical treatment of their liver disease. Clinical and oncologic results were compared to those patients who were managed otherwise. T test, Chi-square test, and Kaplan-Meier survival analyses were performed. There were 16 patients who underwent surgical treatment (laparoscopic liver resection, n = 2 and laparoscopic radiofrequency ablation, n = 14), compared to 28 patients who received systemic therapy. The groups were similar regarding demographics and size of primary tumor. The interval between diagnoses of primary tumor and liver metastases was longer for the surgical group (58 vs 22 months, respectively, p = 0.010). Although the dominant liver tumor size was similar, the average number of liver tumors was 4 in the surgical group and 10 in the systemic therapy group (p < 0.0001). The median survival after diagnosis of liver metastases was 35 months in the surgical group and 15 months in the systemic therapy group (p ≤ 0.0001). Five-year survival was zero in the systemic therapy group and 22 % in the surgical group. This study shows that surgical treatment of liver metastases in selected patients with uveal melanoma, who have limited liver tumor burden and a long interval to metastases development, may result in long-term survival.

Phase II Trial of Sorafenib in Combination with Carboplatin and Paclitaxel in Patients with Metastatic Uveal Melanoma: SWOG S0512

PubMed Central

Bhatia, Shailender; Moon, James; Margolin, Kim A.; Weber, Jeffrey S.; Lao, Christopher D.; Othus, Megan; Aparicio, Ana M.; Ribas, Antoni; Sondak, Vernon K.

2012-01-01

Background Sorafenib, a multikinase inhibitor of cell proliferation and angiogenesis, inhibits the mitogen-activated protein kinase pathway that is activated in most uveal melanoma tumors. This phase II study was conducted by the SWOG cooperative group to evaluate the efficacy of sorafenib in combination with carboplatin and paclitaxel (CP) in metastatic uveal melanoma. Methods Twenty-five patients with stage IV uveal melanoma who had received 0–1 prior systemic therapy were enrolled. Treatment included up to 6 cycles of carboplatin (AUC = 6) and paclitaxel (225 mg/m2) administered IV on day 1 plus sorafenib (400 mg PO twice daily), followed by sorafenib monotherapy until disease progression. The primary endpoint was objective response rate (ORR); a two-stage design was used with the study to be terminated if no confirmed responses were observed in the first 20 evaluable patients. Secondary efficacy endpoints included progression-free survival (PFS) and overall survival (OS). Results No confirmed objective responses occurred among the 24 evaluable patients (ORR = 0% [95% CI: 0–14%]) and the study was terminated at the first stage. Minor responses (tumor regression less than 30%) were seen in eleven of 24 (45%) patients. The median PFS was 4 months [95% CI: 1–6 months] and the 6-month PFS was 29% [95% CI: 13%–48%]. The median OS was 11 months [95% CI: 7–14 months]. Conclusion In this study, the overall efficacy of CP plus sorafenib in metastatic uveal melanoma did not warrant further clinical testing when assessed by ORR, although minor tumor responses and stable disease were observed in some patients. Trial Registration ClinicalTrials.gov NCT00329641 PMID:23226204

CD147 and matrix-metalloproteinase-2 expression in metastatic and non-metastatic uveal melanomas.

PubMed

Lüke, Julia; Vukoja, Vlatka; Brandenbusch, Tim; Nassar, Khaled; Rohrbach, Jens Martin; Grisanti, Salvatore; Lüke, Matthias; Tura, Aysegül

2016-06-03

Extracellular matrix remodelling regulated by matrix-metalloproteinase (MMP) inducer (CD147) is a crucial process during tumor cell invasion and regulation of blood supply. In this study, we evaluated the correlation of CD147 and MMP-2 expression with major prognostic factors for uveal melanoma and the development of metastasis. The expression of CD147 and MMP-2 was analyzed in 49 samples of uveal melanomas. Triple immunofluorescence stainings using markers against glial cells (GFAP), endothelial cells (CD34) and macrophages (CD68) were performed to further analyse the exact localisation of CD147 and MMP-2 positivity. In 28 cases clinical metastatic disease were found. The remaining 21 cases showed no signs of metastatic disease for an average follow-up of 10 years. Correlation analysis (Pearson correlation) was performed to analyse the association of CD147 and MMP-2 expression with known prognostic factors, vasculogenic mimicry (VM), the mature vasculature (von Willebrand Factor) and tumor induced angiogenesis (by means of Endoglin expression). CD147 and MMP-2 were expressed in 47 (96.0 %) of the uveal melanomas. CD147 up-regulation was significantly correlated with a higher MMP-2 expression. The overall expression analysis revealed no significant difference in the metastatic (p = 0.777) and non-metastatic subgroup (p = 0.585). No correlation of CD147 expression and any system of blood supply was evident. In the non-metastatic sub-group a significant correlation of clustered CD147 positive cells with largest basal diameter (p = 0.039), height (p = 0.047) and TNM-stage (p = 0.013) was evident. These data may indicate that CD147 regulates MMP-2 expression in uveal melanoma cells.

Epacadostat and Vaccine Therapy in Treating Patients With Stage III-IV Melanoma

ClinicalTrials.gov

2018-01-09

Mucosal Melanoma; Recurrent Melanoma; Recurrent Uveal Melanoma; Stage IIIA Skin Melanoma; Stage IIIA Uveal Melanoma; Stage IIIB Skin Melanoma; Stage IIIB Uveal Melanoma; Stage IIIC Skin Melanoma; Stage IIIC Uveal Melanoma; Stage IV Skin Melanoma; Stage IV Uveal Melanoma

Unusual presentation of a metastatic uveal melanoma in a cat.

PubMed

Planellas, Marta; Pastor, Josep; Torres, Ma Dolores; Peña, Teresa; Leiva, Marta

2010-11-01

A 10 year-old, spayed female Domestic Short-Haired (DSH) cat was diagnosed with a large primary uveal melanoma and exenteration was recommended. Thoracic radiographs, abdominal ultrasonography, and complete blood count and serum biochemistry panel did not reveal any abnormality compatible with metastatic disease and surgery was performed. Histopathologic study of the eye confirmed a diffuse iris melanoma. Five months later, the cat presented with a lameness of the right anterior extremity. On physical exam the right elbow was swollen and painful. Radiographs showed a severe osteolysis of the radial head and proximal diaphysis. Fine needle aspiration of the radius head identified a round cell neoplasm with scattered cells containing intracytoplasmatic pigmented granules, compatible with metastatic melanoma. The owners decided not to treat the patient with chemotherapy and declined a biopsy. Two months later, the cat died and necropsy was performed confirming bone metastasis of the uveal melanoma. A diagnosis of generalized metastasis from primary diffuse iris melanoma was made. This report describes, for the first time, long bone metastasis from an uveal melanoma in a cat. © 2010 American College of Veterinary Ophthalmologists.

Combined mutation and copy-number variation detection by targeted next-generation sequencing in uveal melanoma.

PubMed

Smit, Kyra N; van Poppelen, Natasha M; Vaarwater, Jolanda; Verdijk, Robert; van Marion, Ronald; Kalirai, Helen; Coupland, Sarah E; Thornton, Sophie; Farquhar, Neil; Dubbink, Hendrikus-Jan; Paridaens, Dion; de Klein, Annelies; Kiliç, Emine

2018-05-01

Uveal melanoma is a highly aggressive cancer of the eye, in which nearly 50% of the patients die from metastasis. It is the most common type of primary eye cancer in adults. Chromosome and mutation status have been shown to correlate with the disease-free survival. Loss of chromosome 3 and inactivating mutations in BAP1, which is located on chromosome 3, are strongly associated with 'high-risk' tumors that metastasize early. Other genes often involved in uveal melanoma are SF3B1 and EIF1AX, which are found to be mutated in intermediate- and low-risk tumors, respectively. To obtain genetic information of all genes in one test, we developed a targeted sequencing method that can detect mutations in uveal melanoma genes and chromosomal anomalies in chromosome 1, 3, and 8. With as little as 10 ng DNA, we obtained enough coverage on all genes to detect mutations, such as substitutions, deletions, and insertions. These results were validated with Sanger sequencing in 28 samples. In >90% of the cases, the BAP1 mutation status corresponded to the BAP1 immunohistochemistry. The results obtained in the Ion Torrent single-nucleotide polymorphism assay were confirmed with several other techniques, such as fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, and Illumina SNP array. By validating our assay in 27 formalin-fixed paraffin-embedded and 43 fresh uveal melanomas, we show that mutations and chromosome status can reliably be obtained using targeted next-generation sequencing. Implementing this technique as a diagnostic pathology application for uveal melanoma will allow prediction of the patients' metastatic risk and potentially assess eligibility for new therapies.

Ocular melanoma: an overview of the current status

PubMed Central

Jovanovic, Predrag; Mihajlovic, Marija; Djordjevic-Jocic, Jasmina; Vlajkovic, Slobodan; Cekic, Sonja; Stefanovic, Vladisav

2013-01-01

Ocular melanoma is the second most common type of melanoma after cutaneous and the most common primary intraocular malignant tumor in adults. Large majority of ocular melanomas originate from uvea, while conjunctival melanomas are far less frequent. Incidence of uveal melanoma has remained stable over last three decades. Diagnosis is in most cases established by clinical examination with great accuracy. Local treatment of uveal melanoma has improved, with increased use of conservative methods and preservation of the eye, but survival rates have remained unchanged. Recent advances in cytogenetics and genetics enhanced prognostication and enabled to determine tumors with high metastatic potential. However, due to lack of effective systemic therapy, prognosis of patients with metastasis remains poor and metastatic disease remains the leading cause of death among patients with uveal melanoma. Conjunctival melanoma is rare, but its incidence is increasing. It mostly occurs among white adults. In majority of cases it originates from preceding primary acquired melanosis. Current standard treatment for conjunctival melanoma is wide local excision with adjuvant therapy, including brachytherapy, cryotherapy and topical application of chemotherapeutic agent. Rarity of this tumor limits conduction of controlled trials to define the best treatment modality. As well as for uveal melanoma, prognosis of patients with metastasis is poor because there is no effective systemic therapy. Better understanding of underlying genetic and molecular abnormalities implicated in development and progression of ocular melanomas provides a great opportunity for development of targeted therapy, which will hopefully improve prognosis of patients with metastatic disease. PMID:23826405

Prognostic Factors and Decision Tree for Long-term Survival in Metastatic Uveal Melanoma.

PubMed

Lorenzo, Daniel; Ochoa, María; Piulats, Josep Maria; Gutiérrez, Cristina; Arias, Luis; Català, Jaum; Grau, María; Peñafiel, Judith; Cobos, Estefanía; Garcia-Bru, Pere; Rubio, Marcos Javier; Padrón-Pérez, Noel; Dias, Bruno; Pera, Joan; Caminal, Josep Maria

2017-12-04

The purpose of this study was to demonstrate the existence of a bimodal survival pattern in metastatic uveal melanoma. Secondary aims were to identify the characteristics and prognostic factors associated with long-term survival and to develop a clinical decision tree. The medical records of 99 metastatic uveal melanoma patients were retrospectively reviewed. Patients were classified as either short (≤ 12 months) or long-term survivors (> 12 months) based on a graphical interpretation of the survival curve after diagnosis of the first metastatic lesion. Ophthalmic and oncological characteristics were assessed in both groups. Of the 99 patients, 62 (62.6%) were classified as short-term survivors, and 37 (37.4%) as long-term survivors. The multivariate analysis identified the following predictors of long-term survival: age ≤ 65 years (p=0.012) and unaltered serum lactate dehydrogenase levels (p=0.018); additionally, the size (smaller vs. larger) of the largest liver metastasis showed a trend towards significance (p=0.063). Based on the variables significantly associated with long-term survival, we developed a decision tree to facilitate clinical decision-making. The findings of this study demonstrate the existence of a bimodal survival pattern in patients with metastatic uveal melanoma. The presence of certain clinical characteristics at diagnosis of distant disease is associated with long-term survival. A decision tree was developed to facilitate clinical decision-making and to counsel patients about the expected course of disease.

Evidence for the Role of Blue Light in the Development of Uveal Melanoma

PubMed Central

Logan, Patrick; Bernabeu, Miguel; Ferreira, Alberto; Burnier, Miguel N.

2015-01-01

Uveal melanoma is the most common malignancy of the adult eye. Although it is a relatively infrequent tumor, clinical prognosis is often poor owing to a high incidence of aggressive metastatic disease, for which there are limited treatment options. Little is known about the etiology of this condition, although several risk factors have been identified. Unlike cutaneous melanoma, however, ultraviolet radiation does not figure prominently among these risk factors. In this review, we focus on an associated form of visible electromagnetic radiation, high-energy short-wave (blue) light, a causative agent in various forms of age-related retina damage, as a previously overlooked risk factor in uveal melanoma development and progression. Finally, we discuss the impact of these data on contemporary ocular therapy, particularly the debate surrounding the filtering capabilities of intraocular lenses used to replace dysfunctional crystalline lenses during cataract surgery. PMID:26075084

Decreased endothelin receptor B expression in large primary uveal melanomas is associated with early clinical metastasis and short survival

PubMed Central

Smith, S L; Damato, B E; Scholes, A G M; Nunn, J; Field, J K; Heighway, J

2002-01-01

The most devastating aspect of cancer is the metastasis of tumour cells to organs distant from the original tumour site. The major problem facing oncologists treating uveal melanoma, the most common cancer of the eye, is metastatic disease. To lower mortality, it is necessary to increase our understanding of the molecular genetic alterations involved in this process. Using suppression subtractive hybridisation, we have analysed differential gene expression between four primary tumours from patients who have developed clinical metastasis and four primary tumours from patients with no evidence of metastasis to date. We have identified endothelin receptor type B as differentially expressed between these tumours and confirmed this observation using comparative multiplex RT–PCR. In a further 33 tumours, reduced endothelin receptor type B expression correlated with death from metastatic disease. Reduced expression also correlated with other known prognostic indicators, including the presence of epithelioid cells, chromosome 3 allelic imbalance and chromosome 8q allelic imbalance. Endothelin receptor type B expression was also reduced in four out of four primary small cell lung carcinomas compared to normal bronchial epithelium. We also show that the observed down-regulation of endothelin receptor type B in uveal melanoma was not due to gene deletion. Our findings suggest a role for endothelin receptor type B in the metastasis of uveal melanoma and, potentially, in the metastasis of other neural crest tumours. British Journal of Cancer (2002) 87, 1308–1313. doi:10.1038/sj.bjc.6600620 www.bjcancer.com © 2002 Cancer Research UK PMID:12439722

Clinical outcomes in metastatic uveal melanoma treated with PD-1 and PD-L1 antibodies.

PubMed

Algazi, Alain P; Tsai, Katy K; Shoushtari, Alexander N; Munhoz, Rodrigo R; Eroglu, Zeynep; Piulats, Josep M; Ott, Patrick A; Johnson, Douglas B; Hwang, Jimmy; Daud, Adil I; Sosman, Jeffrey A; Carvajal, Richard D; Chmielowski, Bartosz; Postow, Michael A; Weber, Jeffrey S; Sullivan, Ryan J

2016-11-15

Antibodies inhibiting the programmed death receptor 1 (PD-1) have demonstrated significant activity in the treatment of advanced cutaneous melanoma. The efficacy and safety of PD-1 blockade in patients with uveal melanoma has not been well characterized. Fifty-eight patients with stage IV uveal melanoma received PD-1 or PD-1 ligand (PD-L1) antibodies between 2009 and 2015 at 9 academic centers. Patients who were evaluable for response were eligible for the analysis. Imaging was performed every 12 weeks and at the investigators' discretion. Safety and clinical efficacy outcomes, including the best overall response, progression-free survival (PFS), and overall survival (OS), were retrospectively determined. Of 56 eligible patients, 48 (86%) had received prior therapy, and 35 (63%) had received treatment with ipilimumab. Three patients had an objective response to ipilimumab, and 8 had stable disease as their best response. Thirty-eight patients (68%) received pembrolizumab, 16 (29%) received nivolumab, and 2 (4%) received atezolizumab. Objective tumor responses were observed in 2 patients for an overall response rate of 3.6% (95% confidence interval [CI], 1.8%-22.5%). Stable disease (≥6 months) was observed in 5 patients (9%). The median PFS was 2.6 months (95% CI, 2.4-2.8 months), and the median OS was 7.6 months (95% CI, 0.7-14.6 months). There was no association between prior treatment with ipilimumab or liver-directed therapy and PFS or OS. Treatment was well tolerated, and only 1 patient discontinued treatment because of toxicity. PD-1 and PD-L1 antibodies rarely confer durable remissions in patients with metastatic uveal melanoma. Clinical trial enrollment should be prioritized in this population. Cancer 2016;122:3344-3353. © 2016 American Cancer Society. © 2016 American Cancer Society.

Stereotactic Radiosurgery and Fractionated Stereotactic Radiation Therapy for the Treatment of Uveal Melanoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yazici, Gozde; Kiratli, Hayyam; Ozyigit, Gokhan

Purpose: To evaluate treatment results of stereotactic radiosurgery or fractionated stereotactic radiation therapy (SRS/FSRT) for uveal melanoma. Methods and Materials: We retrospectively evaluated 181 patients with 182 uveal melanomas receiving SRS/FSRT between 2007 and 2013. Treatment was administered with CyberKnife. Results: According to Collaborative Ocular Melanoma Study criteria, tumor size was small in 1%, medium in 49.5%, and large in 49.5% of the patients. Seventy-one tumors received <45 Gy, and 111 received ≥45 Gy. Median follow-up time was 24 months. Complete and partial response was observed in 8 and 104 eyes, respectively. The rate of 5-year overall survival was 98%, disease-free survival 57%,more » local recurrence-free survival 73%, distant metastasis-free survival 69%, and enucleation-free survival 73%. There was a significant correlation between tumor size and disease-free survival, SRS/FSRT dose and enucleation-free survival; and both were prognostic for local recurrence-free survival. Enucleation was performed in 41 eyes owing to progression in 26 and complications in 11. Conclusions: The radiation therapy dose is of great importance for local control and eye retention; the best treatment outcome was achieved using ≥45 Gy in 3 fractions.« less

Modelling uveal melanoma

PubMed Central

Foss, A.; Cree, I.; Dolin, P.; Hungerford, J.

1999-01-01

BACKGROUND/AIM—There has been no consistent pattern reported on how mortality for uveal melanoma varies with age. This information can be useful to model the complexity of the disease. The authors have examined ocular cancer trends, as an indirect measure for uveal melanoma mortality, to see how rates vary with age and to compare the results with their other studies on predicting metastatic disease.
METHODS—Age specific mortality was examined for England and Wales, the USA, and Canada. A log-log model was fitted to the data. The slopes of the log-log plots were used as measure of disease complexity and compared with the results of previous work on predicting metastatic disease.
RESULTS—The log-log model provided a good fit for the US and Canadian data, but the observed rates deviated for England and Wales among people over the age of 65 years. The log-log model for mortality data suggests that the underlying process depends upon four rate limiting steps, while a similar model for the incidence data suggests between three and four rate limiting steps. Further analysis of previous data on predicting metastatic disease on the basis of tumour size and blood vessel density would indicate a single rate limiting step between developing the primary tumour and developing metastatic disease.
CONCLUSIONS—There is significant underreporting or underdiagnosis of ocular melanoma for England and Wales in those over the age of 65 years. In those under the age of 65, a model is presented for ocular melanoma oncogenesis requiring three rate limiting steps to develop the primary tumour and a fourth rate limiting step to develop metastatic disease. The three steps in the generation of the primary tumour involve two key processes—namely, growth and angiogenesis within the primary tumour. The step from development of the primary to development of metastatic disease is likely to involve a single rate limiting process.

 PMID:10216060

Tight Junction–Associated Signaling Pathways Modulate Cell Proliferation in Uveal Melanoma

PubMed Central

Jayagopal, Ashwath; Yang, Jin-Long; Haselton, Frederick R.; Chang, Min S.

2011-01-01

Purpose. To investigate the role of tight junction (TJ)–associated signaling pathways in the proliferation of uveal melanoma. Methods. Human uveal melanoma cell lines overexpressing the TJ molecule blood vessel epicardial substance (Bves) were generated. The effects of Bves overexpression on TJ protein expression, cell proliferation, and cell cycle distribution were quantified. In addition, localization and transcription activity of the TJ-associated protein ZO-1–associated nucleic acid binding protein (ZONAB) were evaluated using immunofluorescence and bioluminescence reporter assays to study the involvement of Bves signaling in cell proliferation-associated pathways. Results. Bves overexpression in uveal melanoma cell lines resulted in increased expression of the TJ proteins occludin and ZO-1, reduced cell proliferation, and increased sequestration of ZONAB at TJs and reduced ZONAB transcriptional activity. Conclusions. TJ proteins are present in uveal melanoma, and TJ-associated signaling pathways modulate cell signaling pathways relevant to proliferation in uveal melanoma. PMID:20861479

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

PubMed

Economou, Mario A; Andersson, Sandra; Vasilcanu, Diana; All-Ericsson, Charlotta; Menu, Eline; Girnita, Ada; Girnita, Leonard; Axelson, Magnus; Seregard, Stefan; Larsson, Olle

2008-11-01

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. 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. 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. 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.

Ovarian metastasis from uveal melanoma with MLH1/PMS2 protein loss in a patient with germline MLH1 mutated Lynch syndrome: consequence or coincidence?

PubMed

Lobo, João; Pinto, Carla; Freitas, Micaela; Pinheiro, Manuela; Vizcaino, Rámon; Oliva, Esther; Teixeira, Manuel R; Jerónimo, Carmen; Bartosch, Carla

2017-03-01

Currently, uveal melanoma is not considered within the Lynch syndrome tumor spectrum. However, there are studies suggesting a contribution of microsatellite instability in sporadic uveal melanoma tumorigenesis. We report a 45-year-old woman who was referred for genetic counseling due to a family history of Lynch syndrome caused by a MLH1 mutation. She originally underwent enucleation of the right eye secondary to a uveal spindle cell melanoma diagnosed at age 25. The tumor recurred 22 years later presenting as an ovarian metastasis and concurrently a microscopic endometrial endometrioid carcinoma, grade 1/3 was diagnosed. Subsequent studies highlighted that the uveal melanoma showed high microsatellite instability and loss of MLH1 and PMS2 protein expression, with no MLH1 promoter methylation or BRAF mutation. Additionally, a GNAQ mutation was found. We conclude that our patient's uveal melanoma is most likely related to MLH1 germline mutation and thus Lynch syndrome related. To the best of our knowledge, this is the first report of uveal melanoma showing MLH1/PMS2 protein loss in the context of Lynch syndrome.

Ultrasound, histopathological, and genetic features of uveal melanoma in a Mexican-Mestizo population.

PubMed

Delgado, S; Rodriguez Reyes, A; Mora Rios, L; Dueñas-González, A; Taja-Chayeb, L; Moragrega Adame, E

2018-01-01

To describe the ultrasound, histopathological and genetic characteristics of uveal melanoma in a Mexican-Mestizo population. A total of 39 enucleated eyes with a histopathological diagnosis of uveal melanoma were assessed by describing the clinical findings, and ultrasound, histopathological and genetic features. A high correlation was observed between tumour height measurement using ultrasound and histopathology. In our cases, tumour size and reflectivity were higher compared with those reported in the literature. The preliminary data on the molecular assessment of the tumours show the presence of an unreported polymorphism (T>C IVS5+34) and one sample with GNAQ mutation (A>C CAA>CCA Gln 209 Pro). Ultrasound is a reliable method to identify the size of the tumour. Furthermore, knowledge of the molecular mechanisms promises new perspectives for the development of new targeted therapeutics. Fortunately this leads to progress in the treatment of patients with metastatic disease or prevents it in those at high risk. Copyright © 2017 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.

Fulminant hepatic failure due to metastatic choroidal melanoma

PubMed Central

Escobar-Valdivia, Emmanuel; Monreal-Robles, Roberto; Delgado-García, Guillermo; Hernández-Velazquez, Badir

2017-01-01

Background: Acute liver failure (ALF) as a consequence of metastatic disease is extremely uncommon. The liver is the most commonly affected organ by metastatic disease, but only a few cases of ALF in the setting of metastatic choroidal melanoma have been reported. Case Presentation: We describe the case of a 47-year-old man with right upper quadrant pain, progressive jaundice, and unintentional weight loss. He also reported that he had experienced reduced left visual acuity which progressed to blindness over 2 months. On physical examination, we found a pigmented scleral lesion in the left eye. He had a coagulopathy and, during his hospital stay, he also developed encephalopathy. The diagnosis of ALF was therefore established and was later attributed to metastatic uveal melanoma. In addition, we briefly review the relevant literature. Conclusion: Liver metastasis should be kept in mind when assessing abnormal liver function tests in patients with uveal malignant melanoma. PMID:28503286

Fisetin induces apoptosis through mitochondrial apoptosis pathway in human uveal melanoma cells.

PubMed

Wang, Kai; Hu, Dan-Ning; Lin, Hui-Wen; Yang, Wei-En; Hsieh, Yi-Hsien; Chien, Hsiang-Wen; Yang, Shun-Fa

2018-05-01

Fisetin, a diatery flavonoid, been reported that possess anticancer effects in various cancers. The purpose of the study was to investigate the antitumor effects of fisetin in cultured uveal melanoma cell lines and compared with normal retinal pigment epithelial (RPE) cells. MTT assay was used for evaluating cytotoxic effects of fisetin. Flow cytometry study was used for the determination of apoptosis. JC-1 fluorescent reader was used to determine mitochondrial transmembrane potential changes. The results shown that fisetin dose-dependently decreased the cell viability of uveal melanoma cells but not influenced the cell viability of RPE cells. Apoptosis of uveal melanoma cells was induced by fisetin efficiently. Fisetin inhibited antiapoptotic Bcl-2 family proteins and damaged the mitochondrial transmembrane potential. The levels of proapoptotic Bcl-2 proteins, cytochrome c, and various caspase activities were increased by fisetin. In conclusion, fisetin induces apoptosis of uveal melanoma cells selectively and may be a promising agent to be explored for the treatment of uveal melanoma. © 2018 Wiley Periodicals, Inc.

Tumor Cell Plasticity in Uveal Melanoma

PubMed Central

Folberg, Robert; Arbieva, Zarema; Moses, Jonas; Hayee, Amin; Sandal, Tone; Kadkol, ShriHari; Lin, Amy Y.; Valyi-Nagy, Klara; Setty, Suman; Leach, Lu; Chévez-Barrios, Patricia; Larsen, Peter; Majumdar, Dibyen; Pe’er, Jacob; Maniotis, Andrew J.

2006-01-01

The histological detection of laminin-rich vasculogenic mimicry patterns in human primary uveal melanomas is associated with death from metastases. We therefore hypothesized that highly invasive uveal melanoma cells forming vasculogenic mimicry patterns after exposure to a laminin-rich three-dimensional microenvironment would differentially express genes associated with invasive and metastatic behavior. However, we discovered that genes associated with differentiation (GDF15 and ATF3) and suppression of proliferation (CDKNa1/p21) were up-regulated in highly invasive uveal melanoma cells forming vasculogenic mimicry patterns, and genes associated with promotion of invasive and metastatic behavior such as CD44, CCNE2 (cyclin E2), THBS1 (thrombospondin 1), and CSPG2 (chondroitin sulfate proteoglycan; versican) were down-regulated. After forming vasculogenic mimicry patterns, uveal melanoma cells invaded only short distances, failed to replicate, and changed morphologically from the invasive epithelioid to the indolent spindle A phenotype. In human tissue samples, uveal melanoma cells within vasculogenic mimicry patterns assumed the spindle A morphology, and the expression of Ki67 was significantly reduced in adjacent melanoma cells. Thus, the generation of vasculogenic mimicry patterns is accompanied by dampening of the invasive and metastatic uveal melanoma genotype and phenotype and underscores the plasticity of these cells in response to cues from the microenvironment. PMID:17003493

[Expression of EphA2 in Metastatic and Non-Metastatic Primary Uveal Melanoma].

PubMed

Vukoja, V; Brandenbusch, T; Tura, A; Nassar, K; Rohrbach, D J M; Lüke, M; Grisanti, S; Lüke, J

2016-03-01

Little is known about how the expression of Ephrin type-A receptor 2 (EphA2) influences cell-cell adhesion, migration, angiogenesis, and the formation of vasculogenic mimicry (VM) channels in uveal melanomas or how this may be related to the rate of metastasis. Paraffin embedded sections of 50 histopathologically well characterised primary uveal melanomas (mean largest tumour diameter: 16.3 mm) were evaluated with respect to the expression of EphA2. Systemic metastasis was detected in 29 patients. The remaining 21 patients were followed for a mean of 10 years. Tumour angiogensis was analysed by endoglin expression (CD105), the activity of the mature vascular system (von Willebrand factor) and the presence of VM (CD31/PAS staining). All uveal melanomas expressed EphA2, with a mean of 95.93 % positive cells ± SD: 6.3 %. There was no significant association between EphA2 and the rate of metastases (p = 0.196), endoglin expression (p = 0.652), VM (p = 0.267) or with any other clinical or histopathological factors (p < 0.05). However, there was significant up-regulation of EphA2 in the nucleus of the metastatic uveal melanoma subgroup, while cytoplasmatic localisation in the subgroup was associated with better prognosis (p = 0.006). There were low levels of EphA2 expression in the specific retinal layers, the ciliary and corneal epithelium, and the choroidal and corneal endothelium. Nuclear expression of EphA2 in this series of large tumours was significantly associated with an increased rate of metastasis. On the other hand, cytoplasmic localisation was associated with a better prognosis. As there was no correlation between EphA2 expression and angiogenesis, the mature vasculature or VM, EphA2 appears to become less important in the advanced stages of the disease. Georg Thieme Verlag KG Stuttgart · New York.

Psychosocial impact of prognostic genetic testing in the care of uveal melanoma patients: protocol of a controlled prospective clinical observational study.

PubMed

Erim, Yesim; Scheel, Jennifer; Breidenstein, Anja; Metz, Claudia Hd; Lohmann, Dietmar; Friederich, Hans-Christoph; Tagay, Sefik

2016-07-07

Uveal melanoma patients with a poor prognosis can be detected through genetic analysis of the tumor, which has a very high sensitivity. A large number of patients with uveal melanoma decide to receive information about their individual risk and therefore routine prognostic genetic testing is being carried out on a growing number of patients. It is obvious that a positive prediction for recidivism in the future will emotionally burden the respective patients, but research on the psychosocial impact of this innovative method is lacking. The aim of the current study is therefore to investigate the psychosocial impact (psychological distress and quality of life) of prognostic genetic testing in patients with uveal melanoma. This study is a non-randomized controlled prospective clinical observational trial. Subjects are patients with uveal melanoma, in whom genetic testing is possible. Patients who consent to genetic testing are allocated to the intervention group and patients who refuse genetic testing form the observational group. Both groups receive cancer therapy and psycho-oncological intervention when needed. The psychosocial impact of prognostic testing is investigated with the following variables: resilience, social support, fear of tumor progression, depression, general distress, cancer-specific and general health-related quality of life, attitude towards genetic testing, estimation of the perceived risk of metastasis, utilization and satisfaction with psycho-oncological crisis intervention, and sociodemographic data. Data are assessed preoperatively (at initial admission in the clinic) and postoperatively (at discharge from hospital after surgery, 6-12 weeks, 6 and 12 months after initial admission). Genetic test results are communicated 6-12 weeks after initial admission to the clinic. We created optimal conditions for investigation of the psychosocial impact of prognostic genetic testing. This study will provide information on the course of disease and psychosocial outcomes after prognostic genetic testing. We expect that empirical data from our study will give a scientific basis for medico-ethical considerations.

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

PubMed

Economou, Mario A; Andersson, Sandra; Vasilcanu, Diana; All-Ericsson, Charlotta; Menu, Eline; Girnita, Ada; Girnita, Leonard; Axelson, Magnus; Seregard, Stefan; Larsson, Olle

2008-06-01

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. 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. 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. Oral PPP was well tolerated in vivo, caused total growth inhibition of uveal melanoma xenografts, and decreased VEGF levels in the tumors.

[Telomerase activity in uveal melanomas].

PubMed

Rohrbach, J M; Riedinger, C; Wild, M; Partsch, M

2000-05-01

The maximum number of cell divisions of a certain cell population is genetically fixed so that aging cells become non-dividing (senescent) at least. This replicative life span, also known as "Hayflick limit", is probably defined by a "critical" length of the telomeres. Telomeres are special DNA-sequences located at the four ends of the chromosomes which are shortened with each cell cycle. Cells of most, but not all malignant tumours have been shown to reactivate the enzyme telomerase so that telomeres can be reconstructed, "Hayflick limit" can be overcome, and unlimited cell division can be established. This study was undertaken to elucidate whether telomerase reactivation is used by uveal melanoma cells. Fresh tumour tissue was removed from 10 untreated uveal melanomas after enucleation. Telomerase activity was determined using a PCR ELISA according to the Telomeric Repeat Amplification Protocol (TRAP). Normal tissue of the skin and the conjunctiva served as control. Telomerase activity was detectable in 90% of the investigated uveal melanomas. All control specimens were telomerase negative. Uveal melanoma growth seems to depend on telomerase reactivation. Thus, telomerase inhibition could offer a new principle for uveal melanoma therapy in the future.

Meridional lenticular astigmatism associated with bilateral concurrent uveal metastases in renal cell carcinoma.

PubMed

Priluck, Joshua C; Grover, Sandeep; Chalam, Kv

2012-01-01

To demonstrate a case illustrating meridional lenticular astigmatism as a result of renal cell carcinoma uveal metastases. Case report with images. Clinical findings and diagnostic testing of a patient with acquired meridional lenticular astigmatism are described. The refraction revealed best-corrected visual acuity of 20/20-1 OD (-2.50 + 0.25 × 090) and 20/50 OS (-8.25 + 3.25 × 075). Bilateral concurrent renal cell carcinoma metastases to the choroid and ciliary body are demonstrated by utilizing ultrasonography, ultrawidefield fluorescein angiography, and unique spectral-domain optical coherence tomography. Metastatic disease should be included in the differential of acquired astigmatism. Spectral-domain optical coherence tomography, ultrawidefield fluorescein angiography, and ultrasonography have roles in delineating choroidal metastases.

Liver metastases from melanoma: hepatic intra-arterial chemotherapy. A retrospective study.

PubMed

Farolfi, A; Ridolfi, L; Guidoboni, M; Milandri, C; Calzolari, F; Scarpi, E; Amadori, D; Ridolfi, R

2011-10-01

The liver is the primary site of metastases in most uveal melanoma patients. We retrospectively investigated intraarterial chemotherapy (IAC) as treatment for patients with hepatic melanoma metastases.Twenty-three patients (18 with uveal melanoma) received fotemustine (14 patients, 61.9%) or carboplatin (9 patients, 31.1%) via hepatic IAC delivery. The catheter was introduced through percutaneous access to the femoral artery with drugs delivered directly to the hepatic artery, and was removed at the end of each treatment cycle. A total of 3 cycles was planned, repeated every 21 days. However, patients with a clinical response could receive more than 3 cycles, provided that the toxic effects were acceptable.IAC was well tolerated and no catheter-related complications or grade 4 toxicities were reported. Considering only uveal melanoma patients, the overall response rate and disease control rate was 16.7% and 38.9%, respectively. Median time to progression was 6.2 months (95% CI 3.7-10.5) and median overall survival was 21 months (95% CI 8-39).IAC is well tolerated and is a valid choice for patients with a poor prognosis since median survival rates are among the longest reported.

GNQ-209P Mutation in Metastatic Uveal Melanoma and Treatment Outcome.

PubMed

Abdel Karim, Nagla; Eldessouki, Ihab; Taftaf, Ahmad; Ayham, Deeb; Gaber, Ola; Makramalla, Abouelmagd; Correa, Zelia M

2018-01-01

Metastatic prognosis in uveal melanoma is assessed by gene expression profiling (GEP) testing of the tumor cells, usually obtained by fine needle aspiration (FNA). GEP has demonstrated high accuracy in distinguishing class I and II tumors, both having different metastatic potential. Transcriptomic studies identified distinct mutations including somatic mutations in GNAQ and GNA11 , detected in more than 80%, and contribute to the upregulation of the mitogen-activated protein kinase (MAPK) pathway and the development of uveal melanoma (UM). The role of these mutations in treatment selection and possible benefit from targeted therapy are somewhat unclear. However, until the discovery of novel agents, local versus systemic therapies remain options for treatment that can still be considered for disease control in certain cases. We report a series of patients with metastatic UM with distinct mutational profiles. One had significant liver metastases with proven GNQ-209P mutation on tissue biopsy while peripheral blood molecular profiling did not show these mutations. The other three cases had no GNQ-209P mutation. All cases received nab-paclitaxel (Abraxane) as a treatment drug, and we record their responses to treatment and their molecular-profiling results.

Meridional lenticular astigmatism associated with bilateral concurrent uveal metastases in renal cell carcinoma

PubMed Central

Priluck, Joshua C; Grover, Sandeep; Chalam, KV

2012-01-01

Purpose To demonstrate a case illustrating meridional lenticular astigmatism as a result of renal cell carcinoma uveal metastases. Methods Case report with images. Results Clinical findings and diagnostic testing of a patient with acquired meridional lenticular astigmatism are described. The refraction revealed best-corrected visual acuity of 20/20–1 OD (−2.50 + 0.25 × 090) and 20/50 OS (−8.25 + 3.25 × 075). Bilateral concurrent renal cell carcinoma metastases to the choroid and ciliary body are demonstrated by utilizing ultrasonography, ultrawidefield fluorescein angiography, and unique spectral-domain optical coherence tomography. Conclusions Metastatic disease should be included in the differential of acquired astigmatism. Spectral-domain optical coherence tomography, ultrawidefield fluorescein angiography, and ultrasonography have roles in delineating choroidal metastases. PMID:23152663

Association between choroidal pigmentation and posterior uveal melanoma in a white population

PubMed Central

Harbour, J W; Brantley, M A; Hollingsworth, H; Gordon, M

2004-01-01

Background/aims: It is well known that light skin pigmentation is a risk factor for cutaneous melanoma. The aim of this study was to investigate the analogous association between choroidal pigmentation and posterior uveal melanoma. Methods: Cross sectional study of 65 consecutive patients diagnosed with posterior uveal melanoma (melanoma group) and 218 consecutive patients referred for general retinal evaluation (control group). All patients were white. A clinical grading system for estimating choroidal pigmentation was developed and histologically validated in seven patients. Results: Melanoma patients with light iris colour were significantly more likely to have darker choroidal pigmentation than controls (p = 0.005). Darker choroidal pigmentation was associated histologically with increased density of choroidal melanocytes (p = 0.005). Conclusions: Increased choroidal pigmentation, as a result of an increase in the density of pigmented choroidal melanocytes, is not protective but may actually be a risk factor for the development of posterior uveal melanoma in white patients. This finding may have implications for understanding the pathogenesis of uveal melanoma. PMID:14693770

Uveal melanoma in relation to ultraviolet light exposure and host factors.

PubMed

Holly, E A; Aston, D A; Char, D H; Kristiansen, J J; Ahn, D K

1990-09-15

We conducted a case-control interview study among 1277 subjects (407 patients, 870 controls selected by using random digit dial) in 11 western United States to determine whether uveal melanoma and cutaneous melanoma shared common risk factors. After adjustment for other factors, the risk of uveal melanoma was increased for those with green, gray, or hazel eyes [relative risk (RR) = 2.5, P less than 0.001] or blue eyes (RR = 2.2, P less than 0.001) when compared to brown. A tendency to sunburn after 0.5 h midday summer sun exposure increased risk for uveal melanoma (burn with tanning RR = 1.5, P = 0.02; burn with little tanning RR = 1.8, P less than 0.001; burn with no tanning RR = 1.7, P = 0.002); as did exposure to UV or black lights (RR = 3.7, P = 0.003); and welding burn, sunburn of the eye, or snow blindness (RR = 7.2, P less than 0.001). An association with uveal melanoma was also noted with an increasing number of large nevi (P = 0.04 for trend), although the individual risk estimates were not remarkable. These data suggest that host factors and exposure to UV light are risk factors for uveal melanoma.

Distribution of CD163-positive cell and MHC class II-positive cell in the normal equine uveal tract.

PubMed

Sano, Yuto; Matsuda, Kazuya; Okamoto, Minoru; Takehana, Kazushige; Hirayama, Kazuko; Taniyama, Hiroyuki

2016-02-01

Antigen-presenting cells (APCs) in the uveal tract participate in ocular immunity including immune homeostasis and the pathogenesis of uveitis. In horses, although uveitis is the most common ocular disorder, little is known about ocular immunity, such as the distribution of APCs. In this study, we investigated the distribution of CD163-positive and MHC II-positive cells in the normal equine uveal tract using an immunofluorescence technique. Eleven eyes from 10 Thoroughbred horses aged 1 to 24 years old were used. Indirect immunofluorescence was performed using the primary antibodies CD163, MHC class II (MHC II) and CD20. To demonstrate the site of their greatest distribution, positive cells were manually counted in 3 different parts of the uveal tract (ciliary body, iris and choroid), and their average number was assessed by statistical analysis. The distribution of pleomorphic CD163- and MHC II-expressed cells was detected throughout the equine uveal tract, but no CD20-expressed cells were detected. The statistical analysis demonstrated the distribution of CD163- and MHC II-positive cells focusing on the ciliary body. These results demonstrated that the ciliary body is the largest site of their distribution in the normal equine uveal tract, and the ciliary body is considered to play important roles in uveal and/or ocular immune homeostasis. The data provided in this study will help further understanding of equine ocular immunity in the normal state and might be beneficial for understanding of mechanisms of ocular disorders, such as equine uveitis.

Resveratrol inhibits uveal melanoma tumor growth via early mitochondrial dysfunction.

PubMed

van Ginkel, Paul R; Darjatmoko, Soesiawati R; Sareen, Dhruv; Subramanian, Lalita; Bhattacharya, Saswati; Lindstrom, Mary J; Albert, Daniel M; Polans, Arthur S

2008-04-01

To test the efficacy of resveratrol, a nontoxic plant product, in the treatment of uveal melanoma. The effect of oral administration and peritumor injection of resveratrol was tested on tumor growth in two animal models of uveal melanoma. The mechanism of resveratrol action on uveal melanoma cells was studied in vitro in a cell-viability assay: with JC-1 dye, to measure mitochondrial membrane potential; by Western blot analysis, to analyze the cellular redistribution of cytochrome c and Smac/diablo; and in a fluorescence assay with specific substrates, to measure activation of different caspases. Resveratrol treatment inhibited tumor growth in animal models of uveal melanoma. Since oral administration resulted in relatively low bioavailability of resveratrol, the effect of increased local levels was tested by peritumor injection of the drug. This method resulted in tumor cell death and tumor regression. In vitro experiments with multiple uveal melanoma cell lines demonstrate that resveratrol causes a decrease in cell viability, resulting at least in part from an increase in apoptosis through a mitochondrial pathway. An early event in drug action is the direct targeting of mitochondria by resveratrol, which leads to a decrease in mitochondrial membrane potential and the eventual activation of caspase-3. These data suggest that resveratrol can inhibit tumor growth and can induce apoptosis via the intrinsic mitochondrial pathway and that by further increasing bioavailability of resveratrol the potency of the drug can be increased, leading to tumor regression. The nontoxic nature of the drug at levels needed for therapy make resveratrol an attractive candidate for the treatment of uveal melanoma.

Time trends and latitude dependence of uveal and cutaneous malignant melanoma induced by solar radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moan, J.; Setlow, R.; Cicarma, E.

2010-01-01

In order to evaluate the role of solar radiation in uveal melanoma etiology, the time and latitude dependency of the incidence rates of this melanoma type were studied in comparison with those of cutaneous malignant melanoma (CMM). Norway and several other countries with Caucasian populations were included. There is a marked north - south gradient of the incidence rates of CMM in Norway, with three times higher rates in the south than in the north. No such gradient is found for uveal melanoma. Similar findings have been published for CMM in other Caucasian populations, with the exception of Europe asmore » a whole. In most populations the ratios of uveal melanoma incidence rates to those of CMM tend to decrease with increasing CMM rates. This is also true for Europe, in spite of the fact that in this region there is an inverse latitude gradient of CMM, with higher rates in the north than in the south. In Norway the incidence rates of CMM have increased until about 1990 but have been constant, or even decreased (for young people) after that time, indicating constant or decreasing sun exposure. The uveal melanoma rates have been increasing after 1990. In most other populations the incidence rates of CMM have been increasing until recently while those of uveal melanoma have been decreasing. These data generally support the assumption that uveal melanomas are not generated by ultraviolet (UV) radiation and that solar UV, via its role in vitamin D photosynthesis, may have a protective effect.« less

Intraocular inflammation in autoimmune diseases.

PubMed

Pras, Eran; Neumann, Ron; Zandman-Goddard, Gisele; Levy, Yair; Assia, Ehud I; Shoenfeld, Yehuda; Langevitz, Pnina

2004-12-01

The uveal tract represents the vascular organ of the eye. In addition to providing most of the blood supply to the intraocular structures, it acts as a conduit for immune cells, particularly lymphocytes, to enter the eye. Consequently, the uveal tract is represented in many intraocular inflammatory processes. Uveitis is probably a misnomer unless antigens within the uvea are the direct targets of the inflammatory process. A better term of the condition is "intraocular inflammation" (IOI). To review the presence of IOI in autoimmune diseases, the immunopathogenic mechanisms leading to disease, and treatment. We reviewed the English medical literature by using MEDLINE (1984-2003) employing the terms "uveitis," "intraocular inflammation," and "autoimmune diseases." An underlying autoimmune disease was identified in up to 40% of patients with IOI, and included spondyloarthropathies, Behcets disease, sarcoidosis, juvenile chronic arthritis, Vogt-Koyanagi-Harada syndrome (an inflammatory syndrome including uveitis with dermatologic and neurologic manifestations), immune recovery syndrome, and uveitis with tubulointerstitial disease. The immunopathogenesis of IOI involves enhanced T-cell response. Recently, guidelines for the use of immunosuppressive drugs for inflammatory eye disease were established and include: corticosteroids, azathioprine, methotrexate, mycophenolate mofetil, cyclosporine, tacrolimus, cyclophosphamide, and chlorambucil. New therapies with limited experience include the tumor necrosis factor alpha inhibitors, interferon alfa, monoclonal antibodies against lymphocyte surface antigens, intravenous immunoglobulin (IVIG), and the intraocular delivery of immunosuppressive agents. An underlying autoimmune disease was identified in up to 40% of patients with IOI. Immunosuppressive drugs, biologic agents, and IVIG are employed for the treatment of IOI in autoimmune diseases.

Radioembolization as Locoregional Therapy of Hepatic Metastases in Uveal Melanoma Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Klingenstein, A., E-mail: annemarie.klingenstein@med.uni-muenchen.de; Haug, A. R.; Zech, C. J.

2013-02-15

To retrospectively evaluate the overall survival, safety, and efficacy of metastatic uveal melanoma patients after radioembolization as salvage therapy. Thirteen patients were treated with radioembolization of branches of the hepatic artery with resin-based yttrium-90 ({sup 90}Y)-labelled microspheres. Twelve patients underwent a single application, and 1 patient underwent 4 interventions. Dosages from 644 to 2,450 MBq (mean activity 1,780) were applied. Treatment response was evaluated by way of liver magnetic resonance imaging and computed tomography (CT) as well as whole-body fluorodeoxyglucose positron emission tomography (PET)/CT with evaluation of percentage changes in SUV{sub max} before and at 2-3 months after therapy. Kaplan-Meiermore » analysis was calculated to determine overall survival. Partial remission (PR) was observed in 8 (62 %), stable disease (SD) in 2 (15 %), and progressive disease (PD) in 3 (23 %) patients under terms of standard criteria and PR in 3 (23 %), SD in 3 (23 %), and PD in 7 (54 %) patients according to PET criteria. Neither RECIST nor PET criteria showed a significant difference in predicting overall survival (P = 0.12 and 0.11, respectively). Median survival time after radioembolization was 7 months. No acute toxicity with in-hospital morbidity was observed. One patient developed hepatomegaly, and 1 patient developed gastric ulceration. Throughout follow-up, progression of extrahepatic metastases was observed. Radioembolization may be a promising therapy in uveal melanoma patients with predominant hepatic metastases. At first follow-up, we observed PR or SD in 77 % patients under terms of standard criteria with an acceptable toxicity profile.« less

[Equine recurrent uveitis].

PubMed

Spiess, B M

1997-01-01

Equine recurrent uveitis is an important ocular disease and the most common cause for blindness in horses and mules worldwide. The anatomy, physiology, immunology and inflammatory reactions of the uveal tract are discussed. Possible etiologies and the clinical signs are described. A detailed description of possible therapies is given and the prognosis is discussed.

Outcomes and Control Rates for I-125 Plaque Brachytherapy for Uveal Melanoma: A Community-Based Institutional Experience

PubMed Central

Cook, Taylor

2014-01-01

Purpose. To evaluate our community-based institutional experience with plaque brachytherapy for uveal melanomas with a focus on local control rates, factors impacting disease progression, and dosimetric parameters impacting treatment toxicity. Methods and Materials. Our institution was retrospectively reviewed from 1996 to 2011; all patients who underwent plaque brachytherapy for uveal melanoma were included. Follow-up data were collected regarding local control, distant metastases, and side effects from treatment. Analysis was performed on factors impacting treatment outcomes and treatment toxicity. Results. A total of 107 patients underwent plaque brachytherapy, of which 88 had follow-up data available. Local control at 10 years was 94%. Freedom from progression (FFP) and overall survival at 10 years were 83% and 79%, respectively. On univariate analysis, there were no tumor or dosimetric treatment characteristics that were found to have a prognostic impact on FFP. Brachytherapy treatment was well tolerated, with clinically useful vision (>20/200) maintained in 64% of patients. Statistically significant dosimetric relationships were established with cataract, glaucoma, and retinopathy development (greatest P = 0.05). Conclusions. Treatment with plaque brachytherapy demonstrates excellent outcomes in a community-based setting. It is well tolerated and should remain a standard of care for COMS medium sized tumors. PMID:24734198

Early diagnosis and successful treatment of paraneoplastic melanocytic proliferation

PubMed Central

Jansen, Joyce C G; Van Calster, Joachim; Pulido, Jose S; Miles, Sarah L; Vile, Richard G; Van Bergen, Tine; Cassiman, Catherine; Spielberg, Leigh H; Leys, Anita M

2015-01-01

Background Paraneoplastic melanocytic proliferation (bilateral diffuse uveal melanocytic proliferation, BDUMP) is a rare but devastating disease that causes progressive visual loss in patients who usually have an occult malignancy. Visual loss occurs as a result of paraneoplastic changes in the uveal tissue. Methods In a masked fashion, the serum of two patients with BDUMP was evaluated for the presence of cultured melanocyte elongation and proliferation (CMEP) factor using cultured human melanocytes. We evaluated the efficacy of plasmapheresis as a treatment modality early in the disease in conjunction with radiation and chemotherapy. Results The serum of the first case patient was investigated after plasmapheresis and did not demonstrate proliferation of cultured human melanocytes. The serum of the second case was evaluated prior to treatment with plasmapheresis and did induce this proliferation. These findings are in accordance with the diminution of CMEP factor after plasmapheresis. Treatment with plasmapheresis managed to stabilise the ocular disease progression in both patients. Conclusions In the past, visual loss due to paraneoplastic melanocytic proliferation was considered progressive and irreversible. We treated two patients successfully with plasmapheresis and demonstrated a relation between CMEP factor in the serum of these patients and proliferation of cultured melanocytes. PMID:25908835

Assessment of the influence of one's education on early diagnosis of multiple primary cancer in patients with uveal melanoma.

PubMed

Mierzwa-Dobranowska, Marzena; Romanowska-Dixon, Bozena

2012-01-01

This study will show a comparison of two groups of patients with uveal melanoma; one group with multiple primary cancer, and a second group with no identifiable second cancer, in terms of education and occupation. Study concerns 240 patients, who were isolated from patients being treated with uveal melanoma at the Department of Ophthalmology and Ocular Oncology Jagiellonian University Medical College in the period from 1998 to 2007. On the basis of medical history and medical records 97 patients were diagnosed with the one or more independent primary cancers. These patients were subjected to comparative analysis with a group of 143 patients with uveal melanoma as a control group. Analyzing the impact of education on the recognition of multiple primary cancer, there were significantly more frequent diagnoses of second primary cancers among patients with secondary and higher education than among those who had primary and vocational education. Among the obtained data on patients in the study group, the largest occupational group (according to the ISCO-88 (COM)) constituted "professionals". In the control group prevailed "craft and related trades workers". The results suggest the great importance of knowledge about risk factors for the development of cancer among patients with uveal melanoma and the ensuing more scrupulous search for succesive primary neoplasm and indicate the neccesity of organizing broad prophylactic actions. uveal melanoma, multiple primary cancer.

Incidence and Management of Glaucoma in Vogt Koyanagi Harada Disease.

PubMed

Pandey, Amit; Balekudaru, Shantha; Venkatramani, Devendra V; George, Amala E; Lingam, Vijaya; Biswas, Jyotirmay

2016-08-01

To analyse the prevalence, incidence, and risk factors of glaucoma in Vogt Koyanagi Harada (VKH) disease and study the changes in visual acuity and intraocular pressure (IOP) with treatment. Retrospective chart analysis of 448 eyes of 224 patients of Indian origin diagnosed with VKH disease from January 1990 to December 2013, who had a minimum follow-up of 3 months was performed. Seventy-one eyes (15.8%) developed sustained elevation in IOP. The prevalence of glaucoma at presentation was 15.8% and the cumulative incidence of glaucoma was 11.7%. The mechanisms of glaucoma were open-angle glaucoma in 46 eyes, (64.8%), angle closure in 21 eyes (29.6%), and of combined mechanisms in the remainder (4 eyes, 5.6%). Acute angle-closure crisis developed in 9 eyes (12.6%). Uveal effusion (odds ratio 9.47; confidence interval, 4.08-20.03) and increased number of recurrences (odds ratio 1.31; confidence interval, 1.13-1.53) were found to be significant risk factors for the development of glaucoma. Successful control of IOP was achieved in 64% at 12 months using medical/ laser treatment for glaucoma and was 50 % at 12 months following surgical management. Glaucoma is a frequent complication of uveitis in VKH disease. Presence of uveal effusion and increased number of recurrences of inflammation are significant risk factors.

Activation of the MAPK pathway is a common event in uveal melanomas although it rarely occurs through mutation of BRAF or RAS.

PubMed

Zuidervaart, W; van Nieuwpoort, F; Stark, M; Dijkman, R; Packer, L; Borgstein, A-M; Pavey, S; van der Velden, P; Out, C; Jager, M J; Hayward, N K; Gruis, N A

2005-06-06

In contrast to cutaneous melanoma, there is no evidence that BRAF mutations are involved in the activation of the mitogen-activated protein kinase (MAPK) pathway in uveal melanoma, although there is increasing evidence that this pathway is activated frequently in the latter tumours. In this study, we performed mutation analysis of the RAS and BRAF genes in a panel of 11 uveal melanoma cell lines and 19 primary uveal melanoma tumours. In addition, Western blot and immunohistochemical analyses were performed on downstream members of the MAPK pathway in order to assess the contribution of each of these components. No mutations were found in any of the three RAS gene family members and only one cell line carried a BRAF mutation (V599E). Despite this, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK), ERK and ELK were constitutively activated in all samples. These data suggest that activation of the MAPK pathway is commonly involved in the development of uveal melanoma, but occurs through a mechanism different to that of cutaneous melanoma.

Activation of the MAPK pathway is a common event in uveal melanomas although it rarely occurs through mutation of BRAF or RAS

PubMed Central

Zuidervaart, W; van Nieuwpoort, F; Stark, M; Dijkman, R; Packer, L; Borgstein, A-M; Pavey, S; van der Velden, P; Out, C; Jager, M J; Hayward, N K; Gruis, N A

2005-01-01

In contrast to cutaneous melanoma, there is no evidence that BRAF mutations are involved in the activation of the mitogen-activated protein kinase (MAPK) pathway in uveal melanoma, although there is increasing evidence that this pathway is activated frequently in the latter tumours. In this study, we performed mutation analysis of the RAS and BRAF genes in a panel of 11 uveal melanoma cell lines and 19 primary uveal melanoma tumours. In addition, Western blot and immunohistochemical analyses were performed on downstream members of the MAPK pathway in order to assess the contribution of each of these components. No mutations were found in any of the three RAS gene family members and only one cell line carried a BRAF mutation (V599E). Despite this, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK), ERK and ELK were constitutively activated in all samples. These data suggest that activation of the MAPK pathway is commonly involved in the development of uveal melanoma, but occurs through a mechanism different to that of cutaneous melanoma. PMID:15928660

Intraocular (Eye) Melanoma—Health Professional Version

Cancer.gov

Intraocular (uveal) melanoma of the uveal tract (iris, ciliary body, and choroid), though rare, is the most common primary intraocular malignancy in adults. Find evidence-based information on intraocular melanoma treatment.

Tropical Spastic Paraparesis

MedlinePlus

... rare cases individuals with HAM/TSP also exhibit uveitis (inflammation of the uveal tract of the eye), ... rare cases individuals with HAM/TSP also exhibit uveitis (inflammation of the uveal tract of the eye), ...

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vogl, Thomas J., E-mail: t.vogl@em.uni-frankfurt.de; Koch, Silvia A., E-mail: silvia.koch@web.de; Lotz, Gösta, E-mail: goesta.lotz@kgu.de

PurposePercutaneous isolated hepatic perfusion (PIHP) with Melphalan has been developed as a treatment for patients with isolated hepatic metastases of uveal melanoma. We discuss patient outcome and safety in a retrospective multi-centre study.Materials and MethodsBetween 2012 and 2016 18 patients with un-resectable isolated hepatic metastases of uveal melanoma received single or repeated PIHP with Melphalan (n = 35) at seven sites. Progression-free time, overall survival time (OS) and tumour response by means of RECIST 1.1 criteria were evaluated. Peri- and post-procedural adverse events (AE) were registered. Patients’ life quality was assessed using four-point scale questionnaires.ResultsOf 18 patients, initial PIHP treatment resulted inmore » partial response (PR) in eight, stable disease (SD) in seven and progressive disease (PD) in three cases. Nine patients underwent second PIHP with PR in eight cases and PD in one case. Six patients were evaluated after third PIHP with PR in five patients and SD in one patient. Two patients received fourth PIHP with PD in both cases. Median OS was 9.6 months (range 1.6–41.0 months). Median progression-free survival time was 12.4 months (range 0.9–41.0 months) with 1-year survival of 44%. Most common post-procedural AE grade 3 and 4 were temporary leukopenia (n = 11) and thrombocytopenia (n = 8). Patients’ self-assessments showed good ratings for overall health and quality of life with only slight changes after PIHP, and a high degree of satisfaction with PIHP treatment.ConclusionPIHP with Melphalan proved to be a relatively safe, minimal-invasive and repeatable treatment for patients with non-resectable hepatic metastases of uveal melanoma.« less

Targeted Silencing of MART-1 Gene Expression by RNA Interference Enhances the Migration Ability of Uveal Melanoma Cells

PubMed Central

Zhang, Yidan; Jia, Renbing; Wang, Jing; Xu, Xiaofang; Yao, Yuting; Ge, Shengfan; Fan, Xianqun

2013-01-01

Uveal melanoma (UM) is the most common primary intraocular malignancy and the leading potentially fatal primary intraocular disease in adults. Melanoma antigen recognized by T-cells (MART-1) has been studied extensively as a clinically important diagnostic marker for melanoma, however, its biological function remains unclear. In the present study, the UM cell line SP6.5, which showed a high level of MART-1 expression, was subjected to small interfering RNA-mediated silencing of MART-1. Silencing of MART-1 expression increased the migration ability of SP6.5 cells and down-regulated the expression of the metastasis suppressor NM23. Our results suggest that MART-1 is a candidate target for the development of therapeutic strategies for UM and in particular for the suppression of metastasis associated with this malignancy. PMID:23877836

iTRAQ Quantitative Proteomic Comparison of Metastatic and Non-Metastatic Uveal Melanoma Tumors

PubMed Central

Crabb, John W.; Hu, Bo; Crabb, John S.; Triozzi, Pierre; Saunthararajah, Yogen; Singh, Arun D.

2015-01-01

Background Uveal melanoma is the most common malignancy of the adult eye. The overall mortality rate is high because this aggressive cancer often metastasizes before ophthalmic diagnosis. Quantitative proteomic analysis of primary metastasizing and non-metastasizing tumors was pursued for insights into mechanisms and biomarkers of uveal melanoma metastasis. Methods Eight metastatic and 7 non-metastatic human primary uveal melanoma tumors were analyzed by LC MS/MS iTRAQ technology with Bruch’s membrane/choroid complex from normal postmortem eyes as control tissue. Tryptic peptides from tumor and control proteins were labeled with iTRAQ tags, fractionated by cation exchange chromatography, and analyzed by LC MS/MS. Protein identification utilized the Mascot search engine and the human Uni-Prot/Swiss-Protein database with false discovery ≤ 1%; protein quantitation utilized the Mascot weighted average method. Proteins designated differentially expressed exhibited quantitative differences (p ≤ 0.05, t-test) in a training set of five metastatic and five non-metastatic tumors. Logistic regression models developed from the training set were used to classify the metastatic status of five independent tumors. Results Of 1644 proteins identified and quantified in 5 metastatic and 5 non-metastatic tumors, 12 proteins were found uniquely in ≥ 3 metastatic tumors, 28 were found significantly elevated and 30 significantly decreased only in metastatic tumors, and 31 were designated differentially expressed between metastatic and non-metastatic tumors. Logistic regression modeling of differentially expressed collagen alpha-3(VI) and heat shock protein beta-1 allowed correct prediction of metastasis status for each of five independent tumor specimens. Conclusions The present data provide new clues to molecular differences in metastatic and non-metastatic uveal melanoma tumors. While sample size is limited and validation required, the results support collagen alpha-3(VI) and heat shock protein beta-1 as candidate biomarkers of uveal melanoma metastasis and establish a quantitative proteomic database for uveal melanoma primary tumors. PMID:26305875

Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated rho GTPase signaling circuitry.

PubMed

Feng, Xiaodong; Degese, Maria Sol; Iglesias-Bartolome, Ramiro; Vaque, Jose P; Molinolo, Alfredo A; Rodrigues, Murilo; Zaidi, M Raza; Ksander, Bruce R; Merlino, Glenn; Sodhi, Akrit; Chen, Qianming; Gutkind, J Silvio

2014-06-16

Mutually exclusive activating mutations in the GNAQ and GNA11 oncogenes, encoding heterotrimeric Gαq family members, have been identified in ∼ 83% and ∼ 6% of uveal and skin melanomas, respectively. However, the molecular events underlying these GNAQ-driven malignancies are not yet defined, thus limiting the ability to develop cancer-targeted therapies. Here, we focused on the transcriptional coactivator YAP, a critical component of the Hippo signaling pathway that controls organ size. We found that Gαq stimulates YAP through a Trio-Rho/Rac signaling circuitry promoting actin polymerization, independently of phospholipase Cβ and the canonical Hippo pathway. Furthermore, we show that Gαq promotes the YAP-dependent growth of uveal melanoma cells, thereby identifying YAP as a suitable therapeutic target in uveal melanoma, a GNAQ/GNA11-initiated human malignancy. Copyright © 2014 Elsevier Inc. All rights reserved.

Monosomy 3 by FISH in uveal melanoma: variability in techniques and results.

PubMed

Aronow, Mary; Sun, Yang; Saunthararajah, Yogen; Biscotti, Charles; Tubbs, Raymond; Triozzi, Pierre; Singh, Arun D

2012-09-01

Tumor monosomy 3 confers a poor prognosis in patients with uveal melanoma. We critically review the techniques used for fluorescence in situ hybridization (FISH) detection of monosomy 3 in order to assess variability in practice patterns and to explain differences in results. Significant variability that has likely affected reported results was found in tissue sampling methods, selection of FISH probes, number of cells counted, and the cut-off point used to determine monosomy 3 status. Clinical parameters and specific techniques employed to report FISH results should be specified so as to allow meta-analysis of published studies. FISH-based detection of monosomy 3 in uveal melanoma has not been performed in a standardized manner, which limits conclusions regarding its clinical utility. FISH is a widely available, versatile technology, and when performed optimally has the potential to be a valuable tool for determining the prognosis of uveal melanoma. Copyright © 2012 Elsevier Inc. All rights reserved.

Expression of Antimicrobial Peptides by Uveal and Cutaneous Melanoma Cells and Investigation of Their Role in Tumor Cell Migration and Vasculogenic Mimicry.

PubMed

Manarang, Joseph C; Otteson, Deborah C; McDermott, Alison M

2017-11-01

Antimicrobial peptides (AMPs) have been implicated in the pathogenesis of several cancers, although there is also evidence suggesting potential for novel, AMP-based antitumor therapies. Discerning potential roles of AMPs in tumor pathogenesis may provide valuable insight into the mechanisms of novel AMP-based antitumor therapy. mRNA expression of the AMPs α defensin (HNP-1); cathelicidin (LL-37); and β defensins (hBD-1, hBD-2, hBD-3, hBD-4) in human uveal and cutaneous melanoma cell lines, primary human uveal melanocytes, and primary human uveal melanoma cells was determined by reverse transcriptase polymerase chain reaction. An in vitro scratch assay and custom Matlab analysis were used to determine the AMP effects on melanoma cell migration. Last, the effect of specific AMPs on vasculogenic mimicry was determined by three-dimensional (3D) culture and light and fluorescence microscopy. Low-to-moderate AMP transcript levels were detected, and these varied across the cells tested. Overall, LL-37 expression was increased while hBD-4 was decreased in most melanoma cell lines, compared to primary cultured uveal melanocytes. There was no observable influence of HNP-1 and LL-37 on tumor cell migration. Additionally, aggressive cutaneous melanoma cells grown in 3D cultures exhibited vasculogenic mimicry, although AMP exposure did not alter this process. Collectively, our data show that although AMP mRNA expression is variable between uveal and cutaneous melanoma cells, these peptides have little influence on major characteristics that contribute to tumor aggressiveness and progression.

Early diagnosis and successful treatment of paraneoplastic melanocytic proliferation.

PubMed

Jansen, Joyce C G; Van Calster, Joachim; Pulido, Jose S; Miles, Sarah L; Vile, Richard G; Van Bergen, Tine; Cassiman, Catherine; Spielberg, Leigh H; Leys, Anita M

2015-07-01

Paraneoplastic melanocytic proliferation (bilateral diffuse uveal melanocytic proliferation, BDUMP) is a rare but devastating disease that causes progressive visual loss in patients who usually have an occult malignancy. Visual loss occurs as a result of paraneoplastic changes in the uveal tissue. In a masked fashion, the serum of two patients with BDUMP was evaluated for the presence of cultured melanocyte elongation and proliferation (CMEP) factor using cultured human melanocytes. We evaluated the efficacy of plasmapheresis as a treatment modality early in the disease in conjunction with radiation and chemotherapy. The serum of the first case patient was investigated after plasmapheresis and did not demonstrate proliferation of cultured human melanocytes. The serum of the second case was evaluated prior to treatment with plasmapheresis and did induce this proliferation. These findings are in accordance with the diminution of CMEP factor after plasmapheresis. Treatment with plasmapheresis managed to stabilise the ocular disease progression in both patients. In the past, visual loss due to paraneoplastic melanocytic proliferation was considered progressive and irreversible. We treated two patients successfully with plasmapheresis and demonstrated a relation between CMEP factor in the serum of these patients and proliferation of cultured melanocytes. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

[Lymphocytic infiltration in uveal melanoma].

PubMed

Sach, J; Kocur, J

1993-11-01

After our observation of lymphocytic infiltration in uveal melanomas we present theoretical review to this interesting topic. Due to relatively low incidence of this feature we haven't got sufficiently large collection of cases for presentation of our statistically significant conclusions.

Occupational exposure to electromagnetic fields and sex-differential risk of uveal melanoma.

PubMed

Behrens, Thomas; Lynge, Elsebeth; Cree, Ian; Sabroe, Svend; Lutz, Jean-Michel; Afonso, Noemia; Eriksson, Mikael; Guénel, Pascal; Merletti, Franco; Morales-Suarez-Varela, Maria; Stengrevics, Aivars; Févotte, Joëlle; Llopis-González, Agustin; Gorini, Giuseppe; Sharkova, Galina; Hardell, Lennart; Ahrens, Wolfgang

2010-11-01

The association between occupational exposure to electromagnetic fields (EMF) and the risk of uveal melanoma was investigated in a case-control study in nine European countries. Incident cases of uveal melanoma and population as well as hospital controls were included and frequency matched by country, 5-year birth cohort and sex. Subjects were asked whether they had worked close to high-voltage electrical transmission installations, computer screens and various electrical machines, or in complex electrical environments. Measurements of two Scandinavian job-exposure matrices were applied to estimate lifelong cumulative EMF exposure. Unconditional logistic regression analyses, stratified by sex and eye colour were calculated, adjusting for several potential confounders. 293 patients with uveal melanoma and 3198 control subjects were interviewed. Women exposed to electrical transmission installations showed elevated risks (OR 5.81, 95% CI 1.72 to 19.66). Positive associations with exposure to control rooms were seen among men and women, but most risk increases were restricted to subjects with dark iris colour. Application of published EMF measurements revealed stronger risk increases among women compared to men. Again, elevated risks were restricted to subjects with dark eye colour. Although based on a low prevalence of exposure to potential occupational sources of EMF, our data indicate that exposed dark-eyed women may be at particular risk for uveal melanoma.

Posterior Segment Toxicity Following Gemcitabine and Docetaxel Chemotherapy

PubMed Central

Valeshabad, Ali Kord; Mieler, William F.; Setlur, Vikram; Thomas, Merina; Shahidi, Mahnaz

2015-01-01

Purpose To report outer retinal disruption and uveal effusion following gemcitabine and docetaxel combination therapy. Case Report A 78-year-old woman presented with blurry vision following two cycles of gemcitabine and docetaxel combination chemotherapy for stage IV sarcoma. At presentation, visual acuity (VA) was finger counting and 20/25 in the right and left eyes, respectively. Slit lamp examination and B scan ultrasonography revealed severe uveal effusion in the right eye and choroidal folds in the left eye. Spectral domain optical coherence tomography showed disruption of photoreceptor inner segment ellipsoid band in the right eye. The patient was monitored weekly with ophthalmic examination and B scan ultrasonography, while continuing with gemcitabine monotherapy. At 8 weeks follow up, uveal effusion improved considerably and VA was 20/40 and 20/20 in the right and left eyes, respectively. Conclusions Uveal effusion and outer retinal disruption were reported following gemcitabine and docetaxel chemotherapy. Early detection and close ophthalmic monitoring may allow concurrent cancer treatment and prevention of possible chemotherapy-induced ocular side effects. PMID:25822016

Intraocular ALλ amyloidoma with plasma cell neoplasia in a cat.

PubMed

Kershaw, Olivia; Linek, Jens; Linke, Reinhold P; Gruber, Achim D

2011-09-01

An 11-year-old, neutered male domestic short-hair cat was presented with buphthalmos of the right eye and diagnosed with advanced glaucoma. Sonographic examination revealed an iridial thickening. Neoplasia was suspected and an enucleation was performed. Histopathology of the enucleated eye revealed abundant amyloid deposition predominantly in the anterior uveal tract accompanied by few to moderate numbers of well-differentiated plasma cells. The amyloid deposits were identified by staining with Congo red and showing green birefringence under polarized light. Immunohistochemically, amyloid and plasma cells stained intensely only with anti-ALλ antibody, supporting the amyloid tumor being an immunoglobulin-λ-light chain origin. Additional abnormalities included narrowing of the filtration angle and collapse of the ciliary cleft, and trabecular meshwork. One year post-enucleation, the cat was still healthy without signs of systemic amyloidosis or apparent metastatic disease. This is the first report of a cat with noncutaneous extramedullary plasmacytoma originating in the anterior uveal tract with resulting local amyloid. © 2011 American College of Veterinary Ophthalmologists.

Utilizing T-cell Activation Signals 1, 2, and 3 for Tumor-infiltrating Lymphocytes (TIL) Expansion: The Advantage Over the Sole Use of Interleukin-2 in Cutaneous and Uveal Melanoma.

PubMed

Tavera, René J; Forget, Marie-Andrée; Kim, Young Uk; Sakellariou-Thompson, Donastas; Creasy, Caitlin A; Bhatta, Ankit; Fulbright, Orenthial J; Ramachandran, Renjith; Thorsen, Shawne T; Flores, Esteban; Wahl, Arely; Gonzalez, Audrey M; Toth, Christopher; Wardell, Seth; Mansaray, Rahmatu; Radvanyi, Laszlo G; Gombos, Dan S; Patel, Sapna P; Hwu, Patrick; Amaria, Rodabe N; Bernatchez, Chantale; Haymaker, Cara

2018-05-11

In this study, we address one of the major critiques for tumor-infiltrating lymphocyte (TIL) therapy-the time needed for proper expansion of a suitable product. We postulated that T-cell receptor activation in the first phase of expansion combined with an agonistic stimulation of CD137/4-1BB and interleukin-2 would favor preferential expansion of CD8 TIL. Indeed, this novel 3-signal approach for optimal T-cell activation resulted in faster and more consistent expansion of CD8CD3 TIL. This new method allowed for successful expansion of TIL from cutaneous and uveal melanoma tumors in 100% of the cultures in <3 weeks. Finally, providing the 3 signals attributed to optimal T-cell activation led to expansion of TIL capable of recognizing their tumor counterpart in cutaneous and uveal melanoma. This new methodology for the initial phase of TIL expansion brings a new opportunity for translation of TIL therapy in challenging malignancies such as uveal melanoma.

NEAR-INFRARED AUTOFLUORESCENCE IN BILATERAL DIFFUSE UVEAL MELANOCYTIC PROLIFERATION ASSOCIATED WITH ESOPHAGEAL CARCINOMA AND CHOROIDAL METASTASIS.

PubMed

Golshahi, Azadeh; Bornfeld, Norbert; Weinitz, Silke; Kellner, Ulrich

2016-01-01

To investigate the advantage of near-infrared autofluorescence (787 nm) for the detection of melanocytic lesions in a patient with bilateral diffuse uveal melanocytic proliferation in association with esophageal carcinoma complicated by most likely unilateral choroidal metastasis. In this retrospective case report, a 55-year-old woman referred for the evaluation of sudden visual loss underwent normal ophthalmological evaluation and, in addition, was examined with near-infrared reflectance, near-infrared autofluorescence, fundus autofluorescence (Heidelberg Retina Angiograph II [HRA2; Heidelberg Engineering]), spectral domain optical coherence tomography (Spectralis OCT; Heidelberg Engineering), and multifocal electroretinography (RetiScan; Roland Consult). The patient had been diagnosed with esophageal carcinoma 3 months before the onset of visual symptoms. The visual acuity was 20/40 in the right eye and 20/20 in the left eye. Bilateral patchy melanocytic proliferation was detected on ophthalmoscopy. The extent of lesions was best detected with near-infrared reflectance and near-infrared autofluorescence, whereas fundus autofluorescence and spectral domain optical coherence tomography did not reveal alterations of the outer retina or retinal pigment epithelium in this early stage of bilateral diffuse uveal melanocytic proliferation. The right eye showed in addition to the findings on the left eye choroidal folds in the fovea and an elevated lesion inferotemporal of the fovea suspicious of a choroidal metastasis. In the B-scan ultrasonography, a homogenous lesion was seen. Spectral domain optical coherence tomography demonstrated a mild accumulation of subretinal fluid adjacent to and over the choroidal metastasis. Transretinal biopsy of this elevated lesion revealed a low differentiated carcinoma of squamous epithelium, compatible with choroidal metastasis of the esophageal carcinoma. The choroidal metastasis increased within 3 months after the first visit. The visual acuity dropped in both eyes. The patient died 6 months after her first visit. Bilateral diffuse uveal melanocytic proliferation can be associated with esophageal carcinoma as a systemic malignancy. Near-infrared imaging can be helpful to detect early stages of BDUMP and can help offer recently reported treatment options at an early stage of disease.

Progress in the management of patients with uveal melanoma. The 2012 Ashton Lecture

PubMed Central

Damato, B

2012-01-01

Uveal melanomas are diverse in their clinical features and behaviour. More than 90% involve the choroid, the remainder being confined to the ciliary body and iris. Most patients experience visual loss and more than a third require enucleation, in some cases because of pain. Diagnosis is based on slit-lamp biomicroscopy and/or ophthalmoscopy, with ultrasonography, autofluorescence photography, and/or biopsy in selected cases. Conservation of the eye with useful vision has improved with advances in brachytherapy, proton beam radiotherapy, endoresection, exoresection, transpupillary thermotherapy, and photodynamic therapy. Despite ocular treatment, almost 50% of patients develop metastatic disease, which occurs almost exclusively in patients whose tumour shows chromosome 3 loss and/or class 2 gene expression profile. When the tumour shows such lethal genetic changes, the survival time depends on the anatomical stage and the histological grade of malignancy. Prognostication has improved as a result of progress in multivariate analysis including all the major risk factors. Screening for metastases is more sensitive as a consequence of advances in liver scanning with magnetic resonance imaging and other methods. More patients with metastases are living longer, benefiting from therapies such as: partial hepatectomy; radiofrequency ablation; ipilumumab immunotherapy; selective internal radiotherapy; intra-hepatic chemotherapy, possibly with isolated liver perfusion; and systemic chemotherapy. There is scope for improvement in the detection of uveal melanoma so as to maximise any opportunities for conserving the eye and vision, as well as preventing metastatic spread. Patient management has been enhanced by the formation of multidisciplinary teams in specialised ocular oncology centres. PMID:22744385

Physiological characterization of ocular melanosis-affected canine melanocytes.

PubMed

Dawson-Baglien, Ethan M; Noland, Erica L; Sledge, Dodd G; Kiupel, Matti; Petersen-Jones, Simon M

2018-04-27

Cairn terriers with ocular melanosis (OM) accumulate large, heavily pigmented melanocytes in the anterior uvea. Darkly pigmented plaques develop within the sclera, leading us to hypothesize that OM uveal melanocytes may have an abnormal migratory capacity. Globes from OM-affected Cairn terriers and unaffected control eyes enucleated for reasons unrelated to this study were used for immunohistochemistry and to culture melanocytes for in vitro cell behavior assays. The scleral plaques of six dogs were immunolabeled for HMB-45, MelanA, PNL2, CD18, CD204, and Iba-1 and compared with the pigment cells accumulated within the irides. Cultured uveal melanocytes from OM-affected and control dogs were compared using conventional assays measuring cell proliferation, invasion capability, and melanin production. Melanocytes isolated from OM eyes had significantly elevated levels of per-cell melanin content and production compared to controls. The majority of pigmented cells in the scleral plaques were HMB45 positive indicating a melanocytic origin. Many were also CD18 positive. No differences were observed between cultured melanocytes from OM-affected and control uvea for standard in vitro proliferation or invasion assays. Pigmented cells which accumulate in the sclera of OM-affected Cairn terriers are predominantly melanocytes; however, in vitro assays of uveal melanocytes did not reveal differences in migratory behavior between OM and control cells. Migratory behavior of OM-melanocytes may be environment-dependent. We suggest that RNA sequencing and differential expression analysis would be a useful next step in understanding this disease. © 2018 American College of Veterinary Ophthalmologists.

Scientists repurpose HPV vaccine technology to fight eye cancer | Center for Cancer Research

Cancer.gov

Uveal melanoma is a rare eye cancer that affects about 1,600 people in the United States. A study by scientists in the Center for Cancer Research and Aura Biosciences, Cambridge, Mass., published December 14, 2017, in Molecular Cancer Therapeutics, provides new hope for the early treatment of uveal melanoma. Read more…

Late prostatic metastasis of an uveal melanoma in a miniature Schnauzer dog.

PubMed

Delgado, Esmeralda; Silva, João X; Pissarra, Hugo; Peleteiro, Maria C; Dubielzig, Richard R

2016-07-01

This manuscript describes a previously unreported clinical case of canine uveal melanoma in a miniature Schnauzer dog with an unusual location of metastasis (prostate) and delayed occurrence (3 years after primary tumor diagnosis and enucleation). Immunohistochemical labeling of both tumors with Melan A, Ki-67, and c-kit added some valuable information.

Morphological significance of the pectineal ligament of the eye.

PubMed

Costa-Vila, J; Barastegui, C; Ruano-Gil, D

1987-01-01

We have studied the arrangement of the pectineal ligament or its equivalent, the uveal trabecula, in herbivores, carnivores, primates and humans. From our investigations, the pectineal ligament, the uveal trabecula and the so-called processes of the iris form a morphological unit that is made up of the tendinous fibres of the longitudinal portion of the ciliary muscle, that are inserted into the periphery of Descemet's membrane and send out ahead prolongations that extend to the anterior face of the iris. The so-called processes of the iris cannot be considered as independent structures since they represent the innermost fibres of the trabecular or uveal meshwork; in some species these have a thicker appearance, an arrangement that can occasionally be found in the human eye.

The phosphoinositide 3-kinase α selective inhibitor BYL719 enhances the effect of the protein kinase C inhibitor AEB071 in GNAQ/GNA11-mutant uveal melanoma cells.

PubMed

Musi, Elgilda; Ambrosini, Grazia; de Stanchina, Elisa; Schwartz, Gary K

2014-05-01

G-protein mutations are one of the most common mutations occurring in uveal melanoma activating the protein kinase C (PKC)/mitogen-activated protein kinase and phosphoinositide 3-kinase (PI3K)/AKT pathways. In this study, we described the effect of dual pathway inhibition in uveal melanoma harboring GNAQ and GNA11 mutations via PKC inhibition with AEB071 (sotrastaurin) and PI3K/AKT inhibition with BYL719, a selective PI3Kα inhibitor. Growth inhibition was observed in GNAQ/GNA11-mutant cells with AEB071 versus no activity in wild-type cells. In the GNAQ-mutant cells, AEB071 decreased phosphorylation of myristoylated alanine-rich C-kinase substrate, a substrate of PKC, along with ERK1/2 and ribosomal S6, but persistent AKT activation was present. BYL719 had minimal antiproliferative activity in all uveal melanoma cell lines, and inhibited phosphorylation of AKT in most cell lines. In the GNA11-mutant cell line, similar effects were observed with ERK1/2 inhibition, mostly inhibited by BYL719. With the combination treatment, both GNAQ- and GNA11-mutant cell lines showed synergistic inhibition of cell proliferation and apoptotic cell death. In vivo studies correlated with in vitro findings showing reduced xenograft tumor growth with the combination therapy in a GNAQ-mutant model. These findings suggest a new therapy treatment option for G-protein-mutant uveal melanoma with a focus on specific targeting of multiple downstream pathways as part of combination therapy.

The Phosphoinositide 3-Kinaseα Selective Inhibitor, BYL719, Enhances the Effect of the Protein Kinase C Inhibitor, AEB071, in GNAQ/GNA11 Mutant Uveal Melanoma Cells

PubMed Central

Musi, Elgilda; Ambrosini, Grazia; de Stanchina, Elisa; Schwartz, Gary K.

2014-01-01

G-protein mutations are one of the most common mutations occurring in uveal melanoma activating the protein kinase C (PKC)/mitogen-activated protein kinase (MAPK) and phosphoinositide 3-Kinase (PI3K)/AKT pathways. In this study, we described the effect of dual pathway inhibition in uveal melanoma harboring GNAQ and GNA11 mutations via PKC inhibition with AEB071 (Sotrastaurin) and PI3k/AKT inhibition with BYL719, a selective PI3Kα inhibitor. Growth inhibition was observed in GNAQ/GNA11 mutant cells with AEB071 versus no activity in WT cells. In the GNAQ-mutant cells, AEB071 decreased phosphorylation of MARCKS, a substrate of PKC, along with ERK1/2 and ribosomal S6, but persistent AKT activation was present. BYL719 had minimal anti-proliferative activity in all uveal melanoma cell lines, and inhibited phosphorylation of AKT in most cell lines. In the GNA11 mutant cell line, similar effects were observed with ERK1/2 inhibition, mostly inhibited by BYL719. With the combination treatment, both GNAQ and GNA11 mutant cell lines showed synergistic inhibition of cell proliferation and apoptotic cell death. In vivo studies correlated with in vitro findings showing reduced xenograft tumor growth with the combination therapy in a GNAQ mutant model. These findings suggest a new therapy treatment option for G-protein mutant uveal melanoma with a focus on specific targeting of multiple downstream pathways as part of combination therapy. PMID:24563540

Management of Radiation-induced Severe Anophthalmic Socket Contracture in Patients with Uveal Melanoma

PubMed Central

Nasser, Qasiem J.; Gombos, Dan S.; Williams, Michelle D.; Guadagnolo, B. Ashleigh; Morrison, William H.; Garden, Adam S.; Beadle, Beth M.; Canseco, Elvia; Esmaeli, Bita

2012-01-01

Purpose High-dose radiotherapy can cause contracture of the anophthalmic socket, but the incidence of this complication in patients with enucleation for uveal melanoma has not previously been reported. We reviewed the surgical management and outcomes in terms of successful prosthesis wear in patients with severe contracture of the anophthalmic socket treated with high-dose radiotherapy for high-risk uveal melanoma and estimated the relative risk of this complication. Methods The medical records of all consecutive patients enrolled in a prospective uveal-melanoma tissue-banking protocol at our institution who underwent enucleation between January 2003 and December 2010 were reviewed. Patients who underwent adjuvant radiotherapy of the enucleated socket were further studied. Results Of the 68 patients enrolled in the prospective tissue banking protocol, 12 had high-risk histologic features (e.g., extrascleral spread or vortex vein invasion) and were treated with 60 Gy of external-beam radiotherapy after enucleation. Five of these patients (41.7%) experienced severe socket contracture precluding prosthesis wear. The median time to onset of contracture following completion of radiotherapy was 20 months. Three patients underwent surgery, which entailed scar tissue release, oral mucous membrane grafting, and socket reconstruction; 2 patients declined surgery. All 3 patients who had surgery experienced significant improvement of socket contracture that enabled patients to wear a prosthesis again. Conclusion High-dose radiotherapy after enucleation in patients with uveal melanoma caused severe socket contracture and inability to wear a prosthesis in approximately 40% of patients. Surgical repair of the contracted socket using oral mucous membrane grafting can allow resumption of prosthesis wear. PMID:22581085

Melanocytoma-like melanoma may be the missing link between benign and malignant uveal melanocytic lesions in humans and dogs: a comparative study.

PubMed

Zoroquiain, Pablo; Mayo-Goldberg, Erin; Alghamdi, Sarah; Alhumaid, Sulaiman; Perlmann, Eduardo; Barros, Paulo; Mayo, Nancy; Burnier, Miguel N

2016-12-01

The cutoff presented in the current classification of canine melanocytic lesions by Wilcock and Pfeiffer is based on the clinical outcome rather than morphological concepts. Classification of tumors based on morphology or molecular signatures is the key to identifying new therapies or prognostic factors. Therefore, the aim of this study was to analyze morphological findings in canine melanocytic lesions based on classic malignant morphologic principles of neoplasia and to compare these features with human uveal melanoma (HUM) samples. In total, 64 canine and 111 human morphologically malignant melanocytic lesions were classified into two groups (melanocytoma-like or classic melanoma) based on the presence or absence of M cells, respectively. Histopathological characteristics were compared between the two groups using the χ-test, t-test, and multivariate discriminant analysis. Among the 64 canine tumors, 28 (43.7%) were classic and 36 (56.3%) were melanocytoma-like melanomas. Smaller tumor size, a higher degree of pigmentation, and lower mitotic activity distinguished melanocytoma-like from classic tumors with an accuracy of 100% for melanocytoma-like lesions. From the human series, only one case showed melanocytoma-like features and had a low risk for metastasis characteristics. Canine uveal melanoma showed a morphological spectrum with features similar to the HUM counterpart (classic melanoma) and overlapped features between uveal melanoma and melanocytoma (melanocytoma-like melanoma). Recognition that the subgroup of melanocytoma-like melanoma may represent the missing link between benign and malignant lesions could help explain the progression of uveal melanoma in dogs; these findings can potentially be translated to HUM.

Equine recurrent uveitis: the viewpoint from the USA.

PubMed

Gilger, B C

2010-03-01

Equine recurrent uveitis (ERU) is a common disease in horses in the USA. There have been many advances in the treatment of ERU; however, frequent misdiagnosis of ERU occurs in cases of primary corneal or uveal disease. It is critical to remember that primary uveitis (i.e. one bout of inflammation) is a different disease to ERU, which is an immune mediated recurrent uveitis. Standard symptomatic anti-inflammatory therapy is effective to control most cases of ERU; however, some horses require advanced therapy, such as placement of drug delivery devices or removal of the vitreous, when they fail to respond to the standard therapy.

[Design of computerised database for clinical and basic management of uveal melanoma].

PubMed

Bande Rodríguez, M F; Santiago Varela, M; Blanco Teijeiro, M J; Mera Yañez, P; Pardo Perez, M; Capeans Tome, C; Piñeiro Ces, A

2012-09-01

The uveal melanoma is the most common primary intraocular tumour in adults. The objective of this work is to show how a computerised database has been formed with specific applications, for clinical and research use, to an extensive group of patients diagnosed with uveal melanoma. For the design of the database a selection of categories, attributes and values was created based on the classifications and parameters given by various authors of articles which have had great relevance in the field of uveal melanoma in recent years. The database has over 250 patient entries with specific information on their clinical history, diagnosis, treatment and progress. It enables us to search any parameter of the entry and make quick and simple statistical studies of them. The database models have been transformed into a basic tool for clinical practice, as they are an efficient way of storing, compiling and selective searching of information. When creating a database it is very important to define a common strategy and the use of a standard language. Copyright © 2011 Sociedad Española de Oftalmología. Published by Elsevier Espana. All rights reserved.

Uveal Melanoma: Identifying Immunological and Chemotherapeutic Targets to Treat Metastases.

PubMed

Jager, Martine J; Dogrusöz, Mehmet; Woodman, Scott E

2017-01-01

Uveal melanoma is an intraocular malignancy that, depending on its size and genetic make-up, may lead to metastases in up to 50% of cases. Currently, no therapy has been proven to improve survival. However, new therapies exploiting immune responses against metastases are being developed. The primary tumor is well characterized: tumors at high risk of developing metastases often contain macrophages and lymphocytes. However, these lymphocytes are often regulatory T cells that may suppress immune response. Currently, immune checkpoint inhibitors have shown marked efficacy in multiple cancers (eg, cutaneous melanoma) but do not yet improve survival in uveal melanoma patients. More knowledge needs to be acquired regarding the function of T cells in uveal melanoma. Other therapeutic options are related to the biochemical pathways. Targeting the RAF-MEK-ERK pathway with small molecule MEK inhibitors abrogates the growth of UM cells harboring GNAQ/GNA11 Q209 mutations, suggesting that these aberrant G-protein oncogenes mediate, at least in part, their effect through this hallmark proliferation pathway. Other pathways are also implicated, such as those involving c-Jun and YAP. Further studies may show how interference in the different pathways may affect survival. Copyright 2017 Asia-Pacific Academy of Ophthalmology.

Charged Particle Radiation Therapy for Uveal Melanoma: A Systematic Review and Meta-Analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Zhen, E-mail: Wang.Zhen@mayo.edu; Nabhan, Mohammed; Schild, Steven E.

2013-05-01

Charged particle therapy (CPT) delivered with either protons, helium ions, or carbon ions, has been used to treat uveal melanoma. The present analysis was performed to systematically evaluate the efficacy and adverse effects of CPT for uveal melanoma. We searched EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and SciVerse Scopus and cross-referenced recent systematic reviews through January 2012. Two independent reviewers identified clinical trials and observational studies of CPT (protons, helium ions, and carbon ions). These reviewers extracted data and assessed study quality. Twenty-seven studies enrolling 8809 uveal melanoma patients met inclusion criteria. Themore » rate of local recurrence was significantly less with CPT than with brachytherapy (odds ratio [OR] = 0.22, 95% confidence interval [CI], 0.21-0.23). There were no significant differences in mortality or enucleation rates. Results were robust in multiple sensitivity analyses. CPT was also associated with lower retinopathy and cataract formation rates. Data suggest better outcomes may be possible with charged particle therapy with respect to local recurrence, retinopathy, and cataract formation rates. The overall quality of the evidence is low, and higher quality comparative effectiveness studies are needed to provide better evidence.« less

Gamma Knife Radiosurgery for Uveal Metastases: Report of Three Cases and a Review of the Literature.

PubMed

Ares, William J; Tonetti, Daniel; Yu, Jenny Y; Monaco, Edward A; Flickinger, John C; Lunsford, L Dade

2017-02-01

Uveal metastases are ophthalmologic tumors that have historically been treated by fractionated external beam radiation therapy or invasive brachytherapy. The need for rapid response and less invasive management options led the authors to explore the use of Gamma Knife stereotactic radiosurgery (SRS) for this common problem. Interventional case series. To prevent eye movement during the procedure, all 3 patients underwent a retrobulbar anesthetic block followed by magnetic resonance imaging to detect the target. All tumors were treated in a single procedure using the 4C or Perfexion Gamma Knife. The tumors received a minimal tumor dose of 14-20 Gy. Two patients also underwent SRS for additional intracranial metastases. At follow-up, performed between 4 and 15 months after SRS, all 3 patients demonstrated a reduction in uveal tumor volumes. One patient developed decreased visual acuity secondary to radiation retinopathy. In this early experience, SRS was found to be an effective management option for uveal metastases associated with systemic cancer. Patients can be screened and treated effectively early after diagnosis using a joint approach between ophthalmologists and neurosurgeons. Systemic oncologic care can continue without interruption. Copyright © 2016 Elsevier Inc. All rights reserved.

Development and External Validation of a Prognostic Nomogram for Metastatic Uveal Melanoma

PubMed Central

Valpione, Sara; Moser, Justin C.; Parrozzani, Raffaele; Bazzi, Marco; Mansfield, Aaron S.; Mocellin, Simone; Pigozzo, Jacopo; Midena, Edoardo; Markovic, Svetomir N.; Aliberti, Camillo; Campana, Luca G.; Chiarion-Sileni, Vanna

2015-01-01

Background Approximately 50% of patients with uveal melanoma (UM) will develop metastatic disease, usually involving the liver. The outcome of metastatic UM (mUM) is generally poor and no standard therapy has been established. Additionally, clinicians lack a validated prognostic tool to evaluate these patients. The aim of this work was to develop a reliable prognostic nomogram for clinicians. Patients and Methods Two cohorts of mUM patients, from Veneto Oncology Institute (IOV) (N=152) and Mayo Clinic (MC) (N=102), were analyzed to develop and externally validate, a prognostic nomogram. Results The median survival of mUM was 17.2 months in the IOV cohort and 19.7 in the MC cohort. Percentage of liver involvement (HR 1.6), elevated levels of serum LDH (HR 1.6), and a WHO performance status=1 (HR 1.5) or 2–3 (HR 4.6) were associated with worse prognosis. Longer disease-free interval from diagnosis of UM to that of mUM conferred a survival advantage (HR 0.9). The nomogram had a concordance probability of 0.75 (SE .006) in the development dataset (IOV), and 0.80 (SE .009) in the external validation (MC). Nomogram predictions were well calibrated. Conclusions The nomogram, which includes percentage of liver involvement, LDH levels, WHO performance status and disease free-interval accurately predicts the prognosis of mUM and could be useful for decision-making and risk stratification for clinical trials. PMID:25780931

Activating cysteinyl leukotriene receptor 2 (CYSLTR2) mutations in blue nevi

PubMed Central

Möller, Inga; Murali, Rajmohan; Müller, Hansgeorg; Wiesner, Thomas; Jackett, Louise A; Scholz, Simone L; Cosgarea, Ioana; van de Nes, Johannes AP; Sucker, Antje; Hillen, Uwe; Schilling, Bastian; Paschen, Annette; Kutzner, Heinz; Rütten, Arno; Böckers, Martin; Scolyer, Richard A; Schadendorf, Dirk; Griewank, Klaus G

2017-01-01

Blue nevi are common melanocytic tumors arising in the dermal layer of the skin. Similar to uveal melanomas, blue nevi frequently harbor GNAQ and GNA11 mutations. Recently, recurrent CYSLTR2 and PLCB4 mutations were identified in uveal melanomas not harboring GNAQ or GNA11 mutations. All four genes (GNAQ, GNA11, CYSLTR2, and PLCB4) code for proteins involved in the same signaling pathway, which is activated by mutations in these genes. Given the related functional consequences of these mutations and the known genetic similarities between uveal melanoma and blue nevi, we analyzed a cohort of blue nevi to investigate whether CYSLTR2 and PLCB4 mutations occur in tumors lacking GNAQ or GNA11 mutations (as in uveal melanoma). A targeted next-generation sequencing assay covering known activating mutations in GNAQ, GNA11, CYSLTR2, PLCB4, KIT, NRAS, and BRAF was applied to 103 blue nevi. As previously reported, most blue nevi were found to harbor activating mutations in GNAQ (59%, n = 61), followed by less frequent mutations in GNA11 (16%, n = 17). Additionally, one BRAF (1%) and three NRAS (3%) mutations were detected. In three tumors (3%) harboring none of the aforementioned gene alterations, CYSLTR2 mutations were identified. All three CYSLTR2 mutations were the same c.386T > A, L129Q mutation previously identified in uveal melanoma that has been shown to lead to increased receptor activation and signaling. In summary, our study identifies CYSLTR2 L129Q alterations as a previously unrecognized activating mutation in blue nevi, occuring in a mutually exclusive fashion with known GNAQ and GNA11 mutations. Similar to GNAQ and GNA11 mutations, CYSLTR2 mutations, when present, are likely defining pathogenetic events in blue nevi. PMID:27934878

Activating cysteinyl leukotriene receptor 2 (CYSLTR2) mutations in blue nevi.

PubMed

Möller, Inga; Murali, Rajmohan; Müller, Hansgeorg; Wiesner, Thomas; Jackett, Louise A; Scholz, Simone L; Cosgarea, Ioana; van de Nes, Johannes Ap; Sucker, Antje; Hillen, Uwe; Schilling, Bastian; Paschen, Annette; Kutzner, Heinz; Rütten, Arno; Böckers, Martin; Scolyer, Richard A; Schadendorf, Dirk; Griewank, Klaus G

2017-03-01

Blue nevi are common melanocytic tumors arising in the dermal layer of the skin. Similar to uveal melanomas, blue nevi frequently harbor GNAQ and GNA11 mutations. Recently, recurrent CYSLTR2 and PLCB4 mutations were identified in uveal melanomas not harboring GNAQ or GNA11 mutations. All four genes (GNAQ, GNA11, CYSLTR2, and PLCB4) code for proteins involved in the same signaling pathway, which is activated by mutations in these genes. Given the related functional consequences of these mutations and the known genetic similarities between uveal melanoma and blue nevi, we analyzed a cohort of blue nevi to investigate whether CYSLTR2 and PLCB4 mutations occur in tumors lacking GNAQ or GNA11 mutations (as in uveal melanoma). A targeted next-generation sequencing assay covering known activating mutations in GNAQ, GNA11, CYSLTR2, PLCB4, KIT, NRAS, and BRAF was applied to 103 blue nevi. As previously reported, most blue nevi were found to harbor activating mutations in GNAQ (59%, n=61), followed by less frequent mutations in GNA11 (16%, n=17). Additionally, one BRAF (1%) and three NRAS (3%) mutations were detected. In three tumors (3%) harboring none of the aforementioned gene alterations, CYSLTR2 mutations were identified. All three CYSLTR2 mutations were the same c.386T>A, L129Q mutation previously identified in uveal melanoma that has been shown to lead to increased receptor activation and signaling. In summary, our study identifies CYSLTR2 L129Q alterations as a previously unrecognized activating mutation in blue nevi, occuring in a mutually exclusive fashion with known GNAQ and GNA11 mutations. Similar to GNAQ and GNA11 mutations, CYSLTR2 mutations, when present, are likely defining pathogenetic events in blue nevi.

Scleral patch grafts in the management of uveal and ocular surface tumors.

PubMed

Barman, Manabjyoti; Finger, Paul T; Milman, Tatyana

2012-12-01

To evaluate the outcome of scleral patch grafts in a series of patients undergoing management for uveal and ocular surface tumors. Case series. Ten patients underwent scleral patch grafting. Five patients had uveal melanoma with extrascleral extension, 2 patients had scleromalacia secondary to plaque radiotherapy for uveal melanoma, 2 patients had suspicious uveoscleral nevi, and 1 patient had invasive conjunctival squamous cell carcinoma with scleral necrosis. Retrospective, interventional, noncomparative chart review of patients undergoing treatment for ocular tumors followed by scleral grafts in a tertiary eye care center in the United States between September 2003 and January 2011. Sclera was reconstructed with allogenic scleral grafts. Clinical observations were performed after grafting. Structural integrity, appearance, and stability of the grafts. Ten patients were reviewed. All melanoma cases received plaque radiotherapy with palladium 103. The cases with nevi and squamous cell carcinoma underwent local resection with cryotherapy as primary treatment. In 8 cases, scleral grafting was performed as part of the initial surgery. In all of these cases, satisfactory anatomic and functional outcomes were achieved. In 2 cases with scleromalacia secondary to radiotherapy for uveal melanoma, grafts were placed several years after the initial treatment. In these 2 cases, one showed signs of graft retraction, whereas another showed graft thinning. No patients experienced graft infection, rejection, or tumor recurrence. In this series, scleral grafts were well accepted when placed as part of the primary tumor management despite synchronous radiotherapy, scleral resection, or cryotherapy. Grafting was less successful when performed as a late procedure for radiation-induced scleromalacia. The author(s) have no proprietary or commercial interest in any materials discussed in this article. Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

MuSIC report III: tumour microcirculation patterns and development of metastasis in long-term follow-up of melanocytic uveal tumours.

PubMed

Klingenstein, Annemarie; Schaumberger, Markus M; Freeman, William R; Folberg, Robert; Mueller, Arthur J; Schaller, Ulrich C

2016-03-01

To statistically determine differences in microcirculation patterns between nevi and uveal melanomas and the influence of these patterns on metastatic potential in the long-term follow-up of 112 patients with melanocytic uveal tumours. In vivo markers indicating malignancy and metastatic potential have implications for treatment decision. Primary diagnosis and work-up included clinical examination, fundus photography, standardized A and B scan echography as well as evaluation of tumour microcirculation patterns via confocal fluorescein and indocyanine green angiography (ICGA). Patient data were collected from the patient files, the tumour registry or personal contact. Statistical analysis was performed with spss 22.0 using chi-square, Fisher's exact test and Kaplan-Meier survival analysis. Forty-three uveal melanocytic lesions remained untreated and were retrospectively classified as benign nevi, whereas 69 lesions were malignant melanomas (T1: 32, T2: 28, T3: 6 and T4: 3). 'Silent' and 'arcs without branching' were found significantly more often in nevi (p = 0.001 and p = 0.010), whereas 'parallel with cross-linking' and 'networks' were significantly more frequent in melanomas (p = 0.022 and p = 0.029). The microcirculation pattern 'parallel with cross-linking' proved significantly more frequent in patients who developed metastases (p = 0.001). Certain microcirculation patterns may guide us in differentiating uveal nevi from malignant melanomas. A non-invasive prognostic marker can be of great value for borderline lesions in which cytology is less likely taken. 'Parallel with cross-linking' did not only indicate malignancy, but it was also associated with later tumour metastasis. © 2015 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Uveal Melanoma Treated With Iodine-125 Episcleral Plaque: An Analysis of Dose on Disease Control and Visual Outcomes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Perez, Bradford A.; Mettu, Pradeep; Vajzovic, Lejla

2014-05-01

Purpose: To investigate, in the treatment of uveal melanomas, how tumor control, radiation toxicity, and visual outcomes are affected by the radiation dose at the tumor apex. Methods and Materials: A retrospective review was performed to evaluate patients treated for uveal melanoma with {sup 125}I plaques between 1988 and 2010. Radiation dose is reported as dose to tumor apex and dose to 5 mm. Primary endpoints included time to local failure, distant failure, and death. Secondary endpoints included eye preservation, visual acuity, and radiation-related complications. Univariate and multivariate analyses were performed to determine associations between radiation dose and the endpointmore » variables. Results: One hundred ninety patients with sufficient data to evaluate the endpoints were included. The 5-year local control rate was 91%. The 5-year distant metastases rate was 10%. The 5-year overall survival rate was 84%. There were no differences in outcome (local control, distant metastases, overall survival) when dose was stratified by apex dose quartile (<69 Gy, 69-81 Gy, 81-89 Gy, >89 Gy). However, increasing apex dose and dose to 5-mm depth were correlated with greater visual acuity loss (P=.02, P=.0006), worse final visual acuity (P=.02, P<.0001), and radiation complications (P<.0001, P=.0009). In addition, enucleation rates were worse with increasing quartiles of dose to 5 mm (P=.0001). Conclusions: Doses at least as low as 69 Gy prescribed to the tumor apex achieve rates of local control, distant metastasis–free survival, and overall survival that are similar to radiation doses of 85 Gy to the tumor apex, but with improved visual outcomes.« less

Ruthenium brachytherapy for uveal melanoma - single institution experience.

PubMed

Rospond-Kubiak, Iwona; Wróblewska-Zierhoffer, Marta; Twardosz-Pawlik, Hanna; Kocięcki, Jarosław

2017-12-01

The aim of this study was to report on results of uveal melanoma treatment with ruthenium-106 ( 106 Ru) brachytherapy with long-term follow-up, in terms of local tumor control, eye retention rate, radiation retinopathy, and patients' survival. Medical records of patients treated with ruthenium plaque due to uveal melanoma at the Department of Ophthalmology, Poznan University of Medical Sciences, Poland, between 1994 and 2014 were retrospectively reviewed. We identified 126 patients: 53 men, 73 women, mean age 60.04 years (range, 21-89). The largest basal diameter ranged from 4.04 mm to 18.9 mm (median, 10.67 mm), tumor height was 1.9 mm to 7.42 mm (median, 4.8 mm). Median scleral radiation dose was 570 Gy (range, 235-1,500 Gy), median apical dose 100 Gy (range, 60-129 Gy). Median follow-up was 66.5 months (range, 2-261 months). We noted a total of 19 (15%) recurrences. The actuarial rate of recurrence was 9.5% at 3 years, and 13.5% at 5 years postoperatively. Nine (7%) eye globes were lost, median time to enucleation was 5 years. The eye retention rate at 5 years was 92.7% and 81% at 10 years. Forty-three (34%) patients died before the end of the study, 24 (19%) of them due to metastatic disease. Metastatic death was related to: tumor size and TNM stage at presentation ( p = 0.002 vs. p = 0.0006, respectively) but not to age, gender, and plaque dosimetry. 106 Ru brachytherapy is an effective, globe sparing treatment that provides good tumor control and a high rate of survival. However, some ocular complications tend to appear late post-treatment, and therefore long-term follow-up is advised.

Proton beam radiotherapy of uveal melanoma

PubMed Central

Damato, Bertil; Kacperek, Andrzej; Errington, Doug; Heimann, Heinrich

2013-01-01

Proton beam radiotherapy of uveal melanoma can be administered as primary treatment, as salvage therapy for recurrent tumor, and as neoadjuvant therapy prior to surgical resection. The physical properties of proton beams make it possible to deliver high-doses of radiation to the tumor with relative sparing of adjacent tissues. This form of therapy is effective for a wider range of uveal melanoma than any other modality, providing exceptionally-high rates of local tumor control. This is particularly the case with diffuse iris melanomas, many of which are unresectable. The chances of survival, ocular conservation, visual preservation and avoidance of iatrogenic morbidity depend greatly on the tumor size, location and extent. When treating any side-effects and/or complications, it is helpful to consider whether these are the result of collateral damage or persistence of the irradiated tumor (‘toxic tumor syndrome’). PMID:24227980

Ultrasound and MRI of Pediatric Ocular Masses with Histopathologic Correlation

PubMed Central

Brennan, Rachel C.; Wilson, Matthew W.; Kaste, Sue; Helton, Kathleen J.; McCarville, M. Beth

2012-01-01

We review our experience with unusual ocular pathologies mimicking retinoblastoma that were referred to our institution over the past two decades. After presenting the imaging anatomy of the normal eye, we discuss pertinent clinical and pathological features, and illustrate the ultrasound and magnetic resonance imaging appearance of retinoblastoma, medulloepithelioma, uveal melanoma, persistent fetal vasculature, Coats disease, corneal dermoid, retinal dysplasia and toxocara granuloma. Features useful in discriminating between these entities are emphasized. PMID:22466750

Uveal Melanoma Cell Lines: Where do they come from? (An American Ophthalmological Society Thesis).

PubMed

Jager, Martine J; Magner, J Antonio Bermudez; Ksander, Bruce R; Dubovy, Sander R

2016-08-01

To determine whether some of the most often used uveal melanoma cell lines resemble their original tumor. Analysis of the literature, patient charts, histopathology, mutations, chromosome status, HLA type, and expression of melanocyte markers on cell lines and their primary tumors. We examined five cell lines and the primary tumors from which they were derived. Four of the five examined primary tumors were unusual: one occupied the orbit, two were recurrences after prior irradiation, and one developed in an eye with a nevus of Ota. One cell line did not contain the GNA11 mutation, but it was present in the primary tumor. Three of the primary tumors had monosomy 3 (two of these lacked BAP1 expression); however, all five cell lines showed disomy 3 and BAP1 expression. All of the cell lines had gain of 8q. Two cell lines lacked expression of melanocyte markers, although these were present in the corresponding primary tumor. All cell lines could be traced back to their original uveal melanoma. Four of the five primary tumors were unusual. Cell lines often differed from their primary tumor in chromosome status and melanocyte markers. However, their specific chromosome aberrations and capacity to continue proliferation characterize them as uveal melanoma cell lines.

Uveal Melanoma Cell Lines: Where do they come from? (An American Ophthalmological Society Thesis)

PubMed Central

Jager, Martine J.; Magner, J. Antonio Bermudez; Ksander, Bruce R.; Dubovy, Sander R.

2016-01-01

Purpose To determine whether some of the most often used uveal melanoma cell lines resemble their original tumor. Methods Analysis of the literature, patient charts, histopathology, mutations, chromosome status, HLA type, and expression of melanocyte markers on cell lines and their primary tumors. We examined five cell lines and the primary tumors from which they were derived. Results Four of the five examined primary tumors were unusual: one occupied the orbit, two were recurrences after prior irradiation, and one developed in an eye with a nevus of Ota. One cell line did not contain the GNA11 mutation, but it was present in the primary tumor. Three of the primary tumors had monosomy 3 (two of these lacked BAP1 expression); however, all five cell lines showed disomy 3 and BAP1 expression. All of the cell lines had gain of 8q. Two cell lines lacked expression of melanocyte markers, although these were present in the corresponding primary tumor. Conclusions All cell lines could be traced back to their original uveal melanoma. Four of the five primary tumors were unusual. Cell lines often differed from their primary tumor in chromosome status and melanocyte markers. However, their specific chromosome aberrations and capacity to continue proliferation characterize them as uveal melanoma cell lines. PMID:28018010

Malignant anterior uveal melanoma with diffuse metastasis in a dog.

PubMed

Minami, T; Patnaik, A K

1992-12-15

Enucleation was performed in 10-year-old sexually intact female mixed-breed German Shepherd Dog. Histologic examination revealed that the dog had an uveal amelanotic melanoma of the eye. The tumor consisted of anaplastic cells with a high mitotic index, indicating malignancy. On examination 3 months after enucleation, the dog had difficulty breathing and nasal discharge. Radiography revealed pulmonary metastasis. The dog was euthanatized. Necropsy revealed diffuse metastasis involving various organs.

ABCB1 identifies a subpopulation of uveal melanoma cells with high metastatic propensity

PubMed Central

Landreville, Solange; Agapova, Olga A.; Kneass, Zachary T.; Salesse, Christian; Harbour, J. William

2011-01-01

SUMMARY Metastasis of tumor cells to distant organs is the leading cause of death in melanoma. Yet, the mechanisms of metastasis remain poorly understood. One key question is whether all cells in a primary tumor are equally likely to metastasize or whether subpopulations of cells preferentially give rise to metastases. Here, we identified a subpopulation of uveal melanoma cells expressing the multidrug resistance transporter ABCB1 that are highly metastatic compared to ABCB1− bulk tumor cells. ABCB1+ cells also exhibited enhanced clonogenicity, anchorage independent growth, tumorigenicity and mitochondrial activity compared to ABCB1− cells. A375 cutaneous melanoma cells contained a similar subpopulation of highly metastatic ABCB1+ cells. These findings suggest that some uveal melanoma cells have greater potential for metastasis than others, and that a better understanding of such cells may be necessary for more successful therapies for metastatic melanoma. PMID:21575142

Genetics of Primary Intraocular Tumors

PubMed Central

Nagarkatti-Gude, Nisha; Wang, Yujuan; Ali, Mohammad Javed; Honavar, Santosh G.; Jager, Martine J.; Chan, Chi-Chao

2012-01-01

Primary intraocular neoplasms are tumors that originate within the eye. The most common malignant primary intraocular tumor in adults is uveal melanoma and the second is primary intraocular lymphoma or vitreoretinal (intraocular) lymphoma. The most common malignant intraocular tumor in children is retinoblastoma. Genetics plays a vital role in the diagnosis and detection of ocular tumors. In uveal melanoma, monosomy 3 is the most common genetic alteration and somatic mutations of BAP1, a tumor suppressor gene, have been reported in nearly 50% of primary uveal melanomas. The retinoblastoma gene RB1 is the prototype tumor suppressor gene—mutations in RB1 alleles lead to inactivated RB protein and the development of retinoblastoma. Immunoglobulin heavy chain (IgH) or T-cell receptor (TCR) gene rearrangement is observed in B-cell or T-cell primary vitreoretinal lymphoma, respectively. Other factors related to the genetics of these three common malignancies in the eye are discussed and reviewed. PMID:22834783

American Joint Committee on Cancer Classification of Uveal Melanoma (Anatomic Stage) Predicts Prognosis in 7,731 Patients: The 2013 Zimmerman Lecture.

PubMed

Shields, Carol L; Kaliki, Swathi; Furuta, Minoru; Fulco, Enzo; Alarcon, Carolina; Shields, Jerry A

2015-06-01

To analyze the clinical features and prognosis of posterior uveal melanoma based on the American Joint Committee on Cancer (AJCC) (7th edition) tumor staging. Retrospective interventional case series. A total of 7731 patients. Uveal melanoma management. Melanoma-related metastasis and death. Of 7731 patients with posterior uveal (ciliary body and choroidal) melanoma, the AJCC tumor staging was stage I in 2767 (36%), stage II in 3735 (48%), stage III in 1220 (16%), and stage IV in 9 (<1%). Based on tumor staging (I, II, III, and IV), features that showed significant increase with tumor staging included age at presentation (57, 58, 60, 60 years) (P < 0.001), tumor base (8, 12, 17, 17 mm) (P < 0.001), tumor thickness (2.9, 6.0, 10.1, 10.2 mm) (P < 0.001), distance to optic disc (3, 5, 5, 5 mm) (P < 0.001), distance to foveola (3, 5, 5, 5 mm) (P < 0.001), mushroom configuration (6%, 24%, 34%, 33%) (P < 0.001), plateau configuration (3%, 4%, 7%, 11%) (P < 0.001), tumor pigmentation (48%, 53%, 69%, 78%) (P < 0.001), and extraocular extension (0%, 1%, 11%, 22%) (P < 0.001). After therapy, Kaplan-Meier estimates of metastasis at 1, 5, 10, and 20 years were <1%, 5%, 12%, and 20% for stage I, 2%; 17%, 29%, and 44% for stage II; 6%, 44%, 61%, and 73% for stage III, and 100% by 1 year for stage IV. Kaplan-Meier estimates of death at 1, 5, 10, and 20 years were <1%, 3%, 6%, and 8% for stage I; <1%, 9%, 15%, and 24% for stage II; 3%, 27%, 39%, and 53% for stage III, and 100% by 1 year for stage IV. Compared with stage I, the hazard ratio for metastasis/death was 3.1/3.1 for stage II and 9.3/10.1 for stage III. Compared with uveal melanoma classified as AJCC stage I, the rate of metastasis/death was 3 times greater for stage II, 9 to 10 times greater for stage III, and further greater for stage IV. Early detection of posterior uveal melanoma, at a point when the tumor is small, can be lifesaving. Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

CANT1 lncRNA Triggers Efficient Therapeutic Efficacy by Correcting Aberrant lncing Cascade in Malignant Uveal Melanoma.

PubMed

Xing, Yue; Wen, Xuyang; Ding, Xia; Fan, Jiayan; Chai, Peiwei; Jia, Renbing; Ge, Shengfang; Qian, Guanxiang; Zhang, He; Fan, Xianqun

2017-05-03

Uveal melanoma (UM) is an intraocular malignant tumor with a high mortality rate. Recent studies have shown the functions of long non-coding RNAs (lncRNAs) in tumorigenesis; thus, targeting tumor-specific lncRNA abnormalities has become an attractive approach for developing therapeutics to treat uveal melanoma. In this study, we identified a novel nuclear CANT1 lncRNA (CASC15-New-Transcript 1) that acts as a necessary UM suppressor. CANT1 significantly reduced tumor metastatic capacity and tumor formation, either in cell culture or in animals harboring tumor xenograft. Intriguingly, XIST lncRNA serves as a potential target of CANT1, and JPX or FTX lncRNA subsequently serves as a contextual hinge to activate a novel CANT1-JPX/FTX-XIST long non-coding (lncing) pathway in UM. Moreover, CANT1 triggers the expression of JPX and FTX by directly binding to their promoters and promoting H3K4 methylation. These observations delineate a novel lncing cascade in which lncRNAs directly build a lncing cascade without coding genes that aims to modulate UM tumorigenesis, thereby specifying a novel "lncing-cascade renewal" anti-tumor therapeutic strategy by correcting aberrant lncing cascade in uveal melanoma. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Proton beam radiotherapy in the management of uveal melanoma: Clinical experience in Scotland

PubMed Central

Aziz, Samir; Taylor, Alex; McConnachie, Andrzej; Kacperek, Alex; Kemp, Ewan

2009-01-01

Aim: To evaluate proton-beam radiotherapy (PBRT) in the management of uveal melanoma in Scotland. Methods: A retrospective review was undertaken on all patients receiving PBRT for uveal melanoma (1994–2005). Data obtained included: gender, past ocular/medical history, age, presenting complaint(s), diagnosis, laterality, tumor location/ultrasound characteristics, visual acuity (VA) and intraocular pressure. At post-treatment reviews (3, 6, 12, and 24 months), the following data was obtained: VA, intraocular pressure, tumor appearance and ultrasound characteristics. Mean follow up was 38.8 months. Results: Seventy-six patients were included. Mean age was 64 years; male to female ratio was 1.1:1. Ninety-seven percent demonstrated initial treatment response; 87% had successful control of tumor growth. Mean pre-treatment tumor height was 6.2 mm v.s. 4.8 mm post-irradiation (p < 0.001). Pre-irradiation VA was <3/60 in 18.5% compared with 74% post-irradiation (p < 0.0001). There was a statistically significant association between adverse events (enucleation, metastasis) and greater maximal basal tumor diameter. Eighteen eyes were enucleated. The median survival time was estimated to be 54 months. Conclusion: In our experience, PBRT is a precise, reliable and effective treatment in the management of large, and previously treated uveal melanomas. It prevents enucleation in the majority at short term follow-up. PMID:19668544

Histone deacetylase inhibitors induce growth arrest and differentiation in uveal melanoma

PubMed Central

Landreville, Solange; Agapova, Olga A.; Matatall, Katie A.; Kneass, Zachary T.; Onken, Michael D.; Lee, Ryan S.; Bowcock, Anne M.; Harbour, J. William

2011-01-01

Purpose Metastasis is responsible for the death of most cancer patients, yet few therapeutic agents are available which specifically target the molecular events that lead to metastasis. We recently showed that inactivating mutations in the tumor suppressor gene BAP1 are closely associated with loss of melanocytic differentiation in uveal melanoma and metastasis (UM). The purpose of this study was to identify therapeutic agents that reverse the phenotypic effects of BAP1 loss in UM. Experimental Design In silico screens were performed to identify therapeutic compounds predicted to differentiate UM cells using Gene Set Enrichment Analysis and Connectivity Map databases. Valproic acid, trichostatin A, LBH-589 and suberoylanilide hydroxamic acid were evaluated for their effects on UM cells using morphologic evaluation, MTS viability assays, BrdU incorporation, flow cytometry, clonogenic assays, gene expression profiling, histone acetylation and ubiquitination assays, and a murine xenograft tumorigenicity model. Results HDAC inhibitors induced morphologic differentiation, cell cycle exit, and a shift to a differentiated, melanocytic gene expression profile in cultured UM cells. Valproic acid inhibited the growth of UM tumors in vivo. Conclusions These findings suggest that HDAC inhibitors may have therapeutic potential for inducing differentiation and prolonged dormancy of micrometastatic disease in UM. PMID:22038994

Germline BAP1 mutations predispose to malignant mesothelioma

PubMed Central

Testa, Joseph R.; Cheung, Mitchell; Pei, Jianming; Below, Jennifer E.; Tan, Yinfei; Sementino, Eleonora; Cox, Nancy J.; Dogan, A. Umran; Pass, Harvey I.; Trusa, Sandra; Hesdorffer, Mary; Nasu, Masaki; Powers, Amy; Rivera, Zeyana; Comertpay, Sabahattin; Tanji, Mika; Gaudino, Giovanni; Yang, Haining; Carbone, Michele

2011-01-01

Because only a small fraction of asbestos-exposed individuals develop malignant mesothelioma1, and because mesothelioma clustering is observed in some families1, we searched for genetic predisposing factors. We discovered germline mutations in BAP1 (BRCA1-associated protein 1) in two families with a high incidence of mesothelioma. Somatic alterations affecting BAP1 were observed in familial mesotheliomas, indicating biallelic inactivation. Besides mesothelioma, some BAP1 mutation carriers developed uveal melanoma. Germline BAP1 mutations were also found in two of 26 sporadic mesotheliomas: both patients with mutant BAP1 were previously diagnosed with uveal melanoma. Truncating mutations and aberrant BAP1 expression were common in sporadic mesotheliomas without germline mutations. These results reveal a BAP1-related cancer syndrome characterized by mesothelioma and uveal melanoma. We hypothesize that other cancers may also be involved, and that mesothelioma predominates upon asbestos exposure. These findings will help identify individuals at high risk of mesothelioma who could be targeted for early intervention. PMID:21874000

Fucoidan Does Not Exert Anti-Tumorigenic Effects on Uveal Melanoma Cell Lines

PubMed Central

Dithmer, Michaela; Kirsch, Anna-Maria; Richert, Elisabeth; Fuchs, Sabine; Wang, Fanlu; Schmidt, Harald; Coupland, Sarah E.; Roider, Johann; Klettner, Alexa

2017-01-01

Background. The polysaccharide fucoidan is widely investigated as an anti-cancer agent. Here, we tested the effect of fucoidan on uveal melanoma cell lines. Methods. The effect of 100 µM fucoidan was investigated on five cell lines (92.1, Mel270 OMM1, OMM2.3, OMM2.5) and of 1 µg/mL–1 mg/mL fucoidan in two cell lines (OMM1, OMM2.3). Cell proliferation and viability were investigated with a WST-1 assay, migration in a wound healing (scratch) assay. Vascular Endothelial Growth Factor (VEGF) was measured in ELISA. Angiogenesis was evaluated in co-cultures with endothelial cells. Cell toxicity was induced by hydrogen-peroxide. Protein expression (Akt, ERK1/2, Bcl-2, Bax) was investigated in Western blot. Results. Fucoidan increased proliferation in two and reduced it in one cell line. Migration was reduced in three cell lines. The effect of fucoidan on VEGF was cell type and concentration dependent. In endothelial co-culture with 92.1, fucoidan significantly increased tubular structures. Moreover, fucoidan significantly protected all tested uveal melanoma cell lines from hydrogen-peroxide induced cell death. Under oxidative stress, fucoidan did not alter the expression of Bcl-2, Bax or ERK1/2, while inducing Akt expression in 92.1 cells but not in any other cell line. Conclusion. Fucoidan did not show anti-tumorigenic effects but displayed protective and pro-angiogenic properties, rendering fucoidan unsuitable as a potential new drug for the treatment of uveal melanoma. PMID:28640204

Prophylactic use of bevacizumab to avoid anterior segment neovascularization following proton therapy for uveal melanoma.

PubMed

Mantel, Irmela; Schalenbourg, Ann; Bergin, Ciara; Petrovic, Aleksandra; Weber, Damien C; Zografos, Leonidas

2014-10-01

To investigate whether the prophylactic use of bevacizumab reduces the rate of rubeosis after proton therapy for uveal melanoma and improves the possibility to treat ischemic, reapplicated retina with laser photocoagulation. Comparative retrospective case series. Uveal melanoma patients with ischemic retinal detachment and treated with proton therapy were included in this institutional study. Twenty-four eyes received prophylactic intravitreal bevacizumab injections and were compared with a control group of 44 eyes without bevacizumab treatment. Bevacizumab injections were performed at the time of tantalum clip insertion and were repeated every 2 months during 6 months, and every 3 months thereafter. Ultra-widefield angiography allowed determination of the extent of retinal ischemia, which was treated with laser photocoagulation after retinal reapplication. Main outcome measures were the time to rubeosis, the time to retinal reattachment, and the time to laser photocoagulation of ischemic retina. Baseline characteristics were balanced between the groups, except for thicker tumors and larger retinal detachments in the bevacizumab group, potentially to the disadvantage of the study group. Nevertheless, bevacizumab prophylaxis significantly reduced the rate of iris rubeosis from 36% to 4% (log-rank test P = .02) and tended to shorten the time to retinal reapplication until laser photocoagulation of the nonperfusion areas could be performed. Prophylactic intravitreal bevacizumab in patients treated with proton therapy for uveal melanoma with ischemic retinal detachment prevented anterior segment neovascularization, until laser photocoagulation to the reapplied retina could be performed. Copyright © 2014 Elsevier Inc. All rights reserved.

A challenging case of ocular melanoma.

PubMed

Costache, Mariana; Dumitru, Adrian Vasile; Pătraşcu, Oana Maria; Popa-Cherecheanu, Daniela Alina; Bădilă, Patricia; Miu, Jeni Cătălina; Procop, Alexandru; Popa, Manuela; Tampa, Mircea Ştefan; Sajin, Maria; Simionescu, Olga; Cîrstoiu, Monica Mihaela

2015-01-01

Ocular melanoma is a rare malignancy found in clinical practice. In this paper, we present a case of highly aggressive ocular melanoma, which was surgically removed at the Department of Ophthalmology and diagnosed at the Department of Pathology, Emergency University Hospital, Bucharest, Romania, using conventional histopathological techniques. Uveal melanoma, a subset of ocular melanoma, has a distinct behavior in comparison to cutaneous melanoma and has a widely divergent prognosis. Approximately half of patients with ocular melanoma will develop metastatic disease, predominantly with hepatic, pulmonary or cerebral location, over a 10 to 15 years period. No systemic therapy was associated with an evident clinical outcome for patients with advanced disease and overall survival rate remains poor.

Lymphocyte-dependent antibodies in uveitis.

PubMed

Pápai, I; Lehrner, J

1976-01-01

Lymphocyte-dependent antibodies were revealed in the serum of patients suffering from uveitis of various aetiologies. The serum was incubated with normal uveal tissue and the binding of non-immune human lymphocytes was investigated. In three cases of sympathetic ophthalmitis the lymphocytes accumulated around the melanine granules, while in another 17 patients with uveitis cases the lymphocytes accumulated around the capillaries. Uveal tissue incubated with control sera failed to bound lymphocytes. The lymphocytic infiltration in certain cases of chronic uveitis suggested the role of lymphocyte-mediating antibodies in the aetiology of these cases.

Characterization of T-lymphocytes in the anterior uvea of eyes with chronic equine recurrent uveitis.

PubMed

Gilger, B C; Malok, E; Cutter, K V; Stewart, T; Horohov, D W; Allen, J B

1999-10-01

Equine recurrent uveitis (ERU), a chronic, recurrent inflammation primarily of the anterior uveal tract, is the most common cause of blindness in horses. Recently, T-lymphocytes have been found to be the most numerous cell type to infiltrate the anterior uveal of horses with ERU. In the present study, we characterized the T-lymphocyte population in the anterior uveal tract of eyes of horses with chronic ERU by evaluating the microscopic appearance (histopathologic features), the T-lymphocyte subsets, and the relative levels and amounts of T-lymphocyte cytokine mRNA in the anterior uvea. Seven inflamed eyes (from six horses with chronic ERU) and 5 normal eyes (from five horses with nonocular problems) were studied. After clinical examination, the eyes were removed, ocular fluids were aspirated, and anterior uveal tissues (iris and ciliary body) were processed for histologic and molecular (RNA isolation) analyses. Histologic examination by hematoxylin and eosin (H and E) staining and immunohistochemistry evaluating T-lymphocyte subsets (anti-CD4, CD8, CD5) were performed for each sample. RNA samples were analyzed for levels of messenger (m) RNA specific for interleukin (IL)-2, 4, and interferon-gamma (IFNgamma) by quantitative reverse transcriptase polymerase chain reaction (QRT-PCR). Eyes with ERU exhibited characteristic clinical signs, including corneal edema, aqueous flare, posterior synechia, corpora nigra degeneration, and cataract formation. Histologically, infiltration of the uveal tract with lymphocytes, plasma cells, and macrophages was most evident in the ciliary body and base of the iris. Loss of tissue structure (destruction) was most evident in the ciliary processes. Infiltrating lymphocytes were predominantly CD4+ T-cells (e.g. 48% CD4+ and 18% CD8+ in the ciliary body stroma), as determined by immunohistochemistry. Few inflammatory cells were observed in the normal eyes. The QRT-PCR results revealed increased transcription of IL-2 and IFNgamma and low IL-4 mRNA expression in eyes with chronic ERU compared to normal eyes, demonstrating a Thelper (Th) 1-like inflammatory response in eyes with ERU.

Endoresection with adjuvant ruthenium brachytherapy for selected uveal melanoma patients - the Tuebingen experience.

PubMed

Süsskind, Daniela; Dürr, Carina; Paulsen, Frank; Kaulich, Theodor; Bartz-Schmidt, Karl U

2017-12-01

To evaluate the treatment of selected patients with uveal melanoma with endoresection and adjuvant ruthenium brachytherapy. Thirty-five patients with uveal melanoma not suitable for ruthenium plaque monotherapy were treated with endoresection and adjuvant ruthenium brachytherapy between January 2001 and October 2013. Recurrence-free survival, globe retention, course of visual acuity (VA), occurrence of therapy-related complications and metastasis-free and overall survival were analysed retrospectively. Eight patients (22.9%) had a tumour recurrence after a median follow-up of 49.5 months (range: 21-134 months). Enucleation was necessary in eight patients. Thirty-two patients (91%) had a loss of VA with a median loss of nine lines (range: 0 to -39 lines); VA was stable in three patients and no patients had a gain in VA. Four patients (11.4%) developed radiation retinopathy. Metastases were detected in seven patients (20.0%) during follow-up. The occurrence of metastasis was significantly associated with monosomy 3 (p < 0.0001). Twenty-four patients (68.6%) were alive at the end of follow-up. Five patients (14.3%) died because of uveal melanoma (UM) metastasis. Endoresection with adjuvant ruthenium brachytherapy is an option for selected patients with UM who cannot be treated with brachytherapy as monotherapy. About two-thirds of eyes can be retained long term without recurrences. Visual acuity cannot be maintained in most cases, and may even decrease considerably. Radiation complications are comparatively rare and not a significant problem. © 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Inadvertent Evisceration of Eyes Containing Uveal Melanoma

PubMed Central

Eagle, Ralph C.; Grossniklaus, Hans E.; Syed, Nasreen; Hogan, R. Nick; Lloyd, William C.; Folberg, Robert

2010-01-01

Objectives To report an important complication of ocular evisceration therapy for blind, painful eyes that has been unreported in the literature, and to stress the need for careful preoperative evaluation to exclude occult neoplasms prior to therapy. Design Multicenter, retrospective, nonrandomized clinicopathological case series of patients found to have previously unsuspected uveal malignant melanoma during histopathological examination of blind, painful eyes treated by evisceration. Results Histopathological examination of evisceration specimens disclosed previously unsuspected uveal melanoma in 7 patients who were treated for blind, painful eyes. Inflammation caused by necrosis of the tumor and other ocular tissues led to misdiagnosis as endophthalmitis, orbital cellulitis, or idiopathic orbital inflammation in several cases. Preoperative imaging was not performed in 3 cases and failed to detect tumors in the remaining 4 cases. Failure of necrotic tumors to enhance contributed to misdiagnosis. Conclusions The presence of a malignant intraocular neoplasm should be excluded prior to evisceration of any blind eye or blind, painful eye, particularly with opaque media. Necrosis-related inflammation can confound the clinical diagnosis of occult lesions, as can failure of necrotic tumors to enhance on imaging studies. PMID:19204229

Is it sufficient to repeat LINEAR accelerator stereotactic radiosurgery in choroidal melanoma?

PubMed

Furdova, A; Horkovicova, K; Justusova, P; Sramka, M

One day session LINAC based stereotactic radiosurgery (SRS) at LINAC accelerator is a method of "conservative" attitude to treat the intraocular malignant uveal melanoma. We used model Clinac 600 C/D Varian (system Aria, planning system Corvus version 6.2 verification IMRT OmniPro) with 6 MeV X by rigid immobilization of the eye to the Leibinger frame. The stereotactic treatment planning after fusion of CT and MRI was optimized according to the critical structures (lens, optic nerve, also lens and optic nerve at the contralateral side, chiasm). The first plan was compared and the best plan was applied for therapy at C LINAC accelerator. The planned therapeutic dose was 35.0 Gy by 99 % of DVH (dose volume histogram). In our clinical study in the group of 125 patients with posterior uveal melanoma treated with SRS, in 2 patients (1.6 %) was repeated SRS indicated. Patient age of the whole group ranged from 25 to 81 years with a median of 54 TD was 35.0 Gy. In 2 patients after 5 year interval after stereotactic radiosurgery for uveal melanoma stage T1, the tumor volume increased to 50 % of the primary tumor volume and repeated SRS was necessary. To find out the changes in melanoma characteristics after SRS in long term interval after irradiation is necessary to follow up the patient by an ophthalmologist regularly. One step LINAC based stereotactic radiosurgery with a single dose 35.0 Gy is one of treatment options to treat T1 to T3 stage posterior uveal melanoma and to preserve the eye globe. In some cases it is possible to repeat the SRS after more than 5 year interval (Fig. 8, Ref. 23).

Scanning electron microscopy of the trabecular meshwork: understanding the pathogenesis of primary angle closure glaucoma.

PubMed

Sihota, Ramanjit; Goyal, Amita; Kaur, Jasbir; Gupta, Viney; Nag, Tapas C

2012-01-01

To study ultrastructural changes of the trabecular meshwork in acute and chronic primary angle closure glaucoma (PACG) and primary open angle glaucoma (POAG) eyes by scanning electron microscopy. Twenty-one trabecular meshwork surgical specimens from consecutive glaucomatous eyes after a trabeculectomy and five postmortem corneoscleral specimens were fixed immediately in Karnovsky solution. The tissues were washed in 0.1 M phosphate buffer saline, post-fixed in 1% osmium tetraoxide, dehydrated in acetone series (30-100%), dried and mounted. Normal trabecular tissue showed well-defined, thin, cylindrical uveal trabecular beams with many large spaces, overlying flatter corneoscleral beams and numerous smaller spaces. In acute PACG eyes, the trabecular meshwork showed grossly swollen, irregular trabecular endothelial cells with intercellular and occasional basal separation with few spaces. Numerous activated macrophages, leucocytes and amorphous debris were present. Chronic PACG eyes had a few, thickened posterior uveal trabecular beams visible. A homogenous deposit covered the anterior uveal trabeculae and spaces. Converging, fan-shaped trabecular beam configuration corresponded to gonioscopic areas of peripheral anterior synechiae. In POAG eyes, anterior uveal trabecular beams were thin and strap-like, while those posteriorly were wide, with a homogenous deposit covering and bridging intertrabecular spaces, especially posteriorly. Underlying corneoscleral trabecular layers and spaces were visualized in some areas. In acute PACG a marked edema of the endothelium probably contributes for the acute and marked intraocular pressure (IOP) elevation. Chronically raised IOP in chronic PACG and POAG probably results, at least in part, from decreased aqueous outflow secondary to widening and fusion of adjacent trabecular beams, together with the homogenous deposit enmeshing trabecular beams and spaces.

Glembatumumab Vedotin, Nivolumab, and Ipilimumab in Treating Patients With Advanced Metastatic Solid Tumors That Cannot Be Removed by Surgery

ClinicalTrials.gov

2018-06-11

Advanced Malignant Solid Neoplasm; Estrogen Receptor Negative; GPNMB Positive; HER2/Neu Negative; Metastatic Malignant Solid Neoplasm; Metastatic Melanoma; Progesterone Receptor Negative; Stage III Breast Cancer AJCC v7; Stage III Cutaneous Melanoma AJCC v7; Stage III Uveal Melanoma AJCC v7; Stage IIIA Cutaneous Melanoma AJCC v7; Stage IIIB Cutaneous Melanoma AJCC v7; Stage IIIC Cutaneous Melanoma AJCC v7; Stage IV Breast Cancer AJCC v6 and v7; Stage IV Cutaneous Melanoma AJCC v6 and v7; Stage IV Uveal Melanoma AJCC v7; Triple-Negative Breast Carcinoma; Unresectable Solid Neoplasm

GNAQ mutation in a patient with metastatic mucosal melanoma.

PubMed

Kim, Chung-Young; Kim, Dae Won; Kim, Kevin; Curry, Jonathan; Torres-Cabala, Carlos; Patel, Sapna

2014-07-16

Mucosal melanomas represent about 1% of all melanoma cases and classically have a worse prognosis than cutaneous melanomas. Due to the rarity of mucosal melanomas, only limited clinical studies with metastatic mucosal melanoma are available. Mucosal melanomas most commonly contain mutations in the gene CKIT, and treatments have been investigated using targeted therapy for this gene. Mutations in mucosal melanoma are less common than in cutaneous or uveal melanomas and occur in descending order of frequency as: CKIT (20%), NRAS (5%) or BRAF (3%). Mutations in G-alpha proteins, which are associated with activation of the mitogen-activated protein kinase pathway, have not been reported in mucosal melanomas. These G-alpha protein mutations occur in the genes GNAQ and GNA11 and are seen at a high frequency in uveal melanomas, those melanomas that begin in the eye. A 59-year old Caucasian male was diagnosed with a mucosal melanoma after evaluation for what was thought to be a hemorrhoid. Molecular analysis of the tumor revealed a GNAQ mutation. Ophthalmologic exam did not disclose a uveal melanoma. Here we report, to our knowledge, the first known case of GNAQ mutation in a patient with metastatic mucosal melanoma.

GNAQ mutation in a patient with metastatic mucosal melanoma

PubMed Central

2014-01-01

Background Mucosal melanomas represent about 1% of all melanoma cases and classically have a worse prognosis than cutaneous melanomas. Due to the rarity of mucosal melanomas, only limited clinical studies with metastatic mucosal melanoma are available. Mucosal melanomas most commonly contain mutations in the gene CKIT, and treatments have been investigated using targeted therapy for this gene. Mutations in mucosal melanoma are less common than in cutaneous or uveal melanomas and occur in descending order of frequency as: CKIT (20%), NRAS (5%) or BRAF (3%). Mutations in G-alpha proteins, which are associated with activation of the mitogen-activated protein kinase pathway, have not been reported in mucosal melanomas. These G-alpha protein mutations occur in the genes GNAQ and GNA11 and are seen at a high frequency in uveal melanomas, those melanomas that begin in the eye. Case presentation A 59-year old Caucasian male was diagnosed with a mucosal melanoma after evaluation for what was thought to be a hemorrhoid. Molecular analysis of the tumor revealed a GNAQ mutation. Ophthalmologic exam did not disclose a uveal melanoma. Conclusion Here we report, to our knowledge, the first known case of GNAQ mutation in a patient with metastatic mucosal melanoma. PMID:25030020

Isolated hepatic perfusion as a treatment for liver metastases of uveal melanoma.

PubMed

Ben-Shabat, Ilan; Hansson, Christoffer; Sternby Eilard, Malin; Cahlin, Christian; Rizell, Magnus; Lindnér, Per; Mattsson, Jan; Olofsson Bagge, Roger

2015-01-25

Isolated hepatic perfusion (IHP) is a procedure where the liver is surgically isolated and perfused with a high concentration of the chemotherapeutic agent melphalan. Briefly, the procedure starts with the setup of a percutaneous veno-venous bypass from the femoral vein to the external jugular vein. Via a laparotomy, catheters are then inserted into the proper hepatic artery and the caval vein. The portal vein and the caval vein, both supra- and infrahepatically, are then clamped. The arterial and venous catheters are connected to a heart lung machine and the liver is perfused with melphalan (1 mg/kg body weight) for 60 min. This way it is possible to locally perfuse the liver with a high dose of a chemotherapeutic agent, without leakage to the systemic circulation. In previous studies including patients with isolated liver metastases of uveal melanoma, an overall response rate of 33-100% and a median survival between 9 and 13 months, have been reported. The aim of this protocol is to give a clear description of how to perform the procedure and to discuss IHP as a treatment option for liver metastases of uveal melanoma.

The ocular lesions of naturally occurring lymphocystis in fish.

PubMed

Dukes, T W; Lawler, A R

1975-10-01

Six cases of ocular lymphocystis, a virus disease, are described. Lymphocystis is generally known as a benigh, unique, giant cell disease of fishes causing nodules on the skin and fins. It has been studied extensively because of the virus-host cell relationship that results in extreme size and lack of quick cellular destruction or stimulation to neoplasia. Lymphocystis cells were found behind or in one or both eyes and were also found on the cornea or adjacent skin surfaces. A retrobulbar mass produced extreme exophthalmos. Uveal (choroid and iris) masses were present in most cases. Optic nerve involvement was also seen. It is probable that the virus reached the eye by the blood with the resulting masses forming in situ rather than by direct extension from skin lesions.

Integrated genomic classification of melanocytic tumors of the central nervous system using mutation analysis, copy number alterations and DNA methylation profiling.

PubMed

Griewank, Klaus; Koelsche, Christian; van de Nes, Johannes A P; Schrimpf, Daniel; Gessi, Marco; Möller, Inga; Sucker, Antje; Scolyer, Richard A; Buckland, Michael E; Murali, Rajmohan; Pietsch, Torsten; von Deimling, Andreas; Schadendorf, Dirk

2018-06-11

In the central nervous system, distinguishing primary leptomeningeal melanocytic tumors from melanoma metastases and predicting their biological behavior solely using histopathologic criteria can be challenging. We aimed to assess the diagnostic and prognostic value of integrated molecular analysis. Targeted next-generation-sequencing, array-based genome-wide methylation analysis and BAP1 immunohistochemistry was performed on the largest cohort of central nervous system melanocytic tumors analyzed to date, incl. 47 primary tumors of the central nervous system, 16 uveal melanomas. 13 cutaneous melanoma metastasis and 2 blue nevus-like melanomas. Gene mutation, DNA-methylation and copy-number profiles were correlated with clinicopathological features. Combining mutation, copy-number and DNA-methylation profiles clearly distinguished cutaneous melanoma metastases from other melanocytic tumors. Primary leptomeningeal melanocytic tumors, uveal melanomas and blue nevus-like melanoma showed common DNA-methylation, copy-number alteration and gene mutation signatures. Notably, tumors demonstrating chromosome 3 monosomy and BAP1 alterations formed a homogeneous subset within this group. Integrated molecular profiling aids in distinguishing primary from metastatic melanocytic tumors of the central nervous system. Primary leptomeningeal melanocytic tumors, uveal melanoma and blue nevus-like melanoma share molecular similarity with chromosome 3 and BAP1 alterations markers of poor prognosis. Copyright ©2018, American Association for Cancer Research.

Improvement of Uveal and Capsular Biocompatibility of Hydrophobic Acrylic Intraocular Lens by Surface Grafting with 2-Methacryloyloxyethyl Phosphorylcholine-Methacrylic Acid Copolymer

PubMed Central

Tan, Xuhua; Zhan, Jiezhao; Zhu, Yi; Cao, Ji; Wang, Lin; Liu, Sa; Wang, Yingjun; Liu, Zhenzhen; Qin, Yingyan; Wu, Mingxing; Liu, Yizhi; Ren, Li

2017-01-01

Biocompatibility of intraocular lens (IOL) is critical to vision reconstruction after cataract surgery. Foldable hydrophobic acrylic IOL is vulnerable to the adhesion of extracellular matrix proteins and cells, leading to increased incidence of postoperative inflammation and capsule opacification. To increase IOL biocompatibility, we synthesized a hydrophilic copolymer P(MPC-MAA) and grafted the copolymer onto the surface of IOL through air plasma treatment. X-ray photoelectron spectroscopy, atomic force microscopy and static water contact angle were used to characterize chemical changes, topography and hydrophilicity of the IOL surface, respectively. Quartz crystal microbalance with dissipation (QCM-D) showed that P(MPC-MAA) modified IOLs were resistant to protein adsorption. Moreover, P(MPC-MAA) modification inhibited adhesion and proliferation of lens epithelial cells (LECs) in vitro. To analyze uveal and capsular biocompatibility in vivo, we implanted the P(MPC-MAA) modified IOLs into rabbits after phacoemulsification. P(MPC-MAA) modification significantly reduced postoperative inflammation and anterior capsule opacification (ACO), and did not affect posterior capsule opacification (PCO). Collectively, our study suggests that surface modification by P(MPC-MAA) can significantly improve uveal and capsular biocompatibility of hydrophobic acrylic IOL, which could potentially benefit patients with blood-aqueous barrier damage. PMID:28084469

Depression, Anxiety, and Regret Before and After Testing to Estimate Uveal Melanoma Prognosis.

PubMed

Schuermeyer, Isabel; Maican, Anca; Sharp, Richard; Bena, James; Triozzi, Pierre L; Singh, Arun D

2016-01-01

To our knowledge, longitudinal assessment of depression, anxiety, and decision regret (a sense of disappointment or dissatisfaction in the decision) in patients undergoing prognostication for uveal melanoma does not exist. To report on depression, anxiety, and decision regret before and after testing to estimate uveal melanoma prognosis. Prospective interventional case series conducted at an institutional referral practice of 96 patients with clinical diagnosis of uveal melanoma who underwent prognostication at the time of primary therapy. Depression, anxiety, and decision regret prior to prognostication (baseline) and at 3 and 12 months afterwards. The Hospital Anxiety and Depression Scale (HADS) and Decision Regret Scale were self-administered by the patients prior to prognostication (baseline) and at 3 and 12 months afterwards. Data were summarized using means and standard deviations for continuous measures, frequencies, and percentages for categorical factors. A mixed model was used to assess the trajectory of HADS anxiety and the associations between HADS anxiety and baseline HADS depression, baseline decision regret, prognostication test result, and adjuvant therapy, respectively, while adjusting for age and sex. Ninety-six patients (median age 60.7 years) completed baseline questionnaires. The mean (SD) HADS anxiety score at baseline (7.4 [4.0]) was higher than at 3 months (5.4 [3.7]; P < .001) or 12 months (4.7 [3.4]; P < .001), and decreased with older age (coefficient estimate [SD], -0.06 [0.02]; P < .001). The decision regret score was associated with baseline HADS depression score (coefficient estimate [SE], -1.17 [0.43]; P < .007), and HADS depression score increased with baseline HADS anxiety score (coefficient estimate [SE], 0.39 [0.06]; P < .001). Our study raises questions about decision regret in patients who agree to have a prognostic test that may not help guide treatment. Although decision regret appears to lessen or dissipate with time, study on larger numbers of patients is necessary to elucidate factors that may be addressed to mitigate decision regret.

NEW ULTRA-WIDE-FIELD ANGIOGRAPHIC GRADING SCHEME FOR RADIATION RETINOPATHY AFTER IODINE-125 BRACHYTHERAPY FOR UVEAL MELANOMA.

PubMed

McCannel, Tara A; Kim, EunAh; Kamrava, Mitchell; Lamb, James; Caprioli, Joseph; Yang, Dong; McCannel, Colin A

2017-10-06

Radiation retinopathy remains incompletely characterized and may cause severe vision loss. Ultra-wide-field fluorescein angiography provides a pan-fundus view of vascular alterations caused by radiation treatment and may predict visual and ocular outcomes. We have developed a grading scheme to describe pan-fundus severity and to predict the progression of radiation retinopathy in patients treated for uveal melanoma with iodine-125 brachytherapy. A retrospective review of patients treated with standard iodine-125 brachytherapy for uveal melanoma at the Ophthalmic Oncology Center at the University of California, Los Angeles, who had undergone both baseline and postbrachytherapy ultra-wide-field fluorescein angiography. A grading scheme was devised based on observations of vascular leakage, retinal perfusion status, and retinal proliferation. The correlation of grade severity with patient characteristics, tumor features, visual acuity, optical coherence tomography findings, and neovascular glaucoma was measured with chi-square and one-way analysis of variance analyses. Sixty-seven patients were identified for review. Consistent wide-field angiographic patterns after brachytherapy were observed and graded as follows: Grade 0: normal; Grade 1: late foveal leakage; Grade 2: late peripheral leakage; Grade 3: presence of nonperfusion; and Grade 4: retinal neovascularization. Six eyes (8.9%) were Grade 0; 16 (23.8%) were Grade 1; 25 (37.3%) were Grade 2; 16 (23.4%) were Grade 3; and 4 (6.0%) were Grade 4. Higher grade radiation severity correlated significantly with duration of follow-up (P < 0.02); younger age (P = 0.035); worse visual acuity (P = 0.001); cystoid macular edema or atrophy on optical coherence tomography (P < 0.0001); and neovascular glaucoma (P = 0.003). Wide-field fluorescein angiography revealed distinct fundus-wide patterns of vascular damage, which were progressive in nature in eyes treated with iodine-125 brachytherapy for uveal melanoma and correlated with signs of progressive vascular injury. This grading scheme may have prognostic value to predict the progression of radiation retinopathy and to prognosticate visual outcomes in patients undergoing brachytherapy.

Proton Beam Radiotherapy for Uveal Melanomas at Nice Teaching Hospital: 16 Years' Experience

DOE Office of Scientific and Technical Information (OSTI.GOV)

Caujolle, Jean-Pierre, E-mail: ncaujolle@aol.co; Mammar, Hamid; Chamorey, Emmanuel Phar

2010-09-01

Purpose: To present the results of uveal melanomas treated at Nice Teaching Hospital. Methods and Materials: This retrospective study included 886 consecutive patients referred to our clinic for the treatment of uveal melanomas by proton beam radiotherapy from June 1991 to December 2007. Survival rates were determined by using Kaplan-Meier estimates, and prognostic factors were evaluated using the log-rank test or Cox model. Results: The number (percent total) of subjects staged according to the TNM classification system (6th edition) of malignant tumors included 39 stage T1 (4.4%), 420 stage T2 (47.40%), 409 stage T3 (46.16%), and 18 stage T4 (2.03%)more » patients. The median follow-up was 63.7 months. The Kaplan-Meier overall survival rate at 5 years according to the sixth edition TNM classification was 92% for T1, 89% for T2, 67% for T3, and 62% for T4; and at 10 years, 86% for T1, 78% for T2, 43% for T3, and 41% for T4. Five factors were found to be associated with an increased death rate: advanced age, tumor thickness, largest tumor basal diameter, tumor volume, and tumor volume-to-eyeball volume ratio. The metastasis-free survival rates were 88.3 % at 5 years and 76.4 % at 10 years. The local control rates were 93.9% at 5 years and 92.1% at 10 years. The ocular conservation rates were 91.1% at 5 years and 87.3% at 10 years. Conclusions: We report the results of a large series of patients treated for uveal melanomas with a very long follow-up. Despite the large tumor volume treated, our results were similar to previously published findings relating to proton beam therapy.« less

The ocular lesions of naturally occurring lymphocystis in fish.

PubMed Central

Dukes, T W; Lawler, A R

1975-01-01

Six cases of ocular lymphocystis, a virus disease, are described. Lymphocystis is generally known as a benigh, unique, giant cell disease of fishes causing nodules on the skin and fins. It has been studied extensively because of the virus-host cell relationship that results in extreme size and lack of quick cellular destruction or stimulation to neoplasia. Lymphocystis cells were found behind or in one or both eyes and were also found on the cornea or adjacent skin surfaces. A retrobulbar mass produced extreme exophthalmos. Uveal (choroid and iris) masses were present in most cases. Optic nerve involvement was also seen. It is probable that the virus reached the eye by the blood with the resulting masses forming in situ rather than by direct extension from skin lesions. Images Fig. 1. Fig. 2. Fig. 3. Fig. 4. PMID:1175076

Uveal melanoma hepatic metastases mutation spectrum analysis using targeted next-generation sequencing of 400 cancer genes.

PubMed

Luscan, A; Just, P A; Briand, A; Burin des Roziers, C; Goussard, P; Nitschké, P; Vidaud, M; Avril, M F; Terris, B; Pasmant, E

2015-04-01

Uveal melanoma (UM) is the most common malignant tumour of the eye. Diagnosis often occurs late in the course of disease, and prognosis is generally poor. Recently, recurrent somatic mutations were described, unravelling additional specific altered pathways in UM. Targeted next-generation sequencing (NGS) can now be applied to an accurate and fast identification of somatic mutations in cancer. The aim of the present study was to characterise the mutation pattern of five UM hepatic metastases with well-defined clinical and pathological features. We analysed the UM mutation spectrum using targeted NGS on 409 cancer genes. Four previous reported genes were found to be recurrently mutated. All tumours presented mutually exclusive GNA11 or GNAQ missense mutations. BAP1 loss-of-function mutations were found in three UMs. SF3B1 missense mutations were found in the two UMs with no BAP1 mutations. We then searched for additional mutation targets. We identified the Arg505Cys mutation in the tumour suppressor FBXW7. The same mutation was previously described in different cancer types, and FBXW7 was recently reported to be mutated in UM exomes. Further studies are required to confirm FBXW7 implication in UM tumorigenesis. Elucidating the molecular mechanisms underlying UM tumorigenesis holds the promise for novel and effective targeted UM therapies. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Neovascular glaucoma after helium ion irradiation for uveal melanoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, M.K.; Char, D.H.; Castro, J.L.

1986-02-01

Neovascular glaucoma developed in 22 of 169 uveal melanoma patients treated with helium ion irradiation. Most patients had large melanomas; no eyes containing small melanomas developed anterior segment neovascularization. The mean onset of glaucoma was 14.1 months (range, 7-31 months). The incidence of anterior segment neovascularization increased with radiation dosage; there was an approximately three-fold increase at 80 GyE versus 60 GyE of helium ion radiation (23% vs. 8.5%) (P less than 0.05). Neovascular glaucoma occurred more commonly in larger tumors; the incidence was not affected by tumor location, presence of subretinal fluid, nor rate of tumor regression. Fifty-three percentmore » of patients had some response with intraocular pressures of 21 mmHg or less to a combination of antiglaucoma treatments.« less

[Clinical and pathologic observation of uveal metastatic carcinoma].

PubMed

Cong, C X; Lin, J Y; Wang, L H

2016-10-11

Objective: To observe the clinical and pathological features of uveal metastatic carcinoma. Methods: It was a retrospective case series study. The clinical manifestation, growth pattern, tumor types and relative pathological features of 13 patients visiting from January 1980 to December 2014 with uveal metastatic carcinoma in Tianjin Eye Hospital were analyzed retrospectively. Results: There were 13 cases, 6 cases of male and 7 of female. Age was from 37.0 to 66.0 years old. The mean age was 52.1 years old. all cases were monocular. There were 5 cases with right eye and 8 cases with left eye. Among 13 cases, 10 tumors were in posterior choroid, one tumor was in anterior choroid and ciliary body, 2 tumors were in the iris. There were 5 patients with lung cancer, 4 patients with breast cancer, 1 patient with prostate cancer, 1 patient with thyroid cancer and 1 patient with esophageal cancer. The primary tumor wasn't found in 1 patient. The rapid decrease of visual acuity showed in 10 patients with posterior choroidal metastatic carcinoma, 8 of them accompanied with extensive retinal detachment and 6 of them had secondary glaucoma. The multiple gray-white nodule or pink cauliflower mass on the papillary margin of iris were showed respectively in 2 patients with iris metastatic carcinoma. The pathological examination found that posterior choroidal metastatic carcinoma mainly located in temporal or nasal side choroids in 10 cases, among them, local or diffuse flat choroidal masses showed in 6cases, extensive mass involving choroid and ciliary body showed in 1 case, large nodular or globular choroidal mass showed in 2 cases, choroidal mass surrounded the optic disc in 1 case, optic nerve invasion showed in 3 cases and extraocular or orbital invasion showed in 3 cases. The scleral and subconjunctival invasion showed in 1 case of anterior choroid and ciliary body metastatic carcinoma. Conclusions: Uveal metastatic carcinoma manifested various growth pattern, the rapid decrease of visual acuity, flat or nodular choroidal solid mass, secondary retinal detachment and glaucoma were common clinical features. Some cases might invade extraocular or orbital tissue. (Chin J Ophthalmol, 2016, 52: 769-774) .

Orbital exenteration: Institutional review of evolving trends in indications and rehabilitation techniques.

PubMed

Kiratli, Hayyam; Koç, İrem

2018-06-01

To determine the changes in indications for orbital exenteration over 20 years and to assess its impact on patient survival. Evolving techniques of rehabilitation of the orbit in our institution were also evaluated. This was a retrospective review of hospital records of patients who underwent orbital exenteration from 1995 to 2015 in a tertiary care center. Data extracted included primary location of the tumor, preoperative treatments, interval between initial diagnosis and exenteration, status of surgical margins, presence of metastatic disease, and postoperative survival. The types of prosthesis utilized over the years were also reviewed. Cox regression analysis was performed for categorical variables. Kaplan-Meier analysis was used to estimate post-exenteration survival. Over a 20-year period, orbital exenteration was performed on 100 orbits of 100 patients. The mean age was 39.4 years (range: 2 months to 90 years). The most common indications among 98 malignant causes were retinoblastoma, squamous cell carcinoma, basal cell carcinoma, extraocular extension of uveal melanoma, and conjunctival melanoma. Postoperative survival was significantly related to age and tumor location but independent from gender, surgical margin, histopathological diagnosis, previous treatment modality, and preoperative interval. In the whole cohort, 1-year and 5-year survival rates were 97% and 84%, respectively. Exenteration appears to be life-saving in children with orbital extension of retinoblastoma. While patients exenterated for malignant eyelid tumors have the best chance of survival, those with orbital extension of uveal melanoma and adenoid cystic carcinoma of the lacrimal gland have the worst prognosis.

Immunology of intraocular tumors.

PubMed

Niederkorn, Jerry Y; Wang, Shixuan

2005-02-01

The immune surveillance hypothesis was introduced over 30 years ago and proposed that neoplasms express novel antigens that subjected them to immune detection and elimination. In order for immune surveillance to be effective in controlling neoplasms, two requirements must be satisfied: 1) the tumor must arise in a body site that permits the induction the full array of immune responses and 2) the immune elements generated must have unfettered access to the tumor and be able to express their entire range of effector functions at the tumor site. The unique immunologic and anatomic features of the eye prevent the induction and expression of conventional immunity--a phenomenon known as 'immune privilege'. Although ocular immune privilege represents a theoretical obstacle to immune surveillance, some highly immunogenic intraocular tumors can circumvent immune privilege and undergo immune rejection. Uveal melanoma is the most common intraocular malignancy in adults, yet it occurs with a frequency that is no higher than neoplasms arising in conventional bodies. The presence of either tumor-infiltrating lymphocytes (TIL) or tumor-infiltrating macrophages (TIM) is associated with poor prognosis in uveal melanoma patients and suggests that some immune responses to intraocular tumors might exacerbate, rather than mitigate, tumor progression. Although counterintuitive, this proposition is consistent with the 'immune stimulation' hypothesis of tumor progression offered by Richmond Prehn over thirty years ago. It remains to be ascertained if immune stimulation affects the malignancy of ocular tumors, but it represents an intriguing explanation for the paradoxes of uveal melanoma.

Ocular Immune Privilege and Ocular Melanoma: Parallel Universes or Immunological Plagiarism?

PubMed Central

Niederkorn, Jerry Y.

2012-01-01

Evidence of immune privilege in the eye was recorded almost 140 years ago, yet interest in immune privilege languished for almost a century. However, the past 35 years have witnessed a plethora of research and a rekindled interest in the mechanisms responsible for immune privilege in the anterior chamber of the eye. This research has demonstrated that multiple anatomical, structural, physiological, and immunoregulatory processes contribute to immune privilege and remind us of the enormous complexity of this phenomenon. It is widely accepted that immune privilege is an adaptation for reducing the risk of immune-mediated inflammation in organs such as the eye and brain whose tissues have a limited capacity to regenerate. Recent findings suggest that immune privilege also occurs in sites where stem cells reside and raise the possibility that immune privilege is also designed to prevent the unwitting elimination of stem cells by immune-mediated inflammation at these sites. Uveal melanoma arises within the eye and as such, benefits from ocular immune privilege. A significant body of research reveals an intriguing parallel between the mechanisms that contribute to immune privilege in the eye and those strategies used by uveal melanoma cells to evade immune elimination once they have disseminated from the eye and establish metastatic foci in the liver. Uveal melanoma metastases seem to have “plagiarized” the blueprints used for ocular immune privilege to create “ad hoc immune privileged sites” in the liver. PMID:22707951

Intraocular (Eye) Melanoma Treatment (PDQ®)—Health Professional Version

Cancer.gov

Intraocular (uveal) melanoma treatment options include observation, surgery, radiation therapy, and transpupillary thermotherapy. Get detailed information about the diagnosis and treatment of newly diagnosed and recurrent intraocular melanoma in this summary for clinicians.

Stages of Intraocular (Uveal) Melanoma

MedlinePlus

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General Information about Intraocular (Uveal) Melanoma

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Treatment Options for Intraocular (Uveal) Melanoma

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Treatment Option Overview (Intraocular [Uveal] Melanoma)

MedlinePlus

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Effects of radiotherapy on uveal melanomas and adjacent tissues

PubMed Central

Groenewald, C; Konstantinidis, L; Damato, B

2013-01-01

Most uveal melanomas are treated with radiotherapy. An adequate understanding of the effects of radiation on the tumour and the healthy ocular tissues is necessary. Ionizing radiation damages cell membranes, organelles, and DNA. Irradiated cells are lysed or undergo apoptosis, necrosis, and senescence. These effects occur in tumour cells and vascular endothelial cells, resulting in tumour shrinkage, ischaemia, infarction, exudation, and fibrosis, which can cause exudative maculopathy, serous retinal detachment, rubeosis, and neovascular glaucoma (ie, ‘toxic tumour syndrome'). Such abnormalities must be distinguished from collateral damage to healthy ocular tissues that receive high doses of radiation, and these include radiation-induced retinopathy, optic neuropathy, choroidopathy, cataract, and scleral necrosis. Radiation retinopathy can be treated effectively with photodynamic therapy, anti-angiogenic agents, and intravitreal steroid injections. In some patients, optic neuropathy may improve with intravitreal steroids or anti-angiogenic agents. Neovascular glaucoma resolves with intra-cameral bevacizumab. Exudative retinal detachment can regress with intra-vitreal steroid injections. Cataract is treated in the usual manner. Scleral necrosis, if severe, may require grafting, possibly using a lamellar flap from the same eye. Depending on the bulk of the residual toxic tumour, treatment can consist of intra-vitreal steroids and/or anti-angiogenic agents, transpupillary thermotherapy or photodynamic therapy to the tumour, or surgical removal of the tumour by endo- or exo-resection. Measures aimed at preventing collateral damage include eccentric placement of ruthenium plaques or iodine seeds and delivery of a notched proton beam. The decision to treat a uveal melanoma with radiotherapy requires the ability to manage iatrogenic side effects and complications. PMID:23196647

Local Failure After Episcleral Brachytherapy for Posterior Uveal Melanoma: Patterns, Risk Factors, and Management.

PubMed

Bellerive, Claudine; Aziz, Hassan A; Bena, James; Wilkinson, Allan; Suh, John H; Plesec, Thomas; Singh, Arun D

2017-05-01

To evaluate the patterns, the risk factors, and the management of recurrence following brachytherapy in patients with posterior uveal melanoma, given that an understanding of the recurrence patterns can improve early recognition and management of local treatment failure in such patients. Retrospective cohort study. Setting: Multispecialty tertiary care center. A total of 375 eyes treated with episcleral brachytherapy for posterior uveal melanoma from January 2004 to December 2014. Exclusion criteria included inadequate follow-up (<1 year) and previous radiation therapy. Main Outcomes and Measures: Local control rate and time to recurrence were the primary endpoints. Kaplan-Meier estimation and Cox proportional hazards models were conducted to identify risk factors for recurrence. Twenty-one patients (5.6%) experienced recurrence (follow-up range 12-156 months; median 47 months). The median time to recurrence was 18 months (range 4-156 months). Five-year estimated local recurrence rate was 6.6%. The majority (90.5%) of the recurrences occurred within the first 5 years. The predominant site of recurrence was at the tumor margin (12 patients, 57.1%). Univariate analysis identified 3 statistically significant recurrence risk factors: advanced age, largest basal diameter, and the use of adjuvant transpupillary thermotherapy (TTT). Recurrent tumors were managed by repeat brachytherapy, TTT, or enucleation. Local recurrences following brachytherapy are uncommon 5 years after episcleral brachytherapy. Follow-up intervals can be adjusted to reflect time to recurrence. Most of the eyes with recurrent tumor can be salvaged by conservative methods. Copyright © 2017 Elsevier Inc. All rights reserved.

Multimodal imaging of bilateral diffuse uveal melanocytic proliferation associated with an iris mass lesion.

PubMed

Naysan, Jonathan; Pang, Claudine E; Klein, Robert W; Freund, K Bailey

2016-01-01

Bilateral diffuse uveal melanocytic proliferation (BDUMP) is a rare, paraneoplastic syndrome characterized by bilateral painless visual loss and proliferation of choroidal melanocytes in association with an underlying systemic malignancy. We report a case of bilateral diffuse uveal melanocytic proliferation associated with an underlying gynecological malignancy that also features the infrequent finding of an iris mass lesion, using multimodal imaging including ultra-widefield imaging, spectral domain and swept-source optical coherence tomography. A 59-year-old white female with a prior history of gynecological malignancy in remission presented with progressive bilateral visual loss over several weeks. The patient was noted to have a focal iris mass lesion in her right eye. Ultra-widefield color fundus photography showed a characteristic bilateral 'giraffe pattern' of pigmentary changes extending into the periphery as well as multiple discrete deeply pigmented lesions. Ultra-widefield autofluorescence was useful for visualizing the full extent of involvement. Indocyanine green angiography helped to demarcate the discrete pigmented choroidal lesions. Swept-source OCT clearly delineated the alternating zones of retinal pigment epithelium (RPE) thickening and RPE loss, as well as the prominent choroidal infiltration and thickening. BDUMP is an important diagnosis to consider in the presence of multiple discrete melanocytic choroidal lesions, diffuse choroidal thickening, characteristic RPE changes, iris mass lesions and exudative retinal detachment. Ultra-widefield imaging may demonstrate more extensive lesions than that detected on clinical examination or standard field imaging. Imaging with SS-OCT shows choroidal and RPE characteristics that correlate well with known histopathology of this entity.

Immunohistochemical and prognostic analysis of apoptosis and proliferation in uveal melanoma.

PubMed Central

Mooy, C. M.; Luyten, G. P.; de Jong, P. T.; Luider, T. M.; Stijnen, T.; van de Ham, F.; van Vroonhoven, C. C.; Bosman, F. T.

1995-01-01

Neoplasia can be defined as deregulated tissue homeostasis caused by an imbalance between proliferation and apoptosis. Many genes are involved in the maintenance of tissue homeostasis, eg, the c-myc oncoprotein, which is an important regulator of cell proliferation and Bcl-2 protein, which is involved in the regulation of apoptosis. We studied retrospectively indices of proliferation, such as mitotic count and the Mib-1 index, on 51 uveal melanomas and compared their prognostic significance with established indicators of prognosis such as cell type and tumor size. Along the same line we investigated the expression of the regulating proteins c-myc and Bcl-2. Of all parameters tested, the largest tumor diameter and mitotic count were most strongly associated with tumor-related death (P < 0.001 and P = 0.005, respectively). In addition, cell type, the presence of epithelioid cells, the Mib-1 index, and the percentage of cytoplasmic c-myc-positive cells were significant predictive factors. Multivariate analysis showed that the Mib-1 index, largest tumor diameter, and the percentage of cytoplasmic c-myc-positive cells were independent prognostic parameters. Bcl-2 expression did not correlate with clinical outcome. The Mib-1 index correlated with the presence of epithelioid cells (P < 0.03) and the presence of apoptotic bodies (P < 0.001) and c-myc. A strong inverse relationship was found between (nuclear and cytoplasmic) c-myc and Bcl-2 (P < 0.00004 and P < 0.006, respectively), suggesting that Bcl-2 cooperates with c-myc to immortalize uveal melanoma cells. Images Figure 1 Figure 2 PMID:7573354

Local Recurrence After Uveal Melanoma Proton Beam Therapy: Recurrence Types and Prognostic Consequences

DOE Office of Scientific and Technical Information (OSTI.GOV)

Caujolle, Jean-Pierre, E-mail: ncaujolle@aol.com; Paoli, Vincent; Chamorey, Emmanuel

Purpose: To study the prognosis of the different types of uveal melanoma recurrences treated by proton beam therapy (PBT). Methods and Materials: This retrospective study analyzed 61 cases of uveal melanoma local recurrences on a total of 1102 patients treated by PBT between June 1991 and December 2010. Survival rates have been determined by using Kaplan-Meier curves. Prognostic factors have been evaluated by using log-rank test or Cox model. Results: Our local recurrence rate was 6.1% at 5 years. These recurrences were divided into 25 patients with marginal recurrences, 18 global recurrences, 12 distant recurrences, and 6 extrascleral extensions. Fivemore » factors have been identified as statistically significant risk factors of local recurrence in the univariate analysis: large tumoral diameter, small tumoral volume, low ratio of tumoral volume over eyeball volume, iris root involvement, and safety margin inferior to 1 mm. In the local recurrence-free population, the overall survival rate was 68.7% at 10 years and the specific survival rate was 83.6% at 10 years. In the local recurrence population, the overall survival rate was 43.1% at 10 years and the specific survival rate was 55% at 10 years. The multivariate analysis of death risk factors has shown a better prognosis for marginal recurrences. Conclusion: Survival rate of marginal recurrences is superior to that of the other recurrences. The type of recurrence is a clinical prognostic value to take into account. The influence of local recurrence retreatment by proton beam therapy should be evaluated by novel studies.« less

Anterior uveal spindle cell tumor in a cat.

PubMed

Evans, Paige M; Lynch, Gwendolyn L; Dubielzig, Richard R

2010-11-01

To describe a case of anterior uveal spindle cell tumor in a cat with features similar to spindle cell tumor of blue eyed dogs. A 10-year-old female spayed domestic short-haired cat was referred for an iris mass OS. The mass was solitary, nodular, nonpigmented, located medially, and causing dyscoria. A diagnosis of a benign epithelial tumor was suggested by a FNA of the mass. The cat was lost to follow-up for 2 years, after which time she re-presented with glaucoma, blindness and grossly evident iridal mass enlargement OS. Transconjunctival enucleation was performed and the globe submitted for histopathology. Histopathology of the enucleated globe revealed the superior iris to be infiltrated and effaced by a large population of neoplastic spindle cells. The cells were arranged in streams and bundles and exhibited Antoni-A and Antoni-B tissue patterns, which are characteristic of Schwann cell tumors. Mitotic figures were rare and cellular pleomorphism moderate. Immunohistochemical staining was positive for S-100 protein and glial fibrillary acidic protein (GFAP), and negative for Melan-A. Interestingly, there was no histological evidence of glaucoma. Based on its histopathologic characteristics, this iris tumor was diagnosed as a Schwann cell variant of a peripheral nerve sheath tumor (PNST) closely resembling the spindle cell tumor of blue-eyed dogs. Anterior uveal PNST has not been previously reported in cats to the authors' knowledge. The presence of Antoni type A and type B tissue patterns along with immunohistochemical staining may facilitate a diagnosis of PNST and rule out malignant melanoma. © 2010 American College of Veterinary Ophthalmologists.

Association between traditional clinical high-risk features and gene expression profile classification in uveal melanoma.

PubMed

Nguyen, Brandon T; Kim, Ryan S; Bretana, Maria E; Kegley, Eric; Schefler, Amy C

2018-02-01

To evaluate the association between traditional clinical high-risk features of uveal melanoma patients and gene expression profile (GEP). This was a retrospective, single-center, case series of patients with uveal melanoma. Eighty-three patients met inclusion criteria for the study. Patients were examined for the following clinical risk factors: drusen/retinal pigment epithelium (RPE) changes, vascularity on B-scan, internal reflectivity on A-scan, subretinal fluid (SRF), orange pigment, apical tumor height/thickness, and largest basal dimensions (LBD). A novel point system was created to grade the high-risk clinical features of each tumor. Further analyses were performed to assess the degree of association between GEP and each individual risk factor, total clinical risk score, vascularity, internal reflectivity, American Joint Committee on Cancer (AJCC) tumor stage classification, apical tumor height/thickness, and LBD. Of the 83 total patients, 41 were classified as GEP class 1A, 17 as class 1B, and 25 as class 2. The presence of orange pigment, SRF, low internal reflectivity and vascularity on ultrasound, and apical tumor height/thickness ≥ 2 mm were not statistically significantly associated with GEP class. Lack of drusen/RPE changes demonstrated a trend toward statistical association with GEP class 2 compared to class 1A/1B. LBD and advancing AJCC stage was statistically associated with higher GEP class. In this cohort, AJCC stage classification and LBD were the only clinical features statistically associated with GEP class. Clinicians should use caution when inferring the growth potential of melanocytic lesions solely from traditional funduscopic and ultrasonographic risk factors without GEP data.

Ph 1 Study in Subjects With Tumors Requiring Arginine to Assess ADI-PEG 20 With Pemetrexed and Cisplatin

ClinicalTrials.gov

2018-02-21

Pleural Mesothelioma Malignant Advanced; Peritoneal Mesothelioma Malignant Advanced; Non-squamous Non-small Cell Lung Carcinoma Stage IIIB/IV (NSCLC); Metastatic Uveal Melanoma; Hepatocellular Carcinoma (HCC); Glioma; Sarcomatoid Cancers

Facts about Uveal Coloboma

MedlinePlus

... Search Search the NEI Website search NEI on Social Media | Search A-Z | en español | Text size S M ... Contact Us A-Z Site Map NEI on Social Media Information in Spanish (Información en español) Website, Social ...

Serological study of leptospiral infections and endogenous uveitis among horses and ponies in the United Kingdom.

PubMed

Matthews, A G; Waitkins, S A; Palmer, M F

1987-03-01

The prevalence of antibody titres to a range of 20 leptospira antigens in the serum of horses and ponies with no ophthalmic abnormalities and with ophthalmoscopic evidence of endogenous uveal inflammatory disease was determined using a microscopic agglutination technique. Titres against leptospira antigens were observed in 13 out of 138 (9.1 per cent) animals with no ophthalmic abnormalities, and in three out of 27 (11.1 per cent) animals with anterior uveitis. Serovar sejroe was common to all seropositive animals with anterior uveitis. The results show that leptospira infection is not a major factor in the aetiology of equine anterior uveitis in the UK, but suggests that the organism may be associated with some cases of recurrent anterior uveitis.

Intraocular (Eye) Melanoma—Patient Version

Cancer.gov

Intraocular (uveal) melanoma is a rare cancer that forms in the eye. It usually has no early signs or symptoms. As with melanoma of the skin, risk factors include having fair skin and light-colored eyes. Start here to find information on intraocular melanoma treatment.

Differential responses of choroidal melanocytes and uveal melanoma cells to low oxygen conditions

PubMed Central

Weidmann, Cindy; Pomerleau, Jade; Trudel-Vandal, Laurence

2017-01-01

Purpose Tissue culture is traditionally performed at atmospheric oxygen concentration (21%), which induces hyperoxic stress, as endogenous physiologic oxygen tension found in tissues varies between 2% and 9%. This discrepancy may lead to misinterpretation of results and may explain why effects observed in vitro cannot always be reproduced in vivo and vice versa. Only a few studies have been conducted in low physiologic oxygen conditions to understand the development and differentiation of cells from the eye. Methods The aim of this study was to investigate the growth and gene expression profile of melanocytes from the choroid permanently exposed to 21% (hyperoxic) or 3% (physiologic) oxygen with proliferation assays and DNA microarray. The cellular behavior of the melanocytes was then compared to that of cancer cells. Results The gross morphology and melanin content of choroidal melanocytes changed slightly when they were exposed to 3% O2, and the doubling time was statistically significantly faster. There was an increase in the percentage of choroidal melanocytes in the active phases of the cell cycle as observed by using the proliferation marker Ki67. The caveolin-1 senescence marker was not increased in choroidal melanocytes or uveal melanoma cells grown in hyperoxia. In comparison, the morphology of the uveal melanoma cells was similar between the two oxygen levels, and the doubling time was slower at 3% O2. Surprisingly, gene expression profiling of the choroidal melanocytes did not reveal a large list of transcripts considerably dysregulated between the two oxygen concentrations; only the lactate transporter monocarboxylate transporter (MCT4) was statistically significantly upregulated at 3% O2. Conclusions This study showed that the oxygen concentration must be tightly controlled in experimental settings, because it influences the subsequent cellular behavior of human choroidal melanocytes. PMID:28356703

Microbial cultures in open globe injuries in southern India.

PubMed

Gupta, Arvind; Srinivasan, Renuka; Kaliaperumal, Subashini; Setia, Sajita

2007-07-01

To determine the risk factors leading to positive intraocular culture in patients with open globe injury. A prospective interventional study involving 110 eyes of 110 patients of more than 15 years of age, presenting with open globe injury, was undertaken. Emergency repair of the injured globe was done. Prolapsed intraocular tissue or aqueous humour was sent for microbial work up before repair. In endophthalmitis cases intravitreal antibiotics were given according to the antimicrobial sensitivity. Chi-square and logistic regression analysis were used to determine the risk factors. Fifty-six patients showed microbial contamination. Bacteria were cultured in 42 patients and fungi in 14 patients. Nineteen patients developed endophthalmitis, of which 18 patients showed microbial growth initially. In univariate analysis, initial visual acuity (<6/360, P = 0.002), presence of uveal tissue prolapse (P < 0.001), vitreous prolapse (P < 0.001) and length of laceration (>8 mm, P < 0.001) were significantly associated with positive microbial culture, however, in the multivariate stepwise logistic regression delay in surgical intervention (>72 h, P < 0.001), uveal tissue prolapse (P = 0.004) and corneosclearal laceration (>8 mm, P = 0.013) were associated with increased risk of positive microbial culture. Six patients had intraocular foreign body but were culture negative. Age, gender, site of injury and presence of cataract did not significantly affect the culture positivity. Microbial contamination is a risk factor for the development for endophthalmitis. Despite the high frequency of microbial contamination, it develops only in few cases. Systemic antibiotics, virulence of the organism and host factors play a role in the manifestation of endophthalmitis. Prophylaxis with intraocular antibiotics should be strongly considered in cases with poor vision at presentation, larger corneoscleral laceration, delayed surgical intervention and uveal tissue or vitreous prolapse.

Brachytherapy treatment simulation of strontium-90 and ruthenium-106 plaques on small size posterior uveal melanoma using MCNPX code

NASA Astrophysics Data System (ADS)

Barbosa, N. A.; da Rosa, L. A. R.; Facure, A.; Braz, D.

2014-02-01

Concave eye applicators with 90Sr/90Y and 106Ru/106Rh beta-ray sources are usually used in brachytherapy for the treatment of superficial intraocular tumors as uveal melanoma with thickness up to 5 mm. The aim of this work consisted in using the Monte Carlo code MCNPX to calculate the 3D dose distribution on a mathematical model of the human eye, considering 90Sr/90Y and 160Ru/160Rh beta-ray eye applicators, in order to treat a posterior uveal melanoma with a thickness 3.8 mm from the choroid surface. Mathematical models were developed for the two ophthalmic applicators, CGD produced by BEBIG Company and SIA.6 produced by the Amersham Company, with activities 1 mCi and 4.23 mCi respectively. They have a concave form. These applicators' mathematical models were attached to the eye model and the dose distributions were calculated using the MCNPX *F8 tally. The average doses rates were determined in all regions of the eye model. The *F8 tally results showed that the deposited energy due to the applicator with the radionuclide 106Ru/106Rh is higher in all eye regions, including tumor. However the average dose rate in the tumor region is higher for the applicator with 90Sr/90Y, due to its high activity. Due to the dosimetric characteristics of these applicators, the PDD value for 3 mm water is 73% for the 106Ru/106Rh applicator and 60% for 90Sr/90Y applicator. For a better choice of the applicator type and radionuclide it is important to know the thickness of the tumor and its location.

Adjuvant Sunitinib or Valproic Acid in High-Risk Patients With Uveal Melanoma

ClinicalTrials.gov

2017-10-25

Ciliary Body and Choroid Melanoma, Medium/Large Size; Ciliary Body and Choroid Melanoma, Small Size; Iris Melanoma; Stage I Intraocular Melanoma; Stage IIA Intraocular Melanoma; Stage IIB Intraocular Melanoma; Stage IIIA Intraocular Melanoma; Stage IIIB Intraocular Melanoma; Stage IIIC Intraocular Melanoma

Selumetinib-based therapy in uveal melanoma patient-derived xenografts

PubMed Central

Decaudin, Didier; El Botty, Rania; Diallo, Béré; Massonnet, Gerald; Fleury, Justine; Naguez, Adnan; Raymondie, Chloé; Davies, Emma; Smith, Aaron; Wilson, Joanne; Howes, Colin; Smith, Paul D.; Cassoux, Nathalie; Piperno-Neumann, Sophie; Roman-Roman, Sergio; Némati, Fariba

2018-01-01

The prognosis of metastatic uveal melanoma (UM) is among the worst of all human cancers. The identification of near-ubiquitous GNAQ/GNA11 mutations and the activation of MAPK signaling in UM have raised hopes of more effective, targeted therapies, based on MEK inhibition, for example. We evaluated the potential of drug combinations to increase the efficacy of the MEK inhibitor selumetinib (AZD6244, ARRY-142886), in UM cell lines and Patient-Derived Xenografts. We first evaluated the combination of selumetinib and DTIC. We found that DTIC did not improve the in vitro or in vivo antitumor efficacy of selumetinib, consistent with the outcome of the SUMIT clinical trial assessing the efficacy of this combination in UM. We then tested additional selumetinib combinations with the chemotherapy agent docetaxel, the ERK inhibitor AZ6197, and the mTORC1/2 inhibitor, vistusertib (AZD2014). Combinations of selumetinib with ERK and mTORC1/2 inhibitors appeared to be the most effective in UM PDX models. PMID:29774094

Bilateral uveal metastasis of a subcutaneous fibrosarcoma in a cat.

PubMed

Mowat, Freya M; Langohr, Ingeborg M; Bilyk, Olenka; Koterbay, Amy; Pierce, Kenneth E; Petersen-Jones, Simon M

2012-11-01

A 6-year-old neutered male domestic short-haired cat was presented to the Comparative Ophthalmology service at Michigan State University with a 3-week history of decreased appetite and redness of the left eye. The left forelimb had been removed 15 months previously because of the presence of a subcutaneous fibrosarcoma. In the left globe, a large iridal mass was associated with increased intraocular pressure and retinal detachment. A smaller mass involving the right iris was also present. Imaging revealed a 2-cm mass in the left caudodorsal lung lobe, and abdominal ultrasound showed multifocal bilateral renal masses. Aspirates of these masses were nondiagnostic. The left globe was removed for palliative reasons, and histopathology showed that fibrosarcoma was infiltrating the iris, choroid, and optic nerve. Despite systemic chemotherapy with doxorubicin, the animal died 4 months after initial presentation. Histopathology confirmed highly angioinvasive metastatic fibrosarcoma also in the right uveal tract, the lungs, and both kidneys. © 2012 American College of Veterinary Ophthalmologists.

Use of the Toric Surgical Marker to Aid in Intraoperative Plaque Placement for the USC Eye Physics Plaques to Treat Uveal Melanoma: A New Surgical Technique.

PubMed

Berry, Jesse L; Kim, Jonathan W; Jennelle, Richard; Astrahan, Melvin

2015-09-01

To describe a new surgical technique for intraoperative placement of Eye Physics (EP) plaques for uveal melanoma using a toric marker. A toric marker is designed for cataract surgery to align the axis of astigmatism; its use was modified in this protocol to mark the axis of suture coordinates as calculated by Plaque Simulator (PS) software. The toric marker can be used to localize suture coordinates, in degrees, during intraoperative plaque placement. Linear marking using the toric marker decreases potential inaccuracies associated with the surgeon estimating 'clock-hours' by dot placement. Use of the toric marker aided surgical placement of EP plaques. The EP planning protocol is now designed to display the suture coordinates either by clock-hours or degrees, per surgeon preference. Future research is necessary to determine whether routine use of the toric marker improves operative efficiency. [Ophthalmic Surg Lasers Imaging Retina. 2015;46:866-870.]. Copyright 2015, SLACK Incorporated.

Vision Loss Following Episcleral Brachytherapy for Uveal Melanoma: Development of a Vision Prognostication Tool.

PubMed

Aziz, Hassan A; Singh, Nakul; Bena, James; Wilkinson, Allan; Singh, Arun D

2016-06-01

Vision loss following episcleral brachytherapy for uveal melanoma is difficult to predict for individual patients. To generate a risk calculator for vision loss following episcleral brachytherapy for uveal melanoma. A retrospective review of data was conducted at a multispecialty tertiary care center in Cleveland, Ohio. All patients with primary ciliary body or choroidal melanoma treated with iodine 125 or ruthenium 106 episcleral brachytherapy between January 1, 2004, and December 30, 2013, were included. Univariate and multivariable Cox proportional hazards were used to determine the influence of baseline patient factors on vision loss. Kaplan-Meier curves (log-rank analyses) were used to estimate freedom from vision loss. Bootstrap resampling was performed to bias correct this estimate. Vision loss (to visual acuity [VA] worse than 20/50 and worse than 20/200). A total of 311 patients were included in the study, with a mean (SD) age of 62 (14.7) years at start of treatment and a median follow-up of 36 months (interquartile range, 18-60 months). At presentation, VA was better than or equal to 20/50 in 199 patients (64%) and better than or equal to 20/200 in 289 patients (93%). By Kaplan-Meier analysis, VA less than 20/200 at 3 years was not associated with sex, diabetes, systemic hypertension, or hypercholesterolemia but was associated with history of ocular comorbidities, type of isotope (ruthenium 106 or iodine 125), and initial VA ( >20/50 or <20/50). By multivariable analysis, age (hazard ratio [HR], 0.97; 95% CI, 0.94-1.00; P = .06), largest basal diameter (HR, 1.25; 95% CI, 1.16-1.34; P = <.001), total radiation dose to the fovea (HR, 1.03; 95% CI, 1.01-1.04; P = .001) and optic disc (HR, 1.01; 95% CI, 1.00-1.01; P = .005), and initial VA worse than 20/50 (HR, 1.85; 95% CI, 1.20-2.85; P = .005) were predictive of vision loss to a VA of less than 20/200. The concordance index for the full data set was 0.77. Using these data, an online risk calculator was developed to predict vision loss following episcleral brachytherapy. The vision prognostication tool presented herein needs to be validated by independent data sets. This tool may improve counseling for patients being evaluated for episcleral brachytherapy. At-risk individuals identified by this tool could be considered for inclusion into trials exploring prevention or treatment of radiation retinopathy and alternative therapies of uveal melanoma.

Experimental immunotherapy shows promise in treating metastatic uveal melanoma | Center for Cancer Research

Cancer.gov

A team led by Udai S. Kammula, M.D., Investigator in the Surgery Branch, has shown that an immunotherapy known as adoptive cell transfer (ACT) is a promising approach to treating a rare form of melanoma that affects the eye.  Learn more...

Intraocular (Uveal) Melanoma Symptoms, Tests, Prognosis, and Stages (PDQ®)—Patient Version

Cancer.gov

Intraocular melanoma is a rare cancer that forms from cells that make melanin in the eye. It is the most common eye cancer in adults and may not cause early signs or symptoms. Find out risk factors, tests to diagnose, prognosis, and staging for intraocular melanoma.

Treatment strategies for childhood noninfectious chronic uveitis: an update.

PubMed

Cantarini, Luca; Simonini, Gabriele; Frediani, Bruno; Pagnini, Ilaria; Galeazzi, Mauro; Cimaz, Rolando

2012-01-01

Uveitis is an inflammatory disorder involving inflammation of the uveal tract. It is classified as anterior, intermediate, posterior or panuveitis, depending on the part of eye affected by the inflammatory process. In children, noninfectious, chronic uveitis is a relatively uncommon but serious disease, with the potential for significant long-term complications and possible blindness. Although frequently associated with an underlying systemic disease, for example, juvenile idiopathic arthritis, a significant number of cases in children show no associated signs or symptoms and are labeled as idiopathic. We reviewed the available literature. Taking into account this evidence, an anti-inflammatory therapy based on an immunomodulatory approach seems a reasonable strategy for noninfectious chronic uveitis, in children as well as in adults. Due to a lack of controlled studies regarding uveitis in children, immunosuppressive strategy is supported only at evidence level III. Our aim is to review the currently available medical strategies for the treatment of childhood sight-threatening chronic uveitis. Uveitis in children can be severe. Methotrexate is the drug of choice for recalcitrant cases, and biologic therapies can be useful in selected situations.

Current therapeutic approaches to autoimmune chronic uveitis in children.

PubMed

Simonini, Gabriele; Cantarini, Luca; Bresci, Cecilia; Lorusso, Monica; Galeazzi, Mauro; Cimaz, Rolando

2010-08-01

Uveitis is an inflammatory disorder involving inflammation of the uveal tract. It is classified as anterior, intermediate, posterior or panuveitis, depending on the part of eye affected by the inflammatory process. In children, non-infectious, chronic uveitis is a relatively uncommon but serious disease, with the potential for significant long-term complications and possible blindness. Although frequently associated with an underlying systemic disease, e.g. juvenile idiopathic arthritis (JIA), a significant number of cases in children show no associated signs or symptoms, and are labelled as idiopathic. Taking into account this evidence, an anti-inflammatory therapy based on an immuno-modulatory approach seems a reasonable strategy for non-infectious chronic uveitis, in children as well as in adults. Due to a lack of controlled studies regarding uveitis in children, immunosuppressive drugs are supported only at evidence level III. The aim of this review is to report currently available medical strategies for treatment of childhood sight-threatening chronic uveitis; in addition, a step-by-step approach to the use of immunosuppressants in this context is suggested. 2010 Elsevier B.V. All rights reserved.

Intraocular extramedullary plasmacytoma in a cat.

PubMed

Michau, Tammy Miller; Proulx, David R; Rushton, Steven D; Olivry, Thierry; Dunston, Stanley M; Gilger, Brian C; Davidson, Michael G

2003-06-01

An 8-year-old, castrated male Domestic Short-haired cat was referred for evaluation of a possible intraocular neoplasm following previous ocular trauma. The eye was blind, and uveitis and an iridal mass were noted on examination. An enucleation was performed and the mandibular lymph node excised. Histopathologic examination revealed neoplastic proliferation of plasma cells in the iris and lymph node. No other evidence of disseminated disease was detected. This is the first case reported of an intraocular extramedullary plasmacytoma in the cat. The variation in clinical manifestations and potential association with multiple myeloma are not known at this time. Disseminated metastasis from a primary plasmacytoma of the uveal tract could also involve the bone marrow and be indistinguishable from multiple myeloma. Early enucleation, as in trauma-associated sarcomas, may be indicated to prevent metastasis. Periodic systemic evaluation for evidence of multiple myeloma should be performed.

The gamma knife in ophthalmology. Part One--Uveal melanoma.

PubMed

Wygledowska-Promieńska, Dorota; Jurys, Małgorzata; Wilczyński, Tomasz; Drzyzga, Łukasz

2014-01-01

The Gamma Knife was designed by Lars Leksell in the early 1950's. It gave rise to a new discipline of medicine--stereotactic radiosurgery. Primarily dedicated to neurosurgery, the Gamma Knife has become an alternative, widely used surgery technique. According to Elekta's statistics, approximately 60,000 people are treated with Leksell Gamma Knife every year and it is the most extensively studied stereotactic radiosurgery system in the world. The Leksell Gamma Knife can also be used in ophthalmology. The gamma ray beam concentration enables effective treatment of uveal melanoma, choroidal hemangioma, orbital tumors or even choroidal neovascularization. The virtue of Leksell Gamma Knife is its extreme precision, non-invasiveness and the possibility of outpatient treatment, which significantly reduces costs and diminishes post-operative complications. Innovative solutions shorten a single session to a minimum, which is very comfortable and safe for both staff and patients. Advantages and possible side effects of gamma knife radiosurgery are well-documented in the professional literature. The objective of this review is to present the recognized applications of Leksell Gamma Knife in ophthalmology.

Uveal effusion following acute primary angle-closure: a retrospective case series

PubMed Central

Yang, Jian-Gang; Li, Jian-Jun; Tian, Hua; Li, Yan-Hong; Gong, Yu-Jing; Su, An-Le; He, Na

2017-01-01

AIM To evaluate the morphological changes in anterior segment in Chinese patients with uveal effusion (UE) after the attack of acute primary angle-closure (APAC) using ultrasound biomicroscopy (UBM), and to assess the clinical course and prognosis of the disease. METHODS In a retrospective case series, 26 eyes in 26 consecutive patients diagnosed with UE after the treatment of intraocular pressure (IOP)-lowering medication for the attack of APAC were enrolled. The unaffected fellow eyes served as controls. The morphological changes were observed by ultrasonography, slit lamp microscopy and gonioscopy. UBM was used to assess the degree and extent of effusion based on the analysis of parameters associated with UE. RESULTS The mean IOP was 9.2 (SD 2.1) mm Hg at the diagnosis of UE after IOP-lowering medication, while 14.1 (SD, 2.6) mm Hg in the fellow eyes (P=0.000). The anterior chamber depth (ACD) (P=0.000), angle opening distance at 500 µm (AOD500) (P<0.01) and anterior chamber angle (ACA) (P<0.05) were decreased significantly, while ciliary body thickness (CBT) (P<0.05) increased significantly in UE eyes. UE grade analysis showed 7 eyes in grade 1, 9 eyes in grade 2, and 10 eyes in grade 3. Quadrant scores were performed of 4 eyes in 1 quadrant, 3 eyes in 3 quadrants, and 19 eyes in 4 quadrants. There was the positive correlation between grade and quadrant score (r=0.644, P=0.000). The effusion on all eyes were recovered after medication, which mean IOP was 13.9 (SD, 2.8) mm Hg. CONCLUSION UE is a frequent complication in Chinese patients after the attack of APAC, partially associated with hypotony. The severity of UE is correlation with height of effusion, extent of detachment, and shallower ACD. PMID:28393032

The first description of the complete natural history of uveal melanoma by two Scottish surgeons, Allan Burns and James Wardrop.

PubMed

Kivelä, Tero T

2018-03-01

James Wardrop (1782-1869), a young Scottish surgeon and an early ophthalmologist in Edinburgh, is credited for describing in 1809 retinoblastoma as an entity in his treatise 'Observations on Fungus Haematodes or Soft Cancer'. His treatise also reveals that Allan Burns (1781-1813), another young Scottish surgeon and anatomist, had invited Wardrop to assist in enucleating an eye from a 41-year-old Glasgow woman who, in retrospect, had a uveal melanoma. Her eye had become blind 4 months after symptoms of exudative retinal detachment had appeared, and it had become painful after a further 2-4 months. The tumour eventually perforated the sclera, and she died within a year thereafter of hepatic metastases. Burns and Wardrop went on to publish detailed parallel accounts of the symptoms, signs, ophthalmic pathology and post-mortem findings regarding the primary, recurrent and metastatic tumour. Burns may have performed the post-mortem after exhuming the body, a common occurrence in early 19th Century Scotland, a thriving hub for teaching morbid anatomy to young surgeons at the time. © 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

A novel in vivo model of puncture-induced iris neovascularization.

PubMed

Beaujean, Ophélie; Locri, Filippo; Aronsson, Monica; Kvanta, Anders; André, Helder

2017-01-01

To assess iris neovascularization by uveal puncture of the mouse eye and determine the role of angiogenic factors during iris neovascularization. Uveal punctures were performed on BalbC mouse eyes to induce iris angiogenesis. VEGF-blockage was used as an anti-angiogenic treatment, while normoxia- and hypoxia-conditioned media from retinal pigment epithelium (RPE) cells was used as an angiogenic-inducer in this model. Iris vasculature was determined in vivo by noninvasive methods. Iris blood vessels were stained for platelet endothelial cell adhesion molecule-1 and vascular sprouts were counted as markers of angiogenesis. Expression of angiogenic and inflammatory factors in the puncture-induced model were determined by qPCR and western blot. Punctures led to increased neovascularization and sprouting of the iris. qPCR and protein analysis showed an increase of angiogenic factors, particularly in the plasminogen-activating receptor and inflammatory systems. VEGF-blockage partly reduced iris neovascularization, and treatment with hypoxia-conditioned RPE medium led to a statistically significant increase in iris neovascularization. This study presents the first evidence of a puncture-induced iris angiogenesis model in the mouse. In a broader context, this novel in vivo model of neovascularization has the potential for noninvasive evaluation of angiogenesis modulating substances.

Hepatic intra-arterial versus intravenous fotemustine in patients with liver metastases from uveal melanoma (EORTC 18021): a multicentric randomized trial.

PubMed

Leyvraz, S; Piperno-Neumann, S; Suciu, S; Baurain, J F; Zdzienicki, M; Testori, A; Marshall, E; Scheulen, M; Jouary, T; Negrier, S; Vermorken, J B; Kaempgen, E; Durando, X; Schadendorf, D; Gurunath, R Karra; Keilholz, U

2014-03-01

In uveal melanoma (UM) with metastatic disease limited to the liver, the effect of an intrahepatic treatment on survival is unknown. We investigated prospectively the efficacy and toxicity of hepatic intra-arterial (HIA) versus systemic (IV) fotemustine in patients with liver metastases from UM. Patients were randomly assigned to receive either IV or HIA fotemustine at 100 mg/m(2) on days 1, 8, 15 (and 22 in HIA arm only) as induction, and after a 5-week rest period every 3 weeks as maintenance. Primary end point was overall survival (OS). Response rate (RR), progression-free survival (PFS) and safety were secondary end points. Accrual was stopped after randomization of 171 patients based on the results of a futility OS analysis. A total of 155 patients died and 16 were still alive [median follow-up 1.6 years (range 0.25-6 years)]. HIA did not improve OS (median 14.6 months) when compared with the IV arm (median 13.8 months), hazard ratio (HR) 1.09; 95% confidence interval (CI) 0.79-1.50, log-rank P = 0.59. However, there was a significant benefit on PFS for HIA compared with IV with a median of 4.5 versus 3.5 months, respectively (HR 0.62; 95% CI 0.45-0.84, log-rank P = 0.002). The 1-year PFS rate was 24% in the HIA arm versus 8% in the IV arm. An improved RR was seen in the HIA (10.5%) compared with IV treatment (2.4%). In the IV arm, the most frequent grade ≥3 toxicity was thrombocytopenia (42.1%) and neutropenia (62.6%), compared with 21.2% and 28.7% in the HIA arm. The main grade ≥3 toxicity related to HIA was catheter complications (12%) and liver toxicity (4.5%) apart from two toxic deaths. HIA treatment with fotemustine did not translate into an improved OS compared with IV treatment, despite better RR and PFS. Intrahepatic treatment should still be considered as experimental. 2004-002245-12 and NCT00110123.

Kinome-wide transcriptional profiling of uveal melanoma reveals new vulnerabilities to targeted therapeutics.

PubMed

Bailey, Fiona P; Clarke, Kim; Kalirai, Helen; Kenyani, Jenna; Shahidipour, Haleh; Falciani, Francesco; Coulson, Judy M; Sacco, Joseph J; Coupland, Sarah E; Eyers, Patrick A

2018-03-01

Metastatic uveal melanoma (UM) is invariably fatal, usually within a year of diagnosis. There are currently no effective therapies, and clinical studies employing kinase inhibitors have so far demonstrated limited success. This is despite common activating mutations in GNAQ/11 genes, which trigger signalling pathways that might predispose tumours to a variety of targeted drugs. In this study, we have profiled kinome expression network dynamics in various human ocular melanomas. We uncovered a shared transcriptional profile in human primary UM samples and across a variety of experimental cell-based models. The poor overall response of UM cells to FDA-approved kinase inhibitors contrasted with much higher sensitivity to the bromodomain inhibitor JQ1, a broad transcriptional repressor. Mechanistically, we identified a repressed FOXM1-dependent kinase subnetwork in JQ1-exposed cells that contained multiple cell cycle-regulated protein kinases. Consistently, we demonstrated vulnerability of UM cells to inhibitors of mitotic protein kinases within this network, including the investigational PLK1 inhibitor BI6727. We conclude that analysis of kinome-wide signalling network dynamics has the potential to reveal actionable drug targets and inhibitors of potential therapeutic benefit for UM patients. © 2017 The Authors. Pigment Cell & Melanoma Research Published by John Wiley & Sons.

Early experiences of planning stereotactic radiosurgery using 3D printed models of eyes with uveal melanomas

PubMed Central

Furdová, Alena; Sramka, Miron; Thurzo, Andrej; Furdová, Adriana

2017-01-01

Objective The objective of this study was to determine the use of 3D printed model of an eye with intraocular tumor for linear accelerator-based stereotactic radiosurgery. Methods The software for segmentation (3D Slicer) created virtual 3D model of eye globe with tumorous mass based on tissue density from computed tomography and magnetic resonance imaging data. A virtual model was then processed in the slicing software (Simplify3D®) and printed on 3D printer using fused deposition modeling technology. The material that was used for printing was polylactic acid. Results In 2015, stereotactic planning scheme was optimized with the help of 3D printed model of the patient’s eye with intraocular tumor. In the period 2001–2015, a group of 150 patients with uveal melanoma (139 choroidal melanoma and 11 ciliary body melanoma) were treated. The median tumor volume was 0.5 cm3 (0.2–1.6 cm3). The radiation dose was 35.0 Gy by 99% of dose volume histogram. Conclusion The 3D printed model of eye with tumor was helpful in planning the process to achieve the optimal scheme for irradiation which requires high accuracy of defining the targeted tumor mass and critical structures. PMID:28203052

A novel in vivo model of puncture-induced iris neovascularization

PubMed Central

Aronsson, Monica; Kvanta, Anders

2017-01-01

Purpose To assess iris neovascularization by uveal puncture of the mouse eye and determine the role of angiogenic factors during iris neovascularization. Methods Uveal punctures were performed on BalbC mouse eyes to induce iris angiogenesis. VEGF-blockage was used as an anti-angiogenic treatment, while normoxia- and hypoxia-conditioned media from retinal pigment epithelium (RPE) cells was used as an angiogenic-inducer in this model. Iris vasculature was determined in vivo by noninvasive methods. Iris blood vessels were stained for platelet endothelial cell adhesion molecule-1 and vascular sprouts were counted as markers of angiogenesis. Expression of angiogenic and inflammatory factors in the puncture-induced model were determined by qPCR and western blot. Results Punctures led to increased neovascularization and sprouting of the iris. qPCR and protein analysis showed an increase of angiogenic factors, particularly in the plasminogen-activating receptor and inflammatory systems. VEGF-blockage partly reduced iris neovascularization, and treatment with hypoxia-conditioned RPE medium led to a statistically significant increase in iris neovascularization. Conclusions This study presents the first evidence of a puncture-induced iris angiogenesis model in the mouse. In a broader context, this novel in vivo model of neovascularization has the potential for noninvasive evaluation of angiogenesis modulating substances. PMID:28658313

A Case of Uveal Colobomas Showing Marked Left-Right Difference in Diabetic Retinopathy.

PubMed

Moriya, Takeshi; Ochi, Ryosuke; Imagawa, Yukihiro; Sato, Bumpei; Morishita, Seita; Tonari, Masahiro; Fukumoto, Masanori; Suzuki, Hiroyuki; Kobayashi, Takatoshi; Kida, Teruyo; Ikeda, Tsunehiko

2016-01-01

Congenital uveal colobomas, including inferior iris and choroidal colobomas, are associated with microcornea and microphthalmia and often show left-right differences (laterality). The purpose of this study was to report a case of choroidal coloboma associated with left-right differences in diabetic retinopathy (DR). This study reports a 59-year-old male with bilateral iris and choroidal colobomas. The colobomatous area in the patient's right eye extended to the macula, and his right eye had been amblyopic since birth. The colobomatous area in his left eye was less extensive and did not involve the macula. Examination of the patient's left eye revealed multiple hemorrhages and hard exudates in the macula due to DR, but examination of his right eye showed almost no changes in DR, thus revealing a marked left-right difference. Optical coherence tomography showed more extensive retinal thinning in the patient's right eye than in his left eye. Fluorescein fundus angiography revealed a retinal nonperfusion area only in the left eye, and panretinal photocoagulation was subsequently performed. Our findings show that the reason for the left-right difference in DR was attributed to the more severe choroidal coloboma and retinal thinning in the patient's right eye compared to his left eye, thus reducing oxygen demand, as is also seen in eyes with severe myopia.

A 62-MeV Proton Beam for the Treatment of Ocular Melanoma at Laboratori Nazionali del Sud-INFN

NASA Astrophysics Data System (ADS)

Cirrone, G. A. P.; Cuttone, G.; Lojacono, P. A.; Lo Nigro, S.; Mongelli, V.; Patti, I. V.; Privitera, G.; Raffaele, L.; Rifuggiato, D.; Sabini, M. G.; Salamone, V.; Spatola, C.; Valastro, L. M.

2004-06-01

At the Istituto Nazionale di Fisica Nucleare-Laboratori Nazionali del Sud (INFN-LNS) in Catania, Italy, the first Italian protontherapy facility, named Centro di AdroTerapia e Applicazioni Nucleari Avanzate (CATANA) has been built in collaboration with the University of Catania. It is based on the use of the 62-MeV proton beam delivered by the K=800 Superconducting Cyclotron installed and working at INFN-LNS since 1995. The facility is mainly devoted to the treatment of ocular diseases like uveal melanoma. A beam treatment line in air has been assembled together with a dedicated positioning patient system. The facility has been in operation since the beginning of 2002 and 66 patients have been successfully treated up to now. The main features of CATANA together with the clinical and dosimetric features will be extensively described; particularly, the proton beam line, that has been entirely built at LNS, with all its elements, the experimental transversal and depth dose distributions of the 62-MeV proton beam obtained for a final collimator of 25-mm diameter and the experimental depth dose distributions of a modulated proton beam obtained for the same final collimator. Finally, the clinical results over 1 yr of treatments, describing the features of the treated diseases will be reported.

Use of 70 MeV Proton Beam for Medical Applications at INFN-LNS: CATANA Project

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sabini, M.G.; Cirrone, G.A.P.; Barone Tonghi, L.

The project CATANA (Centro di AdroTerapia ed Applicazioni Nucleari Avanzate) is a collaboration between the INFN-Laboratori Nazionali del Sud (LNS), Physics Department, Ophthalmology Institute and Radiology Institute of the Catania University and CSFNSM Catania. The main goal of CATANA is the study and the application of proton therapy for the treatment of shallow tumors (4 cm max) like uveal melanomas and subfoveal macular degenerations.

Use of 70 MeV proton beam for medical applications at INFN-LNS: CATANA project

NASA Astrophysics Data System (ADS)

Sabini, M. G.; Cirrone, G. A. P.; Tonghi, L. Barone; Bartolotta, A.; Brai, M.; Cuttone, G.; Nigro, S. Lo; Marano, F.; Nicoletti, G. A.; Privitera, G.; Raffaele, L.; Reibaldi, A.; Romeo, N.; Rovelli, A.; Salamone, V.; Teri, G.

2000-04-01

The project CATANA (Centro di Adro Terapia ed Applicazioni Nucleari Avanzate) is a collaboration between the INFN-Laboratori Nazionali del Sud (LNS), Physics Department, Ophthalmology Institute and Radiology Institute of the Catania University and CSFNSM Catania. The main goal of CATANA is the study and the application of protontherapy for the treatment of shallow tumors (4 cm max) like uveal melanomas and subfoveal macular degenerations.

Posterior reversible leukoencephalopathy syndrome secondary to hepatic transarterial chemoembolization with doxorubicin drug eluting beads

PubMed Central

Kistler, C. Andrew; McCall, Joseph Caleb; Ghumman, Saad Sultan; Ali, Ijlal Akbar

2014-01-01

Posterior reversible encephalopathy syndrome (PRES) is a rare complication of transarterial chemoembolization (TACE) used to treat liver metastases and has never been reported in a patient with metastatic uveal melanoma (UM) to the liver. We report the first case of PRES secondary to TACE with drug eluting beads (DEBs) loaded with doxorubicin in a 56-year-old woman with metastatic UM to the liver. PMID:24772346

A Safety and Tolerability Study of INCAGN02385 in Select Advanced Malignancies

ClinicalTrials.gov

2018-05-15

Cervical Cancer; Microsatellite Instability (MSI)-High Endometrial Cancer; Gastric Cancer (Including Stomach and Gastroesophageal Junction [GEJ]); Esophageal Cancer; Hepatocellular Carcinoma; Melanoma (Uveal Melanoma Excluded); Merkel Cell Carcinoma; Mesothelioma; MSI-high Colorectal Cancer; Non-small Cell Lung Cancer (NSCLC); Ovarian Cancer; Squamous Cell Carcinoma of the Head and Neck (SCCHN); Small Cell Lung Cancer (SCLC); Renal Cell Carcinoma (RCC); Triple-negative Breast Cancer; Urothelial Carcinoma; Diffuse Large B-cell Lymphoma

Heavy ion therapy: Bevalac epoch

DOE Office of Scientific and Technical Information (OSTI.GOV)

Castro, J.R.

1993-10-01

An overview of heavy ion therapy at the Bevelac complex (SuperHILac linear accelerator + Bevatron) is given. Treatment planning, clinical results with helium ions on the skull base and uveal melanoma, clinical results with high-LET charged particles, neon radiotherapy of prostate cancer, heavy charged particle irradiation for unfavorable soft tissue sarcoma, preliminary results in heavy charged particle irradiation of bone sarcoma, and irradiation of bile duct carcinoma with charged particles and-or photons are all covered. (GHH)

Prevalence of Childhood Blindness and Ocular Morbidity in a Rural Pediatric Population in Southern India: The Pavagada Pediatric Eye Disease Study-1.

PubMed

Kemmanu, Vasudha; Hegde, Kaushik; Giliyar, Subramanya K; Shetty, Bhujanga K; Kumaramanickavel, G; McCarty, Catherine A

2016-06-01

To determine the prevalence of childhood blindness and ocular morbidity in a rural pediatric population in South India. A population-based, cross-sectional survey of children was conducted in three phases in Pavagada and Madhugiri taluks (subdivisions) of Tumkur district in the state of Karnataka, India. In the first phase, trained fieldworkers screened 23,100 children. In the second phase, children with eye diseases were referred to the peripheral hospital to be examined by a general ophthalmologist. In the third phase, children with major eye diseases were examined by a pediatric ophthalmologist. The prevalence of ocular morbidity was 2.66% (95% confidence interval, CI, 2.46-2.87%). The most commonly observed ocular morbidity was Bitot spots (1%) followed by refractive error (0.6%). In total, 18 children were blind and the prevalence of childhood blindness (best-corrected visual acuity <3/60) was 0.08% (95% CI 0.04-0.11%); 8 (44.44%) had retinal blindness, 5 (27.76%) had lens-related blindness, 2 (11.11%) had bilateral microphthalmos, 1 (5.56%) was blind due to anterior staphyloma in the right eye and anophthalmos in the left eye, 1 (5.56%) had bilateral uveal coloboma and 1 (5.56%) had cortical visual impairment. Nearly half of the blindness in the population was due to unavoidable causes (retinal). In addition to providing eye care services, an appropriate service delivery model would include the provision of rehabilitative and low vision services and implementation of genetic studies to understand the causes and increase awareness of inherited eye diseases.

Iodine 125 Brachytherapy With Vitrectomy and Silicone Oil in the Treatment of Uveal Melanoma: 1-to-1 Matched Case-Control Series

DOE Office of Scientific and Technical Information (OSTI.GOV)

McCannel, Tara A., E-mail: TMcCannel@jsei.ucla.edu; McCannel, Colin A.

Purpose: We initially reported the radiation-attenuating effect of silicone oil 1000 centistokes for iodine 125. The purpose of this report was to compare the clinical outcomes in case patients who had iodine 125 brachytherapy with vitrectomy and silicone oil 1000 centistokes with the outcomes in matched control patients who underwent brachytherapy alone. Methods and Materials: Consecutive patients with uveal melanoma who were treated with iodine 125 plaque brachytherapy and vitrectomy with silicone oil with minimum 1-year follow-up were included. Control patients who underwent brachytherapy alone were matched for tumor size, location, and sex. Baseline patient and tumor characteristics and tumor response tomore » radiation, final visual acuity, macular status, central macular thickness by ocular coherence tomography (OCT), cataract progression, and metastasis at last follow-up visit were compared. Surgical complications were also determined. Results: Twenty case patients met the inclusion criteria. The average follow-up time was 22.1 months in case patients and 19.4 months in control patients. The final logMAR vision was 0.81 in case patients and 1.1 in control patients (P=.071); 8 case patients and 16 control patients had abnormal macular findings (P=.011); and the average central macular thickness by OCT was 293.2 μm in case patients and 408.5 μm in control patients (P=.016). Eleven case patients (55%) and 1 control patient (5%) had required cataract surgery at last follow-up (P=.002). Four patients in the case group and 1 patient in the control group experienced metastasis (P=.18). Among the cases, intraoperative retinal tear occurred in 3 patients; total serous retinal detachment and macular hole developed in 1 case patient each. There was no case of rhegmatogenous retinal detachment, treatment failure, or local tumor dissemination in case patients or control patients. Conclusions: With up to 3 years of clinical follow-up, silicone oil during brachytherapy for the treatment of uveal melanoma resulted in fewer abnormal maculas, lower central macular thickness on OCT, and a trend toward better final visual acuity in comparison with matched control patients who underwent brachytherapy alone.« less

Temporal Evolution and Dose-Volume Histogram Predictors of Visual Acuity After Proton Beam Radiation Therapy of Uveal Melanoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Polishchuk, Alexei L.; Mishra, Kavita K., E-mail: Kavita.Mishra@ucsf.edu; Weinberg, Vivian

2017-01-01

Purpose: To perform an in-depth temporal analysis of visual acuity (VA) outcomes after proton beam radiation therapy (PBRT) in a large, uniformly treated cohort of uveal melanoma (UM) patients, to determine trends in VA evolution depending on pretreatment and temporally defined posttreatment VA measurements; and to investigate the relevance of specific patient, tumor and dose-volume parameters to posttreatment vision loss. Methods and Materials: Uveal melanoma patients receiving PBRT were identified from a prospectively maintained database. Included patients (n=645) received 56 GyE in 4 fractions, had pretreatment best corrected VA (BCVA) in the affected eye of count fingers (CF) or better, withmore » posttreatment VA assessment at specified post-PBRT time point(s). Patients were grouped according to the pretreatment BCVA into favorable (≥20/40) or unfavorable (20/50-20/400) and poor (CF) strata. Temporal analysis of BCVA changes was described, and univariate and forward stepwise multivariate logistic regression analyses were performed to identify predictors for VA loss. Results: Median VA follow-up was 53 months (range, 3-213 months). At 60-month follow up, among evaluable treated eyes with favorable pretreatment BCVA, 45% retained BCVA ≥20/40, whereas among evaluable treated eyes with initially unfavorable/poor BCVA, 21% had vision ≥20/100. Among those with a favorable initial BCVA, attaining BCVA of ≥20/40 at any posttreatment time point was associated with subsequent maintenance of excellent BCVA. Multivariate analysis identified volume of the macula receiving 28GyE (P<.0001) and optic nerve (P=.0004) as independent dose-volume histogram predictors of 48-month post-PBRT vision loss among initially favorable treated eyes. Conclusions: Approximately half of PBRT-treated UM eyes with excellent pretreatment BCVA assessed at 5 years after treatment will retain excellent long-term vision. 28GyE macula and optic nerve dose-volume histogram parameters allow for rational treatment planning optimization that may lead to improved visual outcomes. The detailed temporal analysis with intermediate as well as long-term functional prognosis, and the relationship of outcomes with clinical and treatment planning parameters, is critical for informed care of UM patients before and after PBRT.« less

Risk Factors for Neovascular Glaucoma After Proton Beam Therapy of Uveal Melanoma: A Detailed Analysis of Tumor and Dose–Volume Parameters

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mishra, Kavita K., E-mail: kmishra@radonc.ucsf.edu; Daftari, Inder K.; Weinberg, Vivian

2013-10-01

Purpose: To determine neovascular glaucoma (NVG) incidence and identify contributing tumor and dosing factors in uveal melanoma patients treated with proton beam radiation therapy (PBRT). Methods and Materials: A total of 704 PBRT patients treated by a single surgeon (DHC) for uveal melanoma (1996-2010) were reviewed for NVG in our prospectively maintained database. All patients received 56 GyE in 4 fractions. Median follow-up was 58.3 months. Analyses included the Kaplan-Meier method to estimate NVG distributions, univariate log–rank tests, and Cox's proportional hazards multivariate analysis using likelihood ratio tests to identify independent risk factors of NVG among patient, tumor, and dose–volumemore » histogram parameters. Results: The 5-year PBRT NVG rate was 12.7% (95% confidence interval [CI] 10.2%-15.9%). The 5-year rate of enucleation due to NVG was 4.9% (95% CI 3.4%-7.2%). Univariately, the NVG rate increased significantly with larger tumor diameter (P<.0001), greater height (P<.0001), higher T stage (P<.0001), and closer proximity to the disc (P=.002). Dose–volume histogram analysis revealed that if >30% of the lens or ciliary body received ≥50% dose (≥28 GyE), there was a higher probability of NVG (P<.0001 for both). Furthermore, if 100% of the disc or macula received ≥28 GyE, the NVG rate was higher (P<.0001 and P=.03, respectively). If both anterior and posterior doses were above specified cut points, NVG risk was highest (P<.0001). Multivariate analysis confirmed significant independent risk factors to include tumor height (P<.0001), age (P<.0001), %disc treated to ≥50% Dose (<100% vs 100%) (P=.0007), larger tumor diameter (P=.01), %lens treated to ≥90% Dose (0 vs >0%-30% vs >30%) (P=.01), and optic nerve length treated to ≥90% Dose (≤1 mm vs >1 mm) (P=.02). Conclusions: Our current PBRT patients experience a low rate of NVG and resultant enucleation compared with historical data. The present analysis shows that tumor height, diameter, and anterior as well as posterior critical structure dose–volume parameters may be used to predict NVG risk.« less

Effects on Periocular Tissues after Proton Beam Radiation Therapy for Intraocular Tumors

PubMed Central

2018-01-01

Background To present our experience on orbital and periorbital tissue changes after proton beam radiation therapy (PBRT) in patients with intraocular tumors, apart from treatment outcomes and disease control. Methods Medical records of 6 patients with intraocular tumors who had been treated with PBRT and referred to oculoplasty clinics of two medical centers (Seoul National University Hospital and Seoul Metropolitan Government-Seoul National University Boramae Medical Center) from October 2007 to September 2014 were retrospectively reviewed. The types of adverse effects associated with PBRT, their management, and progression were analyzed. In anophthalmic patients who eventually underwent enucleation after PBRT due to disease progression, orbital volume (OV) was assessed from magnetic resonance (MR) images using the Pinnacle3 program. Results Among the six patients with PBRT history, three had uveal melanoma, and three children had retinoblastoma. Two eyes were treated with PBRT only, while the other four eyes ultimately underwent enucleation. Two eyes with PBRT only suffered from radiation dermatitis and intractable epiphora due to canaliculitis or punctal obstruction. All four anophthalmic patients showed severe enophthalmic features with periorbital hollowness. OV analysis showed that the difference between both orbits was less than 0.1 cm before enucleation, but increased to more than 2 cm3 after enucleation. Conclusion PBRT for intraocular tumors can induce various orbital and periorbital tissue changes. More specifically, when enucleation is performed after PBRT due to disease progression, significant enophthalmos and OV decrease can develop and can cause poor facial cosmesis as treatment sequelae. PMID:29651818

A Comprehensive Proteomics Analysis of the Human Iris Tissue: Ready to Embrace Postgenomics Precision Medicine in Ophthalmology?

PubMed

Murthy, Krishna R; Dammalli, Manjunath; Pinto, Sneha M; Murthy, Kalpana Babu; Nirujogi, Raja Sekhar; Madugundu, Anil K; Dey, Gourav; Subbannayya, Yashwanth; Mishra, Uttam Kumar; Nair, Bipin; Gowda, Harsha; Prasad, T S Keshava

2016-09-01

The annual economic burden of visual disorders in the United States was estimated at $139 billion. Ophthalmology is therefore one of the salient application fields of postgenomics biotechnologies such as proteomics in the pursuit of global precision medicine. Interestingly, the protein composition of the human iris tissue still remains largely unexplored. In this context, the uveal tract constitutes the vascular middle coat of the eye and is formed by the choroid, ciliary body, and iris. The iris forms the anterior most part of the uvea. It is a thin muscular diaphragm with a central perforation called pupil. Inflammation of the uvea is termed uveitis and causes reduced vision or blindness. However, the pathogenesis of the spectrum of diseases causing uveitis is still not very well understood. We investigated the proteome of the iris tissue harvested from healthy donor eyes that were enucleated within 6 h of death using high-resolution Fourier transform mass spectrometry. A total of 4959 nonredundant proteins were identified in the human iris, which included proteins involved in signaling, cell communication, metabolism, immune response, and transport. This study is the first attempt to comprehensively profile the global proteome of the human iris tissue and, thus, offers the potential to facilitate biomedical research into pathological diseases of the uvea such as Behcet's disease, Vogt Koyonagi Harada's disease, and juvenile rheumatoid arthritis. Finally, we make a call to the broader visual health and ophthalmology community that proteomics offers a veritable prospect to obtain a systems scale, functional, and dynamic picture of the eye tissue in health and disease. This knowledge is ultimately pertinent for precision medicine diagnostics and therapeutics innovation to address the pressing needs of the 21st century visual health.

Anti-inflammatory effect of Heliotropium indicum Linn on lipopolysaccharide-induced uveitis in New Zealand white rabbits.

PubMed

Kyei, Samuel; Koffuor, George Asumeng; Ramkissoon, Paul; Ameyaw, Elvis Ofori; Asiamah, Emmanuel Akomanin

2016-01-01

To investigate the anti-inflammatory effect of an aqueous whole plant extract of Heliotropium indicum (HIE) on endotoxin-induced uveitis in New Zealand white rabbits. Clinical signs of uveitis including flares, iris hyperemia and miosis, were sought for and scored in 1.0 mg/kg lipopolysaccharide (LPS) -induced uveitic rabbits treated orally with HIE (30-300 mg/kg), prednisolone (30 mg/kg), or normal saline (10 mL/kg). The number of polymorphonuclear neutrophils infiltrating, the protein concentration, as well as levels of tumor necrosis factor-α (TNF-α), prostaglandin E2 (PGE2), and monocyte chemmoattrant protein-1 (MCP-1) in the aqueous humor after the various treatments were also determined. A histopathological study of the anterior uveal was performed. The extract and prednisolone-treatment significantly reduced (P≤0.001) both the clinical scores of inflammation (1.0-1.8 compared to 4.40±0.40 in the normal saline-treated rabbits) and inflammatory cells infiltration. The level of protein, and the concentrations of TNF-α, PGE2 and MCP-1 in the aqueous humor were also significantly reduced (P≤0.001). Histopathological studies showed normal uveal morphology in the HIE and prednisolone-treated rabbits while normal saline-treated rabbits showed marked infiltration of inflammatory cells. The HIE exhibits anti-inflammatory effect on LPS-induced uveitis possibly by reducing the production of pro-inflammatory mediators.

Ion therapy for uveal melanoma in new human eye phantom based on GEANT4 toolkit

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mahdipour, Seyed Ali; Mowlavi, Ali Asghar, E-mail: amowlavi@hsu.ac.ir; ICTP, Associate Federation Scheme, Medical Physics Field, Trieste

Radiotherapy with ion beams like proton and carbon has been used for treatment of eye uveal melanoma for many years. In this research, we have developed a new phantom of human eye for Monte Carlo simulation of tumors treatment to use in GEANT4 toolkit. Total depth−dose profiles for the proton, alpha, and carbon incident beams with the same ranges have been calculated in the phantom. Moreover, the deposited energy of the secondary particles for each of the primary beams is calculated. The dose curves are compared for 47.8 MeV proton, 190.1 MeV alpha, and 1060 MeV carbon ions that havemore » the same range in the target region reaching to the center of tumor. The passively scattered spread-out Bragg peak (SOBP) for each incident beam as well as the flux curves of the secondary particles including neutron, gamma, and positron has been calculated and compared for the primary beams. The high sharpness of carbon beam's Bragg peak with low lateral broadening is the benefit of this beam in hadrontherapy but it has disadvantages of dose leakage in the tail after its Bragg peak and high intensity of neutron production. However, proton beam, which has a good conformation with tumor shape owing to the beam broadening caused by scattering, can be a good choice for the large-size tumors.« less

BRD4-targeted therapy induces Myc-independent cytotoxicity in Gnaq/11-mutatant uveal melanoma cells.

PubMed

Ambrosini, Grazia; Sawle, Ashley D; Musi, Elgilda; Schwartz, Gary K

2015-10-20

Uveal melanoma (UM) is an aggressive intraocular malignancy with limited therapeutic options. Both primary and metastatic UM are characterized by oncogenic mutations in the G-protein alpha subunit q and 11. Furthermore, nearly 40% of UM has amplification of the chromosomal arm 8q and monosomy of chromosome 3, with consequent anomalies of MYC copy number. Chromatin regulators have become attractive targets for cancer therapy. In particular, the bromodomain and extra-terminal (BET) inhibitor JQ1 has shown selective inhibition of c-Myc expression with antiproliferative activity in hematopoietic and solid tumors. Here we provide evidence that JQ1 had cytotoxic activity in UM cell lines carrying Gnaq/11 mutations, while in cells without the mutations had little effects. Using microarray analysis, we identified a large subset of genes modulated by JQ1 involved in the regulation of cell cycle, apoptosis and DNA repair. Further analysis of selected genes determined that the concomitant silencing of Bcl-xL and Rad51 represented the minimal requirement to mimic the apoptotic effects of JQ1 in the mutant cells, independently of c-Myc. In addition, administration of JQ1 to mouse xenograft models of Gnaq-mutant UM resulted in significant inhibition of tumor growth.Collectively, our results define BRD4 targeting as a novel therapeutic intervention against UM with Gnaq/Gna11 mutations.

Tumour regression of uveal melanoma after ruthenium-106 brachytherapy or stereotactic radiotherapy with gamma knife or linear accelerator.

PubMed

Georgopoulos, Michael; Zehetmayer, Martin; Ruhswurm, Irene; Toma-Bstaendig, Sabine; Ségur-Eltz, Nikolaus; Sacu, Stefan; Menapace, Rupert

2003-01-01

This study assesses differences in relative tumour regression and internal acoustic reflectivity after 3 methods of radiotherapy for uveal melanoma: (1) brachytherapy with ruthenium-106 radioactive plaques (RU), (2) fractionated high-dose gamma knife stereotactic irradiation in 2-3 fractions (GK) or (3) fractionated linear-accelerator-based stereotactic teletherapy in 5 fractions (Linac). Ultrasound measurements of tumour thickness and internal reflectivity were performed with standardised A scan pre-operatively and 3, 6, 9, 12, 18, 24 and 36 months postoperatively. Of 211 patients included in the study, 111 had a complete 3-year follow-up (RU: 41, GK: 37, Linac: 33). Differences in tumour thickness and internal reflectivity were assessed with analysis of variance, and post hoc multiple comparisons were calculated with Tukey's honestly significant difference test. Local tumour control was excellent with all 3 methods (>93%). At 36 months, relative tumour height reduction was 69, 50 and 30% after RU, GK and Linac, respectively. In all 3 treatment groups, internal reflectivity increased from about 30% initially to 60-70% 3 years after treatment. Brachytherapy with ruthenium-106 plaques results in a faster tumour regression as compared to teletherapy with gamma knife or Linac. Internal reflectivity increases comparably in all 3 groups. Besides tumour growth arrest, increasing internal reflectivity is considered as an important factor indicating successful treatment. Copyright 2003 S. Karger AG, Basel

Alterations in expression of mucin, tenascin-c and syndecan-1 in the conjunctiva following retinal surgery and plaque radiotherapy.

PubMed

Heimann, H; Coupland, S E; Gochman, R; Hellmich, M; Foerster, M H

2001-07-01

Disturbances of the ocular tear film layer and dry eye symptoms are common complications following retinal surgery and ocular tumour therapy. Examined were the histopathological changes of the conjunctiva following posterior segment surgery and plaque radiotherapy. Biopsy specimens of the superior bulbar conjunctiva were obtained during cataract surgery between 2 weeks and 7 years following vitrectomy (n=92) or plaque radiotherapy for uveal melanoma (n=20) and from control subjects without previous ocular surgery (n=29). These were examined using conventional histology (HE, PAS, Van Gieson) and immunochemistry [APAAP, using antibodies directed against MUC1, MUC5AC, syndecan-1 and tenascin-C (TN-C)]. The histopathological changes were graded and statistical analysis was performed using Wilcoxon and Kruskal-Wallis rank sum tests. Conjunctival specimens of patients following vitrectomy or plaque radiotherapy for uveal melanoma demonstrated increased epithelial stratification, a significant decrease in the number of PAS- and MUC5AC-positive goblet cells, and distributional changes in expression of MUC1, syndecan- and TN-C within conjunctival epithelium or stroma. These alterations - in particular the goblet cell reduction and stromal fibrosis - were most prominent in those patients who had undergone radiotherapy. Posterior segment surgery can lead to morphological alterations of the conjunctiva and distributional changes in ocular mucins, which may cause dry eye symptoms.

The Role of Nitric Oxide in Modulating Retinal, Choroidal, and Anterior Uveal Blood Flows in the Domestic Piglet

DTIC Science & Technology

1993-11-17

that are substituted at the quanidino nitrogens are competitive Inhibitors of nitric ox!de synthase in a dOS&<lependent and enantiomerically specific...by nitric oxide. We were able to reduce basal chorc»dal and ante nor wea blood 99 flOYI by 47% and 43%, respectively, by enantiomeric specific...Atthough competitive blockade of NOS by L-NAME is enantiomerically specKle, It Is possible that there Is an allosteric binding site for these arginine

[Technique for removing donor sclera by eyeball extrusion].

PubMed

González Del Valle, F; Álvarez Portela, M; Lara Medina, J; Celis Sánchez, J; Barrajón Rodríguez, A

2012-09-01

To describe a surgery technique for removing donor sclera tissue after corneo-scleral button excision. The extrusion technique is easy to perform. It allows the complete scleral extraction its total clean up to be performed, as well as making easier to isolate the retina and uveal tissue. This technique could have an important role in the anatomical and morphological study of ocular structures. Copyright © 2011 Sociedad Española de Oftalmología. Published by Elsevier Espana. All rights reserved.

Elucidating the role of the FoxO3a transcription factor in the IGF-1-induced migration and invasion of uveal melanoma cancer cells.

PubMed

Yan, Fengxia; Liao, Rifang; Farhan, Mohd; Wang, Tinghuai; Chen, Jiashu; Wang, Zhong; Little, Peter J; Zheng, Wenhua

2016-12-01

Uveal melanoma (UM) is the most common primary intraocular malignant tumor of adults. It has high mortality rate due to liver metastasis. However, the epidemiology and pathogenesis of liver metastasis in UM are not elucidated and there is no effective therapy available for preventing the development of this disease. IGF-1 is a growth factor involved in cell proliferation, malignant transformation and inhibition of apoptosis. In previous report, IGF-1 receptor was found to be highly expressed in UM and this was related to tumor prognosis. FoxO3a is a Forkhead box O (FOXO) transcription factor and a downstream target of the IGF-1R/PI3K/Akt pathway involved in a number of physiological and pathological processes including cancer. However, the role of FoxO3a in UM is unknown. In the present study, we investigated fundamental mechanisms in the growth, migration and invasion of UM and the involvement of FoxO3a. IGF-1 increased the cell viability, invasion, migration and S-G2/M cell cycle phase accumulation of UM cells. Western blot analysis showed that IGF-1 led to activation of Akt and concomitant phosphorylation of FoxO3a. FoxO3a phosphorylation was associated with its translocation into the cytoplasm from the nucleus and its functional inhibition led to the inhibition of expression of Bim and p27, but an increase in the expression of Cyclin D1. The effects of IGF-1 on UM cells were reversed by LY294002 (a PI3K inhibitor) or Akt siRNA, and the overexpression of FoxO3a also attenuated basal invasion and migration of UM. Taken all together, these results suggest that inhibition of FoxO3a by IGF-1 via the PI3K/Akt pathway has an important role in IGF-1 induced proliferation and invasion of UM cells. These findings also support FoxO3a and IGF signaling may represent a valid target for investigating the development of new strategies for the treatment and prevention of the pathology of UM. Copyright © 2016. Published by Elsevier Masson SAS.

Percutaneous Hepatic Perfusion (PHP) with Melphalan as a Treatment for Unresectable Metastases Confined to the Liver.

PubMed

de Leede, Eleonora M; Burgmans, Mark C; Martini, Christian H; Tijl, Fred G J; van Erkel, Arian R; Vuyk, Jaap; Kapiteijn, Ellen; Verhoef, Cornelis; van de Velde, Cornelis J H; Vahrmeijer, Alexander L

2016-07-31

Unresectable liver metastases of colorectal cancer can be treated with systemic chemotherapy, aiming to limit the disease, extend survival or turn unresectable metastases into resectable ones. Some patients however, suffer from side effects or progression under systemic treatment. For patients with metastasized uveal melanoma there are no standard systemic therapy options. For patients without extrahepatic disease, isolated liver perfusion (IHP) may enable local disease control with limited systemic side effects. Previously, this was performed during open surgery with satisfying results, but morbidity and mortality related to the open procedure, prohibited a widespread application. Therefore, percutaneous hepatic perfusion (PHP) with simultaneous chemofiltration was developed. Besides decreasing morbidity and mortality, this procedure can be repeated, hopefully leading to a higher response rate and improved survival (by local control of disease). During PHP, catheters are placed in the proper hepatic artery, to infuse the chemotherapeutic agent, and in the inferior caval vein to aspirate the chemosaturated blood returning through the hepatic veins. The caval vein catheter is a double balloon catheter that prohibits leakage into the systemic circulation. The blood returning from the hepatic veins is aspirated through the catheter fenestrations and then perfused through an extra-corporeal filtration system. After filtration, the blood is returned to the patient by a third catheter in the right internal jugular vein. During PHP a high dose of melphalan is infused into the liver, which is toxic and would lead to life threatening complications when administered systemically. Because of the significant hemodynamic instability resulting from the combination of caval vein occlusion and chemofiltration, hemodynamic monitoring and hemodynamic support is of paramount importance during this complex procedure.

Anti-inflammatory effect of Heliotropium indicum Linn on lipopolysaccharide-induced uveitis in New Zealand white rabbits

PubMed Central

Kyei, Samuel; Koffuor, George Asumeng; Ramkissoon, Paul; Ameyaw, Elvis Ofori; Asiamah, Emmanuel Akomanin

2016-01-01

AIM To investigate the anti-inflammatory effect of an aqueous whole plant extract of Heliotropium indicum (HIE) on endotoxin-induced uveitis in New Zealand white rabbits. METHODS Clinical signs of uveitis including flares, iris hyperemia and miosis, were sought for and scored in 1.0 mg/kg lipopolysaccharide (LPS) -induced uveitic rabbits treated orally with HIE (30-300 mg/kg), prednisolone (30 mg/kg), or normal saline (10 mL/kg). The number of polymorphonuclear neutrophils infiltrating, the protein concentration, as well as levels of tumor necrosis factor-α (TNF-α), prostaglandin E2 (PGE2), and monocyte chemmoattrant protein-1 (MCP-1) in the aqueous humor after the various treatments were also determined. A histopathological study of the anterior uveal was performed. RESULTS The extract and prednisolone-treatment significantly reduced (P≤0.001) both the clinical scores of inflammation (1.0-1.8 compared to 4.40±0.40 in the normal saline-treated rabbits) and inflammatory cells infiltration. The level of protein, and the concentrations of TNF-α, PGE2 and MCP-1 in the aqueous humor were also significantly reduced (P≤0.001). Histopathological studies showed normal uveal morphology in the HIE and prednisolone-treated rabbits while normal saline-treated rabbits showed marked infiltration of inflammatory cells. CONCLUSION The HIE exhibits anti-inflammatory effect on LPS-induced uveitis possibly by reducing the production of pro-inflammatory mediators. PMID:27162723

Vasculogenic Mimicry and Tumor Angiogenesis

PubMed Central

Folberg, Robert; Hendrix, Mary J. C.; Maniotis, Andrew J.

2000-01-01

Tumors require a blood supply for growth and hematogenous dissemination. Much attention has been focused on the role of angiogenesis—the recruitment of new vessels into a tumor from pre-existing vessels. However, angiogenesis may not be the only mechanism by which tumors acquire a microcirculation. Highly aggressive and metastatic melanoma cells are capable of forming highly patterned vascular channels in vitro that are composed of a basement membrane that stains positive with the periodic acid-Schiff (PAS) reagent in the absence of endothelial cells and fibroblasts. These channels formed in vitro are identical morphologically to PAS-positive channels in histological preparations from highly aggressive primary uveal melanomas, in the vertical growth phase of cutaneous melanomas, and in metastatic uveal and cutaneous melanoma. The generation of microvascular channels by genetically deregulated, aggressive tumor cells was termed “vasculogenic mimicry” to emphasize their de novo generation without participation by endothelial cells and independent of angiogenesis. Techniques designed to identify the tumor microcirculation by the staining of endothelial cells may not be applicable to tumors that express vasculogenic mimicry. Although it is not known if therapeutic strategies targeting endothelial cells will be effective in tumors whose blood supply is formed by tumor cells in the absence of angiogenesis, the biomechanical and molecular events that regulate vasculogenic mimicry provide opportunities for the development of novel forms of tumor-targeted treatments. The unique patterning characteristic of vasculogenic mimicry provides an opportunity to design noninvasive imaging techniques to detect highly aggressive neoplasms and their metastases. PMID:10666364

Melanocytic Ophthalmic Neoplasms of the Domestic Veterinary Species: A Review.

PubMed

Wang, Annie L; Kern, Thomas

2015-12-01

Melanocytic neoplasms in veterinary species occur in various ophthalmic locations including the eyelid, conjunctiva, cornea, sclera, anterior and posterior uvea, and orbit. Histology usually provides the definitive diagnosis for melanocytic ocular neoplasias. The degree of tissue invasiveness and anaplastic cellular characteristics are more reliable indicators of biological behavior than is mitotic index in most ophthalmic melanocytic tumors. Melanocytic neoplasias of the eyelid are predominantly benign in canines and equines, though in felines, there is the potential for metastasis, especially if the conjunctiva is involved. Limbal melanocytic tumors are predominantly benign in all the studied species, though there is a bimodal occurrence with this tumor type in canines, where those that appear in dogs younger than 4 years tended toward active growth, whereas those that appear in dogs older than 8 years tended to progress more slowly, and may not require therapy. The most common location for melanocytic ocular neoplasias in both canines and felines is the anterior uvea. Feline diffuse iris melanoma in particular has a higher incidence of metastasis than does canine nodular anterior uveal melanocytoma. In contrast, posterior uveal melanocytic tumors are rare in both canine and feline species and are considered benign. Orbital melanoma is rare in both canine and feline species; however, it generally carries a grave prognosis owing to its malignant nature. Knowledge of the general biological behavior and its variability among locations within the eye and between species is essential in therapeutic planning. Copyright © 2016 Elsevier Inc. All rights reserved.

Anterior segment sparing to reduce charged particle radiotherapy complications in uveal melanoma

NASA Technical Reports Server (NTRS)

Daftari, I. K.; Char, D. H.; Verhey, L. J.; Castro, J. R.; Petti, P. L.; Meecham, W. J.; Kroll, S.; Blakely, E. A.; Chatterjee, A. (Principal Investigator)

1997-01-01

PURPOSE: The purpose of this investigation is to delineate the risk factors in the development of neovascular glaucoma (NVG) after helium-ion irradiation of uveal melanoma patients and to propose treatment technique that may reduce this risk. METHODS AND MATERIALS: 347 uveal melanoma patients were treated with helium-ions using a single-port treatment technique. Using univariate and multivariate statistics, the NVG complication rate was analyzed according to the percent of anterior chamber in the radiation field, tumor size, tumor location, sex, age, dose, and other risk factors. Several University of California San Francisco-Lawrence Berkeley National Laboratory (LBNL) patients in each size category (medium, large, and extralarge) were retrospectively replanned using two ports instead of a single port. By using appropriate polar and azimuthal gaze angles or by treating patients with two ports, the maximum dose to the anterior segment of the eye can often be reduced. Although a larger volume of anterior chamber may receive a lower dose by using two ports than a single port treatment. We hypothesize that this could reduce the level of complications that result from the irradiation of the anterior chamber of the eye. Dose-volume histograms were calculated for the lens, and compared for the single and two-port techniques. RESULTS: NVG developed in 121 (35%) patients. The risk of NVG peaked between 1 and 2.5 years posttreatment. By univariate and multivariate analysis, the percent of lens in the field was strongly correlated with the development of NVG. Other contributing factors were tumor height, history of diabetes, and vitreous hemorrhage. Dose-volume histogram analysis of single-port vs. two-port techniques demonstrate that for some patients in the medium and large category tumor groups, a significant decrease in dose to the structures in the anterior segment of the eye could have been achieved with the use of two ports. CONCLUSION: The development of NVG after helium-ion irradiation is correlated to the amount of lens, anterior chamber in the treatment field, tumor height, proximity to the fovea, history of diabetes, and the development of vitreous hemorrhage. Although the influence of the higher LET deposition of helium-ions is unclear, this study suggests that by reducing the dose to the anterior segment of the eye may reduce the NVG complications. Based on this retrospective analysis of LBNL patients, we have implemented techniques to reduce the amount of the anterior segment receiving a high dose in our new series of patients treated with protons using the cyclotron at the UC Davis Crocker Nuclear Laboratory (CNL).

CATANA protontherapy facility: The state of art of clinical and dosimetric experience

NASA Astrophysics Data System (ADS)

Cuttone, G.; Cirrone, G. A. P.; Di Franco, G.; La Monaca, V.; Lo Nigro, S.; Ott, J.; Pittera, S.; Privitera, G.; Raffaele, L.; Reibaldi, A.; Romano, F.; Sabini, M. G.; Salamone, V.; Sanfilippo, M.; Spatola, C.; Valastro, L. M.

2011-07-01

After nine years of activity, about 220 patients have been treated at the CATANA Eye Protontherapy facility. A 62MeV proton beam produced by a Superconducting Cyclotron is dedicated to radiotherapy of eye lesions, as uveal melanomas. Research and development work has been done to test different dosimetry devices to be used for reference and relative dosimetry, in order to achieve dose delivering accuracy. The follow-up results demonstrated the efficacy of proton beams and encouraged us in our activity in the fight against cancer.

BAP1 and Cancer

PubMed Central

Carbone, Michele; Yang, Haining; Pass, Harvey I.; Krausz, Thomas; Testa, Joseph R.; Gaudino, Giovanni

2013-01-01

Preface BAP1 is a deubiquitylase that is found associated with multi-protein complexes that regulate key cellular pathways, including the cell cycle, cellular differentiation, cell death, gluconeogenesis and the DNA damage response (DDR). Recent findings indicate that germline BAP1 mutations cause a novel cancer syndrome, characterized, at least in the affected families studied so far, by the onset at an early age of benign melanocytic skin tumours with mutated BAP1, and later in life by a high incidence of mesothelioma, uveal melanoma, cutaneous melanoma and possibly additional cancers. PMID:23550303

Melanoma: Genetic Abnormalities, Tumor Progression, Clonal Evolution and Tumor Initiating Cells.

PubMed

Testa, Ugo; Castelli, Germana; Pelosi, Elvira

2017-11-20

Melanoma is an aggressive neoplasia issued from the malignant transformation of melanocytes, the pigment-generating cells of the skin. It is responsible for about 75% of deaths due to skin cancers. Melanoma is a phenotypically and molecularly heterogeneous disease: cutaneous, uveal, acral, and mucosal melanomas have different clinical courses, are associated with different mutational profiles, and possess distinct risk factors. The discovery of the molecular abnormalities underlying melanomas has led to the promising improvement of therapy, and further progress is expected in the near future. The study of melanoma precursor lesions has led to the suggestion that the pathway of tumor evolution implies the progression from benign naevi, to dysplastic naevi, to melanoma in situ and then to invasive and metastatic melanoma. The gene alterations characterizing melanomas tend to accumulate in these precursor lesions in a sequential order. Studies carried out in recent years have, in part, elucidated the great tumorigenic potential of melanoma tumor cells. These findings have led to speculation that the cancer stem cell model cannot be applied to melanoma because, in this malignancy, tumor cells possess an intrinsic plasticity, conferring the capacity to initiate and maintain the neoplastic process to phenotypically different tumor cells.

Melanoma: Genetic Abnormalities, Tumor Progression, Clonal Evolution and Tumor Initiating Cells

PubMed Central

Castelli, Germana; Pelosi, Elvira

2017-01-01

Melanoma is an aggressive neoplasia issued from the malignant transformation of melanocytes, the pigment-generating cells of the skin. It is responsible for about 75% of deaths due to skin cancers. Melanoma is a phenotypically and molecularly heterogeneous disease: cutaneous, uveal, acral, and mucosal melanomas have different clinical courses, are associated with different mutational profiles, and possess distinct risk factors. The discovery of the molecular abnormalities underlying melanomas has led to the promising improvement of therapy, and further progress is expected in the near future. The study of melanoma precursor lesions has led to the suggestion that the pathway of tumor evolution implies the progression from benign naevi, to dysplastic naevi, to melanoma in situ and then to invasive and metastatic melanoma. The gene alterations characterizing melanomas tend to accumulate in these precursor lesions in a sequential order. Studies carried out in recent years have, in part, elucidated the great tumorigenic potential of melanoma tumor cells. These findings have led to speculation that the cancer stem cell model cannot be applied to melanoma because, in this malignancy, tumor cells possess an intrinsic plasticity, conferring the capacity to initiate and maintain the neoplastic process to phenotypically different tumor cells. PMID:29156643

Results of a Phase II Study to Evaluate the Efficacy of Docetaxel and Carboplatin in Metastatic Malignant Melanoma Patients Who Failed First-Line Therapy Containing Dacarbazine.

PubMed

Lee, Choong-kun; Jung, Minkyu; Choi, Hye Jin; Kim, Hye Ryun; Kim, Hyo Song; Roh, Mi Ryung; Ahn, Joong Bae; Chung, Hyun Cheol; Heo, Su Jin; Rha, Sun Young; Shin, Sang Joon

2015-10-01

There is no standard second-line regimen for malignant melanoma patients with disease progression after first-line chemotherapy, and platinum-alkylating agents combined with paclitaxel have shown modest efficacy. We conducted a phase II, open-label, single-arm study to test the efficacy of docetaxel combined with carboplatin for malignant melanoma patients who failed previous treatment with dacarbazine. Intravenous docetaxel (35 mg/m(2) on days 1 and 8 of each cycle) and carboplatin (area under the curve 3 on days 1 and 8 of each cycle) was administered every 21 days. Primary end point was objective response rate (ORR). Thirty patients were enrolled in the study, and the median follow-up duration was 19.8 months. Among 25 per-protocol patients, there were three responders (1 with complete response and 2 with partial response) and 17 stable disease patients (ORR, 12.0%). Among the per-protocol population, the median progression-free survival (PFS) was 4.3 months and the median overall survival (OS) was 9.6 months. Uveal melanoma patients (n=9) showed the best prognosis compared to other subtypes (median PFS, 7.6 months; OS, 9.9 months). The most common grade 3 or 4 adverse event was neutropenia (n=15, 50.0%). Docetaxel combined with carboplatin showed association with an acceptable safety profile and overall efficacy for patients with malignant melanoma who had progressed on chemotherapy containing dacarbazine.

Cataract Avoidance With Proton Therapy in Ocular Melanomas.

PubMed

Thariat, Juliette; Jacob, Sophie; Caujolle, Jean-Pierre; Maschi, Celia; Baillif, Stéphanie; Angellier, Gaelle; Mathis, Thibaud; Rosier, Laurence; Carnicer, Adela; Hérault, Joel; Salleron, Julia

2017-10-01

The lens is a radiosensitive organ. Any dose of cephalic irradiation can give rise to radiation-induced cataracts. Contrary to other forms of radiotherapy, proton therapy (PT) can spare all or part of the lens due to accurate dose deposition. We investigated whether a lens-sparing approach was relevant to avoid cataracts in uveal melanoma patients. Patients were referred for PT from onco-ophthalmologists of private and academic institutions. Patients without preexisting cataracts or implants were entered in a prospective database. Dose thresholds responsible for cataracts were investigated in volumes of lens or lens periphery. Lens opacifications and de novo vision-impairing cataracts (VICs) had biannual follow up by ophthalmologists blinded to lens dose. Correlations between dose-volume relationships and VICs were assessed using univariate/multivariate regressions. Between 1991 and 2015, 1696 uveal melanoma patients were consecutively treated with PT. After a median follow up of 48 months, 14.4% and 8.7% of patients had cataracts and VIC within median times of 19 and 28 months, respectively. Median values of mean lens and lens periphery doses were 1.1 (radiobiologically effective [RBE] dose in photon-equivalent grays [GyRBE]) and 6.5 GyRBE, respectively. The lens received no dose in 25% of the patients. At an irradiated lens volume of ≤5%, there was no significantly increased risk for VIC below a dose of 10 GyRBE. A lens-sparing approach is feasible and results not only in reduced need for cataract surgery but also in better fundus-based tumor control. Reassessment of radioprotection rules for lens dose thresholds may follow.

Ultraviolet-B phototoxicity and hypothetical photomelanomagenesis: intraocular and crystalline lens photoprotection.

PubMed

Mainster, Martin A; Turner, Patricia L

2010-04-01

Ultraviolet-B (UV-B) radiation can cause phototoxic macular injuries in young people who have been sunbathing but not sungazing and in welders. Welders have a reportedly increased risk of uveal melanoma. We analyze phakic and pseudophakic risks for solar and welding arc UV-B exposure. Optical radiation measurement, analysis, and perspective. Spectral transmittances were measured for UV-transmitting, UV-blocking, and blue-blocking intraocular lenses (IOLs). The photoprotective performances of crystalline and intraocular lenses were analyzed using relevant epidemiologic and laboratory data and action spectra for acute retinal phototoxicity and melanoma photocarcinogenesis. Crystalline lens UV-B retinal protection is deficient in children and young adults, increasing their potential susceptibility to acute retinal phototoxicity and hypothetical photomelanomagenesis. UV-B radiation has sufficient energy/photon to induce primary melanomagenic DNA lesions, unlike blue light or UV-A radiation. UV-blocking and blue-blocking IOLs have negligible UV-B transmittance. UV-transmitting IOL transmittance of UV-B radiation is equivalent to that of a 15-year-old crystalline lens. If optical radiation exposure is responsible for welders' increased risk of uveal melanoma, then UV-B radiation is the most probable causative agent and spectacle wear is a potential confounding factor in epidemiologic studies of ocular melanoma. Welders under 30 years of age are at greater risk for welding maculopathy than older welders. Children, adults under 30 years of age, and pseudophakic individuals with UV-transmitting IOLs should wear sunglasses in bright environments because of the UV-B window in their crystalline lenses or IOLs. Copyright 2010 Elsevier Inc. All rights reserved.

Proton beam irradiation: a safe procedure in post-equatorial extraocular extension from uveal melanoma.

PubMed

Seibel, Ira; Riechardt, Aline I; Erb-Eigner, Katharina; Böker, Alexander; Cordini, Dino; Heufelder, Jens; Joussen, Antonia M

2018-04-12

This study was performed to show long-term outcomes concerning metastasis rates and local recurrence rates after primary proton beam therapy in uveal melanoma with posterior extraocular extension (EOE) with the main focus on optic nerve invasion. Retrospective case series METHODS: All patients treated with primary proton beam therapy for choroidal or ciliary body melanoma with posterior EOE between July 1998 and August 2010 were included. EOE was either detected upon sonography at primary examination or during the surgical application of tantalum clips onto the sclera. Ultrasound was performed in each patient before surgery, and if EOE was detected, a magnetic resonance imaging (MRI) scan was performed to confirm EOE. All patients with tumors exceeding 6 mm in thickness or abutting the optic disc received a 1.5 Tesla MRI scan after clip surgery. To asses EOE during follow-up, either ultrasound examinations or-if initially detected only by MRI-MRI scans were performed during follow-up. A total of 27 patients underwent primary proton beam therapy. The EOE was separated into 3 growth types: Optic nerve infiltration in 10 patients, vortex vein infiltration in 9 patients, and transscleral growth post-equatorially in 8 patients. No local recurrences were found during the overall median follow-up of 80 months (11-168 months). Metastasis rates correlated with AJCC stages but not EOE volume. This study shows that posterior EOE can safely be treated by proton beam therapy, even if the optic nerve is infiltrated. MRI enables safe detection of optic nerve invasion. Copyright © 2018 Elsevier Inc. All rights reserved.

Attenuation of iodine 125 radiation with vitreous substitutes in the treatment of uveal melanoma.

PubMed

Oliver, Scott C N; Leu, Min Y; DeMarco, John J; Chow, Philip E; Lee, Steve P; McCannel, Tara A

2010-07-01

To demonstrate attenuation of radiation from iodine 125 ((125)I) to intraocular structures using liquid vitreous substitutes. Four candidate vitreous substitutes were tested for attenuation using empirical measurement and theoretical calculation. In vitro and ex vivo cadaveric dosimetry measurements were obtained with lithium fluoride thermoluminescent dosimeters to demonstrate the attenuation effect of vitreous substitution during (125)I simulated plaque brachytherapy. Theoretical dosimetry calculations were based on Monte Carlo simulation. In a cylindrical phantom at a 17-mm depth, liquid vitreous substitutes as compared with saline showed significant reduction of radiation penetration (48% for 1000-centistoke [cSt] silicone oil [polydimethyl-n-siloxane], 47% for 5000-cSt silicone oil [polydimethyl-n-siloxane], 40% for heavy oil [perfluorohexyloctane/polydimethyl-n-siloxane], and 35% for perfluorocarbon liquid [perfluoro-n-octane]). Human cadaveric ex vivo measurements demonstrated a 1000-cSt silicone oil to saline dose ratio of 35%, 52%, 55%, and 48% at arc lengths of 7.6, 10.6, 22.3, and 28.6 mm from the plaque edge, respectively, along the surface of the globe. Monte Carlo simulation of a human globe projected attenuation as high as 57% using 1000-cSt silicone oil. Intraocular vitreous substitutes including silicone oil, heavy oil, and perfluorocarbon liquid attenuate the radiation dose from (125)I. Cadaveric ex vivo measurements and Monte Carlo simulation both demonstrate radiation attenuation using 1000-cSt silicone oil at distances corresponding to vital ocular structures. Clinical Relevance Attenuation of radiation with silicone oil endotamponade in the treatment of uveal melanoma may significantly reduce radiation-induced injury to vital ocular structures.

Genetic heterogeneity in uveal melanoma assessed by multiplex ligation-dependent probe amplification.

PubMed

Dopierala, Justyna; Damato, Bertil E; Lake, Sarah L; Taktak, Azzam F G; Coupland, Sarah E

2010-10-01

To determine intratumor genetic heterogeneity in uveal melanoma (UM) by multiplex ligation-dependent probe amplification (MLPA) in formalin-fixed, paraffin-embedded (FFPE) tumor tissues. DNA was extracted from whole tumor sections and from two to nine different areas microdissected from 32 FFPE UMs. Thirty-one loci on chromosomes 1, 3, 6, and 8 were tested with MLPA for copy number changes. The tumor was considered heterogeneous at a locus if (1) the difference in dosage quotients (DQs) of any two areas was 0.2 or more, and (2) the DQs of the areas belonged to different ranges. Comparison of MLPA data obtained from microdissected areas of the UMs showed heterogeneity in 1 to 26 examined loci in 24 (75%) tumors, with only 25% of the tumors being homogeneous. Intratumor heterogeneity of 3p12.2, 6p21.2, and 8q11.23 was most common, occurring in >30% of the UMs. Gains of chromosome 3 were observed in four UMs, with three of these tumors showing the highest degree of heterogeneity. Copy number variation was associated with differences in tumor cell type, but not with differences in tumor pigmentation or reactive inflammation. UMs with genetic heterogeneity across multiple sample sites showed equivocal MLPA results when the whole tumor section was examined. These results suggest that different clones dilute MLPA results. Heterogeneity of chromosomal abnormalities of chromosomes 1, 3, 6, and 8 is present in most UMs. This heterogeneity causes equivocal MLPA results. One random tumor sample may not be representative of the whole tumor and, therefore, may be insufficient for prognostic testing.

Resistance of uveal melanoma to the interstrand cross-linking agent mitomycin C is associated with reduced expression of CYP450R

PubMed Central

Gravells, P; Hoh, L; Canovas, D; Rennie, I G; Sisley, K; Bryant, H E

2011-01-01

Background: Uveal melanoma (UM) is the most common primary intraocular tumour of adults, frequently metastasising to the liver. Hepatic metastases are difficult to treat and are mainly unresponsive to chemotherapy. To investigate why UM are so chemo-resistant we explored the effect of interstrand cross-linking agents mitomycin C (MMC) and cisplatin in comparison with hydroxyurea (HU). Methods: Sensitivity to MMC, cisplatin and HU was tested in established UM cell lines using clonogenic assays. The response of UM to MMC was confirmed in MTT assays using short-term cultures of primary UM. The expression of cytochrome P450 reductase (CYP450R) was analysed by western blotting, and DNA cross-linking was assessed using COMET analysis supported by γ-H2AX foci formation. Results: Both established cell lines and primary cultures of UM were resistant to the cross-linking agent MMC (in each case P<0.001 in Student's t-test compared with controls). In two established UM cell lines, DNA cross-link damage was not induced by MMC (in both cases P<0.05 in Students's t-test compared with damage induced in controls). In all, 6 out of 6 UMs tested displayed reduced expression of the metabolising enzyme CYP450R and transient expression of CYP450R increased MMC sensitivity of UM. Conclusion: We suggest that reduced expression of CYP450R is responsible for MMC resistance of UM, through a lack of bioactivation, which can be reversed by complementing UM cell lines with CYP450R. PMID:21386838

Uptake and metabolism of boronophenylalanine in human uveal melanoma cells in culture Relevance to boron neutron capture therapy of cancer cells.

PubMed

Belkhou, R; Abbé, J C; Pham, P; Jasner, N; Sahel, J; Dreyfus, H; Moutaouakkil, M; Massarelli, R

1995-06-01

The transport of boronophenylalanine (BPA) and its metabolic fate have been studied in a human uveal melanoma cell line isolated from a primary enucleated tumor. The boronated compound was rapidly incorporated into the cells reaching a peak of incorporation in two hours. This was followed by a trough between 10 and 24 hours and by an increase thereafter. The analogy with the amino acids phenylalanine (Phe) and tyrosine (Tyr) was studied in competition experiments incubating cultures of cell line MK-T, isolated in this laboratory, with [(3)H]-Phe and [(125)I]-Tyr, in the presence or absence of various concentrations of BPA, between 0 and 5 min. The presence of BPA severely reduced the uptake of both amino acids. The kinetics of the transport of [(3)H]-Phe and [(3)H]-Tyr in the presence of BPA, measured after 10 sec of incubation, showed that the boronated compound exerted a competitive inhibition on both transport systems. The intracellular metabolism of BPA was followed by measuring boron concentration (measured with Ionization Coupled Mass Spectrometry) in subcellular fractions and after membrane extraction by the detergent Triton X-100. The results showed that BPA remained in the supernatant and was not metabolized into macromolecules. These results and the relative absence of melanine in these cells, as observed by electron microscopy, suggest that BPA may be actively transported into melanoma cells but not metabolized. The results may have a relevance in studies on Boron Neutron Capture Therapy.

Clinical, histopathological and immunohistochemical characterization of a novel equine ocular disorder: heterochromic iridocyclitis with secondary keratitis in adult horses.

PubMed

Pinto, Nelson I; McMullen, Richard J; Linder, Keith E; Cullen, John M; Gilger, Brian C

2015-11-01

To describe the clinical, histopathologic and immunohistochemical characteristics of an equine ocular inflammatory disease resulting in anterior uveitis and corneal endothelial inflammation associated with iris pigment dispersion and retrocorneal fibrous membrane (RFM) formation. Retrospective study. Sixteen horses with evidence of pigmented keratic precipitates (KPs), corneal edema, and/or iris depigmentation. Information collected from the medical records included signalment, clinical signs, prereferral treatment duration and response to therapy, ophthalmic examination findings, postreferral treatment, response to therapy, and outcome. Twenty-one eyes from 16 horses were affected. Age ranged between 9 and 25 years (Average 16.1 years). Blepharospasm, epiphora, and/or corneal opacification were the first clinical signs noted. At the time of referral pigmented KPs, corneal edema, iridal depigmentation, and retrocorneal membranes were commonly seen. Treatment included topical and/or systemic anti-inflammatories and antibiotics with variable response. Reduction or cessation of anti-inflammatory therapy resulted in worsening of clinical signs and disease progression. Eight eyes ultimately required enucleation. Histopathology changes include iridal pigment loss and dispersion, RFM formation, and keratitis. Variable degrees of lymphoplasmacytic inflammation were dominated by T-cells within the corneal stroma, RFM, iris, and ciliary body with occasional multinucleated giant cells. Heterochromic iridocyclitis with secondary keratitis (HIK) is characterized by uveal inflammation with pigment dispersion and suspected corneal endothelial dysfunction. Horses being treated for HIK require diligent and frequent follow-up examinations in combination with aggressive local immune suppression to control the disease. However, HIK may not respond to therapy and enucleation may ultimately be required to ensure the horse's comfort. © 2014 American College of Veterinary Ophthalmologists.

WE-FG-BRA-10: Radiodosimetry of a Novel Alpha Particle Therapy Targeted to Uveal Melanoma: Absorbed Dose to Organs in Mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tichacek, Christopher J.; Tafreshi, Narges K.; Budzevich, Mikalai M.

Purpose: The melanocortin-1 receptor (MC1R) is expressed in 94% of uveal melanomas and is described as an ideal target for this untreatable disease. MC1RL is a high affinity MC1R specific peptidomimetic ligand that can serve as a scaffold for therapeutic conjugates such as alpha particle emitting isotopes. The purpose of this study was to assess normal tissue distribution and risk as a result of using the DOTA chelator conjugated to MC1RL to deliver {sup 225}Ac: MC1RL-DOTA-{sup 225}Ac. Methods: 17 non-tumor bearing BALB/c mice were intravenously injected with the novel MC1RL-DOTA-{sup 225}Ac radiopharmaceutical with an average initial administered activity of 2.5more » µCi. After the injection, three groups of animals (6, 6, and 5 per group) were euthanized at 24, 48, and 96 hour time points. A total of 11 organs of interest were harvested at each time point including kidneys and liver. Since the emitted alpha particles from {sup 225}Ac and its daughter products are not easy to detect directly, the isomeric gamma spectra were measured instead in the tissue samples using a modified Atomlab™ Gamma Counter (Biodex Medical Systems, Inc) and converted using factors for gamma ray abundance per alpha decay. Dosimetry was performed using measured radioactivity distribution in organs and the generalized internal dosimetry schema of MIRD pamphlet #21. Results: Our calculations have shown that the maximum absorbed dose was delivered to the liver with a total of 47 cGy per 96 hour period. The average dose per kidney was calculated to be 21 cGy. Heart, brain, lung, spleen, skin doses ranged from 0.01 to 1 cGy over the same time period. All animals gained weight over the 110 day decay period and no organ damage was observed by pathology. Conclusion: Based on our results, the risk of using the MC1RL-DOTA-{sup 225}Ac compound is relatively small in terms of deterministic radiation effects. Funding Support: NIH/NCI P50CA168536-03 Skin SPORE; NIH/NCI Phase I SBIR Contract #HHSN261201500067C; Imaging and Technology Center of Excellence at Moffitt. Disclosures and Conflict of Interest: Collaboration with Modulation Therapeutics, Inc.(MTI) and has been partially funded by sub-contracts from MTI via collaboration on a NIH/NCI phase I SBIR contract.« less

The Use of Biologic Therapies in Uveitis.

PubMed

Schwartzman, Sergio; Schwartzman, Monica

2015-12-01

Therapy for autoimmune ophthalmic disease is currently evolving. The improved understanding of the abnormal immune response in the various forms of uveitis has resulted in targeted therapy. The aberrations of the immune system have been characterized by atypical cell populations, cytokine expression, and cell-cell interactions. Different patterns of cytokine expression have now been delineated in the abnormal uveal tract with exaggerated and/or abnormal expression of TNF, IL-1, IL-2, IL-6, and IL-17. The development of therapies for other conditions in which these cytokines play an important role has resulted in the availability of biological agents that have been adopted for use in the therapy for uveitis. Adalimumab and infliximab have been the best studied anti-TNF agents and indeed have now been recommended by an expert panel as first-line treatment of ocular manifestations of Behçet's disease and second-line treatment for other forms of uveitis (Levy-Clarke et al. (Ophthalmology, 2013). Other anti-TNF agents have been studied as well. Daclizumab, a monoclonal antibody directed against the IL-2 receptor, has also demonstrated utility in treating uveitis as have some of the anti-IL1 agents. Gevokizumab has been granted orphan drug designation for the treatment of resistant forms of uveitis. Therapies affecting IL-6, including tocilizumab are being studied, and available medications that block antigen presenting cell and T cell interaction such as abatacept have been reported to be effective in uveitis. Interferons as well as rituximab have also been evaluated in small studies. Although these biologic therapies have provided a larger armamentarium to treat uveitis, challenges remain. Uveitis is not a single illness; rather, it is a manifestation of many potential systemic diseases that may have very specific individual therapeutic targets. Identifying and characterizing these underlying diseases is not always achieved, and more importantly, the most effective therapies for each entity have not been defined.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Badiyan, Shahed N.; Rao, Rajesh C.; Apicelli, Anthony J.

Purpose: To assess the impact on local tumor control of intraoperative ultrasonographic plaque visualization and selective application of transpupillary thermotherapy (TTT) in the treatment of posterior uveal melanoma with iodine-125 (I-125) episcleral plaque brachytherapy (EPB). Methods and Materials: Retrospective analysis of 526 patients treated with I-125 EPB for posterior uveal melanoma. Clinical features, dosimetric parameters, TTT treatments, and local tumor control outcomes were recorded. Statistical analysis was performed using Cox proportional hazards and Kaplan-Meier life table method. Results: The study included 270 men (51%) and 256 women (49%), with a median age of 63 years (mean, 62 years; range, 16-91more » years). Median dose to the tumor apex was 94.4 Gy (mean, 97.8; range, 43.9-183.9) and to the tumor base was 257.9 Gy (mean, 275.6; range, 124.2-729.8). Plaque tilt >1 mm away from the sclera at plaque removal was detected in 142 cases (27%). Supplemental TTT was performed in 72 patients (13.7%). One or 2 TTT sessions were required in 71 TTT cases (98.6%). After a median follow-up of 45.9 months (mean, 53.4 months; range, 6-175 months), local tumor recurrence was detected in 19 patients (3.6%). Local tumor recurrence was associated with lower dose to the tumor base (P=.02). Conclusions: Ultrasound-guided plaque localization of I-125 EPB is associated with excellent local tumor control. Detection of plaque tilt by ultrasonography at plaque removal allows supplemental TTT to be used in patients at potentially higher risk for local recurrence while sparing the majority of patients who are at low risk. Most patients require only 1 or 2 TTT sessions.« less

Ipilimumab in pretreated patients with unresectable or metastatic cutaneous, uveal and mucosal melanoma.

PubMed

Alexander, Marliese; Mellor, James D; McArthur, Grant; Kee, Damien

2014-07-07

To evaluate the efficacy and tolerability of ipilimumab in an Australian clinical setting, and to assess the association of response with melanoma subtype, BRAF mutation status, absolute lymphocyte count and incidence of serious immune-related adverse events (AEs). Retrospective review of patients with unresectable or metastatic melanoma treated with ipilimumab at an Australian oncology centre between July 2010 and April 2012. Overall survival (OS), progression-free survival (PFS), incidence and severity of AEs. 104 patients were retrospectively followed for a median of 7 months (range 0-30 months). Median OS was 9.6 months (95% CI, 6.6-12.4), and median PFS was 3.0 months (95% CI, 2.7-3.4). The 1- and 2-year survival rates were 42% (95% CI, 32%-52%) and 18% (95% CI, 9%-30%), respectively. Median OS for patients with non-cutaneous (mucosal and uveal) melanomas was almost half that of patients with cutaneous melanoma: 5.8 months (95% CI, 2.8-12.4) v 11.7 months (95% CI, 7.1-13.8); P = 0.11. Raised absolute lymphocyte count was associated with increased PFS (P ≤ 0.005 at all measured time points) but not with OS (P > 0.15). Sex, age, brain metastases, BRAF mutation status, incidence of severe immune-related AEs and baseline lactate dehydrogenase levels did not affect OS or PFS (P > 0.05). Eighteen of 104 patients experienced serious AEs (≥ grade 3), including two treatment-related deaths. In an Australian clinical practice setting, ipilimumab achieved efficacy and tolerability measures similar to those reported in clinical trials. The frequency and severity of ipilimumab-related AEs (including death) are notable, and treatment should occur under the supervision of an experienced clinical team.

SF3B1 and BAP1 mutations in blue nevus-like melanoma.

PubMed

Griewank, Klaus G; Müller, Hansgeorg; Jackett, Louise A; Emberger, Michael; Möller, Inga; van de Nes, Johannes Ap; Zimmer, Lisa; Livingstone, Elisabeth; Wiesner, Thomas; Scholz, Simone L; Cosgarea, Ioana; Sucker, Antje; Schimming, Tobias; Hillen, Uwe; Schilling, Bastian; Paschen, Annette; Reis, Henning; Mentzel, Thomas; Kutzner, Heinz; Rütten, Arno; Murali, Rajmohan; Scolyer, Richard A; Schadendorf, Dirk

2017-07-01

Blue nevi are melanocytic tumors originating in the cutaneous dermis. Malignant tumors may arise in association with or resembling blue nevi, so called 'blue nevus-like melanoma', which can metastasize and result in patient death. Identifying which tumors will behave in a clinically aggressive manner can be challenging. Identifying genetic alterations in such tumors may assist in their diagnosis and prognostication. Blue nevi are known to be genetically related to uveal melanomas (eg, both harboring GNAQ and GNA11 mutations). In this study, we analyzed a large cohort (n=301) of various morphologic variants of blue nevi and related tumors including tumors diagnosed as atypical blue nevi (n=21), and blue nevus-like melanoma (n=12), screening for all gene mutations known to occur in uveal melanoma. Similar to published reports, we found the majority of blue nevi harbored activating mutations in GNAQ (53%) or GNA11 (15%). In addition, rare CYSLTR2 (1%) and PLCB4 (1%) mutations were identified. EIF1AX, SF3B1, and BAP1 mutations were also detected, with BAP1 and SF3B1 R625 mutations being present only in clearly malignant tumors (17% (n=2) and 25% (n=3) of blue nevus-like melanoma, respectively). In sequencing data from a larger cohort of cutaneous melanomas, this genetic profile was also identified in tumors not originally diagnosed as blue nevus-like melanoma. Our findings suggest that the genetic profile of coexistent GNAQ or GNA11 mutations with BAP1 or SF3B1 mutations can aid the histopathological diagnosis of blue nevus-like melanoma and distinguish blue nevus-like melanoma from conventional epidermal-derived melanomas. Future studies will need to further elucidate the prognostic implications and appropriate clinical management for patients with tumors harboring these mutation profiles.

[Rehabilitation methods for children with complicated cataract].

PubMed

Ivanov, G; Cuşnir, V; Septichina, Natalia; Cuşnir, Vitalie

2010-01-01

The work deals with the results of surgical treatment of 155 patients, who had uveal cataract, by method of facoemulsification with artificial crystalline lens transplanting. The age of the sick varied from 3 to 15 as a result of a complex treatment, involving determination of ethnic factor in the development of uveal cataract, before- and after-operation conservative medical treatment, surgical treatment of abscuration ambliopia 78.1% children and the keenness of sight 0.4 and 68.7% got binocularious sight. The study lot of posttraumatic cataract affected children included 189 patients, from them 68 with stationary cataract, 87 with intumescent cataract and 34 with postoperatorial aphakia. Age from 2 to 15 years. 76.3% cases of evolution without postoperatorial complications, in 13.7% intraoperatorial were observed different complications. The work presents the results of surgical treatment 196 of children, who had innate cataract, by the method of facoasoriation with soft intra-eyepiece lens transplanting from 133 patients who had two-sided cataract, 63 had monolateral cataract. All children underwent laser simulation and videocomputer auto-training in post-operation period. As a result of the treatment, 66.8% patients got the amelioration of sight with 0.4, and 58% got binocular sight. The children's age varied between 6 months and 15 years. This article presents a review of the treatment results of 213 children with posttraumatic, congenital and complicated cataracts. The rehabilitation of the patients with the lens pathology includes a complex of measures of early diagnosis, surgery, optimal correction, medical treatment before and after surgery, the prophilaxis and treatment of complications. This approach permits to increase the visual acuity in 83.8% and to restore the binocular vision in 71.4% patients.

A population-based analysis of germline BAP1 mutations in melanoma.

PubMed

O'Shea, Sally J; Robles-Espinoza, Carla Daniela; McLellan, Lauren; Harrigan, Jeanine; Jacq, Xavier; Hewinson, James; Iyer, Vivek; Merchant, Will; Elliott, Faye; Harland, Mark; Bishop, D Timothy; Newton-Bishop, Julia A; Adams, David J

2017-02-15

Germline mutation of the BRCA1 associated protein-1 (BAP1) gene has been linked to uveal melanoma, mesothelioma, meningioma, renal cell carcinoma and basal cell carcinoma. Germline variants have also been found in familial cutaneous melanoma pedigrees, but their contribution to sporadic melanoma has not been fully assessed. We sequenced BAP1 in 1,977 melanoma cases and 754 controls and used deubiquitinase assays, a pedigree analysis, and a histopathological review to assess the consequences of the mutations found. Sequencing revealed 30 BAP1 variants in total, of which 27 were rare (ExAc allele frequency <0.002). Of the 27 rare variants, 22 were present in cases (18 missense, one splice acceptor, one frameshift and two near splice regions) and five in controls (all missense). A missense change (S98R) in a case that completely abolished BAP1 deubiquitinase activity was identified. Analysis of cancers in the pedigree of the proband carrying the S98R variant and in two other pedigrees carrying clear loss-of-function alleles showed the presence of BAP1-associated cancers such as renal cell carcinoma, mesothelioma and meningioma, but not uveal melanoma. Two of these three probands carrying BAP1 loss-of-function variants also had melanomas with histopathological features suggestive of a germline BAP1 mutation. The remaining cases with germline mutations, which were predominantly missense mutations, were associated with less typical pedigrees and tumours lacking a characteristic BAP1-associated histopathological appearances, but may still represent less penetrant variants. Germline BAP1 alleles defined as loss-of-function or predicted to be deleterious/damaging are rare in cutaneous melanoma. © The Author 2017. Published by Oxford University Press.

A population-based analysis of germline BAP1 mutations in melanoma

PubMed Central

O’Shea, Sally J.; Robles-Espinoza, Carla Daniela; Harrigan, Jeanine; Jacq, Xavier; Hewinson, James; Iyer, Vivek; Merchant, Will; Elliott, Faye; Harland, Mark; Bishop, D. Timothy; Newton-Bishop, Julia A.

2017-01-01

Abstract Germline mutation of the BRCA1 associated protein-1 (BAP1) gene has been linked to uveal melanoma, mesothelioma, meningioma, renal cell carcinoma and basal cell carcinoma. Germline variants have also been found in familial cutaneous melanoma pedigrees, but their contribution to sporadic melanoma has not been fully assessed. We sequenced BAP1 in 1,977 melanoma cases and 754 controls and used deubiquitinase assays, a pedigree analysis, and a histopathological review to assess the consequences of the mutations found. Sequencing revealed 30 BAP1 variants in total, of which 27 were rare (ExAc allele frequency <0.002). Of the 27 rare variants, 22 were present in cases (18 missense, one splice acceptor, one frameshift and two near splice regions) and five in controls (all missense). A missense change (S98R) in a case that completely abolished BAP1 deubiquitinase activity was identified. Analysis of cancers in the pedigree of the proband carrying the S98R variant and in two other pedigrees carrying clear loss-of-function alleles showed the presence of BAP1-associated cancers such as renal cell carcinoma, mesothelioma and meningioma, but not uveal melanoma. Two of these three probands carrying BAP1 loss-of-function variants also had melanomas with histopathological features suggestive of a germline BAP1 mutation. The remaining cases with germline mutations, which were predominantly missense mutations, were associated with less typical pedigrees and tumours lacking a characteristic BAP1-associated histopathological appearances, but may still represent less penetrant variants. Germline BAP1 alleles defined as loss-of-function or predicted to be deleterious/damaging are rare in cutaneous melanoma. PMID:28062663

An Anti-Interleukin-2 Receptor Drug Attenuates T- Helper 1 Lymphocytes-Mediated Inflammation in an Acute Model of Endotoxin-Induced Uveitis

PubMed Central

Navea, Amparo; Almansa, Inmaculada; Muriach, María; Bosch-Morell, Francisco

2014-01-01

The aim of the present study was to evaluate the anti-inflammatory efficacy of Daclizumab, an anti-interleukin-2 receptor drug, in an experimental uveitis model upon a subcutaneous injection of lipopolysaccharide into Lewis rats, a valuable model for ocular acute inflammatory processes. The integrity of the blood-aqueous barrier was assessed 24 h after endotoxin-induced uveitis by evaluating two parameters: cell count and protein concentration in aqueous humors. The histopathology of all the ocular structures (cornea, lens, sclera, choroid, retina, uvea, and anterior and posterior chambers) was also considered. Enzyme-linked immunosorbent assays of the aqueous humor samples were performed to quantify the levels of the different chemokine and cytokine proteins. Similarly, a biochemical analysis of oxidative stress-related markers was also assessed. The inflammation observed in the anterior chamber of the eyes when Daclizumab was administered with endotoxin was largely prevented since the aqueous humor protein concentration substantially lowered concomitantly with a significant reduction in the uveal and vitreous histopathological grading. Th1 lymphocytes-related cytokines, such as Interleukin-2 and Interferon-γ, also significantly reduced with related anti-oxidant systems recovery. Daclizumab treatment in endotoxin-induced uveitis reduced Th1 lymphocytes-related cytokines, such as Interleukin-2 and Interferon gamma, by about 60–70% and presented a preventive role in endotoxin-induced oxidative stress. This antioxidant protective effect of Daclizumab may be related to several of the observed Daclizumab effects in our study, including IL-6 cytokine regulatory properties and a substantial concomitant drop in INFγ. Concurrently, Daclizumab treatment triggered a significant reduction in both the uveal histopathological grading and protein concentration in aqueous humors, but not in cellular infiltration. PMID:24595020

Intraocular biopsy using special forceps: a new instrument and refined surgical technique.

PubMed

Akgul, Harun; Otterbach, Friedrich; Bornfeld, Norbert; Jurklies, Bernhard

2011-01-01

The aim was to investigate the Essen biopsy forceps as a new instrument and surgical approach for biopsy of intraocular tumours. Biopsy is indicated for assessment of any uncertain intraocular process or confirmation for presumed diagnosis before treatment. There is increasing interest for further genetic and immunocytological information in order to characterise the neoplasm, especially grading and prognosis of micrometastasis in uveal melanoma. The authors have developed a new surgical technique using special intraocular biopsy forceps. Twenty patients with uncertain intraocular subretinal tumour underwent biopsies carried out using the special Essen biopsy forceps. Biopsies were obtained through sutureless 23-gauge three-port vitrectomy. A small retinotomy tumour specimen was taken by the forceps branches. For further processing, the specimens were flushed out into a sterile tube and then sent to pathologists. The prebioptical tumour had a mean thickness of 3.48 mm (1.1 to 9.8 mm). In all cases (n=20) biopsies (0.3-2.1 mm in size) were obtained, in 19 cases (95%) allowing precise histological and immunohistochemical typing of the lesions following cytoblock embedding. Uveal melanoma was diagnosed in 50% (n=10), choroidal metastasis in 15% (n=3) and choroidal naevus in 15% (n=3); other diagnoses (n=3) included choroidal haemangioma, B cell lymphoma and old subretinal haemorrhage. Apart from three patients with temporary punctual bleeding on the surface, there were no intra- and postoperative complications. Biopsy using special forceps is a promising new approach and precise surgical procedure. Especially for small intraocular tumours, this technique has the advantage in providing enough tissue for improved histological examination and presenting a low risk for complications.

Chromosomal rearrangements in uveal melanoma: Chromothripsis.

PubMed

van Poppelen, Natasha M; Yavuzyigitoglu, Serdar; Smit, Kyra N; Vaarwater, Jolanda; Eussen, Bert; Brands, Tom; Paridaens, Dion; Kiliç, Emine; de Klein, Annelies

2018-05-04

Uveal melanoma (UM) is the most common primary intraocular malignancy in the Western world. Recurrent mutations in GNAQ, GNA11, CYSLTR2, PLCB4, BAP1, EIF1AX and SF3B1 are described as well as non-random chromosomal aberrations. Chromothripsis is a rare event in which chromosomes are shattered and rearranged and has been reported in a variety of cancers including UM. SNP arrays of 249 UM from patients who underwent enucleation, biopsy or endoresection were reviewed for the presence of chromothripsis. Chromothripsis was defined as ten or more breakpoints per chromosome involved. Genetic analysis of GNAQ, GNA11, BAP1, SF3B1 and EIF1AX was conducted using Sanger and next-generation sequencing. In addition, immunohistochemistry for BAP1 was performed. Chromothripsis was detected in seven out of 249 tumors and the affected chromosomes were chromosomes 3, 5, 6, 8, 12 and 13. The mean total of fragments per chromosome was 39.8 (range 12 - 116). In one UM, chromothripsis was present in two different chromosomes. GNAQ, GNA11 or CYSLTR2 mutations were present in six of these tumors and five tumors harbored a BAP1 mutation and/or lacked BAP1 protein expression by immunohistochemistry. Four of these tumors metastasized and for the fifth only short follow-up data are available. One of these metastatic tumors tumor harbored an SF3B1 mutation. No EIF1AX mutations were detected in any of the tumors. To conclude, chromothripsis is a rare event in UM, occurring in 2.8% of samples and without significant association with mutations in any of the common UM driver genes. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.

miR-137 Targets p160 Steroid Receptor Coactivators SRC1, SRC2, and SRC3 and Inhibits Cell Proliferation

PubMed Central

Eedunuri, Vijay Kumar; Rajapakshe, Kimal; Fiskus, Warren; Geng, Chuandong; Chew, Sue Anne; Foley, Christopher; Shah, Shrijal S.; Shou, John; Mohamed, Junaith S.; O'Malley, Bert W.

2015-01-01

The p160 family of steroid receptor coactivators (SRCs) are pleiotropic transcription factor coactivators and “master regulators” of gene expression that promote cancer cell proliferation, survival, metabolism, migration, invasion, and metastasis. Cancers with high p160 SRC expression exhibit poor clinical outcomes and resistance to therapy, highlighting the SRCs as critical oncogenic drivers and, thus, therapeutic targets. microRNAs are important epigenetic regulators of protein expression. To examine the regulation of p160 SRCs by microRNAs, we used and combined 4 prediction algorithms to identify microRNAs that could target SRC1, SRC2, and SRC3 expression. For validation of these predictions, we assessed p160 SRC protein expression and cell viability after transfection of corresponding microRNA mimetics in breast cancer, uveal melanoma, and prostate cancer (PC) cell lines. Transfection of selected microRNA mimetics into breast cancer, uveal melanoma, and PC cells depleted SRC protein expression levels and exerted potent antiproliferative activity in these cell types. In particular, microRNA-137 (miR-137) depleted expression of SRC1, SRC2, and very potently, SRC3. The latter effect can be attributed to the presence of 3 miR-137 recognition sequences within the SRC3 3′-untranslated region. Using reverse phase protein array analysis, we identified a network of proteins, in addition to SRC3, that were modulated by miR-137 in PC cells. We also found that miR-137 and its host gene are epigenetically silenced in human cancer specimens and cell lines. These results support the development and testing of microRNA-based therapies (in particular based on restoring miR-137 levels) for targeting the oncogenic family of p160 SRCs in cancer. PMID:26066330

Targeting Bcl-2/Bcl-XL induces antitumor activity in uveal melanoma patient-derived xenografts.

PubMed

Némati, Fariba; de Montrion, Catherine; Lang, Guillaume; Kraus-Berthier, Laurence; Carita, Guillaume; Sastre-Garau, Xavier; Berniard, Aurélie; Vallerand, David; Geneste, Olivier; de Plater, Ludmilla; Pierré, Alain; Lockhart, Brian; Desjardins, Laurence; Piperno-Neumann, Sophie; Depil, Stéphane; Decaudin, Didier

2014-01-01

Uveal melanoma (UM) is associated with a high risk of metastases and lack of efficient therapies. Reduced capacity for apoptosis induction by chemotherapies is one obstacle to efficient treatments. Human UM is characterized by high expression of the anti-apoptotic protein Bcl-2. Consequently, regulators of apoptosis such as Bcl-2 family inhibitors may constitute an attractive approach to UM therapeutics. In this aim, we have investigated the efficacy of the Bcl-2/Bcl-XL inhibitor S44563 on 4 UM Patient-Derived Xenografts (PDXs) and derived-cell lines. Four well characterized UM PDXs were used for in vivo experiments. S44563 was administered alone or combined with fotemustine either concomitantly or after the alkylating agent. Bcl-2, Bcl-XL, and Mcl-1 expressions after S44563 administration were evaluated by immunohistochemistry (IHC). S44563 administered alone by at 50 and 100 mg/kg i.p. induced a significant tumour growth inhibition in only one xenograft model with a clear dose effect. However, when S44563 was concomitantly administered with fotemustine, we observed a synergistic activity in 3 out of the 4 tested models. In addition, S44563 administered after fotemustine induced a tumour growth delay in 2 out of 3 tested xenografts. Finally, IHC analyses showed that Bcl-2, Bcl-XL, and Mcl-1 expression were not modified after S44563 administration. The novel anti-apoptotic experimental compound S44563, despite a relative low efficacy when administered alone, increased the efficacy of fotemustine in either concomitant or sequential combinations or indeed subsequent to fotemustine. These data support further exploration of potential therapeutic effect of Bcl-2/Bcl-xl inhibition in human UM.

Ocular pathology in melanomatous Sinclair miniature swine.

PubMed Central

Feeney-Burns, L.; Burns, R. P.; Gao, C. L.

1988-01-01

Eyes of cutaneous melanoma-bearing miniature Sinclair swine were examined by light and electron microscopy during growth and maturation of animals. The histology of ocular depigmentation, which occurs during melanoma arrest and skin depigmentation, was studied in eyes of animals that had successful and unsuccessful tumor regression. In 12 animals one eye was removed at an early stage and the second eye at a later stage of disease or maturation. The histologic and clinical course of the ocular changes was correlated with changes in the cutaneous tumors. Animals showing rapid cutaneous tumor regression developed acute uveitis that was characterized by an influx of mononuclear cells into the stroma of the ciliary body; later this spread to the iris and choroid. In late stages the cornea sometimes developed a band of calcium precipitates beneath the basal epithelial cells (band keratopathy). Uveal melanocytes developed watery cytoplasm typical of cells with ruptured plasma membranes. Released melanin granules were taken up initially into the lysosomal compartment of mononuclear cells having the various morphologic features of lymphocytes and monocytes; later, melanin also appeared in fibrocyte lysosomes. The relationship of these processes to various cell-mediated immunity phenomena is being studied. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 PMID:3354645

Clinical, dermoscopic, histological and molecular analysis of BAP1 inactivated melanocytic nevus/tumor in two familial cases of BAP1 syndrome.

PubMed

Moawad, S; Reigneau, M; de la Fouchardière, A; Soufir, N; Schmutz, J-L; Granel-Brocard, F; Phan, A; Bursztejn, A-C

2018-05-13

BRCA1 associated protein (BAP)1-inactivated melanocytic nevus/tumours (BIMN/Ts) are specific skin tumours that appear during the first two decades of life. These lesions must be recognized by dermatologists and pathologists as an early predictive marker of BAP1 cancer syndrome, as they may precede the development of uveal and cutaneous melanomas, mesotheliomas, lung adenocarcinomas, renal cell carcinomas, and meningiomas by several years. The dermoscopic characteristics of these tumours have not been described. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Vascular endothelial growth factor expression and inhibition in uveal melanoma cell lines

PubMed Central

Logan, Patrick; Burnier, Julia; Burnier, Miguel N.

2013-01-01

Background: Uveal melanoma (UM) is a disease that affects approximately five people per million in the United States. This disease metastasises predominantly to the liver, and treatment options following the clinical detection of these sequelae are limited. Vascular endothelial growth factor-A (VEGF-A) is the primary activator of tumour angiogenesis and functions by binding to VEGF-Receptor 2 (VEGF-R2) and is often required for tumour growth beyond 2–3 mm. The purpose of this study was to investigate the expression of VEGF-A and the primary VEGF-R2 in three UM cell lines. Furthermore, we investigated the effects of VEGF-A inhibition on receptor activation and production of other cytokines. Finally, the effects of VEGF-A inhibition on the proliferation, migration, and invasion in the cell lines were ascertained. Materials: Three UM cell lines (92.1, OCM-1, and UW-1) were incubated with and without the addition of 100 μg/mL of bevacizumab. VEGF-A expression under both conditions was determined by sandwich enzyme-linked immunosorbent assay (ELISA), and phosphorylated VEGF-R2 expression was determined using western blot. The effects of VEGF-A inhibition on 20 cytokines (IL-1a, IL-2, IL-5, IL-8, IL-12p70, GM-CSF, IFNy, CCL3, MMP-9, TNF-a, IL-1b, IL-4, IL-6, IL-10, IL-13, GRO, MCP-1, MIP-1b, and RANTES) were determined using a multiplex sandwich ELISA. Proliferation rates before and after treatment were evaluated via sulforhodamine B assay, and migration and invasion assays implementing the Boyden chamber technique, the latter with artificial extracellular matrix, were used to assess their respective abilities. The Student’s t-test was used to compare changes in cytokine expression following VEGF-A inhibition. Analysis of variance was used to compare changes in the functional abilities of three uveal melanoma cell lines following VEGF-A inhibition. A P-value < 0.05 was considered statistically significant. Results: All three cell lines produced copious amounts of VEGF-A in culture (92.1, 11785.5 ± 231.8 pg/μL; OCM-1, 4608.0 ± 324.0 pg/μL; UW-1, 8309.3 ± 634.5 pg/μL), which was reduced to undetectable levels following the administration of bevacizumab (P< 0.05). Similarly, detectable phosphorylated VEGF-R2 was present in all cells, which was reduced significantly in all cell lines following bevacizumab treatment (107525.2 ± 8602.0 versus 1024.5 ± 98.2, 46587.3 ± 4192.9 versus 12821.1 ± 1666.7, and 60394.3 ± 4026.4 versus 6908.2 ± 607.2; 92.1, OCM-1, and UW-1, respectively; P< 0.05). Of the cytokines investigated, only MMP-9 and CCL3 were ubiquitously altered across all three cell lines following bevacizumab treatment; they were upregulated (CCL3: 1072.50 ± 18.77 pg/mL versus 1281.00 ± 72.34 pg/mL; 22.5 ± 7.85 pg/mL versus 62.00 ± 9.16 pg/mL; 20.33 ± 6.35 pg/mL versus 35.00 ± 6.22 pg/mL; control versus bevacizumab; MMP-9: 25.50 ± 5.47 pg/mL versus 88.25 ± 13.38 pg/mL; 19.75 ± 4.14 pg/mL versus 45.25 ± 8.36 pg/mL; 3.25 ± 1.09 pg/mL versus 19.25 ± 3.77 pg/mL; control versus bevacizumab; 92.1, OCM-1, and UW-1, respectively; P< 0.05). Bevacizumab significantly reduced the proliferation of one cell line (92.1: 0.405 ± 0.012 versus 0.509 ± 0.033; bevacizumab versus control; values OD; P< 0.05), the migration of two cell lines (92.1: 0.071 ± 0.003 versus 0.115 ± 0.003; OCM-1: 0.049 ± 0.005 versus 0.117 ± 0.014; bevacizumab versus control; values OD; P< 0.05), and did not significantly affect invasion. Conclusion: Despite the significant reduction in phosphorylated VEGF-R2 levels, bevacizumab did not have a dramatic impact on the functional abilities of the three UM cell lines studied. Our results indicate that compensatory mechanisms, such as the upregulation of MMP-9 and CCL-3, following bevacizumab administration may mitigate its effects on these abilities. PMID:23914254

Lenticular meridional astigmatism secondary to iris mesectodermal leiomyoma.

PubMed

Chalam, K V; Cutler Peck, Carolee M; Grover, Sandeep; Radhakrishnan, Ravi

2012-01-01

A 61-year-old African American man presented with decreased vision of 2 months duration. Examination revealed a significant lenticular astigmatism and sectoral cataract as a result of an amelanotic iris lesion. Slitlamp optical coherence tomography (OCT) revealed angle crowding. An excisional biopsy was performed along with phacoemulsification in the right eye, with intraocular lens implantation for meridional lenticular astigmatism. Histopathology and histoimmunochemistry confirmed a diagnosis of uveal mesectodermal leiomyoma. Lenticular astigmatism may be a subtle sign of an anterior segment tumor. Anterior segment slitlamp OCT is an effective tool in diagnosing as well as monitoring small interval changes in these types of tumors. Copyright © 2012 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.

Severe Acanthamoeba sclerokeratitis in a non-contact lens wearer.

PubMed

Hirano, K; Sai, S

1999-06-01

To report a case of severe Acanthamoeba sclerokeratitis. A 70-year-old male non-contact lens wearer was examined for severe pain in the left eye which began about 40 days after cataract surgery. In spite of a careful search, it required 6 weeks to detect Acanthamoeba. Systemic and topical fluconazol and miconazol did not help and the keratitis progressed into necrotic sclerokeratitis with protrusion of uveal tissue through the thin sclera. Those findings slowly got worse before the Acanthamoeba sclerokeratitis resolved 6 months later with scar formation. We describe the terminal and cicatricial stages of Acanthamoeba keratitis, and report that the healing process can follow the terminal stage and the eye does not need to be enucleated.

A Novel Uveolymphatic Drainage Pathway-Possible New Target for Glaucoma Treatment.

PubMed

Tomczyk-Socha, Martyna; Turno-Kręcicka, Anna

2017-12-01

Glaucoma is a heterogeneous group of ophthalmic diseases leading to irreversible damage to the optic nerve. While the overall mechanism responsible for glaucoma remains obscure, the most important risk factor is elevated intraocular pressure. The current therapies, whether pharmacological or surgical, are primarily symptomatic with the aim to lower the intraocular pressure (IOP). Poorer response to treatment is associated, for example, with pseudoexfoliation glaucoma, which is determined by blocking the trabecular meshwork (TM) both by pigment grains and the pseudoexfoliation material. It was thought that aqueous humor is drained from the eye by two main pathways: conventional outflow through the TM and Schlemm's canal; and unconventional outflow through the ciliary body through uveal tissue. In 2009 Yucel et al. described and proved the presence of a third pathway for aqueous humor drainage using two specific lymphatic markers: podoplanin, and lymphatic vessel endothelial hyaluronan receptor-1 to identify lymphatic channels in the human ciliary body. The discovery identifies a novel target for IOP-lowering therapies. The most promising group are prostaglandins, which are widely prescribed for glaucoma patients. An intriguing new possibility in glaucoma therapy is using ANGPT agonist. It is still not known if the lymphatic drainage in glaucoma is decreased or dysfunctional and whether lymphatic stimulation can help in removing the improperly accumulated substances, as is seen in pseudoexfoliation glaucoma. However, this new target for glaucoma treatment appears very promising.

Expression of classical components of the renin-angiotensin system in the human eye.

PubMed

White, Andrew J R; Cheruvu, Sarat C; Sarris, Maria; Liyanage, Surabhi S; Lumbers, Eugenie; Chui, Jeanie; Wakefield, Denis; McCluskey, Peter J

2015-03-01

The purpose of this study was to determine the relative expression of clinically-relevant components of the renin-angiotensin system (RAS) in the adult human eye. We obtained 14 post-mortem enucleated human eyes from patients whom had no history of inflammatory ocular disease nor pre-mortem ocular infection. We determined the gene expression for prorenin, renin, prorenin receptor, angiotensin-converting enzyme, angiotensinogen and angiotensin II Type 1 receptor, on tissue sections and in cultured human primary retinal pigment epithelial and iris pigment epithelial (RPE/IPE) cell lines, using both qualitative and quantitative reverse transcription polymerase chain reaction (RT-PCR). Protein expression was studied using indirect immunofluorescence (IF). Almost all components of the classical RAS were found at high levels, at both the transcript and protein level, in the eyes' uvea and retina; and at lower levels in the cornea, conjunctiva and sclera. There was a much lower level of expression in the reference cultured RPE/IPE cells lines. This study describes the distribution of RAS in the normal adult human eye and demonstrates the existence of an independent ocular RAS, with uveal and retinal tissues showing the highest expression of RAS components. These preliminary findings provide scope for examination of additional components of this system in the human eye, as well as possible differential expression under pathological conditions. © The Author(s) 2014.

DNA methylation-induced E-cadherin silencing is correlated with the clinicopathological features of melanoma.

PubMed

Venza, Mario; Visalli, Maria; Catalano, Teresa; Biondo, Carmelo; Beninati, Concetta; Teti, Diana; Venza, Isabella

2016-04-01

E-cadherin, a calcium-dependent cell-cell adhesion molecule, has an important role in epithelial cell function, maintenance of tissue architecture and cancer suppression. Loss of E-cadherin promotes tumor metastatic dissemination and predicts poor prognosis. The present study investigated the clinicopathological significance of E-cadherin expression in cutaneous, mucosal and uveal melanoma related to epigenetic mechanisms that may contribute to E-cadherin silencing. E-cadherin expression was reduced in 55/130 cutaneous (42.3%), 49/82 mucosal (59.7%) and 36/64 uveal (56.2%) melanoma samples as compared to normal skin controls and was inversely associated with promoter methylation. Of the 10 different CpG sites studied (nt 863, 865, 873, 879, 887, 892, 901, 918, 920 and 940), two sites (nt 892 and 940) were 90-100% methylated in all the melanoma specimens examined and the other ones were partially methylated (range, 53-86%). In contrast, the methylation rate of the E-cadherin gene was low in normal tissues (range, 5-24%). In all the three types of melanoma studied, a significant correlation was found between reduced levels of E-cadherin and reduced survival, high mitotic index and metastasis, accounting for the predilection of lymph nodal localization. In cutaneous and mucosal melanoma, low E-cadherin expression was positively correlated also with head/neck localization and ulceration. A high frequency of reduced E-cadherin levels occurred in choroid melanomas. In vitro experiments showed that E-cadherin transcription was restored following 5-aza-2'-deoxycytidine (5-aza-dC) treatment or DNMT1 silencing and was negatively correlated with the invasive potential of melanoma cells. The significant relationship between E-cadherin silencing and several poor prognostic factors indicates that this adhesion molecule may play an important role in melanomagenesis. Therefore, the inverse association of E-cadherin expression with promoter methylation raises the intriguing possibility that reactivation of E-cadherin expression through promoter demethylation may represent a potential therapeutic strategy for the treatment of melanoma.

DNA and aptamer stabilized gold nanoparticles for targeted delivery of anticancer therapeutics

NASA Astrophysics Data System (ADS)

Latorre, Alfonso; Posch, Christian; Garcimartín, Yolanda; Celli, Anna; Sanlorenzo, Martina; Vujic, Igor; Ma, Jeffrey; Zekhtser, Mitchell; Rappersberger, Klemens; Ortiz-Urda, Susana; Somoza, Álvaro

2014-06-01

Gold nanoparticles (GNPs) can be used as carriers of a variety of therapeutics. Ideally, drugs are released in the target cells in response to cell specific intracellular triggers. In this study, GNPs are loaded with doxorubicin or AZD8055, using a self-immolative linker which facilitates the release of anticancer therapeutics in malignant cells without modifications of the active compound. An additional modification with the aptamer AS1411 further increases the selectivity of GNPs towards cancer cells. Both modifications increase targeted delivery of therapeutics with GNPs. Whereas GNPs without anticancer drugs do not affect cell viability in all cells tested, AS1411 modified GNPs loaded with doxorubicin or AZD8055 show significant and increased reduction of cell viability in breast cancer and uveal melanoma cell lines. These results highlight that modified GNPs can be functionalized to increase the efficacy of cancer therapeutics and may further reduce toxicity by increasing targeted delivery towards malignant cells.Gold nanoparticles (GNPs) can be used as carriers of a variety of therapeutics. Ideally, drugs are released in the target cells in response to cell specific intracellular triggers. In this study, GNPs are loaded with doxorubicin or AZD8055, using a self-immolative linker which facilitates the release of anticancer therapeutics in malignant cells without modifications of the active compound. An additional modification with the aptamer AS1411 further increases the selectivity of GNPs towards cancer cells. Both modifications increase targeted delivery of therapeutics with GNPs. Whereas GNPs without anticancer drugs do not affect cell viability in all cells tested, AS1411 modified GNPs loaded with doxorubicin or AZD8055 show significant and increased reduction of cell viability in breast cancer and uveal melanoma cell lines. These results highlight that modified GNPs can be functionalized to increase the efficacy of cancer therapeutics and may further reduce toxicity by increasing targeted delivery towards malignant cells. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr00019f

Relationship between Physician-Adjudicated Adverse Events and Patient-Reported Health-Related Quality of Life in a Phase II Clinical Trial (NCT01143402) of Patients with Metastatic Uveal Melanoma*

PubMed Central

Atkinson, Thomas M.; Hay, Jennifer L.; Shoushtari, Alexander; Li, Yuelin; Paucar, Daniel J.; Smith, Sloane C.; Kudchadkar, Ragini R.; Doyle, Austin; Sosman, Jeffrey A.; Quevedo, Jorge Fernando; Milhem, Mohammed M.; Joshua, Anthony M.; Linette, Gerald P.; Gajewski, Thomas F.; Lutzky, Jose; Lawson, David H.; Lao, Christopher D.; Flynn, Patrick J.; Albertini, Mark R.; Sato, Takami; Lewis, Karl; Marr, Brian; Abramson, David H.; Dickson, Mark Andrew; Schwartz, Gary K.; Carvajal, Richard D.

2016-01-01

Purpose Clinical trials commonly use physician-adjudicated adverse event (AE) assessment via the Common Terminology Criteria for Adverse Events (CTCAE) for decision-making. Patient-reported health-related quality of life (HRQoL) data is becoming more frequent in oncology; however, the relationship between physician-adjudicated AE assessment and HRQoL is understudied. Methods Data from a phase II trial (clinicaltrials.gov identifier: NCT01143402) where patients with metastatic uveal melanoma were randomized to receive selumetinib, an oral MEK inhibitor, or chemotherapy were analyzed. Patients reported HRQoL at baseline, after 1 month, and end of treatment (n=118), whereas physicians adjudicated AEs via CTCAE. Mean HRQoL scores were compared between patient randomization arms, as well as between those patients who did/did not receive dose modifications. Results Ninety-four percent had a CTCAE grade ≥ 1 for at least one treatment-associated AE, with 18% undergoing dose modification due to toxicity. Mean HRQoL scores did not significantly differ at each of the three time points. Patient and physician-adjudicated reports of nausea were significantly correlated at the start (r=0.31, p<0.01) and end of treatment (r=0.42, p<0.05). There were no significant correlations between need for dose modification and HRQoL scores. Conclusions Despite the high rate of physician-adjudicated AEs and need for dose modifications with selumetinib, patient-reported HRQoL was not impacted by treatment. Since HRQoL did not differ in the subgroup of patients who received dosage reductions due to AEs, patients may be willing to tolerate select AEs without dose modification (if medically appropriate). More research is needed to determine how to best integrate HRQoL data into clinical trial conduct. PMID:27921276

Relationship between physician-adjudicated adverse events and patient-reported health-related quality of life in a phase II clinical trial (NCT01143402) of patients with metastatic uveal melanoma.

PubMed

Atkinson, Thomas M; Hay, Jennifer L; Shoushtari, Alexander; Li, Yuelin; Paucar, Daniel J; Smith, Sloane C; Kudchadkar, Ragini R; Doyle, Austin; Sosman, Jeffrey A; Quevedo, Jorge Fernando; Milhem, Mohammed M; Joshua, Anthony M; Linette, Gerald P; Gajewski, Thomas F; Lutzky, Jose; Lawson, David H; Lao, Christopher D; Flynn, Patrick J; Albertini, Mark R; Sato, Takami; Lewis, Karl; Marr, Brian; Abramson, David H; Dickson, Mark Andrew; Schwartz, Gary K; Carvajal, Richard D

2017-03-01

Clinical trials commonly use physician-adjudicated adverse event (AE) assessment via the common terminology criteria for adverse events (CTCAE) for decision-making. Patient-reported health-related quality of life (HRQoL) data are becoming more frequent in oncology; however, the relationship between physician-adjudicated AE assessment and HRQoL is understudied. Data from a phase II trial (clinicaltrials.gov identifier: NCT01143402) where patients with metastatic uveal melanoma were randomized to receive selumetinib, an oral MEK inhibitor, or chemotherapy were analyzed. Patients reported HRQoL at baseline, after 1 month, and end of treatment (n = 118), whereas physicians adjudicated AEs via CTCAE. Mean HRQoL scores were compared between patient randomization arms, as well as between those patients who did/did not receive dose modifications. Ninety-four percent had a CTCAE grade ≥1 for at least one treatment-associated AE, with 18% undergoing dose modification due to toxicity. Mean HRQoL scores did not significantly differ at each of the three time points. Patient and physician-adjudicated reports of nausea were significantly correlated at the start (r = 0.31, p < 0.01) and end of treatment (r = 0.42, p < 0.05). There were no significant correlations between need for dose modification and HRQoL scores. Despite the high rate of physician-adjudicated AEs and need for dose modifications with selumetinib, patient-reported HRQoL was not impacted by treatment. Since HRQoL did not differ in the subgroup of patients who received dosage reductions due to AEs, patients may be willing to tolerate select AEs without dose modification (if medically appropriate). More research is needed to determine how to best integrate HRQoL data into clinical trial conduct.

The biological and prognostic significance of angiotropism in uveal melanoma.

PubMed

Barnhill, Raymond L; Ye, Mengliang; Batistella, Aude; Stern, Marc-Henri; Roman-Roman, Sergio; Dendale, Rémi; Lantz, Olivier; Piperno-Neumann, Sophie; Desjardins, Laurence; Cassoux, Nathalie; Lugassy, Claire

2017-02-27

Angiotropism is a marker of extravascular migration of melanoma cells along vascular and other structures and a prognostic factor in cutaneous melanoma. Because of this biological and prognostic importance in cutaneous melanoma, angiotropism was studied in uveal melanoma (UM). This retrospective study performed at a single ocular oncology referral center included 89 patients from the study period 2006-2008. All patients were diagnosed with UM from the choroid and/or ciliary body. All patients underwent enucleation for prognostic purposes and definitive therapy. Clinical, histopathological, and molecular variables included patient age, gender, extraocular extension, tumor location (ciliary body or not), optic nerve invasion, angiotropism, neurotropism, melanoma cell type, BAP1 mutation, and monosomy 3. Angiotropism was defined as melanoma cells arrayed along the abluminal vascular surfaces without intravasation in the sclera and/or episcleral tissue. The study included 51 women (57.3%) and 38 men with mean and median age: 63 years (range: 25-92). Mean follow-up was 4.4 years (range: 0.2 to 11). Fifty-three (59.6%) patients developed metastases and 48 (53.9%) were dead from metastases at last follow-up. Other principal variables recorded were angiotropism in 43.8%, extraocular extension in 7.9%, epithelioid/mixed cell type in 73.1%, BAP1 mutation in 41.3%, and monosomy 3 in 53.6% of cases. On multivariate analysis, extraocular extension, angiotropism, and monosomy 3 were predictive of metastasis, whereas tumor diameter, epithelioid cell type, angiotropism, and monosomy 3 were predictive of death. Chi-square test confirmed an association between angiotropism and metastasis and death but none with BAP1 mutation and monosomy 3. In conclusion, angiotropism and monosomy 3 were independent prognostic factors for both metastases and death in UM. However, irrespective of any prognostic value, the true importance of angiotropism is its biological significance as a marker of an alternative metastatic pathway.Laboratory Investigation advance online publication, 27 February 2017; doi:10.1038/labinvest.2017.16.

Sector (partial) oculo(dermal) melanocytosis in 89 eyes.

PubMed

Shields, Carol L; Qureshi, Anam; Mashayekhi, Arman; Park, Chantel; Sinha, Neelema; Zolotarev, Felina; Shields, Jerry A

2011-12-01

To describe sector (partial) involvement of the uvea with melanocytosis. Noninterventional, retrospective case series. A total of 89 eyes of 86 patients. Review of medical records, color photographs, and ultrasound images. Clinical features and relationship with uveal melanoma. Approximately all patients were Caucasian (n = 83, 97%), and sector melanocytosis involved the right (n = 41, 46%) or left (n = 48, 54%) eye. The involved tissue included iris (n = 58, 65%), choroid (n = 48, 54%), and both iris and choroid (n = 17, 19%). The melanocytosis affected a mean of 6 clock hours of iris and 5 clock hours of choroid. Related melanocytosis involved the sclera (n = 39, 44%), eyelid (n = 4, 4%), temple (n = 4, 4%), scalp (n = 1, 1%), and palate (n = 1, 1%). Uveal melanoma was found at presentation in 7 patients (8%) and was multifocal in 2 of these patients. A comparison of eyes with versus without melanoma revealed clinically significant factors (odds ratio [OR] > 2) of male gender (71% vs. 43% [OR 3.36]); cutaneous/palate melanocytosis (14% vs. 7% [OR 2.11]); scleral melanocytosis heaviest in superior, temporal, or nasal quadrants (57% vs. 29% [OR 2.41, confidence interval, 2.24-3.92]); and any degree of choroidal melanocytosis (86% vs. 70% [OR 2.63]), particularly diffuse choroidal melanocytosis (29% vs. 16% [OR 3.85]). None of these factors reached statistical significance in this small cohort. Over a mean follow-up of 6 years, there was no metastatic event. Ocular melanocytosis can be sectoral (partial), affecting only a mean of 5 to 6 clock hours of the uvea and can manifest melanoma within the melanocytosis region. There were no specific features of melanocytosis statistically related to the presence of melanoma. The author(s) have no proprietary or commercial interest in any materials discussed in this article. Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

In Vivo High-Frequency, Contrast-Enhanced Ultrasonography of Uveal Melanoma in Mice: Imaging Features and Histopathologic Correlations

PubMed Central

Zhang, Qing; Yang, Hua; Kang, Shin J.; Wang, Yanggan; Wang, Geoffrey D.; Coulthard, Tonya

2011-01-01

Purpose. To evaluate the usefulness of in vivo imaging of uveal melanoma in mice using high-frequency contrast-enhanced ultrasound (HF-CE-US) with 2D or 3D modes and to correlate the sonographic findings with histopathologic characteristics. Methods. Fourteen 12-week-old C57BL6 mice were inoculated into their right eyes with aliquots of 5 × 105/2.5 μL B16LS9 melanoma cells and were randomly assigned to either of two groups. At 7 days after inoculation, tumor-bearing eyes in group 1 (n = 8) were imaged using HF-CE-US to determine the 2D tumor size and relative blood volume; eyes in group 2 (n = 6) were imaged by 3D microbubble contrast-enhanced ultrasound, and the tumor volume was determined. Histologic tumor burden was quantified in enucleated eyes by image processing software, and microvascular density was determined by counting von Willebrand factor-positive vascular channels. Ultrasound images were evaluated and compared with histopathologic findings. Results. Using HF-CE-US, melanomas were visualized as relatively hyperechoic regions. The intraobserver variability of sonographic measurements was 9.65% ± 7.89%, and the coefficient of variation for multiple measurements was 7.33% ± 5.71%. The correlation coefficient of sonographic volume or size and histologic area was 0.71 (P = 0.11) and 0.79 (P = 0.32). The relative blood volume within the tumor demonstrated sonographically correlated significantly with histologic tumor vascularity (r = 0.83; P < 0.001). Conclusions. There was a positive linear correlation between sonographic tumor measurements and histologic tumor burden in the mouse ocular melanoma model. Contrast-enhanced intensity corresponded with microvascular density and blood volume. HF-CE-US is a real-time, noninvasive, reliable method for in vivo evaluation of experimental intraocular melanoma tumor area and relative blood volume. PMID:21245408

[Results of fistulizing and Ahmed valve surgery for treatment of refractory glaucoma].

PubMed

Bikbov, M M; Babushkin, A E; Chaĭka, O V; Orenburkina, O I; Matiukhina, E N

2014-01-01

Surgical results of 76 patients (76 eyes) aged 25-79 years with secondary refractory glaucoma were analyzed. The best hypotensive effect and visual functions integrity were achieved with Ahmed valve implantation (86.7% and 83.3% of cases respectively); after conventional fistulizing surgery the hypotensive effect was observed in 45.5%, noncompromised vision--in 54.5% of cases. Tunnel trabeculectomy with iridocycloretraction led to normalization of intraocular pressure and stabilization of visual functions in 81.3% and 68.8% of cases respectively and thus can be considered as an alternative to fistulizing surgery in patients with secondary refractory glaucoma. Uveal glaucoma is a relative contraindication to Ahmed valve implantation, while neovascular glaucoma is that to tunnel trabeculectomy with iridocycloretraction.

Disseminated gestational choriocarcinoma presenting with hepatic and uveal metastases, hook effect, and choriocarcinoma syndrome.

PubMed

Aswani, Yashant; Thakkar, Hemangini; Hira, Priya

2016-01-01

Choriocarcinoma is a human chorionic gonadotrophin (HCG)-secreting tumor that comprises vascular channels. It has a tendency for widespread metastasis, common sites for which include the lung, vagina, brain, liver, bone, intestine, and kidney. We describe a 30-year-old female who presented with hepatitis-like features and bilateral diminution of vision, and subsequently developed hemothorax and hemoperitoneum-all rare and seemingly unrelated manifestations which were finally attributable to metastases from gestational choriocarcinoma. To further complicate the clinical scenario, the serum HCG of the patient was mildly raised (due to a phenomenon called hook effect). Subsequently, the patient developed disseminated intravascular coagulation and succumbed to her illness. In this report, we discuss the imaging findings of choriocarcinoma, its potential sites of metastases, and the hook effect.

Improving patient outcomes to targeted therapies in melanoma.

PubMed

Eroglu, Zeynep; Smalley, Keiran S M; Sondak, Vernon K

2016-06-01

The arrival of targeted therapies has led to significant improvements in clinical outcomes for patients with BRAFV600 mutated advanced melanoma over the past five years. In several clinical trials, BRAF and MEK inhibitors have shown improvement in progression free and overall survival, along with much higher tumor response rates in comparison to chemotherapy, with the combination of these drugs superior to monotherapy. These agents are also being tested in earlier-stage patients, in addition to alternative dosing regimens and in combinations with other therapeutics. Efforts are also ongoing to expand the success found with targeted therapies to other subtypes of melanoma, including NRAS and c-kit mutated melanomas, uveal melanomas, and BRAF/NRAS wild type melanomas. Expert Commentary: We aim to provide an overview of clinical outcomes with targeted therapies in melanoma patients.

A perspective of gene therapy in the glaucomas.

PubMed

Kaufman, P L; Jia, W W; Tan, J; Chen, Z; Gabelt, B T; Booth, V; Tufaro, F; Cynader, M

1999-06-01

Gene therapy in the anterior and posterior segment tissues may have the potential to favorably influence aqueous hydrodynamics and retinal ganglion cell biology, thereby preventing, delaying, or minimizing glaucomatous damage to the optic nerve. We demonstrated the feasibility of using a herpes viral vector (ribonucleotide reductase defective HSV-1, hrR3) to deliver the lacZ reporter gene to living cat and rat eyes. Cats received injections into the anterior chamber and rats into the vitreous cavity. In cats, lacZ expression was detectable at 1 to 2 days in the anterior outer portion of the ciliary muscle and the lining of the intertrabecular spaces of the corneoscleral and uveal meshwork. Rat eyes showed lacZ expression in the retinal pigment epithelium and photoreceptor outer segments 2 days after injection.

Vitiligo and disorders of the retinal pigment epithelium.

PubMed Central

Albert, D M; Wagoner, M D; Pruett, R C; Nordlund, J J; Lerner, A B

1983-01-01

The association of vitiligo with inflammation of the uveal tract is well established. The relationship between vitiligo and hypopigmentation and/or degeneration of the retinal pigment epithelium (RPE) not secondary to ocular inflammation has not been adequately investigated. Sixty (27%) of 223 consecutive patients with vitiligo were found to have some evidence of RPE hypopigmentation ranging from mild, focal areas of involvement in most cases to extensive RPE degeneration with a retinitis pigmentosa-like syndrome in one patient. Fifteen (25%) patients complained of night blindness. Only 6 (4%) of 148 patients in a control group had similar funduscopic findings (p less than 0.001). None of these patients were symptomatic. There have been isolated reports of vitiligo occurring with tapetoretinal degeneration. We report 2 patients with both vitiligo and retinitis pigmentosa. Images PMID:6824621

Management of posterior uveal melanoma: past, present, and future: the 2014 Charles L. Schepens lecture.

PubMed

Shields, Jerry A; Shields, Carol L

2015-02-01

To review the management of ciliary body and choroidal melanoma (posterior uveal melanoma [PUM]) over the last century with an emphasis on changing concepts. Retrospective review. Review of personal experience over 40 years and pertinent literature on management of PUM. Diagnosis and therapy for PUM. Patient survival. In the early 1900s, most patients presented with a large symptomatic melanoma that necessitated enucleation, and the systemic prognosis was poor. In the 1970s, controversy erupted regarding the role of enucleation for PUM. Some authorities advocated prompt enucleation, and others proposed that enucleation promoted metastasis, known as the "Zimmerman hypothesis." Others recommended observation, withholding treatment until tumor growth was documented. During the 1970s, there was a trend toward eye-saving procedures, including laser photocoagulation, surgical removal of tumor, and techniques of radiotherapy. Despite local treatment success, systemic prognosis remained guarded with approximately 40% mortality overall. However, there was convincing evidence that smaller tumors offered a significantly better prognosis. Currently, there is a movement toward earlier identification and treatment of small melanomas using clinical factors predictive of malignant potential, in keeping with similar philosophy regarding other cancers. Further understanding of melanoma cytogenetics and molecular pathways have helped to recognize patients at risk for metastasis. At-risk patients are offered systemic therapeutic trials to prevent metastasis. We anticipate that the future management of PUM will focus on detection of clinical and imaging clues for earliest diagnosis, prompt local tumor treatment, and systemic targeted therapies for microscopic metastasis or prevention of metastasis. Personalized evaluation of patient-specific melanoma molecular pathway signature could allow for therapeutic intervention at a site specific to the pathway abnormality that leads to the development of melanoma. Management of PUM has made major strides over the past century from the days of enucleation for massive, fatal tumor to early detection of smallest tumors with a more favorable prognosis. Current and future targeted specific tumor pathway interruption using systemic agents could improve survival. Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Plaque Brachytherapy for Uveal Melanoma: A Vision Prognostication Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Khan, Niloufer; Khan, Mohammad K.; Bena, James

Purpose: To generate a vision prognostication model after plaque brachytherapy for uveal melanoma. Methods and Materials: All patients with primary single ciliary body or choroidal melanoma treated with iodine-125 or ruthenium-106 plaque brachytherapy between January 1, 2005, and June 30, 2010, were included. The primary endpoint was loss of visual acuity. Only patients with initial visual acuity better than or equal to 20/50 were used to evaluate visual acuity worse than 20/50 at the end of the study, and only patients with initial visual acuity better than or equal to 20/200 were used to evaluate visual acuity worse than 20/200more » at the end of the study. Factors analyzed were sex, age, cataracts, diabetes, tumor size (basal dimension and apical height), tumor location, and radiation dose to the tumor apex, fovea, and optic disc. Univariate and multivariable Cox proportional hazards were used to determine the influence of baseline patient factors on vision loss. Kaplan-Meier curves (log rank analysis) were used to estimate freedom from vision loss. Results: Of 189 patients, 92% (174) were alive as of February 1, 2011. At presentation, visual acuity was better than or equal to 20/50 and better than or equal to 20/200 in 108 and 173 patients, respectively. Of these patients, 44.4% (48) had post-treatment visual acuity of worse than 20/50 and 25.4% (44) had post-treatment visual acuity worse than 20/200. By multivariable analysis, increased age (hazard ratio [HR] of 1.01 [1.00-1.03], P=.05), increase in tumor height (HR of 1.35 [1.22-1.48], P<.001), and a greater total dose to the fovea (HR of 1.01 [1.00-1.01], P<.001) were predictive of vision loss. This information was used to develop a nomogram predictive of vision loss. Conclusions: By providing a means to predict vision loss at 3 years after treatment, our vision prognostication model can be an important tool for patient selection and treatment counseling.« less

Safety, Antitumor Activity, and Immune Activation of Pegylated Recombinant Human Interleukin-10 (AM0010) in Patients With Advanced Solid Tumors.

PubMed

Naing, Aung; Papadopoulos, Kyriakos P; Autio, Karen A; Ott, Patrick A; Patel, Manish R; Wong, Deborah J; Falchook, Gerald S; Pant, Shubham; Whiteside, Melinda; Rasco, Drew R; Mumm, John B; Chan, Ivan H; Bendell, Johanna C; Bauer, Todd M; Colen, Rivka R; Hong, David S; Van Vlasselaer, Peter; Tannir, Nizar M; Oft, Martin; Infante, Jeffrey R

2016-10-10

Purpose Interleukin-10 (IL-10) stimulates the expansion and cytotoxicity of tumor-infiltrating CD8+ T cells and inhibits inflammatory CD4+ T cells. Pegylation prolongs the serum concentration of IL-10 without changing the immunologic profile. This phase I study sought to determine the safety and antitumor activity of AM0010. Patients and Methods Patients with selected advanced solid tumors were treated with AM0010 in a dose-escalation study, which was followed by a renal cell cancer (RCC) dose-expansion cohort. AM0010 was self-administered subcutaneously at doses of 1 to 40 μg/kg once per day. Primary end points were safety and tolerability; clinical activity and immune activation were secondary end points. Results In the dose-escalation and -expansion cohorts, 33 and 18 patients, respectively, were treated with daily subcutaneous injection of AM0010. AM0010 was tolerated in a heavily pretreated patient population. Treatment-related adverse events (AEs) included anemia, fatigue, thrombocytopenia, fever, and injection site reactions. Grade 3 to 4 nonhematopoietic treatment-related AEs, including rash (n = 2) and transaminitis (n = 1), were observed in five of 33 patients. Grade 3 to 4 anemia or thrombocytopenia was observed in five patients. Most treatment-related AEs were transient or reversible. AM0010 led to systemic immune activation with elevated immune-stimulatory cytokines and reduced transforming growth factor beta in the serum. Partial responses were observed in one patient with uveal melanoma and four of 15 evaluable patients with RCC treated at 20 μg/kg (overall response rate, 27%). Prolonged stable disease of at least 4 months was observed in four patients, including one with colorectal cancer with disease stabilization for 20 months. Conclusion AM0010 has an acceptable toxicity profile with early evidence of antitumor activity, particularly in RCC. These data support the further evaluation of AM0010 both alone and in combination with other immune therapies and chemotherapies.

Expression profiling during ocular development identifies 2 Nlz genes with a critical role in optic fissure closure.

PubMed

Brown, Jacob D; Dutta, Sunit; Bharti, Kapil; Bonner, Robert F; Munson, Peter J; Dawid, Igor B; Akhtar, Amana L; Onojafe, Ighovie F; Alur, Ramakrishna P; Gross, Jeffrey M; Hejtmancik, J Fielding; Jiao, Xiaodong; Chan, Wai-Yee; Brooks, Brian P

2009-02-03

The gene networks underlying closure of the optic fissure during vertebrate eye development are poorly understood. Here, we profile global gene expression during optic fissure closure using laser capture microdissected (LCM) tissue from the margins of the fissure. From these data, we identify a unique role for the C(2)H(2) zinc finger proteins Nlz1 and Nlz2 in normal fissure closure. Gene knockdown of nlz1 and/or nlz2 in zebrafish leads to a failure of the optic fissure to close, a phenotype which closely resembles that seen in human uveal coloboma. We also identify misregulation of pax2 in the developing eye of morphant fish, suggesting that Nlz1 and Nlz2 act upstream of the Pax2 pathway in directing proper closure of the optic fissure.

How Effective Are Percutaneous Liver-Directed Therapies in Patients with Non-Colorectal Liver Metastases?

PubMed Central

Vogl, Thomas J.; Emam, Ahmed; Naguib, Nagy N.; Eichler, Katrin; Zangos, Stefan

2015-01-01

Summary Background The purpose of this review is to demonstrate the clinical indications, technical developments, and outcome of liver-directed therapies in interventional oncology of non-colorectal liver metastases. Methods Liver-directed therapies are classified into vascular transarterial techniques such as chemoperfusion (TACP), chemoembolization (TACE), radioembolization (selective internal radiation therapy (SIRT)), and chemosaturation, as well as thermal ablation techniques like microwave ablation (MWA), radiofrequency ablation (RFA), laser-induced thermotherapy (LITT), cryotherapy, and irreversible electroporation (IRE). The authors searched the database PubMed using the following terms: ‘image-guided tumor ablation’, ‘thermal ablation therapies’, ‘liver metastases of uveal melanoma’, ‘neuroendocrine carcinoma’, ‘breast cancer’, and ‘non-colorectal liver metastases’. Results Various combinations of the above-mentioned therapy protocols are possible. In neuroendocrine carcinomas, oligonodular liver metastases are treated successfully via thermal ablation like RFA, LITT, or MWA, and diffuse involvement via TACE or SIRT. Although liver involvement in breast cancer is a systemic disease, non-responding nodular metastases can be controlled via RFA or LITT. In ocular or cutaneous melanoma, thermal ablation is rarely considered as an interventional treatment option, as opposed to TACE, SIRT, or chemosaturation. Rarely liver-directed therapies are used in pancreatic cancer, most likely due to problems such as biliary digestive communications after surgery and the risk of infections. Rare indications for thermal ablation are liver metastases of other primary cancers like non-small cell lung, gastric, and ovarian cancer. Conclusion Interventional oncological techniques play a role in patients with liver-dominant metastases. PMID:26889144

Genetic risk factors for insidious equine recurrent uveitis in Appaloosa horses.

PubMed

Fritz, K L; Kaese, H J; Valberg, S J; Hendrickson, J A; Rendahl, A K; Bellone, R R; Dynes, K M; Wagner, M L; Lucio, M A; Cuomo, F M; Brinkmeyer-Langford, C L; Skow, L C; Mickelson, J R; Rutherford, M S; McCue, M E

2014-06-01

Appaloosa horses are predisposed to equine recurrent uveitis (ERU), an immune-mediated disease characterized by recurring inflammation of the uveal tract in the eye, which is the leading cause of blindness in horses. Nine genetic markers from the ECA1 region responsible for the spotted coat color of Appaloosa horses, and 13 microsatellites spanning the equine major histocompatibility complex (ELA) on ECA20, were evaluated for association with ERU in a group of 53 Appaloosa ERU cases and 43 healthy Appaloosa controls. Three markers were significantly associated (corrected P-value <0.05): a SNP within intron 11 of the TRPM1 gene on ECA1, an ELA class I microsatellite located near the boundary of the ELA class III and class II regions and an ELA class II microsatellite located in intron 1 of the DRA gene. Association between these three genetic markers and the ERU phenotype was confirmed in a second population of 24 insidious ERU Appaloosa cases and 16 Appaloosa controls. The relative odds of being an ERU case for each allele of these three markers were estimated by fitting a logistic mixed model with each of the associated markers independently and with all three markers simultaneously. The risk model using these markers classified ~80% of ERU cases and 75% of controls in the second population as moderate or high risk, and low risk respectively. Future studies to refine the associations at ECA1 and ELA loci and identify functional variants could uncover alleles conferring susceptibility to ERU in Appaloosa horses. © 2014 Stichting International Foundation for Animal Genetics.

Role of Genetics and Epigenetics in Mucosal, Uveal, and Cutaneous Melanomagenesis.

PubMed

Venza, Mario; Visalli, Maria; Beninati, Concetta; Biondo, Carmelo; Teti, Diana; Venza, Isabella

2016-01-01

Melanoma prevalently occurs on parts of the body that have been overexposed to the sun. However, it can also originate in the nervous system, eye and mucous membranes. Melanoma has been thought for a long time to arise through a series of genetic mechanisms involving numerous irreversible changes within the human genome. However, recently, "epimutations" have attracted considerable attention owing to their high prevalence rate and reversible nature. These observations opened up new perspectives in the use of epidrugs with the potential for restoring the "correct" control of neoplastic genomes. Here, we focused on the common consensus on genetics and epigenetics in melanoma. We also discussed the clinical applications of regulators of epigenetic enzymes able to revert the epigenetic and metabolic hallmarks of melanoma cells. Such anti-neoplastic agents affect the expression profile of antioncogenes, proto-oncogenes, and microRNAs resulting in enhanced differentiation, apoptosis, and growth inhibition.

Loss of the tumor suppressor BAP1 causes myeloid transformation

PubMed Central

Dey, Anwesha; Seshasayee, Dhaya; Noubade, Rajkumar; French, Dorothy M.; Liu, Jinfeng; Chaurushiya, Mira S.; Kirkpatrick, Donald S.; Pham, Victoria C.; Lill, Jennie R.; Bakalarski, Corey E.; Wu, Jiansheng; Phu, Lilian; Katavolos, Paula; Saunders, Lindsay M.; Abdel-Wahab, Omar; Modrusan, Zora; Seshagiri, Somasekar; Dong, Ken; Lin, Zhonghua; Balazs, Mercedesz; Suriben, Rowena; Newton, Kim; Hymowitz, Sarah; Garcia-Manero, Guillermo; Martin, Flavius; Levine, Ross L.; Dixit, Vishva M.

2016-01-01

Deubiquitinating enzyme BAP1 is mutated in a hereditary cancer syndrome with increased risk of mesothelioma and uveal melanoma. Somatic BAP1 mutations occur in various malignancies. We show that mouse Bap1 gene deletion is lethal during embryogenesis, but systemic or hematopoietic-restricted deletion in adults recapitulates features of human myelodysplastic syndrome (MDS). Knock-in mice expressing BAP1 with a 3xFlag tag revealed that BAP1 interacts with HCF-1, OGT, and the polycomb group proteins ASXL1 and ASXL2 in vivo. OGT and HCF-1 levels were decreased by Bap1 deletion, indicating a critical role for BAP1 in stabilizing these epigenetic regulators. Human ASXL1 is mutated frequently in chronic myelomonocytic leukemia (CMML) so an ASXL/BAP1 complex may suppress CMML. A novel BAP1 catalytic mutation found in a MDS patient implies that BAP1 loss of function has similar consequences in mouse and man. PMID:22878500

Evaluation of acute radiation optic neuropathy by B-scan ultrasonography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lovato, A.A.; Char, D.H.; Quivey, J.M.

1990-09-15

We studied the accuracy of B-scan ultrasonography to diagnose radiation-induced optic neuropathy in 15 patients with uveal melanoma. Optic neuropathy was diagnosed by an observer masked as to clinical and photographic data. We analyzed planimetry area measurements of the retrobulbar nerve before and after irradiation. The retrobulbar area of the optic nerve shadow on B-scan was quantitated with a sonic digitizer. Increased optic nerve shadow area was confirmed in 13 of 15 patients who had radiation optic neuropathy (P less than .004). The correct diagnosis was confirmed when the results of ultrasound were compared to fundus photography and fluorescein angiography.more » In 13 patients there was acute radiation optic neuropathy. Two patients did not show an enlarged retrobulbar optic nerve, and the clinical appearance suggested early progression to optic atrophy. Ultrasonography documents the enlargement of the optic nerve caused by acute radiation changes.« less

Topically applied standardized aqueous extract of Curcuma longa Linn. suppresses endotoxin-induced uveal inflammation in rats.

PubMed

Agarwal, Renu; Gupta, S K; Agarwal, Puneet; Srivastava, Sushma

2013-10-01

Aqueous extract of C. longa when administered 4 h after induction of E. coli lipopolysaccharide-induced uveitis in rats showed significantly suppressed inflammation with a significantly lower mean clinical grade, histopathological grade and aqueous humor (AH) protein level compared to vehicle treated group. Although, prednisolone group showed significantly lower clinical grade, histopathological grades and AH protein levels compared to C. longa group, TNF-alpha levels did not differ significantly. Moreover, when the aqueous extract was administered starting from 3 days before induction of uveitis, the mean clinical and histopathological grade as well as AH protein and TNF-alpha levels were comparable to C. longa group when treatment was administered 4 h after induction of uveitis. It is concluded that topically applied standardized aqueous extract of C. longa suppresses endotoxin-induced uveitis in rats by reducing TNF-alpha activity.

Surgical management of a progressive iris melanocytoma in a Mustang.

PubMed

Scotty, Nicole C; Barrie, Kathleen B; Brooks, Dennis E; Taylor, David

2008-01-01

A 7-year-old gray Mustang gelding weighing 454 kg was presented for evaluation of a brown mass within the left eye (OS) of 1 year's duration with recent enlargement. A nonpainful, 8 mm diameter, brown, vascularized mass was identified in the anterior chamber of the OS. Ocular B-scan ultrasound confirmed iris involvement and corneal endothelial contact. Histopathology confirmed the presumptive diagnosis of a uveal melanocytic neoplasm, and revealed 1-3 mitotic figures per high power (400x) field. The mass was removed via sector iridectomy without complications, but without complete margins. Three cutaneous melanocytomas noted 1.5 months postoperatively were completely excised. No tumor regrowth was noted 15 months postoperatively, supporting a diagnosis of melanocytoma for the iridal mass. Sector iridectomy is a reasonable treatment option for uncomplicated iridal melanocytomas in horses. Mitotic index and presence of cutaneous melanocytic neoplasms may be irrelevant to the prognosis of equine iridal melanocytic neoplasms.

Identification and quantitation of carotenoids and their metabolites in the tissues of the human eye.

PubMed

Bernstein, P S; Khachik, F; Carvalho, L S; Muir, G J; Zhao, D Y; Katz, N B

2001-03-01

There is increasing evidence that the macular pigment carotenoids, lutein and zeaxanthin, may play an important role in the prevention of age-related macular degeneration, cataract, and other blinding disorders. Although it is well known that the retina and lens are enriched in these carotenoids, relatively little is known about carotenoid levels in the uveal tract and in other ocular tissues. Also, the oxidative metabolism and physiological functions of the ocular carotenoids are not fully understood. Thus, we have set out to identify and quantify the complete spectrum of dietary carotenoids and their oxidative metabolites in a systematic manner in all tissues of the human eye in order to gain better insight into their ocular physiology. Human donor eyes were dissected, and carotenoid extracts from ocular tissues [retinal pigment epithelium/choroid (RPE/choroid), macula, peripheral retina, ciliary body, iris, lens, vitreous, cornea, and sclera] were analysed by high-performance liquid chromatography (HPLC). Carotenoids were identified and quantified by comparing their chromatographic and spectral profiles with those of authentic standards. Nearly all ocular structures examined with the exception of vitreous, cornea, and sclera had quantifiable levels of dietary (3R,3'R,6'R)-lutein, zeaxanthin, their geometrical (E / Z) isomers, as well as their metabolites, (3R,3'S,6'R)-lutein (3'-epilutein) and 3-hydroxy-beta,epsilon-caroten-3'-one. In addition, human ciliary body revealed the presence of monohydroxycarotenoids and hydrocarbon carotenoids, while only the latter group was detected in human RPE/choroid. Uveal structures (iris, ciliary body, and RPE/choroid) account for approximately 50% of the eye's total carotenoids and approximately 30% of the lutein and zeaxanthin. In the iris, these pigments are likely to play a role in filtering out phototoxic short-wavelength visible light, while they are more likely to act as antioxidants in the ciliary body. Both mechanisms, light screening and antioxidant, may be operative in the RPE/choroid in addition to a possible function of this tissue in the transport of dihydroxycarotenoids from the circulating blood to the retina. This report lends further support for the critical role of lutein, zeaxanthin, and other ocular carotenoids in protecting the eye from light-induced oxidative damage and aging. Copyright 2001 Academic Press.

Proton beam radiotherapy versus fractionated stereotactic radiotherapy for uveal melanomas: A comparative study.

PubMed

Weber, Damien C; Bogner, Joachim; Verwey, Jorn; Georg, Dietmar; Dieckmann, Karin; Escudé, Lluis; Caro, Monica; Pötter, Richard; Goitein, Gudrun; Lomax, Antony J; Miralbell, Raymond

2005-10-01

A comparative treatment planning study was undertaken between proton and photon therapy in uveal melanoma to assess the potential benefits and limitations of these treatment modalities. A fixed proton horizontal beam (OPTIS) and intensity-modulated spot-scanning proton therapy (IMPT), with multiple noncoplanar beam arrangements, was compared with linear accelerator-based stereotactic radiotherapy (SRT), using a static and a dynamic micromultileaf collimator and intensity-modulated RT (IMRS). A planning CT scan was performed on a brain metastasis patient, with a 3-mm acquisition slice spacing and the patient looking at a luminous spot with the eyes in three different positions (neutral and 25 degrees right and left). Four different gross tumor volumes were defined for each treatment technique. These target scenarios represented different locations (involving vs. not involving the macula and temporal vs. nasal) and volumes (10 x 6 mm vs. 16 x 10 mm) to challenge the proton and photon treatment techniques. The planning target volume was defined as the gross tumor volume plus 2 mm laterally and 3 mm craniocaudally for both modalities. A dose homogeneity of 95-99% of the planning target volume was used as the "goal" for all techniques. The dose constraint (maximum) for the organs at risk (OARs) for both the proton and the SRT photon plans was 27.5, 22.5, 20, and 9 CGE-Gy for the optic apparatus, retina, lacrimal gland, and lens, respectively. The dose to the planning target volume was 50 CGE-Gy in 10 CGE-Gy daily fractions. The plans for proton and photon therapy were computed using the Paul Scherrer Institute and BrainSCAN, version 5.2 (BrainLAB, Heimstetten, Germany) treatment planning systems, respectively. Tumor and OARs dose-volume histograms were calculated. The results were analyzed using the dose-volume histogram parameters, conformity index (CI(95%)), and inhomogeneity coefficient. Target coverage of all simulated uveal melanomas was equally conformal with the photon and proton modalities. The median CI(95%) value was 1.74, 1.86, and 1.83 for the static, dynamic, and IMSRT plans, respectively. With proton planning, the median CI(95%) was 1.88 for OPTIS and substantially improved with IMPT in some tumor cases (median CI(95%), 1.29). The tumor dose homogeneity in the proton plans was, however, always better than with SRT photon planning (median inhomogeneity coefficient 0.1 and 0.15 vs. 0.46, 0.41, and 0.23 for the OPTIS and IMPT vs. the static, dynamic, and IMSRT plans, respectively). Compared with the photon plans, the use of protons did not lead to a substantial reduction in the homolateral OAR total integral dose in the low- to high-dose level, except for the lacrimal gland. The median maximal dose and dose at the 10% volume with the static, dynamic, and IMSRT plans was 33-30.8, 31.8-28, and 35.8-49 Gy, respectively, for the lacrimal gland, a critical organ. For protons, only the OPTIS plans were better, with a median maximal dose and dose at the 10% volume using OPTIS and IMPT of 19.2 and 8.8 and 25.6 and 23.6 CGE, respectively. The contralateral OARs were completely spared with the proton plans, but the median dose delivered to these structures was 1.2 Gy (range, 0-6.3 Gy) with the SRT photon plans. These results suggest that the use of SRT photon techniques, compared with protons, can result in similar levels of dose conformation. IMPT did not increase the degree of conformality for this small tumor. Tumor dose inhomogeneity was, however, always increased with photon planning. Except for the lacrimal gland, the use of protons, with or without intensity modulation, did not increase homolateral OAR dose sparing. The dose to all the contralateral OARs was, however, completely eliminated with proton planning.

SF3B1 mutations constitute a novel therapeutic target in breast cancer

PubMed Central

Maguire, Sarah L; Leonidou, Andri; Wai, Patty; Marchiò, Caterina; Ng, Charlotte KY; Sapino, Anna; Salomon, Anne-Vincent; Reis-Filho, Jorge S; Weigelt, Britta; Natrajan, Rachael C

2015-01-01

Mutations in genes encoding proteins involved in RNA splicing have been found to occur at relatively high frequencies in several tumour types including myelodysplastic syndromes, chronic lymphocytic leukaemia, uveal melanoma, and pancreatic cancer, and at lower frequencies in breast cancer. To investigate whether dysfunction in RNA splicing is implicated in the pathogenesis of breast cancer, we performed a re-analysis of published exome and whole genome sequencing data. This analysis revealed that mutations in spliceosomal component genes occurred in 5.6% of unselected breast cancers, including hotspot mutations in the SF3B1 gene, which were found in 1.8% of unselected breast cancers. SF3B1 mutations were significantly associated with ER-positive disease, AKT1 mutations, and distinct copy number alterations. Additional profiling of hotspot mutations in a panel of special histological subtypes of breast cancer showed that 16% and 6% of papillary and mucinous carcinomas of the breast harboured the SF3B1 K700E mutation. RNA sequencing identified differentially spliced events expressed in tumours with SF3B1 mutations including the protein coding genes TMEM14C, RPL31, DYNL11, UQCC, and ABCC5, and the long non-coding RNA CRNDE. Moreover, SF3B1 mutant cell lines were found to be sensitive to the SF3b complex inhibitor spliceostatin A and treatment resulted in perturbation of the splicing signature. Albeit rare, SF3B1 mutations result in alternative splicing events, and may constitute drivers and a novel therapeutic target in a subset of breast cancers. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID:25424858

[Visual impairment and blindness in children in a Malawian school for the blind].

PubMed

Schulze Schwering, M; Nyrenda, M; Spitzer, M S; Kalua, K

2013-08-01

The aim of this study was to determine the anatomic sites of severe visual impairment and blindness in children in an integrated school for the blind in Malawi, and to compare the results with those of previous Malawian blind school studies. Children attending an integrated school for the blind in Malawi were examined in September 2011 using the standard WHO/PBL eye examination record for children with blindness and low vision. Visual acuity [VA] of the better eye was classified using the standardised WHO reporting form. Fifty-five pupils aged 6 to 19 years were examined, 39 (71 %) males, and 16 (29 %) females. Thirty eight (69%) were blind [BL], 8 (15 %) were severely visually impaired [SVI], 8 (15 %) visually impaired [VI], and 1 (1.8 %) was not visually impaired [NVI]. The major anatomic sites of visual loss were optic nerve (16 %) and retina (16 %), followed by lens/cataract (15 %), cornea (11 %) and lesions of the whole globe (11 %), uveal pathologies (6 %) and cortical blindness (2 %). The exact aetiology of VI or BL could not be determined in most children. Albinism accounted for 13 % (7/55) of the visual impairments. 24 % of the cases were considered to be potentially avoidable: refractive amblyopia among pseudophakic patients and corneal scaring. Optic atrophy, retinal diseases (mostly albinism) and cataracts were the major causes of severe visual impairment and blindness in children in an integrated school for the blind in Malawi. Corneal scarring was now the fourth cause of visual impairment, compared to being the commonest cause 35 years ago. Congenital cataract and its postoperative outcome were the commonest remedial causes of visual impairment. Georg Thieme Verlag KG Stuttgart · New York.

Comparison between beta radiation dose distribution due to LDR and HDR ocular brachytherapy applicators using GATE Monte Carlo platform.

PubMed

Mostafa, Laoues; Rachid, Khelifi; Ahmed, Sidi Moussa

2016-08-01

Eye applicators with 90Sr/90Y and 106Ru/106Rh beta-ray sources are generally used in brachytherapy for the treatment of eye diseases as uveal melanoma. Whenever, radiation is used in treatment, dosimetry is essential. However, knowledge of the exact dose distribution is a critical decision-making to the outcome of the treatment. The Monte Carlo technique provides a powerful tool for calculation of the dose and dose distributions which helps to predict and determine the doses from different shapes of various types of eye applicators more accurately. The aim of this work consisted in using the Monte Carlo GATE platform to calculate the 3D dose distribution on a mathematical model of the human eye according to international recommendations. Mathematical models were developed for four ophthalmic applicators, two HDR 90Sr applicators SIA.20 and SIA.6, and two LDR 106Ru applicators, a concave CCB model and a flat CCB model. In present work, considering a heterogeneous eye phantom and the chosen tumor, obtained results with the use of GATE for mean doses distributions in a phantom and according to international recommendations show a discrepancy with respect to those specified by the manufacturers. The QC of dosimetric parameters shows that contrarily to the other applicators, the SIA.20 applicator is consistent with recommendations. The GATE platform show that the SIA.20 applicator present better results, namely the dose delivered to critical structures were lower compared to those obtained for the other applicators, and the SIA.6 applicator, simulated with MCNPX generates higher lens doses than those generated by GATE. Copyright © 2016 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Multi-channel MRI segmentation of eye structures and tumors using patient-specific features

PubMed Central

Ciller, Carlos; De Zanet, Sandro; Kamnitsas, Konstantinos; Maeder, Philippe; Glocker, Ben; Munier, Francis L.; Rueckert, Daniel; Thiran, Jean-Philippe

2017-01-01

Retinoblastoma and uveal melanoma are fast spreading eye tumors usually diagnosed by using 2D Fundus Image Photography (Fundus) and 2D Ultrasound (US). Diagnosis and treatment planning of such diseases often require additional complementary imaging to confirm the tumor extend via 3D Magnetic Resonance Imaging (MRI). In this context, having automatic segmentations to estimate the size and the distribution of the pathological tissue would be advantageous towards tumor characterization. Until now, the alternative has been the manual delineation of eye structures, a rather time consuming and error-prone task, to be conducted in multiple MRI sequences simultaneously. This situation, and the lack of tools for accurate eye MRI analysis, reduces the interest in MRI beyond the qualitative evaluation of the optic nerve invasion and the confirmation of recurrent malignancies below calcified tumors. In this manuscript, we propose a new framework for the automatic segmentation of eye structures and ocular tumors in multi-sequence MRI. Our key contribution is the introduction of a pathological eye model from which Eye Patient-Specific Features (EPSF) can be computed. These features combine intensity and shape information of pathological tissue while embedded in healthy structures of the eye. We assess our work on a dataset of pathological patient eyes by computing the Dice Similarity Coefficient (DSC) of the sclera, the cornea, the vitreous humor, the lens and the tumor. In addition, we quantitatively show the superior performance of our pathological eye model as compared to the segmentation obtained by using a healthy model (over 4% DSC) and demonstrate the relevance of our EPSF, which improve the final segmentation regardless of the classifier employed. PMID:28350816

[Clinical characteristics of paraneoplastic retinopathy and optic neuropathy].

PubMed

Huang, Hou-bin; Wei, Shi-hui; Li, Ying; Wang, Feng-xiang; Yao, Yi; Jiang, Cai-hui; Yin, Zheng-qin; Zhang, Mao-nian; Wei, Wen-bin

2013-06-01

To analyze the clinical characteristics of paraneoplastic retinopathy and optic neuropathy(PRON). Case series study. Eight patients were enrolled from October 2006 to March 2012 visited in ophthalmology department, the People Liberation Army General Hospital. The patients were underwent a series of examinations, including fundus photography, visual electrophysiology, fundus fluorescein angiography, optic coherent tomography,fundus autofluorescent imaging, perimetry, ultrasonography, magnetic resonance imaging, spinal tap and cerebrospinal fluid test, paraneoplastic syndrome (PNS) antibody test. The patients were followed up in outpatient department and(or) by phone. The clinical manifestation,entity types, and treatment were analyzed. Of the eight patients, there were cancer associated retinopathy(CAR) 3 cases, bilateral diffuse uveal melanocytic proliferation (BDUMP) 2 cases and paraneoplastic optic neuropathy(PON) 3 cases. Five patients were detected the PNS antibodies and revealed three patients with positive results. As for the primary malignancy,four of the eight patients were lung carcinoma,others included invasive thymoma, kidney cancer, acute lymphocytic leukemia and cervical cancer, each for one case. All the patients complained vision blurring or progressive visual decrease. Other complaints included dark shadow in two patients, shimmering, dazzling, double vision and eye pain, each in one patient. One patient complained progressive decreased vision in both eyes prior to the diagnosis of lung cancer. Of the 16 eyes of the eight patients, there were six patients with no light perception vision, five from light perception to 0.05, and other five with no less than 0.4 vision, in the end of the follow up. Five patients were treated with steroid with unsatisfactory efficacy. Each entity of PRON has its own clinical characteristics. PRON especially BDUMP may be a pre-metastatic disease.

Waardenburg syndrome: iris and choroidal hypopigmentation: findings on anterior and posterior segment imaging.

PubMed

Shields, Carol L; Nickerson, Stephanie J; Al-Dahmash, Saad; Shields, Jerry A

2013-09-01

Waardenburg syndrome typically manifests with congenital iris pigmentary abnormalities, but careful inspection can reveal additional posterior uveal pigmentary abnormalities. To demonstrate iris and choroidal hypopigmentation in patients with Waardenburg syndrome. Retrospective review of 7 patients referred for evaluation of presumed ocular melanocytosis. To describe the clinical and imaging features of the anterior and posterior uvea. In all patients, the diagnosis of Waardenburg syndrome was established. The nonocular features included white forelock in 4 of 7 (57%), tubular nose in 5 of 6 (83%), and small nasal alae in 5 of 6 (83%) patients. In 2 patients, a hearing deficit was documented on audiology testing. Family history of Waardenburg syndrome was elicited in 5 of 7 (71%) patients. Ocular features (7 patients) included telecanthus in 5 (71%), synophrys in 2 (29%), iris hypopigmentation in 5 (71%), and choroidal hypopigmentation in 5 (71%) patients. No patient had muscle contractures or Hirschsprung disease. Visual acuity was 20/20 to 20/50 in all patients. Iris hypopigmentation in 8 eyes was sector in 6 (75%) and diffuse (complete) in 2 (25%). Choroidal hypopigmentation in 9 eyes (100%) showed a sector pattern in 6 (67%) and a diffuse pattern in 3 (33%). Anterior segment optical coherence tomography revealed the hypopigmented iris to be thinner and with shallower crypts than the normal iris. Posterior segment optical coherence tomography showed a normal retina in all patients, but the subfoveal choroid in the hypopigmented region was slightly thinner (mean, 197 μm) compared with the opposite normal choroid (243 μm). Fundus autofluorescence demonstrated mild hyperautofluorescence (scleral unmasking) in hypopigmented choroid and no lipofuscin abnormality. Waardenburg syndrome manifests hypopigmentation of the iris and choroid with imaging features showing a slight reduction in the thickness of the affected tissue.

Histopathologic and mutational analysis of a case of blue nevus-like melanoma.

PubMed

Dai, Julia; Tetzlaff, Michael T; Schuchter, Lynn M; Elder, David E; Elenitsas, Rosalie

2016-09-01

Blue nevi are a heterogeneous group of dermal melanocytic proliferations that share a common clinical appearance but remain controversial in their histopathologic and biologic distinction. While common blue nevi and cellular blue nevi are well-defined entities that are classified without significant controversy, the distinction between atypical cellular blue nevi and blue nevus-like melanoma remains diagnostically challenging. We report a case of a 46-year-old female with recurrent blue nevus-like melanoma of the scalp with liver metastases; mutational analysis showed GNA11 Q209L and BAP1 Q393 mutations. To our knowledge, this is the first case of blue nevus-like melanoma with GNA11 and BAP1 mutations. These particular mutations and the predilection for liver metastases in our patient's case underscore a fundamental biological relationship between blue nevi and uveal melanoma and suggest the two entities may prove amenable to similar diagnostic and prognostic testing and targeted therapies. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Genetic evolution of nevus of Ota reveals clonal heterogeneity acquiring BAP1 and TP53 mutations.

PubMed

Vivancos, Ana; Caratú, Ginevra; Matito, Judit; Muñoz, Eva; Ferrer, Berta; Hernández-Losa, Javier; Bodet, Domingo; Pérez-Alea, Mileidys; Cortés, Javier; Garcia-Patos, Vicente; Recio, Juan A

2016-03-01

Melanoma presents molecular alterations based on its anatomical location and exposure to environmental factors. Due to its intrinsic genetic heterogeneity, a simple snapshot of a tumor's genetic alterations does not reflect the tumor clonal complexity or specific gene-gene cooperation. Here, we studied the genetic alterations and clonal evolution of a unique patient with a Nevus of Ota that developed into a recurring uveal-like dermal melanoma. The Nevus of Ota and ulterior lesions contained GNAQ mutations were c-KIT positive, and tumors showed an increased RAS pathway activity during progression. Whole-exome sequencing of these lesions revealed the acquisition of BAP1 and TP53 mutations during tumor evolution, thereby unmasking clonal heterogeneity and allowing the identification of cooperating genes within the same tumor. Our results highlight the importance of studying tumor genetic evolution to identify cooperating mechanisms and delineate effective therapies. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The utility of ultrasound in patients with melanoma.

PubMed

Uren, Roger F; Sanki, Amira; Thompson, John F

2007-11-01

The highest quality gray-scale ultrasound images are obtained with high-frequency transducers; however, such high frequencies do not penetrate more than a few centimeters into body tissue. Fortunately, in patients with melanoma, the structures of interest are close to the skin surface, making them ideal targets for examination with high-resolution ultrasound. These include primary cutaneous melanomas, uveal melanomas and the regional lymph nodes draining the skin that lie in the axilla, groin, neck and other locations. Although ultrasound study of primary melanomas arising in the skin and eye has provided some insights, a major role for ultrasound has evolved recently, to provide early detection of metastatic melanoma in regional lymph nodes. Ultrasound is clearly superior to clinical palpation of the nodes during follow-up and, when combined with guided fine-needle biopsy, allows the earliest possible surgical intervention for regional nodal metastases. In the future the use of ultrasound contrast agents may improve the sensitivity of ultrasound in the detection of very small metastatic deposits.

[Effect of Mn(II) on the error-prone DNA polymerase iota activity in extracts from human normal and tumor cells].

PubMed

Lakhin, A V; Efremova, A S; Makarova, I V; Grishina, E E; Shram, S I; Tarantul, V Z; Gening, L V

2013-01-01

The DNA polymerase iota (Pol iota), which has some peculiar features and is characterized by an extremely error-prone DNA synthesis, belongs to the group of enzymes preferentially activated by Mn2+ instead of Mg2+. In this work, the effect of Mn2+ on DNA synthesis in cell extracts from a) normal human and murine tissues, b) human tumor (uveal melanoma), and c) cultured human tumor cell lines SKOV-3 and HL-60 was tested. Each group displayed characteristic features of Mn-dependent DNA synthesis. The changes in the Mn-dependent DNA synthesis caused by malignant transformation of normal tissues are described. It was also shown that the error-prone DNA synthesis catalyzed by Pol iota in extracts of all cell types was efficiently suppressed by an RNA aptamer (IKL5) against Pol iota obtained in our work earlier. The obtained results suggest that IKL5 might be used to suppress the enhanced activity of Pol iota in tumor cells.

Lack of detection of feline leukemia and feline sarcoma viruses in diffuse iris melanomas of cats by immunohistochemistry and polymerase chain reaction.

PubMed

Cullen, Cheryl L; Haines, Deborah M; Jackson, Marion L; Grahn, Bruce H

2002-07-01

Diffuse iris melanoma was confirmed by light-microscopic examination in 10 formalin-fixed, paraffin-embedded globes from 10 cats. To determine if feline leukemia virus or a replication defective feline leukemia virus, feline sarcoma virus, was present in these anterior uveal melanomas, immunohistochemistry and polymerase chain reaction for feline leukemia virus were utilized. Immunohistochemical staining for feline leukemia virus glycoprotein 70 was performed on all 10 tumors using an avidin-biotin complex technique. The DNA was extracted from each specimen and a 166-base pair region of the feline leukemia virus long terminal repeat was targeted by polymerase chain reaction. Immunohistochemical staining for feline leukemia virus glycoprotein 70 and polymerase chain reaction amplification of a feline leukemia virus long terminal repeat region were negative in all cases. Feline leukemia virus/feline sarcoma virus was not detected in any neoplasms and therefore was unlikely to play a role in the tumorigenesis of these feline diffuse iris melanomas.

Multi-dimensional dosimetric verification of stereotactic radiotherapy for uveal melanoma using radiochromic EBT film.

PubMed

Sturtewagen, Eva; Fuss, Martina; Paelinck, Leen; De Wagter, Carlos; Georg, Dietmar

2008-01-01

Since 1997, linac based stereotactic radiotherapy (SRT) of uveal melanoma has been continuously developed at the Department of Radiotherapy, Medical University Vienna. The aim of the present study was (i) to test a new type of radiochromic film (Gafchromic EBT) for dosimetric verification of class solutions for these treatments and (ii) to verify treatment plan acceptance criteria, which are based on gamma values statisitcs. An EPSON Expression 1680 Pro flat bed scanner was utilized for film reading. To establish a calibration curve, films were cut in squares of 2 x 2 cm2, positioned at 5 cm depth in a solid water phantom and were irradiated with different dose levels (0.5 and 5 Gy) in a 5 x 5 cm2 field at 6 MV. A previously developed solid phantom (polystyrene) was used with overall dimensions corresponding to an average human head. EBT films were placed at four different depths (10, 20, 25 and 30 mm) and all films were irradiated simultaneously. Four different treatment plans were verified that resemble typical clinical situations. These plans differed in irradiation technique (conformal mMLC or circular arc SRT) and in tumour size (PTV of 1 or 2.5 cm3). In-house developed software was applied to calculate gamma (gamma) index values and to perform several statistical operations (e.g. gamma-area histograms). At depths of 10 mm gamma1%, (gamma-value where 1% of the points have an equal or higher value in the region of interest) were between 1-3 and maximum gamma > 1 (% of gamma-values > 1 in the region of interest) areas were almost 30%. At larger depths, i.e. more close to the isocenter, gamma 1% was < 1 and gamma > 1 areas were mostly < 5%. Average gamma values were about 0.5. Besides the compromised accuracy in the buildup region, previously defined IMRT acceptance criteria [Stock et al., Phys. Med Biol. 50 (2005) 399-411] could be applied as well to SRT. Radiochromic EBT films, in combination with a flat-bed scanner, were found to be an ideal multidimensional dosimetric tool for treatment plan quality assurance. EBT films are a suitable and reliable dosimetric tool that could replace traditionally used radiographic films. The presented acceptance criteria for SRT treatment plans might be used as a benchmarking data-set for other stereotactic applications and/or other equipment (planning system and delivery hardware) combinations.

Dosimetric properties of a proton beamline dedicated to the treatment of ocular disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Slopsema, R. L., E-mail: rslopsema@floridaproton.org; Mamalui, M.; Yeung, D.

2014-01-15

Purpose: A commercial proton eyeline has been developed to treat ocular disease. Radiotherapy of intraocular lesions (e.g., uveal melanoma, age-related macular degeneration) requires sharp dose gradients to avoid critical structures like the macula and optic disc. A high dose rate is needed to limit patient gazing times during delivery of large fractional dose. Dose delivery needs to be accurate and predictable, not in the least because current treatment planning algorithms have limited dose modeling capabilities. The purpose of this paper is to determine the dosimetric properties of a new proton eyeline. These properties are compared to those of existing systemsmore » and evaluated in the context of the specific clinical requirements of ocular treatments. Methods: The eyeline is part of a high-energy, cyclotron-based proton therapy system. The energy at the entrance of the eyeline is 105 MeV. A range modulator (RM) wheel generates the spread-out Bragg peak, while a variable range shifter system adjusts the range and spreads the beam laterally. The range can be adjusted from 0.5 up to 3.4 g/cm{sup 2}; the modulation width can be varied in steps of 0.3 g/cm{sup 2} or less. Maximum field diameter is 2.5 cm. All fields can be delivered with a dose rate of 30 Gy/min or more. The eyeline is calibrated according to the IAEA TRS-398 protocol using a cylindrical ionization chamber. Depth dose distributions and dose/MU are measured with a parallel-plate ionization chamber; lateral profiles with radiochromic film. The dose/MU is modeled as a function of range, modulation width, and instantaneous MU rate with fit parameters determined per option (RM wheel). Results: The distal fall-off of the spread-out Bragg peak is 0.3 g/cm{sup 2}, larger than for most existing systems. The lateral penumbra varies between 0.9 and 1.4 mm, except for fully modulated fields that have a larger penumbra at skin. The source-to-axis distance is found to be 169 cm. The dose/MU shows a strong dependence on range (up to 4%/mm). A linear increase in dose/MU as a function of instantaneous MU rate is observed. The dose/MU model describes the measurements with an accuracy of ±2%. Neutron dose is found to be 146 ± 102 μSv/Gy at the contralateral eye and 19 ± 13 μSv/Gy at the chest. Conclusions: Measurements show the proton eyeline meets the requirements to effectively treat ocular disease.« less

Significance of the /sup 32/P uptake test in the diagnosis of posterior uveal melanomas

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shields, J.A.; Hagler, W.S.; Federman, J.L.

Several reports in the ophthalmic literature have emphasized the difficulties which may occur in the clinical diagnosis of malignant melanomas of the posterior uvea. As a result of such difficulties, the radioactive phosphorus uptake test (/sup 32/P) was introduced into ophthalmology a number of years ago as a diagnostic adjunct. One of the early problems encountered by physicians utilizing this test was the inability to localize accurately and place the probe over lesions in the posterior segment of the globe. Although certain investigators attempted to use a conjunctival incision and curved probe for gaining access to these posterior lesions, themore » test eventually fell into disfavor. Between 1965 and 1970, articles on this test became scarce in the ophthalmic literature. In 1970, Hagler et al. reintroduced the test into ophthalmology with emphasis on careful localization of the lesion with indirect ophthalmoscopy, a conjunctival incision, and a curved probe for evaluating posteriorly located lesions. Subsequently, the test has enjoyed increasing popularity and is now being utilized with enthusiasm in a number of centers.« less

Bilateral chorioretinal coloboma discovered with ultra-wide field retinal imaging

PubMed Central

Barnard, Simon; Shneor, Einat; Brauner, Joel; Millodot, Michel; Gordon-Shaag, Ariela

2012-01-01

Uveal coloboma results from incomplete closure of the optic cup fissure. While conducting an evaluation of a new ultra-wide field retinal imaging camera (Optomap), which provides a view of the fundus up to 200° at one time without mydriasis, we discovered a case of bilateral chorioretinal coloboma in a 21-year-old student. The lesion was located in the midperiphery of each eye less than 2 disc diameters (DD) below the optic disc in the inferonasal quadrants. The size of the coloboma in the right eye was 1.8 DD in height and 1.3 DD in width, while the left lesion was 2.4 DD in height and 2.6 DD in width. The subject was totally asymptomatic and without any complication such as retinal detachment or choroidal neovascularization, which often accompany this type of lesion. The visual field of each eye displayed an absolute scotoma corresponding to the size and location of the coloboma. No management was necessary but the subject was advised to report for visual examination at regular intervals because complications can occur at any age.

Changing trends over the last decade in the aetiology of childhood blindness: a study from a tertiary referral centre.

PubMed

Ozturk, Taylan; Er, Duygu; Yaman, Aylin; Berk, A Tulin

2016-02-01

To discern treatable and preventable causes of childhood blindness by evaluating the aetiologic factors, and to compare the distribution of the most commonly affected anatomic sites of severe visual impairment (SVI) with our previous published data. The charts of 11 871 patients followed between June 2002 and May 2014 were reviewed retrospectively, and 695 patients (5.9%) who had SVI or blindness in accordance with WHO criteria were enrolled. The results of ophthalmologic examinations and coexistence of any systemic disease were documented and checked against our published clinic data concerning the aetiology of childhood blindness before 2002. χ(2) test was used for statistics. Mean age was 47.0±51.9 months (median: 24 months). Cortical visual impairment (CVI) was present in 212 cases (30.5%) and 20.3% of those had a history of premature birth. The most common anatomic sites of SVI were retina (24.6%) and crystalline lens (17.1%). When compared with our previous data, we found a significant increase in the prevalence of CVI (p=0.046) and decrease in the frequency of SVI due to uveal disorders (p<0.001). Prevalence of blindness secondary to retinopathy of prematurity reduced by a third (p=0.280), and a significant decrease in aphakia-related SVI (p=0.028) was achieved within the last decade. The prevalence of CVI was found to be relatively increased due to the significant reduction in the frequency of preventable causes of SVI. Furthermore our clinical practice for visual rehabilitation in aphakia has resulted in a considerable decrease in SVI in the last decade. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Epidemiological evidence for an association between use of wireless phones and tumor diseases.

PubMed

Hardell, Lennart; Carlberg, Michael; Hansson Mild, Kjell

2009-08-01

During recent years there has been increasing public concern on potential cancer risks from microwave emissions from wireless phones. We evaluated the scientific evidence for long-term mobile phone use and the association with certain tumors in case-control studies, mostly from the Hardell group in Sweden and the Interphone study group. Regarding brain tumors the meta-analysis yielded for glioma odds ratio (OR)=1.0, 95% confidence interval (CI)=0.9-1.1. OR increased to 1.3, 95% CI=1.1-1.6 with 10 year latency period, with highest risk for ipsilateral exposure (same side as the tumor localisation), OR=1.9, 95% CI=1.4-2.4, lower for contralateral exposure (opposite side) OR=1.2, 95% CI=0.9-1.7. Regarding acoustic neuroma OR=1.0, 95% CI=0.8-1.1 was calculated increasing to OR=1.3, 95% CI=0.97-1.9 with 10 year latency period. For ipsilateral exposure OR=1.6, 95% CI=1.1-2.4, and for contralateral exposure OR=1.2, 95% CI=0.8-1.9 were found. Regarding meningioma no consistent pattern of an increased risk was found. Concerning age, highest risk was found in the age group <20 years at time of first use of wireless phones in the studies from the Hardell group. For salivary gland tumors, non-Hodgkin lymphoma and testicular cancer no consistent pattern of an association with use of wireless phones was found. One study on uveal melanoma yielded for probable/certain mobile phone use OR=4.2, 95% CI=1.2-14.5. One study on intratemporal facial nerve tumor was not possible to evaluate due to methodological shortcomings. In summary our review yielded a consistent pattern of an increased risk for glioma and acoustic neuroma after >10 year mobile phone use. We conclude that current standard for exposure to microwaves during mobile phone use is not safe for long-term exposure and needs to be revised.

Herpes zoster ophthalmicus.

PubMed

Sanjay, Srinivasan; Huang, Philemon; Lavanya, Raghavan

2011-02-01

The management of herpes zoster (HZ) usually involves a multidisciplinary approach aiming to reduce complications and morbidity. Patients with herpes zoster ophthalmicus (HZO) are referred to ophthalmologists for prevention or treatment of its potential complications. Without prompt detection and treatment, HZO can lead to substantial visual disability. In our practice, we usually evaluate patients with HZO for corneal complications such as epithelial, stromal, and disciform keratitis; anterior uveitis; necrotizing retinitis; and cranial nerve palsies in relation to the eye. These are acute and usually sight-threatening. We recommend oral acyclovir in conjunction with topical 3% acyclovir ointment, lubricants, and steroids for conjunctival, corneal, and uveal inflammation associated with HZO. Persistent vasculitis and neuritis may result in chronic ocular complications, the most important of which are neurotrophic keratitis, mucus plaque keratitis, and lipid degeneration of corneal scars. Postherpetic complications, especially postherpetic neuralgia (PHN), are observed in well over half of patients with HZO. The severe, debilitating, chronic pain of PHN is treated locally with cold compresses and lidocaine cream (5%). These patients also receive systemic treatment with NSAIDs, and our medical colleagues cooperate in managing their depression and excruciating pain. Pain is the predominant symptom in all phases of HZ disease, being reported by up to 90% of patients. Ocular surgery for HZO-related complications is performed only after adequately stabilizing pre-existing ocular inflammation, raised intraocular pressure, dry eye, neurotrophic keratitis, and lagophthalmos. Cranial nerve palsies are common and most often involve the facial nerve, although palsy of the oculomotor, trochlear, and abducens nerves may occur in isolation or (rarely) simultaneously. In our setting, complete ophthalmoplegia is seen more often than isolated palsies, but recovery is usually complete. Vasculitis within the orbital apex (orbital apex syndrome) or brainstem dysfunction is postulated to be the cause of cranial nerve palsies. A vaccine of a lyophilized preparation of the oka strain of live, attenuated varicella-zoster virus is suggested for patients who are at risk of developing HZ and has been shown to boost immunity against HZ virus in older patients.

Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral, Small-Molecule Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor AZD6244 (ARRY-142886) in Patients With Advanced Cancers

PubMed Central

Adjei, Alex A.; Cohen, Roger B.; Franklin, Wilbur; Morris, Clive; Wilson, David; Molina, Julian R.; Hanson, Lorelei J.; Gore, Lia; Chow, Laura; Leong, Stephen; Maloney, Lara; Gordon, Gilad; Simmons, Heidi; Marlow, Allison; Litwiler, Kevin; Brown, Suzy; Poch, Gregory; Kane, Katie; Haney, Jerry; Eckhardt, S. Gail

2009-01-01

Purpose To assess the tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancer. Patients and Methods In part A, patients received escalating doses to determine the maximum-tolerated dose (MTD). In both parts, blood samples were collected to assess PK and PD parameters. In part B, patients were stratified by cancer type (melanoma v other) and randomly assigned to receive the MTD or 50% MTD. Biopsies were collected to determine inhibition of ERK phosphorylation, Ki-67 expression, and BRAF, KRAS, and NRAS mutations. Results Fifty-seven patients were enrolled. MTD in part A was 200 mg bid, but this dose was discontinued in part B because of toxicity. The 50% MTD (100 mg bid) was well tolerated. Rash was the most frequent and dose-limiting toxicity. Most other adverse events were grade 1 or 2. The PKs were less than dose proportional, with a median half-life of approximately 8 hours and inhibition of ERK phosphorylation in peripheral-blood mononuclear cells at all dose levels. Paired tumor biopsies demonstrated reduced ERK phosphorylation (geometric mean, 79%). Five of 20 patients demonstrated ≥ 50% inhibition of Ki-67 expression, and RAF or RAS mutations were detected in 10 of 26 assessable tumor samples. Nine patients had stable disease (SD) for ≥ 5 months, including two patients with SD for 19 (thyroid cancer) and 22 (uveal melanoma plus renal cancer) 28-day cycles. Conclusion AZD6244 was well tolerated with target inhibition demonstrated at the recommended phase II dose. PK analyses supported twice-daily dosing. Prolonged SD was seen in a variety of advanced cancers. Phase II studies are ongoing. PMID:18390968

Genetic findings in treatment-naïve and proton-beam-radiated iris melanomas.

PubMed

Krishna, Yamini; Kalirai, Helen; Thornton, Sophie; Damato, Bertil E; Heimann, Heinrich; Coupland, Sarah E

2016-07-01

Iris melanomas (IM) are rare and have a lower mortality than posterior uveal melanomas (UM). Our aims were to determine the prevalence of genetic changes associated with prognosis of posterior UM, in both treated and non-treated IM. Retrospective database review and molecular analysis of all patients diagnosed with IM at the Liverpool Ocular Oncology Centre (LOOC) between 1993 and 2015. Archival pathology specimens of confirmed IM cases were analysed for chromosomal alterations, using multiplex ligation-dependent probe amplification (MLPA) or microsatellite analysis (MSA) depending on DNA yield, and BRAF mutation status. 5189 patients were diagnosed with intraocular melanoma at LOOC from 1993 to 2015. Of these, 303 (5.8%) patients were diagnosed with IM. Tissue samples were available for 26 IM cases. Twelve of these cases had biopsies taken post-proton beam radiotherapy (PBR). Histological subtyping showed 14 IM being spindle, 2 epithelioid and 10 were of mixed cell type. Twenty of the 26 IM cases (77%) analysed genetically were classified as either disomy 3 (n=16) or monosomy 3 (n=4). Chromosome 6p gain was detected in 4/18 (22%) IM, and polysomy 8q in 6%. BRAF mutations were not detected in any of the four IM cases examined. One patient with IM died from metastatic disease: this tumour was disomy 3 with 6p and 8q gains. All other patients were alive with no evidence of metastases at study closure. Chromosomal aberrations seen in posterior UM can also be demonstrated using MLPA or MSA in both treatment naïve and PBR-treated IM. Most IM display a low-metastatic risk chromosomal profile. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Histomorphologic spectrum of BAP1 negative melanocytic neoplasms in a family with BAP1-associated cancer susceptibility syndrome.

PubMed

Marušić, Zlatko; Buljan, Marija; Busam, Klaus J

2015-06-01

Multiple BAP1 negative melanocytic neoplasms are a hallmark of familial cancer susceptibility syndrome caused by BAP1 germline mutation. The syndrome is characterized by increased incidence of renal cell carcinoma, mesothelioma, cholangiocarcinoma, cutaneous and uveal melanoma and some other neoplasms. We report histomorphologic characteristics of six cutaneous melanocytic neoplasms with loss of BAP1 expression in two members of a family with BAP1-associated cancer susceptibility syndrome. The neoplasms were dermal melanocytic nevi characterized by a proliferation of large epithelioid (spitzoid) melanocytes, and adipocytic metaplasia. Nuclear pseudoinclusions and multinucleated melanocytes were present in most neoplasms. In two of the cases, a nodular melanoma was found associated with a dermal nevus. None of the melanomas recurred or metastasized after 6 and 3 years of follow up. We report two new cases of melanoma arising in a BAP1-deficient melanocytic nevus in the setting of familial tumor predisposition syndrome. Adipocytic metaplasia and nuclear pseudoinclusions may be additional morphologic clues to a BAP1-deficient nevus. It remains to be seen whether these features are more common in familial than sporadic lesions. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

GNAq mutations are not identified in papillary thyroid carcinomas and hyperfunctioning thyroid nodules.

PubMed

Cassol, Clarissa A; Guo, Miao; Ezzat, Shereen; Asa, Sylvia L

2010-12-01

Activating mutations of GNAq protein in a hotspot at codon 209 have been recently described in uveal melanomas. Since these neoplasms share with thyroid carcinomas a high frequency of MAP kinase pathway-activating mutations, we hypothesized whether GNAq mutations could also play a role in the development of thyroid carcinomas. Additionally, activating mutations of another subtype of G protein (GNAS1) are frequently found in hyperfunctioning thyroid adenomas, making it plausible that GNAq-activating mutations could also be found in some of these nodules. To investigate thyroid papillary carcinomas and thyroid hyperfunctioning nodules for GNAq mutations in exon 5, codon 209, a total of 32 RET/PTC, BRAF, and RAS negative thyroid papillary carcinomas and 13 hyperfunctioning thyroid nodules were evaluated. No mutations were identified. Although plausible, GNAq mutations seem not to play an important role in the development of thyroid follicular neoplasms, either benign hyperfunctioning nodules or malignant papillary carcinomas. Our results are in accordance with the literature, in which no GNAq hotspot mutations were found in thyroid papillary carcinomas, as well as in an extensive panel of other tumors. The molecular basis for MAP-kinase pathway activation in RET-PTC/BRAF/RAS negative thyroid carcinomas remains to be determined.

Lacrimal Gland Radiosensitivity in Uveal Melanoma Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Muller, Karin; Nowak, Peter J.C.M.; Naus, Nicole

2009-06-01

Purpose: To find a dose-volume effect for inhomogeneous irradiated lacrimal glands. Methods and Materials: Between 1999 and 2006, 72 patients (42 men and 30 women) were treated with fractionated stereotactic radiotherapy in a prospective, nonrandomized clinical trial (median follow-up, 32 months). A total dose of 50 Gy was given on 5 consecutive days. The mean of all Schirmer test results obtained {>=}6 months after treatment was correlated with the radiation dose delivered to the lacrimal gland. Also, the appearance of dry eye syndrome (DES) was related to the lacrimal gland dose distribution. Results: Of the 72 patients, 17 developed amore » late Schirmer value <10 mm; 9 patients developed DES. A statistically significant relationship was found between the received median dose in the lacrimal gland vs. reduced tear production (p = 0.000) and vs. the appearance of DES (p = 0.003), respectively. A median dose of 7 Gy/fraction to the lacrimal gland caused a 50% risk of low Schirmer results. A median dose of 10 Gy resulted in a 50% probability of DES. Conclusion: We found a clear dose-volume relationship for irradiated lacrimal glands with regard to reduced tear production and the appearance of DES.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Slopsema, R. L., E-mail: rslopsema@floridaproton.org; Mamalui, M.; Yeung, D.

Purpose: A commercial proton eyeline has been developed to treat ocular disease. Radiotherapy of intraocular lesions (e.g., uveal melanoma, age-related macular degeneration) requires sharp dose gradients to avoid critical structures like the macula and optic disc. A high dose rate is needed to limit patient gazing times during delivery of large fractional dose. Dose delivery needs to be accurate and predictable, not in the least because current treatment planning algorithms have limited dose modeling capabilities. The purpose of this paper is to determine the dosimetric properties of a new proton eyeline. These properties are compared to those of existing systemsmore » and evaluated in the context of the specific clinical requirements of ocular treatments. Methods: The eyeline is part of a high-energy, cyclotron-based proton therapy system. The energy at the entrance of the eyeline is 105 MeV. A range modulator (RM) wheel generates the spread-out Bragg peak, while a variable range shifter system adjusts the range and spreads the beam laterally. The range can be adjusted from 0.5 up to 3.4 g/cm{sup 2}; the modulation width can be varied in steps of 0.3 g/cm{sup 2} or less. Maximum field diameter is 2.5 cm. All fields can be delivered with a dose rate of 30 Gy/min or more. The eyeline is calibrated according to the IAEA TRS-398 protocol using a cylindrical ionization chamber. Depth dose distributions and dose/MU are measured with a parallel-plate ionization chamber; lateral profiles with radiochromic film. The dose/MU is modeled as a function of range, modulation width, and instantaneous MU rate with fit parameters determined per option (RM wheel). Results: The distal fall-off of the spread-out Bragg peak is 0.3 g/cm{sup 2}, larger than for most existing systems. The lateral penumbra varies between 0.9 and 1.4 mm, except for fully modulated fields that have a larger penumbra at skin. The source-to-axis distance is found to be 169 cm. The dose/MU shows a strong dependence on range (up to 4%/mm). A linear increase in dose/MU as a function of instantaneous MU rate is observed. The dose/MU model describes the measurements with an accuracy of ±2%. Neutron dose is found to be 146 ± 102 μSv/Gy at the contralateral eye and 19 ± 13 μSv/Gy at the chest. Conclusions: Measurements show the proton eyeline meets the requirements to effectively treat ocular disease.« less

Endogenous Heat-Shock Protein Induction with or Without Radiofrequency Ablation or Cryoablation in Patients with Stage IV Melanoma.

PubMed

Domingo-Musibay, Evidio; Heun, James M; Nevala, Wendy K; Callstrom, Matthew; Atwell, Thomas; Galanis, Evanthia; Erickson, Lori A; Markovic, Svetomir N

2017-09-01

Percutaneous thermal ablation combined with in situ granulocyte-macrophage colony-stimulating factor cytokine therapy was technically feasible and well tolerated.No significant clinical or immunologic responses were seen. Melanoma tumor-derived heat-shock proteins (HSPs) and HSP-peptide complexes can elicit protective antitumor responses. The granulocyte-macrophage colony-stimulating factor (GM-CSF) chemokine can also promote uptake and processing by professional antigen presenting cells (APCs). On this basis, we designed a pilot study of percutaneous thermal ablation as a means to induce heat-shock protein vaccination plus GM-CSF to determine safety and preliminary antitumor activity of this combination. This study was designed to assess overall safety of percutaneous ablation combined with GM-CSF for unresectable, metastatic melanoma including uveal and mucosal types. All patients received heat-shock therapy (42°C for 30 minutes), then received one of three treatments: (a) intralesional GM-CSF (500 mcg standard dose); (b) radiofrequency ablation (RFA) + GM-CSF; or (c) cryoablation plus GM-CSF. The primary endpoint of the study was the induction of endogenous HSP70 and melanoma-specific cytotoxic T lymphocytes (CTL). Nine patients (three per study arm) were enrolled. No dose-limiting toxicity was observed as specified per protocol. All patients developed progressive disease and went on to receive alternative therapy. Median overall survival (OS) was 8.2 months (95% confidence interval [CI] 2-17.2). The study was not powered to detect a difference in clinical outcome among treatment groups. Percutaneous thermal ablation plus GM-CSF was well tolerated, technically feasible, and demonstrated an acceptable adverse event profile comparable to conventional RFA and cryoablation. While HSP70 was induced following therapy, the degree of HSP70 elevation was not associated with clinical outcome or induced CTL responses. While percutaneous thermal ablation plus GM-CSF combinations including checkpoint inhibitors could be considered in future studies, the use of GM-CSF remains experimental and for use in the context of clinical trials. © AlphaMedPress; the data published online to support this summary is the property of the authors.

Apical localization of glutamate in GLAST-1, glutamine synthetase positive ciliary body nonpigmented epithelial cells

PubMed Central

Langford, Marlyn P; Gosslee, Jeffrey M; Liang, Chanping; Chen, Dequan; Redens, Thomas B.; Welbourne, Tomas C

2007-01-01

The distribution of glutamate (Glu), the Glu transporter GLAST-1, and glutamine synthetase (GS) in human and monkey anterior uveal tissue, as well as serum (S) to aqueous humor (AH) Glu and glutamine (Gln) gradients were investigated. Cross-linked Glu (xGlu), GLAST-1, and GS were detected using the immunofluorescent antibody technique. S/AH Glu, Gln, and alanine (Ala) concentrations were quantified by high performance liquid chromatography. xGlu immunoreactivity was detected in melanocytes, posterior pigmented epithelial/dilator muscle cells, vascular endothelial cells, and lymphocytes of the iris, as well as the pigmented (PE) and nonpigmented epithelial (NPE) cells and muscle cells of ciliary body. xGlu immunoreactivity was highly concentrated at the apices of GLAST-1, GS positive ciliary body NPE cells, and in GLAST-1 positive iris melanocytes and iris dilator muscle cells. AH Glu concentrations were lower (p < 0.001), while Gln was higher in monkey (p = 0.01) and human cataractous (p = 0.15) AH than serum. The results indicate that Glu is concentrated within GLAST-1, GS positive NPE cells and are consistent with the suggestion that Glu and Gln concentrations in AH may be due in part to GLAST-1 and GS activity in iris and ciliary body epithelial cells. PMID:19668465

Uveal Melanoma Regression after Brachytherapy: Relationship with Chromosome 3 Monosomy Status.

PubMed

Salvi, Sachin M; Aziz, Hassan A; Dar, Suhail; Singh, Nakul; Hayden-Loreck, Brandy; Singh, Arun D

2017-07-01

The objective was to evaluate the relationship between the regression rate of ciliary body melanoma and choroidal melanoma after brachytherapy and chromosome 3 monosomy status. We conducted a prospective and consecutive case series of patients who underwent biopsy and brachytherapy for ciliary/choroidal melanoma. Tumor biopsy performed at the time of radiation plaque placement was analyzed with fluorescence in situ hybridization to determine the percentage of tumor cells with chromosome 3 monosomy. The regression rate was calculated as the percent change in tumor height at months 3, 6, and 12. The relationship between regression rate and tumor location, initial tumor height, and chromosome 3 monosomy (percentage) was assessed by univariate linear regression (R version 3.1.0). Of the 75 patients included in the study, 8 had ciliary body melanoma, and 67 were choroidal melanomas. The mean tumor height at the time of diagnosis was 5.2 mm (range: 1.90-13.00). The percentage composition of chromosome 3 monosomy ranged from 0-20% (n = 35) to 81-100% (n = 40). The regression of tumor height at months 3, 6, and 12 did not statistically correlate with tumor location (ciliary or choroidal), initial tumor height, or chromosome 3 monosomy (percentage). The regression rate of choroidal melanoma following brachytherapy did not correlate with chromosome 3 monosomy status.

Methyl-sulfonyl-methane (MSM)-induced acute angle closure.

PubMed

Hwang, Jeremy C; Khine, Kay T; Lee, Jennifer C; Boyer, David S; Francis, Brian A

2015-01-01

To report the first case of presumed bilateral acute angle closure (AAC) secondary to ingestion of the dietary supplement, methyl-sulfonyl-methane (MSM). A 35-year-old woman presented with bilateral AAC 1 week after starting multiple dietary supplements, one of which contained MSM. Ultrasound biomicroscopy demonstrated bilateral anterior rotation of the iris-lens diaphragm, ciliary body edema, and choroidal effusion. Four days after discontinuation of the supplements, her angle closure and uveal effusion resolved, and her best-corrected vision recovered to 20/20 bilaterally. Sulfa-based drugs have been reported to cause AAC, choroidal effusion, and ciliary body edema. In our patient, the coincidence of bilateral AAC with choroidal and ciliary body effusion that began 1 week after starting dietary supplements was suspicious for drug-induced AAC. The dietary supplement Basic Detox Nutrients contains MSM, the only constituent in the patient's medication list with a sulfonyl moiety. Given the similarities in chemical structure and clinical presentation, we postulate that MSM induces AAC in a manner similar to mechanisms previously described for other sulfa-based drugs. As MSM continues to be used and studied for its anti-inflammatory and antioxidative properties, investigators and marketers will need to be cognizant of its potential to cause AAC and provide proper warning to consumers.

Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krauthammer, Michael; Kong, Yong; Ha, Byung Hak

We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas. Sun-exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas. Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS. Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas. This activating mutation, the third most frequentmore » in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1{sup P29S}) in the highly conserved switch I domain. Crystal structures, and biochemical and functional studies of RAC1{sup P29S} showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration. These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit.« less

Whole-body tissue distribution of total radioactivity in rats after oral administration of [¹⁴C]-bilastine.

PubMed

Lucero, María Luisa; Patterson, Andrew B

2012-06-01

This study evaluated the tissue distribution of total radioactivity in male albino, male pigmented, and time-mated female albino rats after oral administration of a single dose of [¹⁴C]-bilastine (20 mg/kg). Although only 1 animal was analyzed at each time point, there were apparent differences in bilastine distribution. Radioactivity was distributed to only a few tissues at low levels in male rats, whereas distribution was more extensive and at higher levels in female rats. This may be a simple sex-related difference. In each group and at each time point, concentrations of radioactivity were high in the liver and kidney, reflecting the role of these organs in the elimination process. In male albino rats, no radioactivity was measurable by 72 hours postdose. In male pigmented rats, only the eye and uveal tract had measurable levels of radioactivity at 24 hours. Measureable levels of radioactivity were retained in these tissues at the final sampling time point (336 hours postdose), indicating a degree of melanin-associated binding. In time-mated female rats, but not in albino or pigmented male rats, there was evidence of low-level passage of radioactivity across the placental barrier into fetal tissues as well as low-level transfer of radioactivity into the brain.

3D medical volume reconstruction using web services.

PubMed

Kooper, Rob; Shirk, Andrew; Lee, Sang-Chul; Lin, Amy; Folberg, Robert; Bajcsy, Peter

2008-04-01

We address the problem of 3D medical volume reconstruction using web services. The use of proposed web services is motivated by the fact that the problem of 3D medical volume reconstruction requires significant computer resources and human expertise in medical and computer science areas. Web services are implemented as an additional layer to a dataflow framework called data to knowledge. In the collaboration between UIC and NCSA, pre-processed input images at NCSA are made accessible to medical collaborators for registration. Every time UIC medical collaborators inspected images and selected corresponding features for registration, the web service at NCSA is contacted and the registration processing query is executed using the image to knowledge library of registration methods. Co-registered frames are returned for verification by medical collaborators in a new window. In this paper, we present 3D volume reconstruction problem requirements and the architecture of the developed prototype system at http://isda.ncsa.uiuc.edu/MedVolume. We also explain the tradeoffs of our system design and provide experimental data to support our system implementation. The prototype system has been used for multiple 3D volume reconstructions of blood vessels and vasculogenic mimicry patterns in histological sections of uveal melanoma studied by fluorescent confocal laser scanning microscope.

Second cancers discovered by (18)FDG PET/CT imaging for choroidal melanoma.

PubMed

Chin, Kimberly; Finger, Paul T; Kurli, Madhavi; Tena, Lawrence B; Reddy, Shantan

2007-08-01

Positron-emission tomography/computed tomography (PET/CT) is a unique imaging tool that aids in the detection of cancerous lesions. It is currently and widely used for cancer staging (both initial and follow-up). Here we report our findings of second primary cancers incidentally discovered during PET/CT staging of patients with choroidal melanomas. We performed a retrospective case review of 139 patients with uveal melanoma who were subsequently evaluated by whole-body [18-fluorine-labeled] 2-deoxy-2-fluoro-D-glucose ((18)FDG) PET/CT imaging. In this series, 93 were scanned before treatment and 46 during the course of their follow-up systemic examinations. Their mean follow-up was 50.9 months. Six patients (4.3%) had second primary cancers revealed by PET/CT imaging. Three patients (50%) were synchronous (found at initial staging), and the remaining 3 patients (50%) were metachronous (found at follow-up staging). Second primary cancers were found in the lung, breast, uterus, colon, and thyroid. Although whole-body PET/CT scans were ordered as part of the staging process of patients with diagnosed choroidal melanoma, both synchronous and metachronous second primary cancers were found. PET/CT has become an indispensable tool for staging, diagnosis, and treatment planning for choroidal melanoma. The possibility of detecting second primary cancers should also be considered valuable.

Hepatic Progression-free and Overall Survival After Regional Therapy to the Liver for Metastatic Melanoma.

PubMed

Abbott, Andrea M; Doepker, Matthew P; Kim, Youngchul; Perez, Matthew C; Gandle, Cassandra; Thomas, Kerry L; Choi, Junsung; Shridhar, Ravi; Zager, Jonathan S

2017-01-04

Regional therapy for metastatic melanoma to the liver represents an alternative to systemic therapy. Hepatic progression-free survival (HPFS), progression-free survival (PFS), and overall survival (OS) were evaluated. A retrospective review of patients with liver metastases from cutaneous or uveal melanoma treated with yttrium-90 (Y90), chemoembolization (CE), or percutaneous hepatic perfusion (PHP) was conducted. Thirty patients (6 Y90, 10 PHP, 12 CE, 1 PHP then Y90, 1 CE then PHP) were included. Multivariate analysis showed improved HPFS for PHP versus Y90 (P=0.004), PHP versus CE (P=0.02) but not for CE versus Y90. PFS was also significantly different: Y90 (54 d), CE (52 d), PHP (245 d), P=0.03. PHP treatment and lower tumor burden were significant predictors of prolonged PFS on multivariate analysis. Median OS from time of treatment was longest, but not significant, for PHP at 608 days versus Y90 (295 d) and CE (265 d), P=0.24. Only PHP treatment versus Y90 and lower tumor burden had improved OS on multivariate analysis (P=0.03, 0.03, respectively). HPFS and PFS were significantly prolonged in patients treated with PHP versus CE or Y90. Median OS in PHP patients was over double that seen in Y90 or CE patients but was significant only between PHP and Y90.

Primary extranodal marginal zone lymphoma of the uvea associated with massive diffuse epibulbar extension and focal infiltration of the optic nerve and meninges, clinically presented as uveitis masquerade syndrome: a case report.

PubMed

Rasić, D M; Stanković, Z; Terzić, T; Kovacević, D; Koturović, Z; Marković, V

2010-09-01

To report a clinical, histopathological and immunohistochemical findings in a case of primary extranodal marginal zone lymphoma of the uvea associated with massive diffuse extraocular episcleral extension and focal infiltration of the optic nerve and meninges, clinically presented as longstanding uveitis masquerade syndrome. Interventional case reports with histopathological correlation. We describe a 80-year-old male patient with a 3-year history of chronic recurrent hypertensive (pan) uveitis associated with ocular pain, unresponsive to topical and systemic anti-inflammatory, immunosuppressive, antibiotic/antiviral and antiglaucomatous therapy. Because the eye was not salvageable with conservative treatment, enucleation of blind and painful eye was performed. Findings from histopathological and immunohistochemistry examination of the enucleated eye showed an extranodal marginal zone lymphoma of the uveal tract with massive epibulbar extension and optic nerve and meningeal penetration. During almost 3 years of clinical course and 6 months after the enucleation, there were no systemic manifestations of lymphoma, and patient has not required subsequent treatment. Primary lymphoproliferative lesions of the uvea, comprising the iris, ciliary body and choroid are very rare, associated with epibulbar extension extremely and with optic nerve and menigeal penetration exceptionally. Despite its rarity, primary lymphoma of the uvea should be included in the differential diagnosis particularly in older patients with longstanding recurrent uveitis.

Morphological Alterations Within the Peripheral Fixation of the Iris Dilator Muscle in Eyes With Pigmentary Glaucoma

PubMed Central

Flügel-Koch, Cassandra M.; Tektas, Ozan Y.; Kaufman, Paul L.; Paulsen, Friedrich P.; Lütjen-Drecoll, Elke

2014-01-01

Purpose. To analyze the peripheral fixation of the iris dilator muscle in normal eyes and in eyes with pigmentary glaucoma (PG). Methods. Using 63 control eyes (age 18 months–99 years), the peripheral iris dilator was investigated by light microscopy, immunohistochemistry, and electron microscopy. Development was studied using 18 differently aged fetal eyes stained immunohistochemically against α-smooth muscle (SM) actin. The peripheral iris dilator muscle in PG was analyzed using semithin and ultrathin sections of six glutaraldehyde-fixed eyes from three donors aged 38, 62, and 74 years. Results. In normal eyes, the peripheral end of the iris dilator muscle is arranged in a sphincter-like manner. Arcade-shaped tendinous connections associated with myofibroblasts (iridial strands) anchor the iris dilator within the elastic–fibromuscular ciliary meshwork that also serves as fixation area for the elastic tendons of the inner ciliary muscle portions. The iridial strands are innervated and can adapt their length during accommodation. The PG eyes show incomplete circular bundles and iridial strands that are mainly anchored to the iris stroma and the flexible uveal parts of the trabecular meshwork. Conclusions. The normal anchorage of the peripheral iris dilator and its presumably neuronally regulated length adaptation stabilize the peripheral iris during accommodation. Insufficient fixation in PG could promote posterior bowing of the iris with rubbing against the zonular fibers and pigment liberation from the iris pigmented epithelium. PMID:24938519

Validation of an NGS mutation detection panel for melanoma.

PubMed

Reiman, Anne; Kikuchi, Hugh; Scocchia, Daniela; Smith, Peter; Tsang, Yee Wah; Snead, David; Cree, Ian A

2017-02-22

Knowledge of the genotype of melanoma is important to guide patient management. Identification of mutations in BRAF and c-KIT lead directly to targeted treatment, but it is also helpful to know if there are driver oncogene mutations in NRAS, GNAQ or GNA11 as these patients may benefit from alternative strategies such as immunotherapy. While polymerase chain reaction (PCR) methods are often used to detect BRAF mutations, next generation sequencing (NGS) is able to determine all of the necessary information on several genes at once, with potential advantages in turnaround time. We describe here an Ampliseq hotspot panel for melanoma for use with the IonTorrent Personal Genome Machine (PGM) which covers the mutations currently of most clinical interest. We have validated this in 151 cases of skin and uveal melanoma from our files, and correlated the data with PCR based assessment of BRAF status. There was excellent agreement, with few discrepancies, though NGS does have greater coverage and picks up some mutations that would be missed by PCR. However, these are often rare and of unknown significance for treatment. PCR methods are rapid, less time-consuming and less expensive than NGS, and could be used as triage for patients requiring more extensive diagnostic workup. The NGS panel described here is suitable for clinical use with formalin-fixed paraffin-embedded (FFPE) samples.

In Vivo High-Frequency Contrast-Enhanced Ultrasonography of Choroidal Melanoma in Rabbits: Imaging Features and Histopathologic Correlations

PubMed Central

Kang, Shin J.; Zhang, Qing; Patel, Samirkumar R.; Berezovsky, Damian; Yang, Hua; Wang, Yanggan; Grossniklaus, Hans E.

2013-01-01

Purpose To evaluate the utility of in vivo imaging of rabbit model of choroidal melanoma utilizing high-frequency contrast-enhanced ultrasound (HF-CE-US) with 2-or 3-dimensional modes, and to correlate the sonographic findings with histopathologic characteristics. Methods Five New Zealand white rabbits which were immunosuppressed with daily cyclosporin A were inoculated into their right eyes with aliquots of 1.5×106 / 50 µL of 92.1 human uveal melanoma cells cultured in RPMI. At week 4, the tumor-bearing eyes were imaged using high-frequency ultrasound with microbubble contrast agent to determine the 2-dimensional tumor size and relative blood volume and by 3-dimensional mode to determine tumor volume. Histologic tumor burden was quantified in enucleated eyes by ImageJ software, and microvascular density (MVD) was determined by counting vascular channels in PAS without hematoxylin sections. Results Utilizing HF-CE-US, melanomas were visualized as relatively hyperechoic regions in the images. The correlation coefficients of sonographic size or volume compared with histologic area were 0.72 and 0.70, respectively. The sonographic tumor relative blood volume correlated with the histologic tumor vascularity (R2=0.92, P=0.04) Conclusions There is a positive correlation between in vivo sonographic tumor volume/size and histologic tumor size in our rabbit choroidal melanoma model. HF-CE-US corresponds to microvascular density and blood volume. PMID:23645822

Cat-scratch uveitis confirmed by histological, serological, and molecular diagnoses.

PubMed

Font, Ramon L; Del Valle, Maria; Mitchell, Bradley M; Boniuk, Milton

2011-04-01

To report a case of a cat-scratch uveitis caused by Bartonella henselae, which was confirmed by histology, serology, and polymerase chain reaction (PCR) methodology. An iris nodule was biopsied from a 4-year-old child who was scratched by a kitten on the side of his face and developed redness of the eye associated with cervical lymphadenopathy. Sections of the iridectomy specimen were stained with hematoxylin-eosin, periodic acid-Schiff, and Warthin-Starry technique for histopathologic evaluation. Additionally, serologic tests and molecular diagnosis using B. henselae-specific PCR were performed. Histopathologically, sections of the iridectomy specimen showed a zonal granulomatous inflammation with a central iris necrotic abscess surrounded by a mantle of epithelioid histiocytes and more peripherally by lymphocytes and plasma cells. The Warthin-Starry stain disclosed scattered short bacilli within the necrotic abscess morphologically compatible with B. henselae. Report of serologic tests for B. henselae disclosed a negative immunoglobulin G antibody (negative: less than 12) and a positive immunoglobulin M antibody of 18 (positive: greater than 15). Other serologic studies including Toxocara, histoplasmin, blastomycin, coccidioidin, aspergillin, and Chlamydia were all negative. PCR was positive for B. henselae DNA. Our case showed a unilateral chronic granulomatous iritis with the histopathologic features compatible with CSD caused by B. henselae bacillus as demonstrated in the iris biopsy and confirmed by serology and PCR technique. This case is an example of a relatively rare uveal manifestation of CSD.

Both Complexity and Location of DNA Damage Contribute to Cellular Senescence Induced by Ionizing Radiation

PubMed Central

Zhang, Xurui; Ye, Caiyong; Sun, Fang; Wei, Wenjun; Hu, Burong; Wang, Jufang

2016-01-01

Persistent DNA damage is considered as a main cause of cellular senescence induced by ionizing radiation. However, the molecular bases of the DNA damage and their contribution to cellular senescence are not completely clear. In this study, we found that both heavy ions and X-rays induced senescence in human uveal melanoma 92–1 cells. By measuring senescence associated-β-galactosidase and cell proliferation, we identified that heavy ions were more effective at inducing senescence than X-rays. We observed less efficient repair when DNA damage was induced by heavy ions compared with X-rays and most of the irreparable damage was complex of single strand breaks and double strand breaks, while DNA damage induced by X-rays was mostly repaired in 24 hours and the remained damage was preferentially associated with telomeric DNA. Our results suggest that DNA damage induced by heavy ion is often complex and difficult to repair, thus presents as persistent DNA damage and pushes the cell into senescence. In contrast, persistent DNA damage induced by X-rays is preferentially associated with telomeric DNA and the telomere-favored persistent DNA damage contributes to X-rays induced cellular senescence. These findings provide new insight into the understanding of high relative biological effectiveness of heavy ions relevant to cancer therapy and space radiation research. PMID:27187621

[Mesectodermal leiomyoma. Unusual tumor of the ciliary body].

PubMed

Rentería-Ruiz, Nancy Paulina; de Wit-Carter, Guillermo; Villaseñor-Diez, Jaime; Flores-Estrada, José Javier; Rodríguez-Reyes, Abelardo Antonio

2014-01-01

Mesectodermal leiomyoma is a benign tumor of smooth muscle of the ciliary body, which is derived from the neural crest. We report the case of a 35-year-old Mexican woman with visually impaired and blurred vision of the right eye of 2 months duration. The clinical and imaging presuntional diagnosis was adenoma of the non pigmented epithelium of the ciliary body and it was surgically resected. Microscopically, the tumor was composed of cells with round nuclei and scant cytoplasm without atypia or mitosis, arranged in a fibrillary background. The immunohistochemical markers for vimentin, muscle specific actin, smooth muscle actin and calponin were strongly positive in the cytoplasm of the neoplastic cells, while for glial fibrillary acidic protein and S-100 protein were negative in the same cellular population. Mesectodermal leiomyoma of the ciliary body is benign tumor of smooth muscle extremely rare in this location. Until now, there are just 25 previous reported cases in the literature and, the main differential diagnosis is uveal malignant melanoma, therefore some eyes were enucleated. The ultrabiomicroscopy, A and B-scan imaging studies are useful in the evaluation, however, is mandatory the microsocpic examination with routine and histochemical stains as well as the use of immunohistochemical markers such as vimentin, specific muscle actin, smooth muscle actin andcalponin to stablish the smooth muscle origin of this neoplasm, and rule out other malignant neoplams such as malignant melanoma.

Ocular and periocular hemangiosarcoma in six horses.

PubMed

Scherrer, Nicole M; Lassaline, Mary; Engiles, Julie

2017-11-07

To determine the characteristics of and prognosis for ocular and periocular hemangiosarcoma in horses. Six horses treated for ocular or periocular hemangiosarcoma. A retrospective review of medical records from 2007 to 2015 was performed to identify horses with a histologic diagnosis of ocular or periocular hemangiosarcoma. Signalment (age, sex, breed), duration of clinical signs, prior treatment, tumor size and location, medical and surgical treatment including postoperative chemotherapy, follow-up time, and outcome were obtained from medical records. Histopathology was reviewed by a board-certified pathologist. In six horses diagnosed with ocular or periocular hemangiosarcoma, no breed, age, or sex was overrepresented. Sites included the temporal limbus (3), third eyelid (2), and uvea (1). With the exception of one horse with uveal hemangiosarcoma, 5/6 horses had lightly pigmented periocular haircoat. Histologic features of ocular hemangiosarcoma in 6/6 cases included high cellularity, nuclear pleomorphism, and inflammation with a mitotic index ranging from 0 to 8 mitoses per 10 consecutive 400× fields. Five of six tumors displayed solar elastosis, indicating ultraviolet light-induced damage to sub-epithelial collagen. Treatment included surgical excision in all cases and was not associated with recurrence in 4/6. Three cases that received ancillary treatment with topical mitomycin C had no postoperative recurrence. Two cases with postexcisional recurrence had histologic evidence of incomplete excision. Complete surgical excision may be associated with resolution of periocular and ocular hemangiosarcoma in horses. Etiopathogenesis may include exposure to ultraviolet light. © 2017 American College of Veterinary Ophthalmologists.

Blindness and Severe Visual Impairment in Pupils at Schools for the Blind in Burundi

PubMed Central

Ruhagaze, Patrick; Njuguna, Kahaki Kimani Margaret; Kandeke, Lévi; Courtright, Paul

2013-01-01

Purpose: To determine the causes of childhood blindness and severe visual impairment in pupils attending schools for the blind in Burundi in order to assist planning for services in the country. Materials and Methods: All pupils attending three schools for the blind in Burundi were examined. A modified WHO/PBL eye examination record form for children with blindness and low vision was used to record the findings. Data was analyzed for those who became blind or severely visually impaired before the age of 16 years. Results: Overall, 117 pupils who became visually impaired before 16 years of age were examined. Of these, 109 (93.2%) were blind or severely visually impaired. The major anatomical cause of blindness or severe visual impairment was cornea pathology/phthisis (23.9%), followed by lens pathology (18.3%), uveal lesions (14.7%) and optic nerve lesions (11.9%). In the majority of pupils with blindness or severe visual impairment, the underlying etiology of visual loss was unknown (74.3%). More than half of the pupils with lens related blindness had not had surgery; among those who had surgery, outcomes were generally poor. Conclusion: The causes identified indicate the importance of continuing preventive public health strategies, as well as the development of specialist pediatric ophthalmic services in the management of childhood blindness in Burundi. The geographic distribution of pupils at the schools for the blind indicates a need for community-based programs to identify and refer children in need of services. PMID:23580854

Blindness and severe visual impairment in pupils at schools for the blind in Burundi.

PubMed

Ruhagaze, Patrick; Njuguna, Kahaki Kimani Margaret; Kandeke, Lévi; Courtright, Paul

2013-01-01

To determine the causes of childhood blindness and severe visual impairment in pupils attending schools for the blind in Burundi in order to assist planning for services in the country. All pupils attending three schools for the blind in Burundi were examined. A modified WHO/PBL eye examination record form for children with blindness and low vision was used to record the findings. Data was analyzed for those who became blind or severely visually impaired before the age of 16 years. Overall, 117 pupils who became visually impaired before 16 years of age were examined. Of these, 109 (93.2%) were blind or severely visually impaired. The major anatomical cause of blindness or severe visual impairment was cornea pathology/phthisis (23.9%), followed by lens pathology (18.3%), uveal lesions (14.7%) and optic nerve lesions (11.9%). In the majority of pupils with blindness or severe visual impairment, the underlying etiology of visual loss was unknown (74.3%). More than half of the pupils with lens related blindness had not had surgery; among those who had surgery, outcomes were generally poor. The causes identified indicate the importance of continuing preventive public health strategies, as well as the development of specialist pediatric ophthalmic services in the management of childhood blindness in Burundi. The geographic distribution of pupils at the schools for the blind indicates a need for community-based programs to identify and refer children in need of services.

Ocular disposition of treosulfan and its active epoxy-transformers following intravenous administration in rabbits.

PubMed

Romański, Michał; Kasprzyk, Anna; Karbownik, Agnieszka; Główka, Franciszek K

2016-10-01

Treosulfan (TREO) has an established position in chemotherapy of advanced ovarian cancer but has been also applied in uveal melanoma patients. Moreover, it is used as an orphan drug for a myeloablative conditioning prior to stem cell transplantation. In this paper, biodistribution of prodrug TREO and its active monoepoxide (S,S-EBDM) and diepoxide (S,S-DEB) into aqueous humor of the eye was studied for the first time. For that purpose, alone TREO and the mixture of TREO, S,S-EBDM and S,S-DEB were administered intravenously to New Zealand White rabbits. The three analytes were determined in plasma and aqueous humor by validated HPLC methods and pharmacokinetic calculations were performed in WinNonlin. After the infusion of TREO, the aqueous humor/plasma C max ratio and area under the curve ratio amounted 0.04 and 0.10 for TREO, and 1.1 and 2.2 for S,S-EBDM, respectively. Following the bolus injection of the mixture of the prodrug and its epoxides, the aqueous humor/plasma C max ratios for TREO, S,S-EBDM and S,S-DEB were 0.05, 0.66, and 4.0, respectively. The presented results indicate a poor penetration of TREO into the eye, which may impair systemic treatment of ocular tumors but is beneficial in terms of a lack of clinically relevant ophthalmic adverse effects. Copyright © 2016 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Investigation of long-term retention of unchanged (-)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide, a novel "funny" If current channel inhibitor, and its metabolites in the eyeball and thoracic aorta of rats.

PubMed

Umehara, Ken-ichi; Nakada, Naoyuki; Noguchi, Kiyoshi; Iwatsubo, Takafumi; Usui, Takashi; Kamimura, Hidetaka

2009-11-01

(-)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide (YM758), a novel "funny" If current channel inhibitor, was being developed as a treatment for stable angina and atrial fibrillation. After a single oral administration of (14)C-YM758, extensive accumulation and long-term retention of radioactivity were observed in the eyeballs of nonalbino rats and in the thoracic aorta of albino/nonalbino rats. Radioluminograms of the eyeballs of nonalbino rats indicated that the radioactivity was localized to the uveal tract, which suggests that the radioactivity may be positively charged and bound mainly to the melanins. Treatment with a mixture of 2 mol/l hydrochloric acid and methanol (5:95, v/v) allowed for the recovery of the major portion of radioactivity from the eyeball, which suggests reversible binding. The radioactive constituents in eyeballs consisted of the unchanged drug (YM758) and three metabolites [mainly 6,7-dimethoxy-2-[(3R)-piperidin-3-ylcarbonyl]-1,2,3,4-tetrahydroisoquinoline (YM-252124)]. Using the organic solvent mixture described above, almost all of the radioactivity was not collected from the thoracic aorta, and approximately 90% was recovered by treatment with elastase, which suggests that some metabolites covalently bind to the elastin fiber localized in the tunica media.

Pharmacokinetics, distribution, metabolism, and excretion of the dual reuptake inhibitor [(14)C]-nefopam in rats.

PubMed

Yu, Jian; Solon, Eric; Shen, Helen; Modi, Nishit B; Mittur, Aravind

2016-11-01

1. This study examined the pharmacokinetics, distribution, metabolism, and excretion of [(14)C] nefopam in rats after a single oral administration. Blood, plasma, and excreta were analyzed for total radioactivity, nefopam, and metabolites. Metabolites were profiled and identified. Radioactivity distribution was determined by quantitative whole-body autoradiography. 2. The pharmacokinetic profiles of total radioactivity and nefopam were similar in male and female rats. Radioactivity partitioned approximately equally between plasma and red blood cells. A majority of the radioactivity was excreted in urine within 24 hours and mass balance was achieved within 7 days. 3. Intact nefopam was a minor component in plasma and excreta. Numerous metabolites were identified in plasma and urine generated by multiple pathways including: hydroxylation/oxidation metabolites (M11, M22a and M22b, M16, M20), some of which were further glucuronidated (M6a to M6c, M7a to M7c, M8a and M8b, M3a to M3d); N-demethylation of nefopam to metabolite M21, which additionally undergoes single or multiple hydroxylations or sulfation (M9, M14, M23), with some of the hydroxylated metabolites further glucuronidated (M2a to M2d). 4. Total radioactivity rapidly distributed with highest concentrations found in the urinary bladder, stomach, liver, kidney medulla, small intestine, uveal tract, and kidney cortex without significant accumulation or persistence. Radioactivity reversibly associated with melanin-containing tissues.

Morphological alterations within the peripheral fixation of the iris dilator muscle in eyes with pigmentary glaucoma.

PubMed

Flügel-Koch, Cassandra M; Tektas, Ozan Y; Kaufman, Paul L; Paulsen, Friedrich P; Lütjen-Drecoll, Elke

2014-06-17

To analyze the peripheral fixation of the iris dilator muscle in normal eyes and in eyes with pigmentary glaucoma (PG). Using 63 control eyes (age 18 months-99 years), the peripheral iris dilator was investigated by light microscopy, immunohistochemistry, and electron microscopy. Development was studied using 18 differently aged fetal eyes stained immunohistochemically against α-smooth muscle (SM) actin. The peripheral iris dilator muscle in PG was analyzed using semithin and ultrathin sections of six glutaraldehyde-fixed eyes from three donors aged 38, 62, and 74 years. In normal eyes, the peripheral end of the iris dilator muscle is arranged in a sphincter-like manner. Arcade-shaped tendinous connections associated with myofibroblasts (iridial strands) anchor the iris dilator within the elastic-fibromuscular ciliary meshwork that also serves as fixation area for the elastic tendons of the inner ciliary muscle portions. The iridial strands are innervated and can adapt their length during accommodation. The PG eyes show incomplete circular bundles and iridial strands that are mainly anchored to the iris stroma and the flexible uveal parts of the trabecular meshwork. The normal anchorage of the peripheral iris dilator and its presumably neuronally regulated length adaptation stabilize the peripheral iris during accommodation. Insufficient fixation in PG could promote posterior bowing of the iris with rubbing against the zonular fibers and pigment liberation from the iris pigmented epithelium. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

Maturation of Rb+ and PAH accumulation by rabbit anterior uvea and choroid plexus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krupin, T.; Fritz, C.; Becker, B.

In vitro accumulation of radioactive para-aminohippuric acid (/sup 3/H-PAH) and rubidium (/sup 86/Rb+) by the anterior uvea, ciliary processes, and the choroid plexus was evaluated in tissues from newborn and various aged rabbits. Accumulation of PAH was present in the anterior uvea at 1 day of age (tissue to media ratio, T/M, of 2.1 +/- 0.2) and remained at this level for the first 14 days of life. Accumulation did not rise to adult levels until 21 days of age (T/M 5.5 +/- 0.6). Rubidium accumulation in the anterior uvea, a measure of Na+, K+-pump activity, was higher than adultmore » values 6 hr after birth (T/M25.2 +/- 0.9). Activity remained elevated through day 28 and did not fall to adult levels until day 60 (T/M 13.4 +/- 0.6). Accumulation studies on isolated ciliary processes were similar to those obtained from anterior uveal tissue. Daily subcutaneous injections of penicillin (300,000 units/kg/day) for 1 week had no effect on anterior uvea PAH accumulation (penicillin T/M was 1.7 +/- 0.1 and saline control T/M was 2.0 +/- 0.2). Accumulation of either /sup 3/H-PAH or /sup 86/Rb+ by the choroid plexus was present 1 day after birth in amounts that were similar to adult values and did not change during the 90 days of testing.« less

Mast cells are present in the choroid of the normal eye in most vertebrate classes.

PubMed

McMenamin, Paul Gerard; Polla, Emily

2013-07-01

Mast cells are bone marrow-derived tissue-homing leukocytes, which have traditionally been regarded as effector cells in allergic disorders, responses against parasites, and regulation of blood flow, but a broader perspective of their functional heterogeneity, such as immunomodulation, angiogenesis, tissue repair, and remodeling after injury, is now emerging. The persistence of mast cells in connective tissues throughout the evolution of vertebrates is evidence of strong selective pressure suggesting that these cells must have multiple beneficial and important roles in normal homeostasis. While mast cells are present within the uveal tract of eutherian mammals, there is little known about their presence in the choroid of other vertebrate classes. Eye tissues from a range of vertebrate species (fish, amphibian, reptiles, birds, marsupials, monotreme, and eutherian mammals) were investigated. Tissues were fixed in either 2% glutaraldehyde, 2% paraformaldehyde or a mixture of both and processed for resin embedding. Semi-thin sections of the retina and choroid were cut and stained with toluidine blue. Mast cells were identified in the choroid of all classes of vertebrates investigated except sharks. Their morphology, location, and staining characteristics were remarkably similar from teleost fish through to eutherian mammals and bore close morphological resemblance to mammalian connective tissue mast cells. The similar morphology and distribution of mast cells in the choroid of all vertebrate classes studied suggest a basic physiological function that has been retained since the evolution of the vertebrate eye. © 2013 American College of Veterinary Ophthalmologists.

Proton beam irradiation inhibits the migration of melanoma cells.

PubMed

Jasińska-Konior, Katarzyna; Pochylczuk, Katarzyna; Czajka, Elżbieta; Michalik, Marta; Romanowska-Dixon, Bożena; Swakoń, Jan; Urbańska, Krystyna; Elas, Martyna

2017-01-01

In recent years experimental data have indicated that low-energy proton beam radiation might induce a difference in cellular migration in comparison to photons. We therefore set out to compare the effect of proton beam irradiation and X-rays on the survival and long-term migratory properties of two cell lines: uveal melanoma Mel270 and skin melanoma BLM. Cells treated with either proton beam or X-rays were analyzed for their survival using clonogenic assay and MTT test. Long-term migratory properties were assessed with time-lapse monitoring of individual cell movements, wound test and transpore migration, while the expression of the related proteins was measured with western blot. Exposure to proton beam and X-rays led to similar survival but the quality of the cell colonies was markedly different. More paraclones with a low proliferative activity and fewer highly-proliferative holoclones were found after proton beam irradiation in comparison to X-rays. At 20 or 40 days post-irradiation, migratory capacity was decreased more by proton beam than by X-rays. The beta-1-integrin level was decreased in Mel270 cells after both types of radiation, while vimentin, a marker of EMT, was increased in BLM cells only. We conclude that proton beam irradiation induced long-term inhibition of cellular motility, as well as changes in the level of beta-1 integrin and vimentin. If confirmed, the change in the quality, but not in the number of colonies after proton beam irradiation might favor tumor growth inhibition after fractionated proton therapy.

Pharmacokinetics, Distribution, Metabolism, and Excretion of Omadacycline following a Single Intravenous or Oral Dose of 14C-Omadacycline in Rats

PubMed Central

Lin, Wen; Flarakos, Jimmy; Du, Yancy; Hu, Wenyu; He, Handan; Mangold, James; Tanaka, S. Ken

2016-01-01

ABSTRACT The absorption, distribution, metabolism, and excretion (ADME) of omadacycline, a first-in-class aminomethylcycline antibiotic with a broad spectrum of activity against Gram-positive, Gram-negative, anaerobic, and atypical bacteria, were evaluated in rats. Tissue distribution was investigated by quantitative whole-body autoradiography in male Long-Evans Hooded (LEH) rats. Following an intravenous (i.v.) dose of 5 mg/kg of body weight, radioactivity widely and rapidly distributed into most tissues. The highest tissue-to-blood concentration ratios (t/b) were observed in bone mineral, thyroid gland, and Harderian gland at 24 h post-i.v. dose. There was no evidence of stable accumulation in uveal tract tissue, suggesting the absence of a stable binding interaction with melanin. Following a 90 mg/kg oral dose in LEH rats, the highest t/b were observed in bone mineral, Harderian gland, liver, spleen, and salivary gland. The plasma protein binding levels were 26% in the rat and 15% to 21% in other species. Omadacycline plasma clearance was 1.2 liters/h/kg, and its half-life was 4.6 h; the steady-state volume of distribution (Vss) was 6.89 liters/kg. Major circulating components in plasma were intact omadacycline and its epimer. Consistent with observations in human, approximately 80% of the dose was excreted into the feces as unchanged omadacycline after i.v. administration. Fecal excretion was primarily the result of biliary excretion (∼40%) and direct gastrointestinal secretion (∼30%). However, urinary excretion (∼30%) was equally prominent after i.v. dosing. PMID:27821446

Prognostication in eye cancer: the latest tumor, node, metastasis classification and beyond

PubMed Central

Kivelä, T; Kujala, E

2013-01-01

The tumour, node, metastasis (TNM) classification is a universal cancer staging system, which has been used for five decades. The current seventh edition became effective in 2010 and covers six ophthalmic sites: eyelids, conjunctiva, uvea, retina, orbit, and lacrimal gland; and five cancer types: carcinoma, sarcoma, melanoma, retinoblastoma, and lymphoma. The TNM categories are based on the anatomic extent of the primary tumour (T), regional lymph node metastases (N), and systemic metastases (M). The T categories of ophthalmic cancers are based on the size of the primary tumour and any invasion of periocular structures. The anatomic category is used to determine the TNM stage that correlates with survival. Such staging is currently implemented only for carcinoma of the eyelid and melanoma of the uvea. The classification of ciliary body and choroidal melanoma is the only one based on clinical evidence so far: a database of 7369 patients analysed by the European Ophthalmic Oncology Group. It spans a prognosis from 96% 5-year survival for stage I to 97% 5-year mortality for stage IV. The most accurate criterion for prognostication in uveal melanoma is, however, analysis of chromosomal alterations and gene expression. When such data are available, the TNM stage may be used for further stratification. Prognosis in retinoblastoma is frequently assigned by using an international classification, which predicts conservation of the eye and vision, and an international staging separate from the TNM system, which predicts survival. The TNM cancer staging manual is a useful tool for all ophthalmologists managing eye cancer. PMID:23258307

Sci—Fri PM: Topics — 07: Monte Carlo Simulation of Primary Dose and PET Isotope Production for the TRIUMF Proton Therapy Facility

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lindsay, C; Jirasek, A; Blackmore, E

Uveal melanoma is a rare and deadly tumour of the eye with primary metastases in the liver resulting in an 8% 2-year survival rate upon detection. Large growths, or those in close proximity to the optic nerve, pose a particular challenge to the commonly employed eye-sparing technique of eye-plaque brachytherapy. In these cases external beam charged particle therapy offers improved odds in avoiding catastrophic side effects such as neuropathy or blindness. Since 1995, the British Columbia Cancer Agency in partnership with the TRIUMF national laboratory have offered proton therapy in the treatment of difficult ocular tumors. Having seen 175 patients,more » yielding 80% globe preservation and 82% metastasis free survival as of 2010, this modality has proven to be highly effective. Despite this success, there have been few studies into the use of the world's largest cyclotron in patient care. Here we describe first efforts of modeling the TRIUMF dose delivery system using the FLUKA Monte Carlo package. Details on geometry, estimating beam parameters, measurement of primary dose and simulation of PET isotope production are discussed. Proton depth dose in both modulated and pristine beams is successfully simulated to sub-millimeter precision in range (within limits of measurement) and 2% agreement to measurement within in a treatment volume. With the goal of using PET signals for in vivo dosimetry (alignment), a first look at PET isotope depth distribution is presented — comparing favourably to a naive method of approximating simulated PET slice activity in a Lucite phantom.« less

Regulators of G-protein signaling and their Gα substrates: promises and challenges in their use as drug discovery targets.

PubMed

Kimple, Adam J; Bosch, Dustin E; Giguère, Patrick M; Siderovski, David P

2011-09-01

Because G-protein coupled receptors (GPCRs) continue to represent excellent targets for the discovery and development of small-molecule therapeutics, it is posited that additional protein components of the signal transduction pathways emanating from activated GPCRs themselves are attractive as drug discovery targets. This review considers the drug discovery potential of two such components: members of the "regulators of G-protein signaling" (RGS protein) superfamily, as well as their substrates, the heterotrimeric G-protein α subunits. Highlighted are recent advances, stemming from mouse knockout studies and the use of "RGS-insensitivity" and fast-hydrolysis mutations to Gα, in our understanding of how RGS proteins selectively act in (patho)physiologic conditions controlled by GPCR signaling and how they act on the nucleotide cycling of heterotrimeric G-proteins in shaping the kinetics and sensitivity of GPCR signaling. Progress is documented regarding recent activities along the path to devising screening assays and chemical probes for the RGS protein target, not only in pursuits of inhibitors of RGS domain-mediated acceleration of Gα GTP hydrolysis but also to embrace the potential of finding allosteric activators of this RGS protein action. The review concludes in considering the Gα subunit itself as a drug target, as brought to focus by recent reports of activating mutations to GNAQ and GNA11 in ocular (uveal) melanoma. We consider the likelihood of several strategies for antagonizing the function of these oncogene alleles and their gene products, including the use of RGS proteins with Gα(q) selectivity.

Reconciling the principle of patient autonomy with the practice of informed consent: decision-making about prognostication in uveal melanoma.

PubMed

Cook, Sharon A; Damato, Bertil; Marshall, Ernie; Salmon, Peter

2011-12-01

Influential views on how to protect patient autonomy in clinical care have been greatly shaped by rational and deliberative models of decision-making. Our aim was to understand how the general principle of respecting autonomy can be reconciled with the local reality of obtaining consent in a clinical situation that precludes extended deliberation. We interviewed 22 patients with intraocular melanoma who had been offered cytogenetic tumour typing to indicate whether the tumour was likely to shorten life considerably. They were interviewed before and/or up to 36 months after receiving cytogenetic results. Patients described their decision-making about the test and how they anticipated and used the results. Their accounts were analysed qualitatively, using inconsistencies at a descriptive level to guide interpretative analysis. Patients did not see a decision to be made. For those who accepted testing, their choice reflected trust of what the clinicians offered them. Patients anticipated that a good prognosis would be reassuring, but this response was not evident. Although they anticipated that a poor prognosis would enable end-of-life planning, adverse results were interpreted hopefully. In general, the meaning of the test for patients was not separable from ongoing care. Models of decision-making and associated consent procedures that emphasize patients' active consideration of isolated decision-making opportunities are invalid for clinical situations such as this. Hence, responsibility for ensuring that a procedure protects patients' interests rests with practitioners who offer it and cannot be delegated to patients. © 2010 Blackwell Publishing Ltd.

Uveitis induction in the rabbit by muramyl dipeptides.

PubMed Central

Waters, R V; Terrell, T G; Jones, G H

1986-01-01

Intraocular inflammation (uveitis) was produced in rabbits by intravenous or subcutaneous treatment with N-acetylmuramyl-L-alanyl-D-isoglutamine and several of its synthetic analogs at doses of greater than or equal to 0.2 mg/kg in saline. A dose-dependent increase in permeability of the ocular blood-aqueous barrier as measured by leakage of protein or fluoresceinated dextran from the serum into the eye was observed from 2 to 14 h after glycopeptide treatment. Peak response occurred at approximately 3 h postdose. The lowest dose found to produce maximal vascular leakage for the most active glycopeptide analogs was 1 mg/kg. The adjuvant-inactive L-L stereoisomer of N-acetylmuramyl-L-alanyl-D-isoglutamine was inactive, even at doses as high as 10 mg/kg. Analogs of N-acetylmuramyl-L-alanyl-D-isoglutamine which were homologous in the lactyl side chain were found to cause less uveitis. Chronic biweekly intravenous treatment of rabbits for 1 month with either N-acetyl-L-alpha-aminobutyryl-D-isoglutamine or its lipophilic 6-O-stearoyl derivative at 1 mg/kg, but not with murabutide, resulted in leukocytic inflammatory lesions unique to the uveal tract of the eye. The uveitis was potentially reversible and occurred with decreased severity as long as 2 months after cessation of chronic treatment. Vascular leakage but not cellular infiltrate in the choroid could be modulated by pharmacologic means. Pyrogenicity but not adjuvanticity correlated with ability of glycopeptides to induce vascular leakage. Several adjuvant-active muramyl dipeptide analogs with minimal ability to cause acute vascular leakage or chronic inflammation in the rabbit eye have been identified. Images PMID:3949381

18 years' experience with high dose rate strontium-90 brachytherapy of small to medium sized posterior uveal melanoma.

PubMed

van Ginderdeuren, R; van Limbergen, E; Spileers, W

2005-10-01

To analyse local tumour control, radiation related complications, visual acuity, enucleation rate, and survival after brachytherapy of small to medium sized choroidal melanoma (CM) with a high dose rate (HDR) strontium-90 (Sr-90) applicator. From 1983 until 2000, 98 eyes with CM were treated with Sr-90 brachytherapy. The main outcome measures were actuarial rates of the patients' survival, ocular conservation rate, tumour regression, complication rates, and preservation of visual acuity. End point rates were estimated using Kaplan-Meier analysis. The median follow up time was 6.7 years (0.5-18.8 years). Actuarial melanoma free patient survival rate was 85% (SE 4.8%) after 18 years. Actuarial rate of ocular conservation and complete tumour regression was 90% (SE 3.8%) after 15 years. In 93% local tumour control was achieved, 88% showed a stable scar. Recurrence of the tumour on the border caused enucleation of six eyes (7%). In three cases (4%) retinal detachment was the end point. No cases of optic atrophy or of sight impairing retinopathy outside the treated area were found. Actuarial rate of preservation of visual acuity of 1/10 was 65% at 5 years and 45% at 15 years of follow up (SE 5.9% and 8.8%). Sr-90 brachytherapy is as effective as iodine or ruthenium brachytherapy for small to medium sized CM but causes fewer complications. The preservation of vision is better than with all other described radioisotopes. HDR Sr-90 brachytherapy can therefore safely be recommended for small to medium sized CM.

18 Years’ experience with high dose rate strontium-90 brachytherapy of small to medium sized posterior uveal melanoma

PubMed Central

van Ginderdeuren, R; van Limbergen, E; Spileers, W

2005-01-01

Aim: To analyse local tumour control, radiation related complications, visual acuity, enucleation rate, and survival after brachytherapy of small to medium sized choroidal melanoma (CM) with a high dose rate (HDR) strontium-90 (Sr-90) applicator. Methods: From 1983 until 2000, 98 eyes with CM were treated with Sr-90 brachytherapy. The main outcome measures were actuarial rates of the patients’ survival, ocular conservation rate, tumour regression, complication rates, and preservation of visual acuity. End point rates were estimated using Kaplan-Meier analysis. Results: The median follow up time was 6.7 years (0.5–18.8 years). Actuarial melanoma free patient survival rate was 85% (SE 4.8%) after 18 years. Actuarial rate of ocular conservation and complete tumour regression was 90% (SE 3.8%) after 15 years. In 93% local tumour control was achieved, 88% showed a stable scar. Recurrence of the tumour on the border caused enucleation of six eyes (7%). In three cases (4%) retinal detachment was the end point. No cases of optic atrophy or of sight impairing retinopathy outside the treated area were found. Actuarial rate of preservation of visual acuity of 1/10 was 65% at 5 years and 45% at 15 years of follow up (SE 5.9% and 8.8%). Conclusions: Sr-90 brachytherapy is as effective as iodine or ruthenium brachytherapy for small to medium sized CM but causes fewer complications. The preservation of vision is better than with all other described radioisotopes. HDR Sr-90 brachytherapy can therefore safely be recommended for small to medium sized CM. PMID:16170122

Reconstruction of delayed scleral flap melting with bovine pericardium after trabeculectomy with mitomycin C

PubMed Central

Coutinho, Inês; Silva, Diana; Mota, Mafalda; Lisboa, Maria; Trancoso Vaz, Fernando; Prieto, Isabel

2017-01-01

Aim: To present a challenging case of hypotony after trabeculectomy and its treatment. Case description: A 22-year-old woman with juvenile glaucoma underwent a conventional trabeculectomy with mitomycin C on the right eye (OD). In the immediate postoperative period, we observed a hyperfiltration bleb with hypotony refractory to conservative measures leading to hypotony maculopathy. A surgical revision with scleral flap resuture and conjunctival graft was performed with a satisfactory result and resolution of hypotony maculopathy. After two years, the patient complained of low visual acuity (VA) of the OD. During examination, we observed a fine and avascular bleb with Seidel and visualization of the underlying uveal tissue, an intraocular pressure (IOP) of 5 mmHg, and chorioretinal folds. A new revision of the trabeculectomy was performed. During the procedure, it was not possible to identify the scleral flap, so the fistula was closed with a patch of collagenous membrane derived from bovine pericardium (Tutopatch® graft). A good clinical evolution occurred. After 2 months, IOP was 15 mmHg without Seidel or changes in the fundus and VA was 20/20. After 8 months of follow-up, the IOP remains stable without further complaints. Conclusion: This case illustrates the difficulties faced in the management of a common complication of trabeculectomy and highlights some of the options available for its treatment. There are few reports of scleral melting after trabeculectomy. However, trauma and scleral necrosis associated with mitomycin are listed as the main causes. The use of a scleral patch derived from bovine pericardium allows effective suturing and closure of the aqueous leak. PMID:28695073

Anticancer compound ABT-263 accelerates apoptosis in virus-infected cells and imbalances cytokine production and lowers survival rates of infected mice.

PubMed

Kakkola, L; Denisova, O V; Tynell, J; Viiliäinen, J; Ysenbaert, T; Matos, R C; Nagaraj, A; Ohman, T; Kuivanen, S; Paavilainen, H; Feng, L; Yadav, B; Julkunen, I; Vapalahti, O; Hukkanen, V; Stenman, J; Aittokallio, T; Verschuren, E W; Ojala, P M; Nyman, T; Saelens, X; Dzeyk, K; Kainov, D E

2013-07-25

ABT-263 and its structural analogues ABT-199 and ABT-737 inhibit B-cell lymphoma 2 (Bcl-2), BCL2L1 long isoform (Bcl-xL) and BCL2L2 (Bcl-w) proteins and promote cancer cell death. Here, we show that at non-cytotoxic concentrations, these small molecules accelerate the deaths of non-cancerous cells infected with influenza A virus (IAV) or other viruses. In particular, we demonstrate that ABT-263 altered Bcl-xL interactions with Bcl-2 antagonist of cell death (Bad), Bcl-2-associated X protein (Bax), uveal autoantigen with coiled-coil domains and ankyrin repeats protein (UACA). ABT-263 thereby activated the caspase-9-mediated mitochondria-initiated apoptosis pathway, which, together with the IAV-initiated caspase-8-mediated apoptosis pathway, triggered the deaths of IAV-infected cells. Our results also indicate that Bcl-xL, Bcl-2 and Bcl-w interact with pattern recognition receptors (PRRs) that sense virus constituents to regulate cellular apoptosis. Importantly, premature killing of IAV-infected cells by ABT-263 attenuated the production of key pro-inflammatory and antiviral cytokines. The imbalance in cytokine production was also observed in ABT-263-treated IAV-infected mice, which resulted in an inability of the immune system to clear the virus and eventually lowered the survival rates of infected animals. Thus, the results suggest that the chemical inhibition of Bcl-xL, Bcl-2 and Bcl-w could potentially be hazardous for cancer patients with viral infections.

Comparison of the clinical presentation and visual outcome in open globe injuries in adults and children over 30 months.

PubMed

Gupta, Arvind; Srinivasan, Renuka; Babu, K Ramesh; Setia, Sajita

2010-01-01

To compare the clinical presentation and final visual outcome of open globe injuries in children and adults in a referral hospital over a 30-month period. This is an institutional-based prospective study of open globe injuries cases presenting in the emergency department between July 2003 and December 2005. Patients were divided in 2 groups: group 1, children (2-15 years), and group 2, adults (>15 years). All the patients were admitted and emergency surgical interventions were undertaken. The clinical features at presentation and the final visual acuity are compared. Chi-square and Fisher exact tests were used for statistical analysis. Ninety and 84 patients were included in group 1 and group 2, respectively. The most common places of injuries were home or while playing outdoor games in group 1 (67%) and workplace in group 2 (53.5%). The presenting features were significantly more grave in group 2. These included poor presenting visual acuity (p=0.012), vitreous prolapse (p=0.002), presence of relative afferent pupillary defect (p=0.001), and incidence of endophthalmitis (p=0.004). Time interval between injury and surgical intervention (p=0.018) was better in group 2. Other features, such as presence of hyphema, uveal tissue prolapse, cataract, intraocular foreign body, and length or location of laceration were similar in both groups. The final visual outcome was similar in the groups (p = 0.21), with approximately half of the patients achieving vision of 20/60 or better in each group. The majority of injuries in children and adults occurred in their homes or workplaces, respectively. Although the clinical presentations of open globe injuries were significantly more grave in adults than in children, the final visual outcomes were similar.

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

PubMed

Economou, Mario A; Wu, Jiangmei; Vasilcanu, Daiana; Rosengren, Linda; All-Ericsson, Charlotta; van der Ploeg, Ingeborg; Menu, Eline; Girnita, Leonard; Axelson, Magnus; Larsson, Olle; Seregard, Stefan; Kvanta, Anders

2008-11-01

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. 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. 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. 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. 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.

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

PubMed

Economou, Mario A; Wu, Jiangmei; Vasilcanu, Daiana; Rosengren, Linda; All-Ericsson, Charlotta; van der Ploeg, Ingeborg; Menu, Eline; Girnita, Leonard; Axelson, Magnus; Larsson, Olle; Seregard, Stefan; Kvanta, Anders

2008-06-01

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 such as vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF)-1 and its receptor, IGF-1R, have been implicated in CNV. A prior study has 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 antiangiogenic consequences in a murine CNV model. C57BL/6J mice with laser-induced CNVs were treated with PPP. Effects on CNV area were assayed by image analysis. VEGF levels in the choroid and retinal pigment epithelial cells (ARPE-19) were measured by Western blot or ELISA. Transcriptional activation of the VEGF promoter was determined by luciferase reporter gene assay. Mice treated with PPP, administered intraperitoneally or orally, showed a 22% to 32% (P = 0.002) decrease in CNV area. Furthermore, VEGF levels in the choroid were significantly reduced. In cultured ARPE-19 cells, IGF-1 was shown to increase VEGF secretion. This increase was completely blocked by PPP. PPP reduced the level of transcriptional activity of the VEGF promoter. PPP reduces IGF-1-dependent VEGF expression and CNV in vivo. Accordingly, IGF-1R inhibitors may be useful tools in the treatment of conditions associated with CNV, including neovascular AMD.

BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation

PubMed Central

Bononi, Angela; Giorgi, Carlotta; Patergnani, Simone; Larson, David; Verbruggen, Kaitlyn; Tanji, Mika; Pellegrini, Laura; Signorato, Valentina; Olivetto, Federica; Pastorino, Sandra; Nasu, Masaki; Napolitano, Andrea; Gaudino, Giovanni; Morris, Paul; Sakamoto, Greg; Ferris, Laura K.; Danese, Alberto; Raimondi, Andrea; Tacchetti, Carlo; Kuchay, Shafi; Pass, Harvey I.; Affar, El Bachir; Yang, Haining; Pinton, Paolo; Carbone, Michele

2017-01-01

BRCA1-associated protein 1 (BAP1) is a potent tumor suppressor gene that modulates environmental carcinogenesis1-3. All carriers of inherited heterozygous germline BAP1 inactivating mutations (BAP1+/-) developed one and often several BAP1-/- malignancies in their lifetime4, mostly malignant mesothelioma (MM), uveal melanoma (UVM)2,5, etc6-10. Moreover, BAP1 acquired biallelic mutations are frequent in human cancers8,11-14. BAP1 tumor suppressor activity has been attributed to its nuclear localization where BAP1 helps maintaining genome integrity15-17. The possible activity of BAP1 in the cytoplasm was unknown. Cells with reduced levels of BAP1 exhibit chromosomal abnormalities and decreased DNA repair by homologous recombination18, indicating that BAP1 dosage is critical. Cells with extensive DNA damage should die and not grow into malignancies. We discovered that BAP1 localizes at the endoplasmic reticulum (ER). Here BAP1 binds, deubiquitylates and stabilizes type-3 inositol-1,4,5-trisphosphate-receptor (IP3R3), modulating calcium (Ca2+) release from the ER into the cytosol and mitochondria, promoting apoptosis. Reduced levels of BAP1 in BAP1+/- carriers caused reduction of both IP3R3 levels and Ca2+ flux, preventing BAP1+/- cells that had accumulated DNA damage from executing apoptosis. A higher fraction of cells exposed to either ionizing or ultraviolet radiation, or to asbestos, survived genotoxic stress resulting in a higher rate of cellular transformation. We propose that the high incidence of cancers in BAP1+/- carriers results from the combined reduced nuclear and cytoplasmic BAP1 activities. Our data provide a mechanistic rationale for the powerful ability of BAP1 to regulate gene-environment interaction. PMID:28614305

Laparoscopic detection and resection of occult liver tumors of multiple cancer types using real-time near-infrared fluorescence guidance.

PubMed

Boogerd, Leonora S F; Handgraaf, Henricus J M; Lam, Hwai-Ding; Huurman, Volkert A L; Farina-Sarasqueta, Arantza; Frangioni, John V; van de Velde, Cornelis J H; Braat, Andries E; Vahrmeijer, Alexander L

2017-02-01

Tumor recurrence after radical resection of hepatic tumors is not uncommon, suggesting that malignant lesions are missed during surgery. Intraoperative navigation using fluorescence guidance is an innovative technique enabling real-time identification of (sub)capsular liver tumors. The objective of the current study was to compare fluorescence imaging (FI) and conventional imaging modalities for laparoscopic detection of both primary and metastatic tumors in the liver. Patients undergoing laparoscopic resection of a malignant hepatic tumor were eligible for inclusion. Patients received standard of care, including preoperative CT and/or MRI. In addition, 10 mg indocyanine green was intravenously administered 1 day prior to surgery. After introduction of the laparoscope, inspection, FI, and laparoscopic ultrasonography (LUS) were performed. Histopathological examination of resected suspect tissue was considered the gold standard. Twenty-two patients suspected of having hepatocellular carcinoma (n = 4), cholangiocarcinoma (n = 2) or liver metastases from colorectal carcinoma (n = 12), uveal melanoma (n = 2), and breast cancer (n = 2) were included. Two patients were excluded because their surgery was unexpectedly postponed several days. Twenty-six malignancies were resected in the remaining 20 patients. Sensitivity for various modalities was 80 % (CT), 84 % (MRI), 62 % (inspection), 86 % (LUS), and 92 % (FI), respectively. Three metastases (12 %) were identified solely by FI. All 26 malignancies could be detected by combining LUS and FI (100 % sensitivity). This study demonstrates added value of FI during laparoscopic resections of several hepatic tumors. Although larger series will be needed to confirm long-term patient outcome, the technology already aids the surgeon by providing real-time fluorescence guidance.

Ocular injuries from exploding glass-bottled Coca-Cola® drinks in Port Harcourt, Nigeria

PubMed Central

Pedro-Egbe, Chinyere Nnenne; Ejimadu, Chibuike Sydney; Nwachukwu, Henrietta

2011-01-01

Background: Eye injuries and subsequent loss of vision from the glass and caps of exploding pressurized bottled drinks have been well reported, and as a result most developed countries now use mainly plastic bottles. In Nigeria, however, most drinks are still sold in glass bottles and ocular injuries from this source are therefore not uncommon. Aim: To retrospectively analyze ocular injuries resulting from exploding glass-bottled Coca-Cola® and propose ways of eliminating such injuries in future. Setting: Eye Clinic, University of Port Harcourt Teaching Hospital, Port Harcourt, Nigeria. Materials and methods: The medical records of all cases of ocular injury that presented at the Eye Clinic of the University of Port Harcourt Teaching Hospital over a 5-year period (January 2006 to December 2010) were retrieved and relevant data including age, sex, occupation, events surrounding bottle explosion, and type of ocular injury sustained were extracted. Results: A total of 426 cases of ocular injuries was seen during the period under review. There were 335 (78.6%) males and 91 (21.4%) females. Six patients had ocular injury from exploding glass-bottled Coca-Cola®, giving an incidence of 1.4%. The presenting visual acuities (VA) were light perception (2 cases), counting fingers (2 cases), and 1 VA of 6/24 and 1 VA of 6/12. There were 4 (66.7%) cases of corneoscleral laceration with uveal prolapse and 1 case of total hyphema. Conclusion: Because pressurized glass-bottles can explode with normal handling, legislation to ban the use of glass containers for bottling carbonated drinks will go a long way to reducing ocular morbidity from this source. Plastic bottles should be introduced as an alternative. PMID:21629570

p21 is Responsible for Ionizing Radiation-induced Bypass of Mitosis.

PubMed

Zhang, Xu Rui; Liu, Yong Ai; Sun, Fang; Li, He; Lei, Su Wen; Wang, Ju Fang

2016-07-01

To explore the role of p21 in ionizing radiation-induced changes in protein levels during the G2/M transition and long-term G2 arrest. Protein expression levels were assessed by western blot in the human uveal melanoma 92-1 cells after treatment with ionizing radiation. Depletion of p21 was carried out by employing the siRNA technique. Cell cycle distribution was determined by flow cytometry combined with histone H3 phosphorylation at Ser28, an M-phase marker. Senescence was assessed by senescence- associated-β-galactosidase (SA-β-gal) staining combined with Ki67 staining, a cell proliferation marker. Accompanying increased p21, the protein levels of G2/M transition genes declined significantly in 92-1 cells irradiated with 5 Gy of X-rays. Furthermore, these irradiated cells were blocked at the G2 phase followed by cellular senescence. Depletion of p21 rescued radiation-induced G2 arrest as demonstrated by the upregulation of G2/M transition kinases, as well as the high expression of histone H3 phosphorylated at Ser28. Knockdown of p21 resulted in entry into mitosis of irradiated 92-1 cells. However, cells with serious DNA damage failed to undergo cytokinesis, leading to the accumulation of multinucleated cells. Our results indicated that p21 was responsible for the downregulation of G2/M transition regulatory proteins and the bypass of mitosis induced by irradiation. Downregulation of p21 by siRNA resulted in G2-arrested cells entering into mitosis with serious DNA damage. This is the first report on elucidating the role of p21 in the bypass of mitosis. Copyright © 2016 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

Generation of erythroid cells from polyploid giant cancer cells: re-thinking about tumor blood supply.

PubMed

Yang, Zhigang; Yao, Hong; Fei, Fei; Li, Yuwei; Qu, Jie; Li, Chunyuan; Zhang, Shiwu

2018-04-01

During development and tumor progression, cells need a sufficient blood supply to maintain development and rapid growth. It is reported that there are three patterns of blood supply for tumor growth: endothelium-dependent vessels, mosaic vessels, and vasculogenic mimicry (VM). VM was first reported in highly aggressive uveal melanomas, with tumor cells mimicking the presence and function of endothelial cells forming the walls of VM vessels. The walls of mosaic vessels are randomly lined with both endothelial cells and tumor cells. We previously proposed a three-stage process, beginning with VM, progressing to mosaic vessels, and eventually leading to endothelium-dependent vessels. However, many phenomena unique to VM channel formation remain to be elucidated, such as the origin of erythrocytes before VM vessels connect with endothelium-dependent vessels. In adults, erythroid cells are generally believed to be generated from hematopoietic stem cells in the bone marrow. In contrast, embryonic tissue obtains oxygen through formation of blood islands, which are largely composed of embryonic hemoglobin with a higher affinity with oxygen, in the absence of mature erythrocytes. Recent data from our laboratory suggest that embryonic blood-forming mechanisms also exist in cancer tissue, particularly when these tissues are under environmental stress such as hypoxia. We review the evidence from induced pluripotent stem cells in vitro and in vivo to support this previously underappreciated cell functionality in normal and cancer cells, including the ability to generate erythroid cells. We will also summarize the current understanding of tumor angiogenesis, VM, and our recent work on polyploid giant cancer cells, with emphasis on their ability to generate erythroid cells and their association with tumor growth under hypoxia. An alternative embryonic pathway to obtain oxygen in cancer cells exists, particularly when they are under hypoxic conditions.

Ocular injuries from exploding glass-bottled Coca-Cola® drinks in Port Harcourt, Nigeria.

PubMed

Pedro-Egbe, Chinyere Nnenne; Ejimadu, Chibuike Sydney; Nwachukwu, Henrietta

2011-01-01

Eye injuries and subsequent loss of vision from the glass and caps of exploding pressurized bottled drinks have been well reported, and as a result most developed countries now use mainly plastic bottles. In Nigeria, however, most drinks are still sold in glass bottles and ocular injuries from this source are therefore not uncommon. To retrospectively analyze ocular injuries resulting from exploding glass-bottled Coca-Cola® and propose ways of eliminating such injuries in future. Eye Clinic, University of Port Harcourt Teaching Hospital, Port Harcourt, Nigeria. The medical records of all cases of ocular injury that presented at the Eye Clinic of the University of Port Harcourt Teaching Hospital over a 5-year period (January 2006 to December 2010) were retrieved and relevant data including age, sex, occupation, events surrounding bottle explosion, and type of ocular injury sustained were extracted. A total of 426 cases of ocular injuries was seen during the period under review. There were 335 (78.6%) males and 91 (21.4%) females. Six patients had ocular injury from exploding glass-bottled Coca-Cola®, giving an incidence of 1.4%. The presenting visual acuities (VA) were light perception (2 cases), counting fingers (2 cases), and 1 VA of 6/24 and 1 VA of 6/12. There were 4 (66.7%) cases of corneoscleral laceration with uveal prolapse and 1 case of total hyphema. Because pressurized glass-bottles can explode with normal handling, legislation to ban the use of glass containers for bottling carbonated drinks will go a long way to reducing ocular morbidity from this source. Plastic bottles should be introduced as an alternative.

Magnetic resonance safety and compatibility of tantalum markers used in proton beam therapy for intraocular tumors: A 7.0 Tesla study.

PubMed

Oberacker, Eva; Paul, Katharina; Huelnhagen, Till; Oezerdem, Celal; Winter, Lukas; Pohlmann, Andreas; Boehmert, Laura; Stachs, Oliver; Heufelder, Jens; Weber, Andreas; Rehak, Matus; Seibel, Ira; Niendorf, Thoralf

2017-10-01

Proton radiation therapy (PRT) is a standard treatment of uveal melanoma. PRT patients undergo implantation of ocular tantalum markers (OTMs) for treatment planning. Ultra-high-field MRI is a promising technique for 3D tumor visualization and PRT planning. This work examines MR safety and compatibility of OTMs at 7.0 Tesla. MR safety assessment included deflection angle measurements (DAMs), electromagnetic field (EMF) simulations for specific absorption rate (SAR) estimation, and temperature simulations for examining radiofrequency heating using a bow-tie dipole antenna for transmission. MR compatibility was assessed by susceptibility artifacts in agarose, ex vivo pig eyes, and in an ex vivo tumor eye using gradient echo and fast spin-echo imaging. DAM (α < 1 °) demonstrated no risk attributed to magnetically induced OTM deflection. EMF simulations showed that an OTM can be approximated by a disk, demonstrated the need for averaging masses of m ave  = 0.01 g to accommodate the OTM, and provided SAR 0.01g,maximum  = 2.64 W/kg (P in  = 1W) in OTM presence. A transfer function was derived, enabling SAR 0.01g estimation for individual patient scenarios without the OTM being integrated. Thermal simulations revealed minor OTM-related temperature increase (δT < 15 mK). Susceptibility artifact size (<8 mm) and location suggest no restrictions for MRI of the nervus opticus. OTMs are not a per se contraindication for MRI. Magn Reson Med 78:1533-1546, 2017. © 2016 International Society for Magnetic Resonance in Medicine. © 2016 International Society for Magnetic Resonance in Medicine.

Ocular and neural distribution of feline herpesvirus-1 during active and latent experimental infection in cats

PubMed Central

2013-01-01

Background Herpes simplex virus 1 (HSV-1) and varicella zoster virus (VZV) cause extensive intra-ocular and neural infections in humans and are closely related to Felid herpes virus 1 (FeHV-1). We report the extent of intra-ocular replication and the extent and morphological aspects of neural replication during the acute and latent phases of FeHV-1 infection. Juvenile, SPF cats were inoculated with FeHV-1. Additional cats were used as negative controls. Cats were euthanized on days 6, 10, and 30 post-inoculation. Results FeHV-1 was isolated from the conjunctiva, cornea, uveal tract, retina, optic nerve, ciliary ganglion (CG), pterygopalatine ganglion (PTPG), trigeminal ganglion (TG), brainstem, visual cortex, cerebellum, and olfactory bulb of infected cats during the acute phase, but not the cranial cervical ganglion (CCG) and optic chiasm. Viral DNA was detected in all tissues during acute infection by a real-time quantitative PCR assay. On day 30, viral DNA was detected in all TG, all CCG, and 2 PTPG. Histologically mild inflammation and ganglion cell loss were noted within the TG during acute, but not latent infection. Using linear regression, a strong correlation existed between clinical score and day 30 viral DNA copy number within the TG. Conclusions The correlation between clinical score and day 30 viral DNA copy number suggests the severity of the acute clinical infection is related to the quantity of latent viral DNA. The histologic response was similar to that seen during HSV-1 or VZV infection. To the author’s knowledge this is the first report of FeHV-1 infection involving intraocular structures and autonomic ganglia. PMID:24053192

Ca2+ Binding to EF Hands 1 and 3 Is Essential for the Interaction of Apoptosis-Linked Gene-2 with Alix/AIP1 in Ocular Melanoma†

PubMed Central

Subramanian, Lalita; Polans, Arthur S.; Walker, Teresa M.; van Ginkel, Paul R.; Bhattacharya, Saswati; Dellaria, Julia M.; Crabb, John W.; Cox, Jos; Durussel, Isabelle; Palczewski, Krzysztof

2005-01-01

Apoptosis-linked gene-2 (ALG-2) encodes a 22 kDa Ca2+-binding protein of the penta EF-hand family that is required for programmed cell death in response to various apoptotic agents. Here, we demonstrate that ALG-2 mRNA and protein are down-regulated in human uveal melanoma cells compared to their progenitor cells, normal melanocytes. The down regulation of ALG-2 may provide melanoma cells with a selective advantage. ALG-2 and its putative target molecule, Alix/AIP1, are localized primarily in the cytoplasm of melanocytes and melanoma cells independent of the intracellular Ca2+ concentration or the activation of apoptosis. Cross-linking and analytical centrifugation studies support a single-species dimer conformation of ALG-2, also independent of Ca2+ concentration. However, binding of Ca2+ to both EF-1 and EF-3 is necessary for ALG-2 interaction with Alix/AIP1 as demonstrated using surface plasmon resonance spectroscopy. Mutations in EF-5 result in reduced target interaction without alteration in Ca2+ affinity. The addition of N-terminal ALG-2 peptides, residues 1–22 or residues 7–17, does not alter the interaction of ALG-2 or an N-terminal deletion mutant of ALG-2 with Alix/AIP1, as might be expected from a model derived from the crystal structure of ALG-2. Fluorescence studies of ALG-2 demonstrate that an increase in surface hydrophobicity is primarily due to Ca2+ binding to EF-3, while Ca2+ binding to EF-1 has little effect on surface exposure of hydrophobic residues. Together, these data indicate that gross surface hydrophobicity changes are insufficient for target recognition. PMID:15366927

Adjuvant Ab Interno Tumor Treatment After Proton Beam Irradiation.

PubMed

Seibel, Ira; Riechardt, Aline I; Heufelder, Jens; Cordini, Dino; Joussen, Antonia M

2017-06-01

This study was performed to show long-term outcomes concerning globe preservation in uveal melanoma patients after proton beam therapy with the main focus on outcomes according to different adjuvant ab interno surgical procedures. Retrospective cohort study. All patients treated with primary proton beam therapy for choroidal or ciliary body melanoma between June 1998 and June 2015 were included. A total of 2499 patients underwent primary proton beam therapy, with local tumor control and globe preservation rates of 95.9% and 94.8% after 5 years, respectively. A total of 110 (4.4%) patients required secondary enucleation. Unresponsive neovascular glaucoma was the leading cause of secondary enucleation in 78 of the 2499 patients (3.1%). The 5-year enucleation-free survival rate was 94.8% in the endoresection group, 94.3% in the endodrainage group, and 93.5% in the comparator group. The log-rank test showed P = .014 (comparator group vs endoresection group) and P = .06 (comparator group vs endodrainage-vitrectomy group). Patients treated with endoresection or endodrainage-vitrectomy developed less radiation retinopathy (30.5% and 37.4% after 5 years, P = .001 and P = .048 [Kaplan-Meier], respectively) and less neovascular glaucoma (11.6% and 21.3% after 5 years, P = .001 and P = .01 [Kaplan-Meier], respectively) compared with the comparator group (52.3% radiation retinopathy and 57.8% neovascular glaucoma after 5 years). This study suggests that in larger tumors the enucleation and neovascular glaucoma rates might be reduced by adjuvant surgical procedures. Although endoresection is the most promising adjuvant treatment option, the endodrainage-vitrectomy is recommended in patients who are ineligible for endoresection. Copyright © 2017 Elsevier Inc. All rights reserved.

Establishment of a 12-gene expression signature to predict colon cancer prognosis

PubMed Central

Zhao, Guangxi; Dong, Pingping; Wu, Bingrui

2018-01-01

A robust and accurate gene expression signature is essential to assist oncologists to determine which subset of patients at similar Tumor-Lymph Node-Metastasis (TNM) stage has high recurrence risk and could benefit from adjuvant therapies. Here we applied a two-step supervised machine-learning method and established a 12-gene expression signature to precisely predict colon adenocarcinoma (COAD) prognosis by using COAD RNA-seq transcriptome data from The Cancer Genome Atlas (TCGA). The predictive performance of the 12-gene signature was validated with two independent gene expression microarray datasets: GSE39582 includes 566 COAD cases for the development of six molecular subtypes with distinct clinical, molecular and survival characteristics; GSE17538 is a dataset containing 232 colon cancer patients for the generation of a metastasis gene expression profile to predict recurrence and death in COAD patients. The signature could effectively separate the poor prognosis patients from good prognosis group (disease specific survival (DSS): Kaplan Meier (KM) Log Rank p = 0.0034; overall survival (OS): KM Log Rank p = 0.0336) in GSE17538. For patients with proficient mismatch repair system (pMMR) in GSE39582, the signature could also effectively distinguish high risk group from low risk group (OS: KM Log Rank p = 0.005; Relapse free survival (RFS): KM Log Rank p = 0.022). Interestingly, advanced stage patients were significantly enriched in high 12-gene score group (Fisher’s exact test p = 0.0003). After stage stratification, the signature could still distinguish poor prognosis patients in GSE17538 from good prognosis within stage II (Log Rank p = 0.01) and stage II & III (Log Rank p = 0.017) in the outcome of DFS. Within stage III or II/III pMMR patients treated with Adjuvant Chemotherapies (ACT) and patients with higher 12-gene score showed poorer prognosis (III, OS: KM Log Rank p = 0.046; III & II, OS: KM Log Rank p = 0.041). Among stage II/III pMMR patients with lower 12-gene scores in GSE39582, the subgroup receiving ACT showed significantly longer OS time compared with those who received no ACT (Log Rank p = 0.021), while there is no obvious difference between counterparts among patients with higher 12-gene scores (Log Rank p = 0.12). Besides COAD, our 12-gene signature is multifunctional in several other cancer types including kidney cancer, lung cancer, uveal and skin melanoma, brain cancer, and pancreatic cancer. Functional classification showed that seven of the twelve genes are involved in immune system function and regulation, so our 12-gene signature could potentially be used to guide decisions about adjuvant therapy for patients with stage II/III and pMMR COAD.

Practice Patterns Analysis of Ocular Proton Therapy Centers: The International OPTIC Survey.

PubMed

Hrbacek, Jan; Mishra, Kavita K; Kacperek, Andrzej; Dendale, Remi; Nauraye, Catherine; Auger, Michel; Herault, Joel; Daftari, Inder K; Trofimov, Alexei V; Shih, Helen A; Chen, Yen-Lin E; Denker, Andrea; Heufelder, Jens; Horwacik, Tomasz; Swakoń, Jan; Hoehr, Cornelia; Duzenli, Cheryl; Pica, Alessia; Goudjil, Farid; Mazal, Alejandro; Thariat, Juliette; Weber, Damien C

2016-05-01

To assess the planning, treatment, and follow-up strategies worldwide in dedicated proton therapy ocular programs. Ten centers from 7 countries completed a questionnaire survey with 109 queries on the eye treatment planning system (TPS), hardware/software equipment, image acquisition/registration, patient positioning, eye surveillance, beam delivery, quality assurance (QA), clinical management, and workflow. Worldwide, 28,891 eye patients were treated with protons at the 10 centers as of the end of 2014. Most centers treated a vast number of ocular patients (1729 to 6369). Three centers treated fewer than 200 ocular patients. Most commonly, the centers treated uveal melanoma (UM) and other primary ocular malignancies, benign ocular tumors, conjunctival lesions, choroidal metastases, and retinoblastomas. The UM dose fractionation was generally within a standard range, whereas dosing for other ocular conditions was not standardized. The majority (80%) of centers used in common a specific ocular TPS. Variability existed in imaging registration, with magnetic resonance imaging (MRI) rarely being used in routine planning (20%). Increased patient to full-time equivalent ratios were observed by higher accruing centers (P=.0161). Generally, ophthalmologists followed up the post-radiation therapy patients, though in 40% of centers radiation oncologists also followed up the patients. Seven centers had a prospective outcomes database. All centers used a cyclotron to accelerate protons with dedicated horizontal beam lines only. QA checks (range, modulation) varied substantially across centers. The first worldwide multi-institutional ophthalmic proton therapy survey of the clinical and technical approach shows areas of substantial overlap and areas of progress needed to achieve sustainable and systematic management. Future international efforts include research and development for imaging and planning software upgrades, increased use of MRI, development of clinical protocols, systematic patient-centered data acquisition, and publishing guidelines on QA, staffing, treatment, and follow-up parameters by dedicated ocular programs to ensure the highest level of care for ocular patients. Copyright © 2016 Elsevier Inc. All rights reserved.

Visual Outcomes of Parapapillary Uveal Melanomas Following Proton Beam Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thariat, Juliette, E-mail: jthariat@gmail.com; Grange, Jean-Daniel; Mosci, Carlo

Purpose: In parapapillary melanoma patients, radiation-induced optic complications are frequent and visual acuity is often compromised. We investigated dose-effect relationships for the optic nerve with respect to visual acuity after proton therapy. Methods and Materials: Of 5205 patients treated between 1991 and 2014, those treated using computed tomography (CT)-based planning to 52 Gy (prescribed dose, not accounting for relative biologic effectiveness correction of 1.1) in 4 fractions, with minimal 6-month follow-up and documented initial and last visual acuity, were included. Deterioration of ≥0.3 logMAR between initial and last visual acuity results was reported. Results: A total of 865 consecutive patients weremore » included. Median follow-up was 69 months, mean age was 61.7 years, tumor abutted the papilla in 35.1% of patients, and tumor-to-fovea distance was ≤3 mm in 74.2% of patients. Five-year relapse-free survival rate was 92.7%. Visual acuity was ≥20/200 in 72.6% of patients initially and 47.2% at last follow-up. A wedge filter was used in 47.8% of the patients, with a positive impact on vision and no impact on relapse. Glaucoma, radiation-induced optic neuropathy, maculopathy were reported in 17.9%, 47.5%, and 33.6% of patients, respectively. On multivariate analysis, age, diabetes, thickness, initial visual acuity and percentage of macula receiving 26 Gy were predictive of visual acuity. Furthermore, patients irradiated to ≥80% of their papilla had better visual acuity when limiting the 50% (30-Gy) and 20% (12-Gy) isodoses to ≤2 mm and 6 mm of optic nerve length, respectively. Conclusions: A personalized proton therapy plan with optic nerve and macular sparing can be used efficiently with good oncological and functional results in parapapillary melanoma patients.« less

The development of the trabecular meshwork and its abnormality in primary infantile glaucoma.

PubMed Central

Anderson, D R

1981-01-01

Tissue from ten eyes with infantile glaucoma and from 40 normal eyes of fetuses and infants without glaucoma were examined by light and electron microscopy. In normal development, the corneoscleral coat grows faster than the uveal tract during the last trimester, leading to a posterior migration of the ciliary body attachment from Schwalbe's line (5th month) to the scleral spur (9th month), and then to a location behind the scleral spur (postnatally). In infantile glaucoma, the insertion of the anterior ciliary body and iris overlaps the trabecular meshwork, similar to the late fetal position. The trabecular sheets are perforated, and there is no membrane over the surface of the trabecular meshwork. The trabecular beams are thicker than in normal infant eyes. There is both histologic and clinical evidence of traction on the iris root exerted by the thickened trabecular beams. These findings suggest that in congenital glaucoma the thickened beams had prevented the normal posterior migration of the ciliary body and iris root. This traction may compact the thickened trabecular beams, obstructing aqueous humor outflow. Release of the traction by an incision (goniotomy or trabeculotomy) of the thickened meshwork may relieve the obstruction. Of uncertain pathological significance is that there are no vacuoles in the endothelium of Schlemm's canal and there is a broad layer of collagen and amorphous material in the juxtacanalicular connective tissue. The ciliary processes are elongated inward, as if they were pulled by zonular traction (perhaps created by an enlarging diameter of the limbus with a fixed lens diameter). Images FIGURE 7 FIGURE 8 FIGURE 10 FIGURE 11 FIGURE 20 A FIGURE 20 B FIGURE 1 FIGURE 3 FIGURE 4 A FIGURE 4 B FIGURE 5 A FIGURE 5 B FIGURE 6 FIGURE 9 FIGURE 12 FIGURE 13 FIGURE 14 FIGURE 15 FIGURE 16 FIGURE 17 FIGURE 18 FIGURE 19 PMID:7342408

Development of a Unique Small Molecule Modulator of CXCR4

PubMed Central

Yoon, Younghyoun; Lin, Songbai; Sasaki, Maiko; Klapproth, Jan-Michael A.; Yang, Hua; Grossniklaus, Hans E.; Xu, Jianguo; Rojas, Mauricio; Voll, Ronald J.; Goodman, Mark M.; Arrendale, Richard F.; Liu, Jin; Yun, C. Chris; Snyder, James P.; Liotta, Dennis C.; Shim, Hyunsuk

2012-01-01

Background Metastasis, the spread and growth of tumor cells to distant organ sites, represents the most devastating attribute and plays a major role in the morbidity and mortality of cancer. Inflammation is crucial for malignant tumor transformation and survival. Thus, blocking inflammation is expected to serve as an effective cancer treatment. Among anti-inflammation therapies, chemokine modulation is now beginning to emerge from the pipeline. CXC chemokine receptor-4 (CXCR4) and its ligand stromal cell-derived factor-1 (CXCL12) interaction and the resulting cell signaling cascade have emerged as highly relevant targets since they play pleiotropic roles in metastatic progression. The unique function of CXCR4 is to promote the homing of tumor cells to their microenvironment at the distant organ sites. Methodology/Principal Findings We describe the actions of N,N′-(1,4-phenylenebis(methylene))dipyrimidin-2-amine (designated MSX-122), a novel small molecule and partial CXCR4 antagonist with properties quite unlike that of any other reported CXCR4 antagonists, which was prepared in a single chemical step using a reductive amination reaction. Its specificity toward CXCR4 was tested in a binding affinity assay and a ligand competition assay using 18F-labeled MSX-122. The potency of the compound was determined in two functional assays, Matrigel invasion assay and cAMP modulation. The therapeutic potential of MSX-122 was evaluated in three different murine models for inflammation including an experimental colitis, carrageenan induced paw edema, and bleomycin induced lung fibrosis and three different animal models for metastasis including breast cancer micrometastasis in lung, head and neck cancer metastasis in lung, and uveal melanoma micrometastasis in liver in which CXCR4 was reported to play crucial roles. Conclusions/Significance We developed a novel small molecule, MSX-122, that is a partial CXCR4 antagonist without mobilizing stem cells, which can be safer for long-term blockade of metastasis than other reported CXCR4 antagonists. PMID:22485156

Proton or photon irradiation for hemangiomas of the choroid? A retrospective comparison

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hoecht, Stefan; Wachtlin, Joachim; Bechrakis, Nikolaos E.

2006-10-01

Purpose: The aim of this study was to compare, on a retrospective basis, the results of therapy in patients with uveal hemangioma treated with photon or proton irradiation at a single center. Methods and Materials: From 1993 to 2002 a total of 44 patients were treated. Until 1998 radiotherapy was given with 6 MV photons in standard fractionation of 2.0 Gy 5 times per week. In 1998 proton therapy became available and was used since then. A dose of 20 to 22.5 Cobalt Gray Equivalent (CGE) 68 MeV protons was given on 4 consecutive days. Progressive symptoms or deterioration ofmore » vision were the indications for therapy. Results: Of the 44 patients treated, 36 had circumscribed choroidal hemangiomas and 8 had diffuse choroidal hemangiomas (DCH) and Sturge-Weber syndrome. Of the patients, 19 were treated with photons with a total dose in the range of 16 to 30 Gy. A total of 25 patients were irradiated with protons. All patients with DCH but 1 were treated with photons. Stabilization of visual acuity was achieved in 93.2% of all patients. Tumor thickness decreased in 95.4% and retinal detachment resolved in 92.9%. Late effects, although generally mild or moderate, were frequently detected. In all, 40.9% showed radiation-induced optic neuropathy, maximum Grade I. Retinopathy was found in 29.5% of cases, but only 1 patient experienced more than Grade II severity. Retinopathy and radiation-induced optic neuropathy were reversible in some of the patients and in some resolved completely. No differences could be detected between patients with circumscribed choroidal hemangiomas treated with protons and photons. Treatment was less effective in DCH patients (75%). Conclusions: Radiotherapy is effective in treating choroidal hemangiomas with respect to visual acuity and tumor thickness but a benefit of proton therapy could not be detected. Side effects are moderate but careful monitoring for side effects should be part of the follow-up procedures.« less

Circulating tumor DNA changes for early monitoring of anti-PD1 immunotherapy: a proof-of-concept study.

PubMed

Cabel, L; Riva, F; Servois, V; Livartowski, A; Daniel, C; Rampanou, A; Lantz, O; Romano, E; Milder, M; Buecher, B; Piperno-Neumann, S; Bernard, V; Baulande, S; Bieche, I; Pierga, J Y; Proudhon, C; Bidard, F-C

2017-08-01

Recent clinical results support the use of new immune checkpoint blockers (ICB), such as anti-PD-1 (e.g. nivolumab and pembrolizumab) and anti-PD-L1 antibodies. Radiological evaluation of ICB efficacy during therapy is challenging due to tumor immune infiltration. Changes of circulating tumor DNA (ctDNA) levels during therapy could be a promising tool for very accurate monitoring of treatment efficacy, but data are lacking with ICB. This prospective pilot study was conducted in patients with nonsmall cell lung cancer, uveal melanoma, or microsatellite-instable colorectal cancer treated by nivolumab or pembrolizumab monotherapy at Institut Curie. ctDNA levels were assessed at baseline and after 8 weeks (w8) by bidirectional pyrophosphorolysis-activated polymerization, droplet digital PCR or next-generation sequencing depending on the mutation type. Radiological evaluation of efficacy of treatment was carried out by using immune-related response criteria. ctDNA was detected at baseline in 10 out of 15 patients. At w8, a significant correlation (r = 0.86; P = 0.002) was observed between synchronous changes in ctDNA levels and tumor size. Patients in whom ctDNA levels became undetectable at w8 presented a marked and lasting response to therapy. ctDNA detection at w8 was also a significant prognostic factor in terms of progression-free survival (hazard ratio = 10.2; 95% confidence interval 2.5-41, P < 0.001) and overall survival (hazard ratio = 15; 95% confidence interval 2.5-94.9, P = 0.004). This proof-of-principle study is the first to demonstrate that quantitative ctDNA monitoring is a valuable tool to assess tumor response in patients treated with anti-PD-1 drugs. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Cyclodiode photocoagulation for refractory glaucoma after penetrating keratoplasty.

PubMed

Shah, P; Lee, G A; Kirwan, J K; Bunce, C; Bloom, P A; Ficker, L A; Khaw, P T

2001-11-01

This study analyzes the results of intraocular pressure (IOP) reduction by contact diode cycloablation (cyclodiode) in cases of refractory glaucoma after penetrating keratoplasty. Retrospective noncomparative, interventional case series. Twenty-eight eyes in 28 patients attending the Moorfields Eye Hospital. Cyclodiode (40 applications x 1.5 W x 1.5 seconds over 270-300 degrees ) was used to control the IOP in refractory glaucoma after penetrating keratoplasty. Postoperative IOP, graft status, visual acuity, and number of antiglaucoma medications were recorded after cyclodiode treatment. Cyclodiode resulted in a reduction of IOP from a median of 33 mmHg (interquartile range [28, 40.5]) to a median of 15 mmHg (interquartile range [12, 20.5]). Most patients had a significant lowering in IOP with a median reduction of 16 mmHg (interquartile range [12, 25]; P < 0.0001). IOPs of 6 to 21 mmHg were achieved in 22 patients (79%). Sixteen patients (57%) required more than one treatment with cyclodiode to control the IOP, with three patients (11%) requiring three treatments and two patients (7%) requiring four treatments. Visual acuity improved (> two Snellen lines of acuity) in three patients (11%) and remained the same (+/- one Snellen line) in 17 patients (61%). The mean number of antiglaucoma medications before cycloablation was 2.6 and was 1.8 after treatment (P < 0.001). Of the 19 patients (68%) with originally clear grafts, three grafts (16%) developed opacification. One patient (4%), with a history of nanophthalmos and recurrent uveal effusion, had delayed hypotony (IOP < 6 mmHg) occurring 46 months after the diode treatment. All patients had at least 6 months follow-up. These patients have often undergone multiple previous complicated ocular interventions and are often not suitable for filtration surgery. Reduction of IOP with maintenance of visual acuity and a good safety profile was achieved in most patients in this study but may require multiple treatments. We propose cyclodiode as an effective treatment for many patients in the management of refractory glaucoma after penetrating keratoplasty.

ELIMED: a new hadron therapy concept based on laser driven ion beams

NASA Astrophysics Data System (ADS)

Cirrone, Giuseppe A. P.; Margarone, Daniele; Maggiore, Mario; Anzalone, Antonello; Borghesi, Marco; Jia, S. Bijan; Bulanov, Stepan S.; Bulanov, Sergei; Carpinelli, Massimo; Cavallaro, Salvatore; Cutroneo, Mariapompea; Cuttone, Giacomo; Favetta, Marco; Gammino, Santo; Klimo, Ondrej; Manti, Lorenzo; Korn, Georg; La Malfa, Giuseppe; Limpouch, Jiri; Musumarra, Agatino; Petrovic, Ivan; Prokupek, Jan; Psikal, Jan; Ristic-Fira, Aleksandra; Renis, Marcella; Romano, Francesco P.; Romano, Francesco; Schettino, Giuseppe; Schillaci, Francesco; Scuderi, Valentina; Stancampiano, Concetta; Tramontana, Antonella; Ter-Avetisyan, Sargis; Tomasello, Barbara; Torrisi, Lorenzo; Tudisco, Salvo; Velyhan, Andriy

2013-05-01

Laser accelerated proton beams have been proposed to be used in different research fields. A great interest has risen for the potential replacement of conventional accelerating machines with laser-based accelerators, and in particular for the development of new concepts of more compact and cheaper hadrontherapy centers. In this context the ELIMED (ELI MEDical applications) research project has been launched by INFN-LNS and ASCR-FZU researchers within the pan-European ELI-Beamlines facility framework. The ELIMED project aims to demonstrate the potential clinical applicability of optically accelerated proton beams and to realize a laser-accelerated ion transport beamline for multi-disciplinary user applications. In this framework the eye melanoma, as for instance the uveal melanoma normally treated with 62 MeV proton beams produced by standard accelerators, will be considered as a model system to demonstrate the potential clinical use of laser-driven protons in hadrontherapy, especially because of the limited constraints in terms of proton energy and irradiation geometry for this particular tumour treatment. Several challenges, starting from laser-target interaction and beam transport development up to dosimetry and radiobiology, need to be overcome in order to reach the ELIMED final goals. A crucial role will be played by the final design and realization of a transport beamline capable to provide ion beams with proper characteristics in terms of energy spectrum and angular distribution which will allow performing dosimetric tests and biological cell irradiation. A first prototype of the transport beamline has been already designed and other transport elements are under construction in order to perform a first experimental test with the TARANIS laser system by the end of 2013. A wide international collaboration among specialists of different disciplines like Physics, Biology, Chemistry, Medicine and medical doctors coming from Europe, Japan, and the US is growing up around the ELIMED project with the aim to work on the conceptual design, technical and experimental realization of this core beamline of the ELI Beamlines facility.

Corticosteroid implants for chronic non-infectious uveitis

PubMed Central

Brady, Christopher J; Villanti, Andrea C; Law, Hua Andrew; Rahimy, Ehsan; Reddy, Rahul; Sieving, Pamela C; Garg, Sunir J; Tang, Johnny

2016-01-01

Background Uveitis is a term used to describe a heterogeneous group of intraocular inflammatory diseases of the anterior, intermediate, and posterior uveal tract (iris, ciliary body, choroid). Uveitis is the fifth most common cause of vision loss in high-income countries, accounting for 5% to 20% of legal blindness, with the highest incidence of disease in the working-age population. Corticosteroids are the mainstay of acute treatment for all anatomical subtypes of non-infectious uveitis and can be administered orally, topically with drops or ointments, by periocular (around the eye) or intravitreal (inside the eye) injection, or by surgical implantation. Objectives To determine the efficacy and safety of steroid implants in people with chronic non-infectious posterior uveitis, intermediate uveitis, and panuveitis. Search methods We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (Issue 10, 2015), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to November 2015), EMBASE (January 1980 to November 2015), PubMed (1948 to November 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to November 2015), the metaRegister of Controlled Trials (mRCT) (www.controlledtrials.com) (last searched 15 April 2013), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform(ICTRP) (www.who.int/ictrp/search/en).We did not use any date or language restrictions in the electronic search for studies. We last searched the electronic databases on 6 November 2015. We also searched reference lists of included study reports, citation databases, and abstracts and clinical study presentations from professional meetings. Selection criteria We included randomized controlled trials comparing either fluocinolone acetonide (FA) or dexamethasone intravitreal implants with standard-of-care therapy with at least six months of follow-up after treatment. We included studies that enrolled participants of all ages who had chronic non-infectious posterior uveitis, intermediate uveitis, or panuveitis with vision that was better than hand-motion. Data collection and analysis Two review authors independently reviewed studies for inclusion. Two review authors independently extracted data and assessed the risk of bias for each study. Main results We included data from two studies (619 eyes of 401 participants) that compared FA implants with standard-of-care therapy. Both studies used similar standard-of-care therapy that included administration of prednisolone and, if needed, immunosuppressive agents. The studies included participants from Australia, France, Germany, Israel, Italy, Portugal, Saudi Arabia, Spain, Switzerland, Turkey, the United Kingdom, and the United States. We assessed both studies at high risk of performance and detection bias. Only one study reported our primary outcome, recurrence of uveitis at any point during the study through 24 months. The evidence, judged as moderate-quality, showed that a FA implant probably prevents recurrence of uveitis compared with standard-of-care therapy (risk ratio (RR) 0.29, 95% confidence interval (CI) 0.14 to 0.59; 132 eyes). Both studies reported safety outcomes, and moderate-quality evidence showed increased risks of needing cataract surgery (RR 2.98, 95% CI 2.33 to 3.79; 371 eyes) and surgery to lower intraocular pressure (RR 7.48, 95% CI 3.94 to 14.19; 599 eyes) in the implant group compared with standard-of-care therapy through two years of follow-up. No studies compared dexamethasone implants with standard-of-care therapy. Authors’ conclusions After considering both benefits and harms reported from two studies in which corticosteroids implants were compared with standard-of-care therapy, we are unable to conclude that the implants are superior to traditional systemic therapy for the treatment of noninfectious uveitis. These studies exhibited heterogeneity in design and outcomes that measured efficacy. Pooled findings regarding safety outcomes suggest increased risks of post-implant surgery for cataract and high intraocular pressure compared with standard-of-care therapy. PMID:26866343

Ophthalmic magnetic resonance imaging at 7 T using a 6-channel transceiver radiofrequency coil array in healthy subjects and patients with intraocular masses.

PubMed

Graessl, Andreas; Muhle, Maximilian; Schwerter, Michael; Rieger, Jan; Oezerdem, Celal; Santoro, Davide; Lysiak, Darius; Winter, Lukas; Hezel, Fabian; Waiczies, Sonia; Guthoff, Rudolf F; Falke, Karen; Hosten, Norbert; Hadlich, Stefan; Krueger, Paul-Christian; Langner, Soenke; Stachs, Oliver; Niendorf, Thoralf

2014-05-01

This study was designed to examine the feasibility of ophthalmic magnetic resonance imaging (MRI) at 7 T using a local 6-channel transmit/receive radiofrequency (RF) coil array in healthy volunteers and patients with intraocular masses. A novel 6-element transceiver RF coil array that makes uses of loop elements and that is customized for eye imaging at 7 T is proposed. Considerations influencing the RF coil design and the characteristics of the proposed RF coil array are presented. Numerical electromagnetic field simulations were conducted to enhance the RF coil characteristics. Specific absorption rate simulations and a thorough assessment of RF power deposition were performed to meet the safety requirements. Phantom experiments were carried out to validate the electromagnetic field simulations and to assess the real performance of the proposed transceiver array. Certified approval for clinical studies was provided by a local notified body before the in vivo studies. The suitability of the RF coil to image the human eye, optical nerve, and orbit was examined in an in vivo feasibility study including (a) 3-dimensional (3D) gradient echo (GRE) imaging, (b) inversion recovery 3D GRE imaging, and (c) 2D T2-weighted fast spin-echo imaging. For this purpose, healthy adult volunteers (n = 17; mean age, 34 ± 11 years) and patients with intraocular masses (uveal melanoma, n = 5; mean age, 57 ± 6 years) were investigated. All subjects tolerated all examinations well with no relevant adverse events. The 6-channel coil array supports high-resolution 3D GRE imaging with a spatial resolution as good as 0.2 × 0.2 × 1.0 mm, which facilitates the depiction of anatomical details of the eye. Rather, uniform signal intensity across the eye was found. A mean signal-to-noise ratio of approximately 35 was found for the lens, whereas the vitreous humor showed a signal-to-noise ratio of approximately 30. The lens-vitreous humor contrast-to-noise ratio was 8, which allows good differentiation between the lens and the vitreous compartment. Inversion recovery prepared 3D GRE imaging using a spatial resolution of 0.4 × 0.4 × 1.0 mm was found to be feasible. T2-weighted 2D fast spin-echo imaging with the proposed RF coil afforded a spatial resolution of 0.25 × 0.25 × 0.7 mm. This work provides valuable information on the feasibility of ophthalmic MRI at 7 T using a dedicated 6-channel transceiver coil array that supports the acquisition of high-contrast, high-spatial resolution images in healthy volunteers and patients with intraocular masses. The results underscore the challenges of ocular imaging at 7 T and demonstrate that these issues can be offset by using tailored RF coil hardware. The benefits of such improvements would be in positive alignment with explorations that are designed to examine the potential of MRI for the assessment of spatial arrangements of the eye segments and their masses with the ultimate goal to provide imaging means for guiding treatment decisions in ophthalmological diseases.

Prevalence, type, and prognosis of ocular lesions in shelter and owned-client dogs naturally infected by Leishmania infantum

PubMed Central

Pietro, Simona Di; Bosco, Valentina Rita Francesca; Crinò, Chiara; Francaviglia, Francesco; Giudice, Elisabetta

2016-01-01

Aim: The point prevalence of ocular lesions due to leishmaniasis was evaluated in 127 dogs living in a municipal shelter placed in a highly endemic area (Sicily, Italy). Moreover, the period prevalence, the type, and prognosis of lesions due to leishmaniasis were evaluated in 132 dogs with ocular pathologies referred to a Veterinary Teaching Hospital (VTH) in the same endemic area over a 3-year period. Materials and Methods: All the dogs were submitted to ophthalmological examination. The diagnosis of leishmaniasis was made by cytological, serological (immune-fluorescent antibody test), and molecular (quantitative polymerase chain reaction) tests. Results: The point prevalence of ocular lesions in 45 shelter dogs with leishmaniasis was 71.11% (45/127 dogs). The most frequent ocular lesion was blepharitis (50%) while anterior uveitis was observed in only 9.37% of cases. The period prevalence of ocular lesions due to leishmaniasis in the VTH group was 36.36% (48/132 dogs). In both groups, most of the lesions were bilateral and involved the anterior segment. Anterior uveitis was the most frequent ophthalmic finding in client-owned dogs (37.50%), but it occurred in only 9.37% of the shelter dogs. Keratouveitis often occurred during or after antiprotozoal treatment (14.58%; 7/48). In this study, the healing of eye injury following systemic antiprotozoal treatment was recorded in about half of cases (48%; 12/25 dogs), in which follow-up was possible. In more than 1/3 of cases (36%; 9/25), there was an improvement, but it was necessary to associate a long-term topical treatment; most of them, as well as those who had not responded to systemic therapy (16%; 4/25), had anterior uveitis or keratoconjunctivitis sicca. Conclusions: Ocular manifestations involve up to 2/3 of animals affected by canine leishmaniasis and lesions account for over 1/3 of ophthalmic pathologies observed at a referral clinic in an endemic area. The occurrence of anterior uveitis is more frequent in client-owned dogs than in shelter dogs. The onset of keratouveitis during or after antiprotozoal treatment could be attributed to the treatment or to a recurrence of the systemic form. The post-treatment uveal immune reaction, already observed in humans, could explain the difference in the frequency of keratouveitis between client-owned and shelter dogs, which have never been treated. PMID:27397988

The proliferation of malignant melanoma cells could be inhibited by ranibizumab via antagonizing VEGF through VEGFR1.

PubMed

Li, Jiao; Cui, Yan; Wang, Qin; Guo, Dadong; Pan, Xuemei; Wang, Xingrong; Bi, Hongsheng; Chen, Wei; Liu, Zhengfeng; Zhao, Shengya

2014-01-01

Angiogenesis is an important mediator in tumor progression. Vascular endothelial growth factor (VEGF) is one of the major cytokines that can influence angiogenesis. However, the potential mechanism of tumor growth inhibition through anti-VEGF agents is still unclear. This study was performed to examine whether ranibizumab could inhibit malignant melanoma growth in vitro and to determine the safety of ranibizumab on human adult retinal pigment epithelium cell line (ARPE-19 cells). Malignant melanoma cells obtained from a clinic were cultured in vitro. VEGF concentrations secreted by malignant melanoma cells and the ARPE-19 cells were examined by enzyme-linked immunosorbent assay (ELISA). The two kinds of cells were both treated with VEGF and its antagonist, ranibizumab. The dynamic changes of the two types of cells were monitored by real-time cell electronic sensing (RT-CES) assay. The effect of ranibizumab on both types of cells was verified by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl (MTT) assay. The expression of VEGF receptor 1 (VEGFR1) RNA in uveal melanoma was further investigated through the PCR technique. The levels of VEGF secreted by malignant melanoma cells were much higher than those of ARPE-19 cells, and were markedly decreased in the action of 0.1 mg/ml ranibizumab. However, there was no obvious reduction of VEGF in the presence of ranibizumab for ARPE-19 (p>0.05). Meanwhile, RT-CES showed that the viability of malignant melanoma cells increased greatly in the presence of VEGF. When VEGF was 20 ng/ml, viability of the malignant melanoma cells increased by 40% compared with the negative control. There was no evident effect on proliferation of ARPE-19 (p>0.05). Furthermore, the growth of malignant melanoma cells was obviously inhibited after ranibizumab intervention. When ranibizumab was administered at 0.25 mg/ml, the survival rate of the malignant melanoma cells decreased to 57.5%. Nevertheless, low-dose exposure to ranibizumab had only a slight effect on the growth of ARPE-19, and PCR result demonstrated that VEGFR1 plays a role in this tumor tissue rather than VEGFR2. Ranibizumab can selectively inhibit malignant melanoma cell proliferation by decreasing the expression of VEGF; the possible mechanism of the inhibitory effect may involve VEGFR1 antagonism.

Absorption, Distribution, and Excretion of 14C-APX001 after Single-Dose Administration to Rats and Monkeys

PubMed Central

Mansbach, Robert; Shaw, Karen J; Hodges, Michael R; Coleman, Samantha; Fitzsimmons, Michael E

2017-01-01

Abstract Background APX001 is a small-molecule therapeutic agent in clinical development for the treatment of invasive fungal infections (IFI). Methods The absorption, distribution and excretion profiles of [14C]APX001-derived radioactivity were determined in rats (albino and pigmented) and monkeys. Rats (some implanted with bile duct cannulae) were administered a single 100 mg/kg oral dose or a 30 mg/kg intravenous (IV) dose. Monkeys were administered a single 6 mg/kg IV dose. Samples of blood, urine, feces and bile, as well as carcasses, were collected through 168 hours after dosing. Samples were analyzed for total radioactivity content by liquid scintillation counting, and carcasses were analyzed by quantitative whole-body autoradiography. Results [14C]APX001-derived radioactivity was rapidly and extensively absorbed and extensively distributed to most tissues for both routes of administration in both species. In rats, tissues with the highest radioactivity Cmax values included bile, abdominal fat, reproductive fat, subcutaneous fat, and liver, but radioactivity was also detected in tissues associated with IFI, including lung, brain and eye. In monkeys, the highest Cmax values were in bile, urine, uveal tract, bone marrow, abdominal fat, liver, and kidney cortex. Liver and kidney were the tissues with highest radioactivity, but as in the rat, radioactivity was also detected in lung, brain and eye tissues. In pigmented rats, radiocarbon was densely distributed into pigmented tissue and more slowly cleared than from other tissues. Mean recovery of radioactivity in rats was approximately 95–100%. In bile duct-intact rats, >90% of radioactivity was recovered in feces. In cannulated rats, biliary excretion of radioactivity was the major route of elimination and accounted for 88.8% of the dose, whereas urinary and fecal excretion of radioactivity was minor and accounted for 2.56% and 5.42% of the dose, respectively. In monkeys, the overall recovery of radioactivity was 87.6%, and was eliminated in feces (49.8% of dose) and to a lesser extent in urine (20.6% of dose). Conclusion Together, the results indicate that APX001-related radioactivity is extensively distributed to major tissues (including tissues relevant to IFI) in both rats and monkeys and cleared primarily by biliary/fecal excretion. Disclosures R. Mansbach, Amplyx Pharmaceuticals Inc.: Consultant, Consulting fee; K. J. Shaw, Amplyx Pharmaceuticals Inc.: Employee, Salary; M. R. Hodges, Amplyx Pharmaceuticals: Employee, Salary; S. Coleman, Covance Laboratories: Employee, Salary; M. E. Fitzsimmons, Covance Laboratories: Employee, Salary

The Expression and Prognostic Impact of Immune Cytolytic Activity-Related Markers in Human Malignancies: A Comprehensive Meta-analysis.

PubMed

Roufas, Constantinos; Chasiotis, Dimitrios; Makris, Anestis; Efstathiades, Christodoulos; Dimopoulos, Christos; Zaravinos, Apostolos

2018-01-01

Recently, immune-checkpoint blockade has shown striking clinical results in different cancer patients. However, a significant inter-individual and inter-tumor variability exists among different cancers. The expression of the toxins granzyme A (GZMA) and perforin 1 (PRF1), secreted by effector cytotoxic T cells and natural killer (NK) cells, were recently used as a denominator of the intratumoral immune cytolytic activity (CYT). These levels are significantly elevated upon CD8+ T-cell activation as well as during a productive clinical response against immune-checkpoint blockade therapies. Still, it is not completely understood how different tumors induce and adapt to immune responses. Here, we calculated the CYT across different cancer types and focused on differences between primary and metastatic tumors. Using data from 10,355, primary tumor resection samples and 2,787 normal samples that we extracted from The Cancer Genome Atlas and Genotype-Tissue Expression project databases, we screened the variation of CYT across 32 different cancer types and 28 different normal tissue types. We correlated the cytolytic levels in each cancer type with the corresponding patient group's overall survival, the expression of several immune-checkpoint molecules, as well as with the load of tumor-infiltrating lymphocytes (TILs), and tumor-associated neutrophils (TANs) in these tumors. We found diverse levels of CYT across different cancer types, with highest levels in kidney, lung, and cervical cancers, and lowest levels in glioma, adrenocortical carcinoma (ACC), and uveal melanoma. GZMA protein was either lowly expressed or absent in at least half of these tumors; whereas PRF1 protein was not detected in almost any of the different tumor types, analyzing tissue microarrays from 20 different tumor types. CYT was significantly higher in metastatic skin melanoma and correlated significantly to the TIL load. In TCGA-ACC, skin melanoma, and bladder cancer, CYT was associated with an improved patient outcome and high levels of both GZMA and PRF1 synergistically affected patient survival in these cancers. In bladder, breast, colon, esophageal, kidney, ovarian, pancreatic, testicular, and thyroid cancers, high CYT was accompanied by upregulation of at least one immune-checkpoint molecule, indicating that similar to melanoma and prostate cancer, immune responses in cytolytic-high tumors elicit immune suppression in the tumor microenvironment. Overall, our data highlight the existence of diverse levels of CYT across different cancer types and suggest that along with the existence of complicated associations among various tumor-infiltrated immune cells, it is capable to promote or inhibit the establishment of a permissive tumor microenvironment, depending on the cancer type. High levels of immunosuppression seem to exist in several tumor types.

Fundus image fusion in EYEPLAN software: An evaluation of a novel technique for ocular melanoma radiation treatment planning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Daftari, Inder K.; Mishra, Kavita K.; O'Brien, Joan M.

Purpose: The purpose of this study is to evaluate a novel approach for treatment planning using digital fundus image fusion in EYEPLAN for proton beam radiation therapy (PBRT) planning for ocular melanoma. The authors used a prototype version of EYEPLAN software, which allows for digital registration of high-resolution fundus photographs. The authors examined the improvement in tumor localization by replanning with the addition of fundus photo superimposition in patients with macular area tumors. Methods: The new version of EYEPLAN (v3.05) software allows for the registration of fundus photographs as a background image. This is then used in conjunction with clinicalmore » examination, tantalum marker clips, surgeon's mapping, and ultrasound to draw the tumor contour accurately. In order to determine if the fundus image superimposition helps in tumor delineation and treatment planning, the authors identified 79 patients with choroidal melanoma in the macular location that were treated with PBRT. All patients were treated to a dose of 56 GyE in four fractions. The authors reviewed and replanned all 79 macular melanoma cases with superimposition of pretreatment and post-treatment fundus imaging in the new EYEPLAN software. For patients with no local failure, the authors analyzed whether fundus photograph fusion accurately depicted and confirmed tumor volumes as outlined in the original treatment plan. For patients with local failure, the authors determined whether the addition of the fundus photograph might have benefited in terms of more accurate tumor volume delineation. Results: The mean follow-up of patients was 33.6{+-}23 months. Tumor growth was seen in six eyes of the 79 macular lesions. All six patients were marginal failures or tumor miss in the region of dose fall-off, including one patient with both in-field recurrence as well as marginal. Among the six recurrences, three were managed by enucleation and one underwent retreatment with proton therapy. Three patients developed distant metastasis and all three patients have since died. The replanning of six patients with their original fundus photograph superimposed showed that in four cases, the treatment field adequately covered the tumor volume. In the other two patients, the overlaid fundus photographs indicated the area of marginal miss. The replanning with the fundus photograph showed improved tumor coverage in these two macular lesions. For the remaining patients without local failure, replanning with fundus photograph superimposition confirmed the tumor volume as drawn in the original treatment plan. Conclusions: Local control was excellent in patients receiving 56 GyE of PBRT for uveal melanomas in the macular region, which traditionally can be more difficult to control. Posterior lesions are better defined with the additional use of fundus image since they can be difficult to mark surgically. In one-third of treatment failing patients, the superposition of the fundus photograph would have clearly allowed improved localization of tumor. The current practice standard is to use the superimposition of the fundus photograph in addition to the surgeon's clinical and clip mapping of the tumor and ultrasound measurement to draw the tumor volume.« less

Biomarker for Glycogen Storage Diseases

ClinicalTrials.gov

2017-07-03

Fructose Metabolism, Inborn Errors; Glycogen Storage Disease; Glycogen Storage Disease Type I; Glycogen Storage Disease Type II; Glycogen Storage Disease Type III; Glycogen Storage Disease Type IV; Glycogen Storage Disease Type V; Glycogen Storage Disease Type VI; Glycogen Storage Disease Type VII; Glycogen Storage Disease Type VIII

Longitudinal Study of Neurodegenerative Disorders

ClinicalTrials.gov

2018-01-31

MLD; Krabbe Disease; ALD; MPS I; MPS II; MPS III; Vanishing White Matter Disease; GM3 Gangliosidosis; PKAN; Tay-Sachs Disease; NP Deficiency; Osteopetrosis; Alpha-Mannosidosis; Sandhoff Disease; Niemann-Pick Diseases; MPS IV; Gaucher Disease; GAN; GM1 Gangliosidoses; Morquio Disease; S-Adenosylhomocysteine Hydrolase Deficiency; Batten Disease; Pelizaeus-Merzbacher Disease; Leukodystrophy; Lysosomal Storage Diseases; Purine Nucleoside Phosphorylase Deficiency; Multiple Sulfatase Deficiency Disease

A pathway-based view of human diseases and disease relationships.

PubMed

Li, Yong; Agarwal, Pankaj

2009-01-01

It is increasingly evident that human diseases are not isolated from each other. Understanding how different diseases are related to each other based on the underlying biology could provide new insights into disease etiology, classification, and shared biological mechanisms. We have taken a computational approach to studying disease relationships through 1) systematic identification of disease associated genes by literature mining, 2) associating diseases to biological pathways where disease genes are enriched, and 3) linking diseases together based on shared pathways. We identified 4,195 candidate disease associated genes for 1028 diseases. On average, about 50% of disease associated genes of a disease are statistically mapped to pathways. We generated a disease network which consists of 591 diseases and 6,931 disease relationships. We examined properties of this network and provided examples of novel disease relationships which cannot be readily captured through simple literature search or gene overlap analysis. Our results could potentially provide insights into the design of novel, pathway-guided therapeutic interventions for diseases.

Safety and Efficacy Study of VY-AADC01 for Advanced Parkinson's Disease

ClinicalTrials.gov

2018-02-27

Idiopathic Parkinson's Disease; Parkinson's Disease; Basal Ganglia Disease; Brain Diseases; Central Nervous System Diseases; Movement Disorders; Nervous System Diseases; Neurodegenerative Diseases; Parkinsonian Disorders

Natural History Study of Children With Metachromatic Leukodystrophy

ClinicalTrials.gov

2016-04-19

Lipid Metabolism Disorders; Metachromatic Leukodystrophy (MLD); Nervous System Diseases; Brain Diseases; Central Nervous System Diseases; Demyelinating Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Sphingolipidoses; Hereditary Central Nervous System Demyelinating Diseases; Metabolic Inborn Brain Diseases; Lysosomal Storage Diseases; Metabolic Diseases; Sulfatidosis

Influence of cerebrovascular disease on brain networks in prodromal and clinical Alzheimer's disease.

PubMed

Chong, Joanna Su Xian; Liu, Siwei; Loke, Yng Miin; Hilal, Saima; Ikram, Mohammad Kamran; Xu, Xin; Tan, Boon Yeow; Venketasubramanian, Narayanaswamy; Chen, Christopher Li-Hsian; Zhou, Juan

2017-11-01

Network-sensitive neuroimaging methods have been used to characterize large-scale brain network degeneration in Alzheimer's disease and its prodrome. However, few studies have investigated the combined effect of Alzheimer's disease and cerebrovascular disease on brain network degeneration. Our study sought to examine the intrinsic functional connectivity and structural covariance network changes in 235 prodromal and clinical Alzheimer's disease patients with and without cerebrovascular disease. We focused particularly on two higher-order cognitive networks-the default mode network and the executive control network. We found divergent functional connectivity and structural covariance patterns in Alzheimer's disease patients with and without cerebrovascular disease. Alzheimer's disease patients without cerebrovascular disease, but not Alzheimer's disease patients with cerebrovascular disease, showed reductions in posterior default mode network functional connectivity. By comparison, while both groups exhibited parietal reductions in executive control network functional connectivity, only Alzheimer's disease patients with cerebrovascular disease showed increases in frontal executive control network connectivity. Importantly, these distinct executive control network changes were recapitulated in prodromal Alzheimer's disease patients with and without cerebrovascular disease. Across Alzheimer's disease patients with and without cerebrovascular disease, higher default mode network functional connectivity z-scores correlated with greater hippocampal volumes while higher executive control network functional connectivity z-scores correlated with greater white matter changes. In parallel, only Alzheimer's disease patients without cerebrovascular disease showed increased default mode network structural covariance, while only Alzheimer's disease patients with cerebrovascular disease showed increased executive control network structural covariance compared to controls. Our findings demonstrate the differential neural network structural and functional changes in Alzheimer's disease with and without cerebrovascular disease, suggesting that the underlying pathology of Alzheimer's disease patients with cerebrovascular disease might differ from those without cerebrovascular disease and reflect a combination of more severe cerebrovascular disease and less severe Alzheimer's disease network degeneration phenotype. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

Influence of cerebrovascular disease on brain networks in prodromal and clinical Alzheimer’s disease

PubMed Central

Chong, Joanna Su Xian; Liu, Siwei; Loke, Yng Miin; Hilal, Saima; Ikram, Mohammad Kamran; Xu, Xin; Tan, Boon Yeow; Venketasubramanian, Narayanaswamy; Chen, Christopher Li-Hsian

2017-01-01

Abstract Network-sensitive neuroimaging methods have been used to characterize large-scale brain network degeneration in Alzheimer’s disease and its prodrome. However, few studies have investigated the combined effect of Alzheimer’s disease and cerebrovascular disease on brain network degeneration. Our study sought to examine the intrinsic functional connectivity and structural covariance network changes in 235 prodromal and clinical Alzheimer’s disease patients with and without cerebrovascular disease. We focused particularly on two higher-order cognitive networks—the default mode network and the executive control network. We found divergent functional connectivity and structural covariance patterns in Alzheimer’s disease patients with and without cerebrovascular disease. Alzheimer’s disease patients without cerebrovascular disease, but not Alzheimer’s disease patients with cerebrovascular disease, showed reductions in posterior default mode network functional connectivity. By comparison, while both groups exhibited parietal reductions in executive control network functional connectivity, only Alzheimer’s disease patients with cerebrovascular disease showed increases in frontal executive control network connectivity. Importantly, these distinct executive control network changes were recapitulated in prodromal Alzheimer’s disease patients with and without cerebrovascular disease. Across Alzheimer’s disease patients with and without cerebrovascular disease, higher default mode network functional connectivity z-scores correlated with greater hippocampal volumes while higher executive control network functional connectivity z-scores correlated with greater white matter changes. In parallel, only Alzheimer’s disease patients without cerebrovascular disease showed increased default mode network structural covariance, while only Alzheimer’s disease patients with cerebrovascular disease showed increased executive control network structural covariance compared to controls. Our findings demonstrate the differential neural network structural and functional changes in Alzheimer’s disease with and without cerebrovascular disease, suggesting that the underlying pathology of Alzheimer’s disease patients with cerebrovascular disease might differ from those without cerebrovascular disease and reflect a combination of more severe cerebrovascular disease and less severe Alzheimer’s disease network degeneration phenotype. PMID:29053778

Network analysis of human diseases using Korean nationwide claims data.

PubMed

Kim, Jin Hee; Son, Ki Young; Shin, Dong Wook; Kim, Sang Hyuk; Yun, Jae Won; Shin, Jung Hyun; Kang, Mi So; Chung, Eui Heon; Yoo, Kyoung Hun; Yun, Jae Moon

2016-06-01

To investigate disease-disease associations by conducting a network analysis using Korean nationwide claims data. We used the claims data from the Health Insurance Review and Assessment Service-National Patient Sample for the year 2011. Among the 2049 disease codes in the claims data, 1154 specific disease codes were used and combined into 795 representative disease codes. We analyzed for 381 representative codes, which had a prevalence of >0.1%. For disease code pairs of a combination of 381 representative disease codes, P values were calculated by using the χ(2) test and the degrees of associations were expressed as odds ratios (ORs). For 5515 (7.62%) statistically significant disease-disease associations with a large effect size (OR>5), we constructed a human disease network consisting of 369 nodes and 5515 edges. The human disease network shows the distribution of diseases in the disease network and the relationships between diseases or disease groups, demonstrating that diseases are associated with each other, forming a complex disease network. We reviewed 5515 disease-disease associations and classified them according to underlying mechanisms. Several disease-disease associations were identified, but the evidence of these associations is not sufficient and the mechanisms underlying these associations have not been clarified yet. Further research studies are needed to investigate these associations and their underlying mechanisms. Human disease network analysis using claims data enriches the understanding of human diseases and provides new insights into disease-disease associations that can be useful in future research. Copyright © 2016 Elsevier Inc. All rights reserved.

Evaluating Innovations in Transition From Pediatric to Adult Care - The Transition Navigator Trial

ClinicalTrials.gov

2018-06-06

Diabetes; Endocrine System Diseases; Gastro-Intestinal Disorder; Neuro-Degenerative Disease; Epilepsy; Autoimmune Diseases; Renal Disease; Cardiac Disease; Metabolic Disease; Genetic Diseases, Inborn; Respiratory Disease; Hematologic Diseases; Autism Spectrum Disorder; Fetal Alcohol Spectrum Disorders; Traumatic Brain Injury; Stroke

Rodent-borne diseases and their public health importance in Iran.

PubMed

Rabiee, Mohammad Hasan; Mahmoudi, Ahmad; Siahsarvie, Roohollah; Kryštufek, Boris; Mostafavi, Ehsan

2018-04-01

Rodents are reservoirs and hosts for several zoonotic diseases such as plague, leptospirosis, and leishmaniasis. Rapid development of industry and agriculture, as well as climate change throughout the globe, has led to change or increase in occurrence of rodent-borne diseases. Considering the distribution of rodents throughout Iran, the aim of this review is to assess the risk of rodent-borne diseases in Iran. We searched Google Scholar, PubMed, Science Direct, Scientific Information Database (SID), and Magiran databases up to September 2016 to obtain articles reporting occurrence of rodent-borne diseases in Iran and extract information from them. Out of 70 known rodent-borne diseases, 34 were reported in Iran: 17 (50%) parasitic diseases, 13 (38%) bacterial diseases, and 4 (12%) viral diseases. Twenty-one out of 34 diseases were reported from both humans and rodents. Among the diseases reported in the rodents of Iran, plague, leishmaniasis, and hymenolepiasis were the most frequent. The most infected rodents were Rattus norvegicus (16 diseases), Mus musculus (14 diseases), Rattus rattus (13 diseases), Meriones persicus (7 diseases), Apodemus spp. (5 diseases), Tatera indica (4 diseases), Meriones libycus (3 diseases), Rhombomys opimus (3 diseases), Cricetulus migratorius (3 diseases), and Nesokia indica (2 diseases). The results of this review indicate the importance of rodent-borne diseases in Iran. Considering notable diversity of rodents and their extensive distribution throughout the country, it is crucial to pay more attention to their role in spreading infectious diseases for better control of the diseases.

The Lolland-Falster Health Study

ClinicalTrials.gov

2016-10-06

Impaired Health; Disease; Wellbeing; Mental Disorders; Atherosclerosis; Renal Insufficiency, Chronic; Skin Diseases; Urinary Incontinence; Personality; Coronary Disease; Ear Diseases; Nose Diseases; Pharyngeal Diseases; Chronic Disease

A literature-driven method to calculate similarities among diseases.

PubMed

Kim, Hyunjin; Yoon, Youngmi; Ahn, Jaegyoon; Park, Sanghyun

2015-11-01

"Our lives are connected by a thousand invisible threads and along these sympathetic fibers, our actions run as causes and return to us as results". It is Herman Melville's famous quote describing connections among human lives. To paraphrase the Melville's quote, diseases are connected by many functional threads and along these sympathetic fibers, diseases run as causes and return as results. The Melville's quote explains the reason for researching disease-disease similarity and disease network. Measuring similarities between diseases and constructing disease network can play an important role in disease function research and in disease treatment. To estimate disease-disease similarities, we proposed a novel literature-based method. The proposed method extracted disease-gene relations and disease-drug relations from literature and used the frequencies of occurrence of the relations as features to calculate similarities among diseases. We also constructed disease network with top-ranking disease pairs from our method. The proposed method discovered a larger number of answer disease pairs than other comparable methods and showed the lowest p-value. We presume that our method showed good results because of using literature data, using all possible gene symbols and drug names for features of a disease, and determining feature values of diseases with the frequencies of co-occurrence of two entities. The disease-disease similarities from the proposed method can be used in computational biology researches which use similarities among diseases. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Rodent-borne diseases and their public health importance in Iran

PubMed Central

Mahmoudi, Ahmad; Siahsarvie, Roohollah; Kryštufek, Boris; Mostafavi, Ehsan

2018-01-01

Background Rodents are reservoirs and hosts for several zoonotic diseases such as plague, leptospirosis, and leishmaniasis. Rapid development of industry and agriculture, as well as climate change throughout the globe, has led to change or increase in occurrence of rodent-borne diseases. Considering the distribution of rodents throughout Iran, the aim of this review is to assess the risk of rodent-borne diseases in Iran. Methodology/Principal finding We searched Google Scholar, PubMed, Science Direct, Scientific Information Database (SID), and Magiran databases up to September 2016 to obtain articles reporting occurrence of rodent-borne diseases in Iran and extract information from them. Out of 70 known rodent-borne diseases, 34 were reported in Iran: 17 (50%) parasitic diseases, 13 (38%) bacterial diseases, and 4 (12%) viral diseases. Twenty-one out of 34 diseases were reported from both humans and rodents. Among the diseases reported in the rodents of Iran, plague, leishmaniasis, and hymenolepiasis were the most frequent. The most infected rodents were Rattus norvegicus (16 diseases), Mus musculus (14 diseases), Rattus rattus (13 diseases), Meriones persicus (7 diseases), Apodemus spp. (5 diseases), Tatera indica (4 diseases), Meriones libycus (3 diseases), Rhombomys opimus (3 diseases), Cricetulus migratorius (3 diseases), and Nesokia indica (2 diseases). Conclusions/Significance The results of this review indicate the importance of rodent-borne diseases in Iran. Considering notable diversity of rodents and their extensive distribution throughout the country, it is crucial to pay more attention to their role in spreading infectious diseases for better control of the diseases. PMID:29672510

75 FR 51823 - Government-Owned Inventions; Availability for Licensing

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-23

... be involved in the progression of several diseases including many cancers, cardiovascular diseases, CNS diseases, respiratory diseases, and arthritis. In cancer, MMP-9 is thought to promote growth... diseases, cardiovascular diseases, CNS diseases, respiratory diseases, angiogenesis and arthritis...

Inference of domain-disease associations from domain-protein, protein-disease and disease-disease relationships.

PubMed

Zhang, Wangshu; Coba, Marcelo P; Sun, Fengzhu

2016-01-11

Protein domains can be viewed as portable units of biological function that defines the functional properties of proteins. Therefore, if a protein is associated with a disease, protein domains might also be associated and define disease endophenotypes. However, knowledge about such domain-disease relationships is rarely available. Thus, identification of domains associated with human diseases would greatly improve our understanding of the mechanism of human complex diseases and further improve the prevention, diagnosis and treatment of these diseases. Based on phenotypic similarities among diseases, we first group diseases into overlapping modules. We then develop a framework to infer associations between domains and diseases through known relationships between diseases and modules, domains and proteins, as well as proteins and disease modules. Different methods including Association, Maximum likelihood estimation (MLE), Domain-disease pair exclusion analysis (DPEA), Bayesian, and Parsimonious explanation (PE) approaches are developed to predict domain-disease associations. We demonstrate the effectiveness of all the five approaches via a series of validation experiments, and show the robustness of the MLE, Bayesian and PE approaches to the involved parameters. We also study the effects of disease modularization in inferring novel domain-disease associations. Through validation, the AUC (Area Under the operating characteristic Curve) scores for Bayesian, MLE, DPEA, PE, and Association approaches are 0.86, 0.84, 0.83, 0.83 and 0.79, respectively, indicating the usefulness of these approaches for predicting domain-disease relationships. Finally, we choose the Bayesian approach to infer domains associated with two common diseases, Crohn's disease and type 2 diabetes. The Bayesian approach has the best performance for the inference of domain-disease relationships. The predicted landscape between domains and diseases provides a more detailed view about the disease mechanisms.

Phenotype and Clinical Course of Inflammatory Bowel Disease with Co-Existent Celiac Disease.

PubMed

Tse, Chung Sang; Deepak, Parakkal; De La Fuente, Jaime; Bledsoe, Adam C; Larson, Joseph J; Murray, Joseph A; Papadakis, Konstantinos A

2018-05-07

Inflammatory bowel diseases, principally Crohn's disease and ulcerative colitis, and celiac disease are among the most common immune-mediated gastrointestinal diseases. We aim to elucidate the clinical course and outcomes of patients with concomitant inflammatory bowel disease and celiac disease, a unique population that remains scarcely studied to date. A retrospective matched case-control study of adults with coexistent inflammatory bowel disease and celiac disease was performed at a tertiary referral institution in North America. Logistic regression and Kaplan-Meier curves compared disease characteristics and clinical outcomes of the two groups. A total of 342 inflammatory bowel disease patients were included in this study, of which 114 had coexistent celiac disease and 228 did not. Patients with coexistent inflammatory bowel disease and celiac disease had higher rates of primary sclerosing cholangitis (19.3% vs 5.7%; odds ratio, 4.4; 95% confidence interval, 2.1-9.4; p<0.001), extensive ulcerative colitis (78.1% vs 59.0%; odds ratio, 2.8; 95% confidence interval 1.5-5.5, p=0.002), and family history of celiac disease (10.5% vs 3.5%; odds ratio 3.2; 95% confidence interval 1.3-8.2; p=0.01), compared to patients without concomitant celiac disease. Patients with inflammatory bowel disease with concomitant celiac disease have unique phenotypic features compared to non-celiac inflammatory bowel disease, with higher risks for colitis-related hospitalizations, extensive colitis, and primary sclerosing cholangitis. Increased recognition of coexistent IBD and celiac disease can prompt clinicians to investigate for concomitant disease sooner, particularly in patients with seemingly refractory disease.

GORE Flow Reversal System and GORE Embolic Filter Extension Study

ClinicalTrials.gov

2016-01-22

Carotid Stenosis; Constriction, Pathologic; Carotid Artery Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical

The dawn of a new era in onco-cardiology: The Kumamoto Classification.

PubMed

Sueta, Daisuke; Tabata, Noriaki; Akasaka, Tomonori; Yamashita, Takayoshi; Ikemoto, Tomokazu; Hokimoto, Seiji

2016-10-01

The term "onco-cardiology" has been used in reference to cardiotoxicity in the treatment of malignant disease. In actual clinical situations, however, cardiovascular disease (CVD) associated with malignant disease and the concurrence of atherosclerotic disease with malignant disease are commonly observed, complicating the course of treatment. Patients with malignant disease associated with coronary artery disease often die from the cardiovascular disease, so it is essential to classify these disease states. Additionally, the prevalence of these classifications makes it easy to manage patients with malignant disease and coronary artery disease. We divided the broad field of onco-cardiology into 4 classifications based on clinical scenarios (CSs): CS1 represents the so-called paraneoplastic syndrome. CS2 represents cardiotoxicity during treatment of malignant diseases. CS3 represents the concurrence of atherosclerotic disease with malignant disease, and CS4 represents cardiovascular disease with benign tumors. This classification facilitates the management of patients with malignant disease and coronary artery disease by promoting not only the primary but also the secondary prevention of CVD. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The Relationship Between Fatty Liver Disease and Periodontal Disease

DTIC Science & Technology

2017-03-22

Periodontitis is a highly prevalent and destructive chronic disease. Numerous studies support an association between periodontal disease and other...systemic diseases (diabetes, cardiovascular disease, chronic kidney disease, adverse pregnancy outcome, etc.). Non-alcoholic fatty liver disease is a... chronic inflammatory disease that is characterized by accumulation of triglycerides and fat in the liver which may lead to fibrosis and even cirrhosis

Some Important Diseases of Tree Fruits - Diseases of Vegetable Crops - Diseases of Grapes - Diseases of Tree Nuts.

ERIC Educational Resources Information Center

Petersen, Donald H.; And Others

This agriculture extension service publication from Pennsylvania State University consists of four sections on plant disease recognition and control. The titles of these four sections are: (1) Some Important Diseases of Tree Fruits; (2) Diseases of Vegetable Crops; (3) Diseases of Crops; and (4) Diseases of Tree Nuts. The first section discusses…

CytoCom: a Cytoscape app to visualize, query and analyse disease comorbidity networks.

PubMed

Moni, Mohammad Ali; Xu, Haoming; Liò, Pietro

2015-03-15

CytoCom is an interactive plugin for Cytoscape that can be used to search, explore, analyse and visualize human disease comorbidity network. It represents disease-disease associations in terms of bipartite graphs and provides International Classification of Diseases, Ninth Revision (ICD9)-centric and disease name centric views of disease information. It allows users to find associations between diseases based on the two measures: Relative Risk (RR) and [Formula: see text]-correlation values. In the disease network, the size of each node is based on the prevalence of that disease. CytoCom is capable of clustering disease network based on the ICD9 disease category. It provides user-friendly access that facilitates exploration of human diseases, and finds additional associated diseases by double-clicking a node in the existing network. Additional comorbid diseases are then connected to the existing network. It is able to assist users for interpretation and exploration of the human diseases by a variety of built-in functions. Moreover, CytoCom permits multi-colouring of disease nodes according to standard disease classification for expedient visualization. © The Author 2014. Published by Oxford University Press.

ABSORB: Postmarketing Surveillance Registry to Monitor the Everolimus-eluting Bioresorbable Vascular Scaffold in Patients With Coronary Artery Disease

ClinicalTrials.gov

2016-12-08

Cardiovascular Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Coronary Restenosis; Heart Diseases; Coronary Stenosis; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases

Ask a Periodontist (Frequently Asked Questions about Gum Disease)

MedlinePlus

... collapse all] How is gum disease linked to cardiovascular disease? Research has shown that periodontal disease may increase the risk for developing cardiovascular disease. Both periodontal disease and cardiovascular disease are chronic ...

Antioxidants: In Depth

MedlinePlus

... supplements can help prevent chronic diseases, such as cardiovascular diseases, cancer, and cataracts. In most instances, antioxidants did ... role in a variety of diseases including cancer, cardiovascular diseases, diabetes, Alzheimer’s disease, Parkinson’s disease, and eye diseases ...

National Infectious Diseases Surveillance data of South Korea.

PubMed

Park, Sunhee; Cho, Eunhee

2014-01-01

The Korea Centers for Disease Control and Prevention (KCDC) operate infectious disease surveillance systems to monitor national disease incidence. Since 1954, Korea has collected data on various infectious diseases in accordance with the Infectious Disease Control and Prevention Act. All physicians (including those working in Oriental medicine) who diagnose a patient with an infectious disease or conduct a postmortem examination of an infectious disease case are obliged to report the disease to the system. These reported data are incorporated into the database of the National Infectious Disease Surveillance System, which has been providing web-based real-time surveillance data on infectious diseases since 2001. In addition, the KCDC analyzes reported data and publishes the Infectious Disease Surveillance Yearbook annually.

Renal disease in patients with celiac disease.

PubMed

Boonpheng, Boonphiphop; Cheungpasitporn, Wisit; Wijarnpreecha, Karn

2018-04-01

Celiac disease, an inflammatory disease of small bowel caused by sensitivity to dietary gluten and related protein, affects approximately 0.5-1% of the population in the Western world. Extra-intestinal symptoms and associated diseases are increasingly recognized including diabetes mellitus type 1, thyroid disease, dermatitis herpetiformis and ataxia. There have also been a number of reports of various types of renal involvement in patients with celiac disease including diabetes nephropathy, IgA nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis, nephrotic syndrome related to malabsorption, oxalate nephropathy, and associations of celiac disease with chronic kidney disease and end-stage kidney disease. This review aims to present the current literature on possible pathologic mechanisms underlying renal disease in patients with celiac disease.

UCB Transplant of Inherited Metabolic Diseases With Administration of Intrathecal UCB Derived Oligodendrocyte-Like Cells

ClinicalTrials.gov

2018-03-15

Adrenoleukodystrophy; Batten Disease; Mucopolysaccharidosis II; Leukodystrophy, Globoid Cell; Leukodystrophy, Metachromatic; Neimann Pick Disease; Pelizaeus-Merzbacher Disease; Sandhoff Disease; Tay-Sachs Disease; Brain Diseases, Metabolic, Inborn; Alpha-Mannosidosis; Sanfilippo Mucopolysaccharidoses

Disease networks. Uncovering disease-disease relationships through the incomplete interactome.

PubMed

Menche, Jörg; Sharma, Amitabh; Kitsak, Maksim; Ghiassian, Susan Dina; Vidal, Marc; Loscalzo, Joseph; Barabási, Albert-László

2015-02-20

According to the disease module hypothesis, the cellular components associated with a disease segregate in the same neighborhood of the human interactome, the map of biologically relevant molecular interactions. Yet, given the incompleteness of the interactome and the limited knowledge of disease-associated genes, it is not obvious if the available data have sufficient coverage to map out modules associated with each disease. Here we derive mathematical conditions for the identifiability of disease modules and show that the network-based location of each disease module determines its pathobiological relationship to other diseases. For example, diseases with overlapping network modules show significant coexpression patterns, symptom similarity, and comorbidity, whereas diseases residing in separated network neighborhoods are phenotypically distinct. These tools represent an interactome-based platform to predict molecular commonalities between phenotypically related diseases, even if they do not share primary disease genes. Copyright © 2015, American Association for the Advancement of Science.

No Geographic Correlation between Lyme Disease and Death Due to 4 Neurodegenerative Disorders, United States, 2001-2010.

PubMed

Forrester, Joseph D; Kugeler, Kiersten J; Perea, Anna E; Pastula, Daniel M; Mead, Paul S

2015-11-01

Associations between Lyme disease and certain neurodegenerative diseases have been proposed, but supportive evidence for an association is lacking. Similar geographic distributions would be expected if 2 conditions were etiologically linked. Thus, we compared the distribution of Lyme disease cases in the United States with the distributions of deaths due to Alzheimer disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Parkinson disease; no geographic correlations were identified. Lyme disease incidence per US state was not correlated with rates of death due to ALS, MS, or Parkinson disease; however, an inverse correlation was detected between Lyme disease and Alzheimer disease. The absence of a positive correlation between the geographic distribution of Lyme disease and the distribution of deaths due to Alzheimer disease, ALS, MS, and Parkinson disease provides further evidence that Lyme disease is not associated with the development of these neurodegenerative conditions.

HGPEC: a Cytoscape app for prediction of novel disease-gene and disease-disease associations and evidence collection based on a random walk on heterogeneous network.

PubMed

Le, Duc-Hau; Pham, Van-Huy

2017-06-15

Finding gene-disease and disease-disease associations play important roles in the biomedical area and many prioritization methods have been proposed for this goal. Among them, approaches based on a heterogeneous network of genes and diseases are considered state-of-the-art ones, which achieve high prediction performance and can be used for diseases with/without known molecular basis. Here, we developed a Cytoscape app, namely HGPEC, based on a random walk with restart algorithm on a heterogeneous network of genes and diseases. This app can prioritize candidate genes and diseases by employing a heterogeneous network consisting of a network of genes/proteins and a phenotypic disease similarity network. Based on the rankings, novel disease-gene and disease-disease associations can be identified. These associations can be supported with network- and rank-based visualization as well as evidences and annotations from biomedical data. A case study on prediction of novel breast cancer-associated genes and diseases shows the abilities of HGPEC. In addition, we showed prominence in the performance of HGPEC compared to other tools for prioritization of candidate disease genes. Taken together, our app is expected to effectively predict novel disease-gene and disease-disease associations and support network- and rank-based visualization as well as biomedical evidences for such the associations.

Coeliac disease in autoimmune liver disease: a cross-sectional study and a systematic review.

PubMed

Mirzaagha, Foroozandeh; Azali, Sepideh Hagh; Islami, Farhad; Zamani, Farhad; Khalilipour, Elias; Khatibian, Morteza; Malekzadeh, Reza

2010-09-01

Several studies have reported an association between coeliac disease and autoimmune liver disease, but there is little information on the prevalence of coeliac disease in certain autoimmune liver diseases, particularly from non-European, non-American countries. To investigate prevalence of coeliac disease in autoimmune liver disease in Iran and to summarize previous literature. We investigated prevalence of coeliac disease among 100 autoimmune liver disease patients and compared it with the prevalence in healthy individuals. We also performed an extensive search of the English literature in PubMed Database. We found substantially elevated prevalence of coeliac disease in patients with overlap syndrome (10-15%) compared to the general population (0.1-1%). To a lesser extent, the prevalence was high in patients with autoimmune hepatitis (2-4%). In our systematic review, prevalence of coeliac disease in autoimmune hepatitis in the majority of studies was 4% or more; several studies also reported such prevalence in primary biliary cirrhosis. Since coeliac disease is common among patients with autoimmune liver disease, screening autoimmune liver disease patients for coeliac disease is indicated. Although the magnitude of benefit from a gluten-free diet in reversing autoimmune liver disease in patients with coeliac disease is controversial, it may reduce the risk of further complications of coeliac disease. Copyright (c) 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

[Autoimmune thyroid disease and other non-endocrine autoimmune diseases].

PubMed

Dilas, Ljiljana Todorović; Icin, Tijana; Paro, Jovanka Novaković; Bajkin, Ivana

2011-01-01

Autoimmune diseases are chronic conditions initiated by the loss of immunological tolerance to self-antigens. They constitute heterogeneous group of disorders, in which multiple alterations in the immune system result in a spectrum of syndromes that either target specific organs or affect the body systematically. Recent epidemiological studies have shown a possible shift of one autoimmune disease to another or the fact that more than one autoimmune disease may coexist in a single patient or in the same family. Numerous autoimmune diseases have been shown to coexist frequently with thyroid autoimmune diseases. AUTOIMMNUNE THYROID DISEASE AND OTHER ORGAN SPECIFIC NON-ENDOCRINE AUTOIMMUNE DISEASES: This part of the study reviews the prevalence of autoimmune thyroid disease coexisting with: pernicious anaemia, vitiligo, celiac disease, autoimmune liver disease, miastenia gravis, alopecia areata and sclerosis multiplex, and several recommendations for screening have been given. AUTOIMMUNE THYROID DISEASE AND OTHER ORGAN NON-SPECIFIC NON-ENDOCRINE AUTOIMMUNE DISEASES: Special attention is given to the correlation between autoimmune thyroid disease and rheumatoid arthritis, systemic lupus erythematosus, syndrome Sjögren, systemic sclerosis and mixed connective tissue disease. Screening for autoimmune thyroid diseases should be recommended in everyday clinical practice, in patients with primary organ-specific or organ non-specific autoimmune disease. Otherwise, in patients with primary thyroid autoimmune disease, there is no good reason of seeking for all other autoimmune diseases, although these patients have a greater risk of developing other autoimmune disease. Economic aspects of medicine require further analyzing of these data, from cost/benefit point of view to justified either mandatory screening or medical practitioner judgment.

Identification of susceptible genes for complex chronic diseases based on disease risk functional SNPs and interaction networks.

PubMed

Li, Wan; Zhu, Lina; Huang, Hao; He, Yuehan; Lv, Junjie; Li, Weimin; Chen, Lina; He, Weiming

2017-10-01

Complex chronic diseases are caused by the effects of genetic and environmental factors. Single nucleotide polymorphisms (SNPs), one common type of genetic variations, played vital roles in diseases. We hypothesized that disease risk functional SNPs in coding regions and protein interaction network modules were more likely to contribute to the identification of disease susceptible genes for complex chronic diseases. This could help to further reveal the pathogenesis of complex chronic diseases. Disease risk SNPs were first recognized from public SNP data for coronary heart disease (CHD), hypertension (HT) and type 2 diabetes (T2D). SNPs in coding regions that were classified into nonsense and missense by integrating several SNP functional annotation databases were treated as functional SNPs. Then, regions significantly associated with each disease were screened using random permutations for disease risk functional SNPs. Corresponding to these regions, 155, 169 and 173 potential disease susceptible genes were identified for CHD, HT and T2D, respectively. A disease-related gene product interaction network in environmental context was constructed for interacting gene products of both disease genes and potential disease susceptible genes for these diseases. After functional enrichment analysis for disease associated modules, 5 CHD susceptible genes, 7 HT susceptible genes and 3 T2D susceptible genes were finally identified, some of which had pleiotropic effects. Most of these genes were verified to be related to these diseases in literature. This was similar for disease genes identified from another method proposed by Lee et al. from a different aspect. This research could provide novel perspectives for diagnosis and treatment of complex chronic diseases and susceptible genes identification for other diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

Gene-Disease Network Analysis Reveals Functional Modules in Mendelian, Complex and Environmental Diseases

PubMed Central

Bauer-Mehren, Anna; Bundschus, Markus; Rautschka, Michael; Mayer, Miguel A.; Sanz, Ferran; Furlong, Laura I.

2011-01-01

Background Scientists have been trying to understand the molecular mechanisms of diseases to design preventive and therapeutic strategies for a long time. For some diseases, it has become evident that it is not enough to obtain a catalogue of the disease-related genes but to uncover how disruptions of molecular networks in the cell give rise to disease phenotypes. Moreover, with the unprecedented wealth of information available, even obtaining such catalogue is extremely difficult. Principal Findings We developed a comprehensive gene-disease association database by integrating associations from several sources that cover different biomedical aspects of diseases. In particular, we focus on the current knowledge of human genetic diseases including mendelian, complex and environmental diseases. To assess the concept of modularity of human diseases, we performed a systematic study of the emergent properties of human gene-disease networks by means of network topology and functional annotation analysis. The results indicate a highly shared genetic origin of human diseases and show that for most diseases, including mendelian, complex and environmental diseases, functional modules exist. Moreover, a core set of biological pathways is found to be associated with most human diseases. We obtained similar results when studying clusters of diseases, suggesting that related diseases might arise due to dysfunction of common biological processes in the cell. Conclusions For the first time, we include mendelian, complex and environmental diseases in an integrated gene-disease association database and show that the concept of modularity applies for all of them. We furthermore provide a functional analysis of disease-related modules providing important new biological insights, which might not be discovered when considering each of the gene-disease association repositories independently. Hence, we present a suitable framework for the study of how genetic and environmental factors, such as drugs, contribute to diseases. Availability The gene-disease networks used in this study and part of the analysis are available at http://ibi.imim.es/DisGeNET/DisGeNETweb.html#Download. PMID:21695124

DNetDB: The human disease network database based on dysfunctional regulation mechanism.

PubMed

Yang, Jing; Wu, Su-Juan; Yang, Shao-You; Peng, Jia-Wei; Wang, Shi-Nuo; Wang, Fu-Yan; Song, Yu-Xing; Qi, Ting; Li, Yi-Xue; Li, Yuan-Yuan

2016-05-21

Disease similarity study provides new insights into disease taxonomy, pathogenesis, which plays a guiding role in diagnosis and treatment. The early studies were limited to estimate disease similarities based on clinical manifestations, disease-related genes, medical vocabulary concepts or registry data, which were inevitably biased to well-studied diseases and offered small chance of discovering novel findings in disease relationships. In other words, genome-scale expression data give us another angle to address this problem since simultaneous measurement of the expression of thousands of genes allows for the exploration of gene transcriptional regulation, which is believed to be crucial to biological functions. Although differential expression analysis based methods have the potential to explore new disease relationships, it is difficult to unravel the upstream dysregulation mechanisms of diseases. We therefore estimated disease similarities based on gene expression data by using differential coexpression analysis, a recently emerging method, which has been proved to be more potential to capture dysfunctional regulation mechanisms than differential expression analysis. A total of 1,326 disease relationships among 108 diseases were identified, and the relevant information constituted the human disease network database (DNetDB). Benefiting from the use of differential coexpression analysis, the potential common dysfunctional regulation mechanisms shared by disease pairs (i.e. disease relationships) were extracted and presented. Statistical indicators, common disease-related genes and drugs shared by disease pairs were also included in DNetDB. In total, 1,326 disease relationships among 108 diseases, 5,598 pathways, 7,357 disease-related genes and 342 disease drugs are recorded in DNetDB, among which 3,762 genes and 148 drugs are shared by at least two diseases. DNetDB is the first database focusing on disease similarity from the viewpoint of gene regulation mechanism. It provides an easy-to-use web interface to search and browse the disease relationships and thus helps to systematically investigate etiology and pathogenesis, perform drug repositioning, and design novel therapeutic interventions.Database URL: http://app.scbit.org/DNetDB/ #.

Disease Compass- a navigation system for disease knowledge based on ontology and linked data techniques.

PubMed

Kozaki, Kouji; Yamagata, Yuki; Mizoguchi, Riichiro; Imai, Takeshi; Ohe, Kazuhiko

2017-06-19

Medical ontologies are expected to contribute to the effective use of medical information resources that store considerable amount of data. In this study, we focused on disease ontology because the complicated mechanisms of diseases are related to concepts across various medical domains. The authors developed a River Flow Model (RFM) of diseases, which captures diseases as the causal chains of abnormal states. It represents causes of diseases, disease progression, and downstream consequences of diseases, which is compliant with the intuition of medical experts. In this paper, we discuss a fact repository for causal chains of disease based on the disease ontology. It could be a valuable knowledge base for advanced medical information systems. We developed the fact repository for causal chains of diseases based on our disease ontology and abnormality ontology. This section summarizes these two ontologies. It is developed as linked data so that information scientists can access it using SPARQL queries through an Resource Description Framework (RDF) model for causal chain of diseases. We designed the RDF model as an implementation of the RFM for the fact repository based on the ontological definitions of the RFM. 1554 diseases and 7080 abnormal states in six major clinical areas, which are extracted from the disease ontology, are published as linked data (RDF) with SPARQL endpoint (accessible API). Furthermore, the authors developed Disease Compass, a navigation system for disease knowledge. Disease Compass can browse the causal chains of a disease and obtain related information, including abnormal states, through two web services that provide general information from linked data, such as DBpedia, and 3D anatomical images. Disease Compass can provide a complete picture of disease-associated processes in such a way that fits with a clinician's understanding of diseases. Therefore, it supports user exploration of disease knowledge with access to pertinent information from a variety of sources.

Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer’s Coordinating Centre

PubMed Central

Toledo, Jon B.; Arnold, Steven E.; Raible, Kevin; Brettschneider, Johannes; Xie, Sharon X.; Grossman, Murray; Monsell, Sarah E.; Kukull, Walter A.

2013-01-01

Cerebrovascular disease and vascular risk factors are associated with Alzheimer’s disease, but the evidence for their association with other neurodegenerative disorders is limited. Therefore, we compared the prevalence of cerebrovascular disease, vascular pathology and vascular risk factors in a wide range of neurodegenerative diseases and correlate them with dementia severity. Presence of cerebrovascular disease, vascular pathology and vascular risk factors was studied in 5715 cases of the National Alzheimer’s Coordinating Centre database with a single neurodegenerative disease diagnosis (Alzheimer’s disease, frontotemporal lobar degeneration due to tau, and TAR DNA-binding protein 43 immunoreactive deposits, α-synucleinopathies, hippocampal sclerosis and prion disease) based on a neuropathological examination with or without cerebrovascular disease, defined neuropathologically. In addition, 210 ‘unremarkable brain’ cases without cognitive impairment, and 280 cases with pure cerebrovascular disease were included for comparison. Cases with cerebrovascular disease were older than those without cerebrovascular disease in all the groups except for those with hippocampal sclerosis. After controlling for age and gender as fixed effects and centre as a random effect, we observed that α-synucleinopathies, frontotemporal lobar degeneration due to tau and TAR DNA-binding protein 43, and prion disease showed a lower prevalence of coincident cerebrovascular disease than patients with Alzheimer’s disease, and this was more significant in younger subjects. When cerebrovascular disease was also present, patients with Alzheimer’s disease and patients with α-synucleinopathy showed relatively lower burdens of their respective lesions than those without cerebrovascular disease in the context of comparable severity of dementia at time of death. Concurrent cerebrovascular disease is a common neuropathological finding in aged subjects with dementia, is more common in Alzheimer’s disease than in other neurodegenerative disorders, especially in younger subjects, and lowers the threshold for dementia due to Alzheimer’s disease and α-synucleinopathies, which suggests that these disorders should be targeted by treatments for cerebrovascular disease. PMID:23842566

Borrelia infection and risk of celiac disease.

PubMed

Alaedini, Armin; Lebwohl, Benjamin; Wormser, Gary P; Green, Peter H; Ludvigsson, Jonas F

2017-09-15

Environmental factors, including infectious agents, are speculated to play a role in the rising prevalence and the geographic distribution of celiac disease, an autoimmune disorder. In the USA and Sweden where the regional variation in the frequency of celiac disease has been studied, a similarity with the geographic distribution of Lyme disease, an emerging multisystemic infection caused by Borrelia burgdorferi spirochetes, has been found, thus raising the possibility of a link. We aimed to determine if infection with Borrelia contributes to an increased risk of celiac disease. Biopsy reports from all of Sweden's pathology departments were used to identify 15,769 individuals with celiac disease. Through linkage to the nationwide Patient Register, we compared the rate of earlier occurrence of Lyme disease in the patients with celiac disease to that in 78,331 matched controls. To further assess the temporal relationship between Borrelia infection and celiac disease, we also examined the risk of subsequent Lyme disease in patients with a diagnosis of celiac disease. Twenty-five individuals (0.16%) with celiac disease had a prior diagnosis of Lyme disease, whereas 79 (0.5%) had a subsequent diagnosis of Lyme disease. A modest association between Lyme disease and celiac disease was seen both before (odds ratio, 1.61; 95% confidence interval (CI), 1.06-2.47) and after the diagnosis of celiac disease (hazard ratio, 1.82; 95% CI, 1.40-2.35), with the risk of disease being highest in the first year of follow-up. Only a minor fraction of the celiac disease patient population had a prior diagnosis of Lyme disease. The similar association between Lyme disease and celiac disease both before and after the diagnosis of celiac disease is strongly suggestive of surveillance bias as a likely contributor. Taken together, the data indicate that Borrelia infection is not a substantive risk factor in the development of celiac disease.

Gene-disease network analysis reveals functional modules in mendelian, complex and environmental diseases.

PubMed

Bauer-Mehren, Anna; Bundschus, Markus; Rautschka, Michael; Mayer, Miguel A; Sanz, Ferran; Furlong, Laura I

2011-01-01

Scientists have been trying to understand the molecular mechanisms of diseases to design preventive and therapeutic strategies for a long time. For some diseases, it has become evident that it is not enough to obtain a catalogue of the disease-related genes but to uncover how disruptions of molecular networks in the cell give rise to disease phenotypes. Moreover, with the unprecedented wealth of information available, even obtaining such catalogue is extremely difficult. We developed a comprehensive gene-disease association database by integrating associations from several sources that cover different biomedical aspects of diseases. In particular, we focus on the current knowledge of human genetic diseases including mendelian, complex and environmental diseases. To assess the concept of modularity of human diseases, we performed a systematic study of the emergent properties of human gene-disease networks by means of network topology and functional annotation analysis. The results indicate a highly shared genetic origin of human diseases and show that for most diseases, including mendelian, complex and environmental diseases, functional modules exist. Moreover, a core set of biological pathways is found to be associated with most human diseases. We obtained similar results when studying clusters of diseases, suggesting that related diseases might arise due to dysfunction of common biological processes in the cell. For the first time, we include mendelian, complex and environmental diseases in an integrated gene-disease association database and show that the concept of modularity applies for all of them. We furthermore provide a functional analysis of disease-related modules providing important new biological insights, which might not be discovered when considering each of the gene-disease association repositories independently. Hence, we present a suitable framework for the study of how genetic and environmental factors, such as drugs, contribute to diseases. The gene-disease networks used in this study and part of the analysis are available at http://ibi.imim.es/DisGeNET/DisGeNETweb.html#Download.

AMX0035 in Patients With Amyotrophic Lateral Sclerosis (ALS)

ClinicalTrials.gov

2018-05-21

Amyotrophic Lateral Sclerosis; Motor Neuron Disease; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Nervous System Diseases; Central Nervous System Diseases

Stem Cell Transplant for Inborn Errors of Metabolism

ClinicalTrials.gov

2017-12-03

Adrenoleukodystrophy; Metachromatic Leukodystrophy; Globoid Cell Leukodystrophy; Gaucher's Disease; Fucosidosis; Wolman Disease; Niemann-Pick Disease; Batten Disease; GM1 Gangliosidosis; Tay Sachs Disease; Sandhoff Disease

Study of a Monoclonal Antibody KHK4083 in Moderate Ulcerative Colitis

ClinicalTrials.gov

2018-05-15

Ulcerative Colitis; Digestive System Diseases; Colitis, Ulcerative; Colitis; Gastrointestinal Diseases; Inflammatory Bowel Diseases; Intestinal Diseases; Colonic Diseases; Autoimmune Disease; Abdominal Pain

The importance of selected spices in cardiovascular diseases.

PubMed

Kulczyński, Bartosz; Gramza-Michałowska, Anna

2016-11-14

Cardiovascular diseases are the leading cause of death worldwide. Literature data indicate that, due to these diseases, approximately 17.5 million people died in 2012. Types of cardiovascular disease include ischemic heart disease, cerebrovascular disease, peripheral vascular disease, congenital heart disease, rheumatic heart disease, cardiomyopathy and arrhythmia. Proper nutrition is an important factor in reducing the risk of cardiovascular events. An interesting element of our diets is spices. For thousands of years, they have been used in the treatment of many diseases: bacterial infections, coughs, colds, and liver diseases. Many studies also demonstrate their antioxidant, chemopreventive, anti-inflammatory and immunomodulatory properties. This paper focuses on discussing the importance of selected spices (garlic, cinnamon, ginger, coriander and turmeric) in the prevention and treatment of cardiovascular diseases.

Evolutionary history of human disease genes reveals phenotypic connections and comorbidity among genetic diseases

NASA Astrophysics Data System (ADS)

Park, Solip; Yang, Jae-Seong; Kim, Jinho; Shin, Young-Eun; Hwang, Jihye; Park, Juyong; Jang, Sung Key; Kim, Sanguk

2012-10-01

The extent to which evolutionary changes have impacted the phenotypic relationships among human diseases remains unclear. In this work, we report that phenotypically similar diseases are connected by the evolutionary constraints on human disease genes. Human disease groups can be classified into slowly or rapidly evolving classes, where the diseases in the slowly evolving class are enriched with morphological phenotypes and those in the rapidly evolving class are enriched with physiological phenotypes. Our findings establish a clear evolutionary connection between disease classes and disease phenotypes for the first time. Furthermore, the high comorbidity found between diseases connected by similar evolutionary constraints enables us to improve the predictability of the relative risk of human diseases. We find the evolutionary constraints on disease genes are a new layer of molecular connection in the network-based exploration of human diseases.

Evolutionary history of human disease genes reveals phenotypic connections and comorbidity among genetic diseases.

PubMed

Park, Solip; Yang, Jae-Seong; Kim, Jinho; Shin, Young-Eun; Hwang, Jihye; Park, Juyong; Jang, Sung Key; Kim, Sanguk

2012-01-01

The extent to which evolutionary changes have impacted the phenotypic relationships among human diseases remains unclear. In this work, we report that phenotypically similar diseases are connected by the evolutionary constraints on human disease genes. Human disease groups can be classified into slowly or rapidly evolving classes, where the diseases in the slowly evolving class are enriched with morphological phenotypes and those in the rapidly evolving class are enriched with physiological phenotypes. Our findings establish a clear evolutionary connection between disease classes and disease phenotypes for the first time. Furthermore, the high comorbidity found between diseases connected by similar evolutionary constraints enables us to improve the predictability of the relative risk of human diseases. We find the evolutionary constraints on disease genes are a new layer of molecular connection in the network-based exploration of human diseases.

Long-Term Outcomes of Ataluren in Duchenne Muscular Dystrophy

ClinicalTrials.gov

2018-05-16

Muscular Dystrophy, Duchenne; Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Disease; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn

Arboviruses pathogenic for domestic and wild animals.

PubMed

Hubálek, Zdenek; Rudolf, Ivo; Nowotny, Norbert

2014-01-01

The objective of this chapter is to provide an updated and concise systematic review on taxonomy, history, arthropod vectors, vertebrate hosts, animal disease, and geographic distribution of all arboviruses known to date to cause disease in homeotherm (endotherm) vertebrates, except those affecting exclusively man. Fifty arboviruses pathogenic for animals have been documented worldwide, belonging to seven families: Togaviridae (mosquito-borne Eastern, Western, and Venezuelan equine encephalilitis viruses; Sindbis, Middelburg, Getah, and Semliki Forest viruses), Flaviviridae (mosquito-borne yellow fever, Japanese encephalitis, Murray Valley encephalitis, West Nile, Usutu, Israel turkey meningoencephalitis, Tembusu and Wesselsbron viruses; tick-borne encephalitis, louping ill, Omsk hemorrhagic fever, Kyasanur Forest disease, and Tyuleniy viruses), Bunyaviridae (tick-borne Nairobi sheep disease, Soldado, and Bhanja viruses; mosquito-borne Rift Valley fever, La Crosse, Snowshoe hare, and Cache Valley viruses; biting midges-borne Main Drain, Akabane, Aino, Shuni, and Schmallenberg viruses), Reoviridae (biting midges-borne African horse sickness, Kasba, bluetongue, epizootic hemorrhagic disease of deer, Ibaraki, equine encephalosis, Peruvian horse sickness, and Yunnan viruses), Rhabdoviridae (sandfly/mosquito-borne bovine ephemeral fever, vesicular stomatitis-Indiana, vesicular stomatitis-New Jersey, vesicular stomatitis-Alagoas, and Coccal viruses), Orthomyxoviridae (tick-borne Thogoto virus), and Asfarviridae (tick-borne African swine fever virus). They are transmitted to animals by five groups of hematophagous arthropods of the subphyllum Chelicerata (order Acarina, families Ixodidae and Argasidae-ticks) or members of the class Insecta: mosquitoes (family Culicidae); biting midges (family Ceratopogonidae); sandflies (subfamily Phlebotominae); and cimicid bugs (family Cimicidae). Arboviral diseases in endotherm animals may therefore be classified as: tick-borne (louping ill and tick-borne encephalitis, Omsk hemorrhagic fever, Kyasanur Forest disease, Tyuleniy fever, Nairobi sheep disease, Soldado fever, Bhanja fever, Thogoto fever, African swine fever), mosquito-borne (Eastern, Western, and Venezuelan equine encephalomyelitides, Highlands J disease, Getah disease, Semliki Forest disease, yellow fever, Japanese encephalitis, Murray Valley encephalitis, West Nile encephalitis, Usutu disease, Israel turkey meningoencephalitis, Tembusu disease/duck egg-drop syndrome, Wesselsbron disease, La Crosse encephalitis, Snowshoe hare encephalitis, Cache Valley disease, Main Drain disease, Rift Valley fever, Peruvian horse sickness, Yunnan disease), sandfly-borne (vesicular stomatitis-Indiana, New Jersey, and Alagoas, Cocal disease), midge-borne (Akabane disease, Aino disease, Schmallenberg disease, Shuni disease, African horse sickness, Kasba disease, bluetongue, epizootic hemorrhagic disease of deer, Ibaraki disease, equine encephalosis, bovine ephemeral fever, Kotonkan disease), and cimicid-borne (Buggy Creek disease). Animals infected with these arboviruses regularly develop a febrile disease accompanied by various nonspecific symptoms; however, additional severe syndromes may occur: neurological diseases (meningitis, encephalitis, encephalomyelitis); hemorrhagic symptoms; abortions and congenital disorders; or vesicular stomatitis. Certain arboviral diseases cause significant economic losses in domestic animals-for example, Eastern, Western and Venezuelan equine encephalitides, West Nile encephalitis, Nairobi sheep disease, Rift Valley fever, Akabane fever, Schmallenberg disease (emerged recently in Europe), African horse sickness, bluetongue, vesicular stomatitis, and African swine fever; all of these (except for Akabane and Schmallenberg diseases) are notifiable to the World Organisation for Animal Health (OIE, 2012). © 2014 Elsevier Inc. All rights reserved.

The ASSURE ROT Registry: Bioresorbable Vascular Scaffold Following Rotablation for Complex Coronary Lesions

ClinicalTrials.gov

2015-02-05

Cardiovascular Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Coronary Restenosis; Heart Diseases; Coronary Stenosis; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases

The human disease network in terms of dysfunctional regulatory mechanisms.

PubMed

Yang, Jing; Wu, Su-Juan; Dai, Wen-Tao; Li, Yi-Xue; Li, Yuan-Yuan

2015-10-08

Elucidation of human disease similarities has emerged as an active research area, which is highly relevant to etiology, disease classification, and drug repositioning. In pioneer studies, disease similarity was commonly estimated according to clinical manifestation. Subsequently, scientists started to investigate disease similarity based on gene-phenotype knowledge, which were inevitably biased to well-studied diseases. In recent years, estimating disease similarity according to transcriptomic behavior significantly enhances the probability of finding novel disease relationships, while the currently available studies usually mine expression data through differential expression analysis that has been considered to have little chance of unraveling dysfunctional regulatory relationships, the causal pathogenesis of diseases. We developed a computational approach to measure human disease similarity based on expression data. Differential coexpression analysis, instead of differential expression analysis, was employed to calculate differential coexpression level of every gene for each disease, which was then summarized to the pathway level. Disease similarity was eventually calculated as the partial correlation coefficients of pathways' differential coexpression values between any two diseases. The significance of disease relationships were evaluated by permutation test. Based on mRNA expression data and a differential coexpression analysis based method, we built a human disease network involving 1326 significant Disease-Disease links among 108 diseases. Compared with disease relationships captured by differential expression analysis based method, our disease links shared known disease genes and drugs more significantly. Some novel disease relationships were discovered, for example, Obesity and cancer, Obesity and Psoriasis, lung adenocarcinoma and S. pneumonia, which had been commonly regarded as unrelated to each other, but recently found to share similar molecular mechanisms. Additionally, it was found that both the type of disease and the type of affected tissue influenced the degree of disease similarity. A sub-network including Allergic asthma, Type 2 diabetes and Chronic kidney disease was extracted to demonstrate the exploration of their common pathogenesis. The present study produces a global view of human diseasome for the first time from the viewpoint of regulation mechanisms, which therefore could provide insightful clues to etiology and pathogenesis, and help to perform drug repositioning and design novel therapeutic interventions.

Temporal Change in Phenotypic Behaviour in Patients with Crohn's Disease: Do Indian Patients Behave Differently from Western and Other Asian Patients?

PubMed

Kalaria, Rishikesh; Desai, Devendra; Abraham, Philip; Joshi, Anand; Gupta, Tarun; Shah, Sudeep

2016-03-01

In Western studies, one-third of patients with Crohn's disease have stricturing or penetrating disease at presentation and one-half will progress to complicated disease in 20 years. Asian studies indicate that the Asian disease phenotype may be different. Our aim was to study the disease behaviour in Indian patients with Crohn's disease. In this hospital-based study, we analysed [Montreal classification] disease phenotype, presence of perianal disease, need for intestinal surgery, and changes in the Montreal classification over time in Crohn's disease patients from our database. In the 178 patients (median age 35, interquartile range [IQR] 21 years; 97 males) with Crohn's disease, the proportion of various features was as follows. More patients had ileo-colonic[L3: 43.8%] than ileal[L1: 27.5%] or colonic[L2: 28.7%] disease. Perianal disease was seen in 11.8% at baseline. Non-stricturing, non-fistulising disease[B1] was seen in 74.7%, 65.7%, 50%, and 44.4% at baseline, at 5, 10 and 15 years, respectively. Stricturing disease[B2] was seen in 21.4%, 21.9%, 28.9%, and 33.3%; penetrating disease[B3] in 3.9%, 11.4%, 21%, and 16.7%; and intestinal surgery was required in 10.7%, 20%, 34.2%, and 55.5%, respectively. KaplanMeier analysis showed no association between progression of disease and patient age or the location of the disease. Gender distribution and predominant ileo-colonic location of disease were similar to earlier Asian reports on Crohn's disease. Perianal disease was less frequent than reported in Western and other Asian studies. One-fourth of Indian patients had aggressive disease at diagnosis, but the tendency to progress towards aggressive disease over time was less pronounced than in Western patients. Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Prevalence of coeliac disease in Italian patients affected by Addison's disease.

PubMed

Biagi, Federico; Campanella, Jonia; Soriani, Alessandra; Vailati, Alberto; Corazza, Gino R

2006-03-01

It is well known that coeliac disease is associated with autoimmune endocrine diseases, such as autoimmune thyroid disease and insulin-dependent diabetes mellitus. Recently, coeliac disease has been shown in approximately 10% of patients with autoimmune Addison's disease. Addison's disease is the most common cause of primary adrenocortical insufficiency and it shares several clinical features with coeliac disease. Although hyperpigmentation and hypotension are the most specific signs, gastrointestinal symptoms are common and can be the first complaints of the patients. The aim of our study was to investigate the prevalence of coeliac disease in Italian patients with Addison's disease. Seventeen consecutive patients affected by Addison's disease (14 F, mean age 53.9 years, range 26-79 years) were enrolled in the study. Eleven of them were affected by Addison's disease associated with autoimmune thyroid disease and/or insulin-dependent diabetes mellitus; the other 6 patients were suffering from isolated Addison's disease. Diagnosis had been performed at the age of 40.5 years (range 23-55). Steroid treatment had already been started in 16 of the patients. Endomysial antibodies were tested in all of them and a duodenal biopsy was taken in those found to be positive for antiendomysial antibody (EMA). One out of 17 patients was found to be EMA positive. Duodenal biopsy confirmed the diagnosis of coeliac disease by showing subtotal villous atrophy. Although we studied only a small sample, our preliminary results confirmed that Addison's disease is associated with coeliac disease, being present in 5.9% of patients with Addison's disease. Since the symptoms can be similar and treatment of Addison's disease can mask coeliac disease, this association should always be actively investigated.

Disease-aging network reveals significant roles of aging genes in connecting genetic diseases.

PubMed

Wang, Jiguang; Zhang, Shihua; Wang, Yong; Chen, Luonan; Zhang, Xiang-Sun

2009-09-01

One of the challenging problems in biology and medicine is exploring the underlying mechanisms of genetic diseases. Recent studies suggest that the relationship between genetic diseases and the aging process is important in understanding the molecular mechanisms of complex diseases. Although some intricate associations have been investigated for a long time, the studies are still in their early stages. In this paper, we construct a human disease-aging network to study the relationship among aging genes and genetic disease genes. Specifically, we integrate human protein-protein interactions (PPIs), disease-gene associations, aging-gene associations, and physiological system-based genetic disease classification information in a single graph-theoretic framework and find that (1) human disease genes are much closer to aging genes than expected by chance; and (2) diseases can be categorized into two types according to their relationships with aging. Type I diseases have their genes significantly close to aging genes, while type II diseases do not. Furthermore, we examine the topological characters of the disease-aging network from a systems perspective. Theoretical results reveal that the genes of type I diseases are in a central position of a PPI network while type II are not; (3) more importantly, we define an asymmetric closeness based on the PPI network to describe relationships between diseases, and find that aging genes make a significant contribution to associations among diseases, especially among type I diseases. In conclusion, the network-based study provides not only evidence for the intricate relationship between the aging process and genetic diseases, but also biological implications for prying into the nature of human diseases.

Perianal disease, small bowel disease, smoking, prior steroid or early azathioprine/biological therapy are predictors of disease behavior change in patients with Crohn's disease.

PubMed

Lakatos, Peter Laszlo; Czegledi, Zsofia; Szamosi, Tamas; Banai, Janos; David, Gyula; Zsigmond, Ferenc; Pandur, Tunde; Erdelyi, Zsuzsanna; Gemela, Orsolya; Papp, Janos; Lakatos, Laszlo

2009-07-28

To assess the combined effect of disease phenotype, smoking and medical therapy [steroid, azathioprine (AZA), AZA/biological therapy] on the probability of disease behavior change in a Caucasian cohort of patients with Crohn's disease (CD). Three hundred and forty well-characterized, unrelated, consecutive CD patients were analyzed (M/F: 155/185, duration: 9.4 +/- 7.5 years) with a complete clinical follow-up. Medical records including disease phenotype according to the Montreal classification, extraintestinal manifestations, use of medications and surgical events were analyzed retrospectively. Patients were interviewed on their smoking habits at the time of diagnosis and during the regular follow-up visits. A change in disease behavior was observed in 30.8% of patients with an initially non-stricturing, non-penetrating disease behavior after a mean disease duration of 9.0 +/- 7.2 years. In a logistic regression analysis corrected for disease duration, perianal disease, smoking, steroid use, early AZA or AZA/biological therapy use were independent predictors of disease behavior change. In a subsequent Kaplan-Meier survival analysis and a proportional Cox regression analysis, disease location (P = 0.001), presence of perianal disease (P < 0.001), prior steroid use (P = 0.006), early AZA (P = 0.005) or AZA/biological therapy (P = 0.002), or smoking (P = 0.032) were independent predictors of disease behavior change. Our data suggest that perianal disease, small bowel disease, smoking, prior steroid use, early AZA or AZA/biological therapy are all predictors of disease behavior change in CD patients.

[Prevalence of severe periodontal disease and its association with respiratory disease in hospitalized adult patients in a tertiary care center].

PubMed

Fernández-Plata, Rosario; Olmedo-Torres, Daniel; Martínez-Briseño, David; García-Sancho, Cecilia; Franco-Marina, Francisco; González-Cruz, Herminia

2015-01-01

Severe periodontal disease is a chronic inflammatory gingival process associated with systemic diseases. To determine the prevalence of severe periodontal disease and its association with respiratory diseases among hospitalized patients at the Institute of Respiratory Diseases "Ismael Cosio Villegas" (INER) in 2011. A cross-sectional study was developed. The severe periodontal disease was diagnosed by the Department of Stomatology. The International Classification of Diseases 10th revision was used. A multinomial logistic was fit to estimate relative-risk. Three thousand and fifty-nine patients were included; 772/3,059 (25.2%) had severe periodontal disease. After controlling for age, sex, inpatient days, death, and socioeconomic status, the infectious respiratory diseases that were significantly associated with severe periodontal disease were: HIV/AIDS (RR: 10.6; 95% CI: 9.1-23.3; p < 0.0001); pneumonia (RR: 2.6; 95% CI: 2.2-5.7; p < 0.0001); pulmonary tuberculosis and its sequels (RR: 2.1; 95% CI: 1.6-4.9; p < 0.0001); and lung abscess (RR: 2.6; 95% CI: 1.6-7.8; p = 0.002). Lung cancer and pleural diseases were also significantly associated with severe periodontal disease. High prevalence of severe periodontal disease was observed in the different respiratory diseases. Severe periodontal disease was associated with both infectious and non-infectious respiratory diseases. It is important to study an oral health intervention.

A Network Based Method for Analysis of lncRNA-Disease Associations and Prediction of lncRNAs Implicated in Diseases

PubMed Central

Yang, Xiaofei; Gao, Lin; Guo, Xingli; Shi, Xinghua; Wu, Hao; Song, Fei; Wang, Bingbo

2014-01-01

Increasing evidence has indicated that long non-coding RNAs (lncRNAs) are implicated in and associated with many complex human diseases. Despite of the accumulation of lncRNA-disease associations, only a few studies had studied the roles of these associations in pathogenesis. In this paper, we investigated lncRNA-disease associations from a network view to understand the contribution of these lncRNAs to complex diseases. Specifically, we studied both the properties of the diseases in which the lncRNAs were implicated, and that of the lncRNAs associated with complex diseases. Regarding the fact that protein coding genes and lncRNAs are involved in human diseases, we constructed a coding-non-coding gene-disease bipartite network based on known associations between diseases and disease-causing genes. We then applied a propagation algorithm to uncover the hidden lncRNA-disease associations in this network. The algorithm was evaluated by leave-one-out cross validation on 103 diseases in which at least two genes were known to be involved, and achieved an AUC of 0.7881. Our algorithm successfully predicted 768 potential lncRNA-disease associations between 66 lncRNAs and 193 diseases. Furthermore, our results for Alzheimer's disease, pancreatic cancer, and gastric cancer were verified by other independent studies. PMID:24498199

DiseaseConnect: a comprehensive web server for mechanism-based disease–disease connections

PubMed Central

Liu, Chun-Chi; Tseng, Yu-Ting; Li, Wenyuan; Wu, Chia-Yu; Mayzus, Ilya; Rzhetsky, Andrey; Sun, Fengzhu; Waterman, Michael; Chen, Jeremy J. W.; Chaudhary, Preet M.; Loscalzo, Joseph; Crandall, Edward; Zhou, Xianghong Jasmine

2014-01-01

The DiseaseConnect (http://disease-connect.org) is a web server for analysis and visualization of a comprehensive knowledge on mechanism-based disease connectivity. The traditional disease classification system groups diseases with similar clinical symptoms and phenotypic traits. Thus, diseases with entirely different pathologies could be grouped together, leading to a similar treatment design. Such problems could be avoided if diseases were classified based on their molecular mechanisms. Connecting diseases with similar pathological mechanisms could inspire novel strategies on the effective repositioning of existing drugs and therapies. Although there have been several studies attempting to generate disease connectivity networks, they have not yet utilized the enormous and rapidly growing public repositories of disease-related omics data and literature, two primary resources capable of providing insights into disease connections at an unprecedented level of detail. Our DiseaseConnect, the first public web server, integrates comprehensive omics and literature data, including a large amount of gene expression data, Genome-Wide Association Studies catalog, and text-mined knowledge, to discover disease–disease connectivity via common molecular mechanisms. Moreover, the clinical comorbidity data and a comprehensive compilation of known drug–disease relationships are additionally utilized for advancing the understanding of the disease landscape and for facilitating the mechanism-based development of new drug treatments. PMID:24895436

Prolactinoma

MedlinePlus

... Creutzfeldt-Jakob Disease Resource List Health Alert: Adrenal Crisis Causes Death in Some People Who Were Treated ... Health Information Diabetes Digestive Diseases Kidney Disease Weight Management Liver Disease Urologic Diseases Endocrine Diseases Diet & Nutrition ...

Neurological Complications Comparing Endoscopically vs. Open Harvest of the Radial Artery

ClinicalTrials.gov

2016-07-05

Complications Due to Coronary Artery Bypass Graft; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases

Diseases of Pacific Coast conifers. Agriculture handbook

DOE Office of Scientific and Technical Information (OSTI.GOV)

Scharpf, R.F.

1993-06-01

The handbook provides basic information needed to identify the common diseases of Pacific Coast conifers. Hosts, distribution, disease cycles, and identifying characteristics are described for more than 150 diseases, including cankers, diebacks, galls, rusts, needle diseases, root diseases, mistletoes, and rots. Diseases in which abiotic factors are involved are also described. For some groups of diseases, a descriptive key to field identification is included.

Coronary Artery Disease | Coronary Artery Disease | NIH MedlinePlus the Magazine

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... of this page please turn Javascript on. Feature: Coronary Artery Disease Coronary Artery Disease Past Issues / Fall 2010 Table of Contents David ... up inside your arteries. One atherosclerosis-related disease, coronary artery disease (CAD) is the most common heart disease and ...

Induced Pluripotent Stem Cells for Disease Modeling and Drug Discovery in Neurodegenerative Diseases.

PubMed

Cao, Lei; Tan, Lan; Jiang, Teng; Zhu, Xi-Chen; Yu, Jin-Tai

2015-08-01

Although most neurodegenerative diseases have been closely related to aberrant accumulation of aggregation-prone proteins in neurons, understanding their pathogenesis remains incomplete, and there is no treatment to delay the onset or slow the progression of many neurodegenerative diseases. The availability of induced pluripotent stem cells (iPSCs) in recapitulating the phenotypes of several late-onset neurodegenerative diseases marks the new era in in vitro modeling. The iPSC collection represents a unique and well-characterized resource to elucidate disease mechanisms in these diseases and provides a novel human stem cell platform for screening new candidate therapeutics. Modeling human diseases using iPSCs has created novel opportunities for both mechanistic studies as well as for the discovery of new disease therapies. In this review, we introduce iPSC-based disease modeling in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. In addition, we discuss the implementation of iPSCs in drug discovery associated with some new techniques.

Predicting disease-related proteins based on clique backbone in protein-protein interaction network.

PubMed

Yang, Lei; Zhao, Xudong; Tang, Xianglong

2014-01-01

Network biology integrates different kinds of data, including physical or functional networks and disease gene sets, to interpret human disease. A clique (maximal complete subgraph) in a protein-protein interaction network is a topological module and possesses inherently biological significance. A disease-related clique possibly associates with complex diseases. Fully identifying disease components in a clique is conductive to uncovering disease mechanisms. This paper proposes an approach of predicting disease proteins based on cliques in a protein-protein interaction network. To tolerate false positive and negative interactions in protein networks, extending cliques and scoring predicted disease proteins with gene ontology terms are introduced to the clique-based method. Precisions of predicted disease proteins are verified by disease phenotypes and steadily keep to more than 95%. The predicted disease proteins associated with cliques can partly complement mapping between genotype and phenotype, and provide clues for understanding the pathogenesis of serious diseases.

Why the concept ''lifestyle diseases'' should be avoided.

PubMed

Vallgårda, Signild

2011-11-01

The concept lifestyle disease is used about a number of different diseases such as coronary heart disease, diabetes, lung cancer etc. The concept indicates that people's behaviours cause the diseases. This is only partly true. All diseases, both so-called lifestyle diseases and infectious diseases, have multiple causes. Singling out only one type of causes, such as is implied in the concept of lifestyle diseases can lead prevention to focus only on changing people s behaviours or lifestyles, and thus to neglect other possibilities to improve health. Mortality due to chronic diseases has increased during the last century and the main cause behind this is the decrease in the mortality in infectious diseases among younger people. More people live long enough to develop the chronic diseases. The concept lifestyle disease gives a too narrow picture of causes death and should be abandoned and give place for a broader understanding of causes and preventive options.

Phase 3 Study of Ataluren in Patients With Nonsense Mutation Duchenne Muscular Dystrophy

ClinicalTrials.gov

2017-12-11

Muscular Dystrophy, Duchenne; Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn

Heart Disease

MedlinePlus

... receive Heart Disease and Stroke email updates Submit Heart disease Heart disease is the number one killer of ... about heart disease on other websites View more Heart disease resources Related information Heart-healthy eating Diabetes Stress ...

Phase 3 Extension Study of Ataluren (PTC124) in Patients With Nonsense Mutation Dystrophinopathy

ClinicalTrials.gov

2018-01-16

Muscular Dystrophy, Duchenne; Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn

Exploring the quality of life issues in people with retinal diseases: a qualitative study.

PubMed

Prem Senthil, Mallika; Khadka, Jyoti; Gilhotra, Jagjit Singh; Simon, Sumu; Pesudovs, Konrad

2017-01-01

The lack of an appropriate retina-specific patient-reported outcome instrument restricts the understanding of the full impact of hereditary retinal diseases and other less common but potentially blinding acquired retinal diseases such as, vascular occlusions, epiretinal membrane, macular hole, central serous retinopathy and other vitreoretinopathies on quality of life. This study aims to explore the quality of life issues in people with hereditary retinal diseases and acquired retinal diseases to develop disease-specific patient-reported outcome instruments. A qualitative research methodology to understand the lived experiences of people with retinal diseases was carried out. Data were collected through semistructured interviews. The coding, aggregation and theme development was carried out using the NVivo -10 software. Seventy-nine interviews were conducted with participants with hereditary retinal diseases ( n  = 32; median age = 57 years) and acquired retinal diseases ( n  = 47; median age = 73 years). We identified nine quality of life themes (domains) relevant to people with retinal diseases. Difficulty in performing important day-to-day activities (activity limitation) was the most prominent quality of life issue in the hereditary retinal diseases group whereas concerns about health, disease outcome and personal safety (health concerns) was the most prominent quality of life issue in the acquired retinal diseases group. Participants with hereditary retinal diseases had more issues with social interaction (social well-being), problems with mobility and orientation (mobility), and effect on work and finance (economic) than participants with acquired retinal diseases. On the contrary, participants with acquired retinal diseases reported more inconveniences (conveniences) than participants with hereditary retinal diseases, which were mostly attributed to treatment. Participants with hereditary retinal diseases were coping better compared to participants with acquired retinal diseases. Our study found that participants with both hereditary and acquired retinal diseases are living with myriad of disease-specific quality of life issues. Many of these issues are completely different and unique to each disease group. Hence, these group of diseases would need separate patient-reported outcome instruments to capture the disease-specific quality of life impacts.

Increased risk of non-alcoholic fatty liver disease after diagnosis of celiac disease.

PubMed

Reilly, Norelle R; Lebwohl, Benjamin; Hultcrantz, Rolf; Green, Peter H R; Ludvigsson, Jonas F

2015-06-01

Non-alcoholic fatty liver disease is a common cause of chronic liver disease. Celiac disease alters intestinal permeability and treatment with a gluten-free diet often causes weight gain, but so far there are few reports of non-alcoholic fatty liver disease in patients with celiac disease. Population-based cohort study. We compared the risk of non-alcoholic fatty liver disease diagnosed from 1997 to 2009 in individuals with celiac disease (n = 26,816) to matched reference individuals (n = 130,051). Patients with any liver disease prior to celiac disease were excluded, as were individuals with a lifetime diagnosis of alcohol-related disorder to minimize misclassification of non-alcoholic fatty liver disease. Cox regression estimated hazard ratios for non-alcoholic fatty liver disease were determined. During 246,559 person-years of follow-up, 53 individuals with celiac disease had a diagnosis of non-alcoholic fatty liver disease (21/100,000 person-years). In comparison, we identified 85 reference individuals diagnosed with non-alcoholic fatty liver disease during 1,488,413 person-years (6/100,000 person-years). This corresponded to a hazard ratio of 2.8 (95% CI 2.0-3.8), with the highest risk estimates seen in children (HR = 4.6; 95% CI 2.3-9.1). The risk increase in the first year after celiac disease diagnosis was 13.3 (95% CI 3.5-50.3) but remained significantly elevated even beyond 15 years after the diagnosis of celiac disease (HR = 2.5; 95% CI 1.0-5.9). Individuals with celiac disease are at increased risk of non-alcoholic fatty liver disease compared to the general population. Excess risks were highest in the first year after celiac disease diagnosis, but persisted through 15 years after diagnosis with celiac disease. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Walking the interactome to identify human miRNA-disease associations through the functional link between miRNA targets and disease genes

PubMed Central

2013-01-01

Background MicroRNAs (miRNAs) are important post-transcriptional regulators that have been demonstrated to play an important role in human diseases. Elucidating the associations between miRNAs and diseases at the systematic level will deepen our understanding of the molecular mechanisms of diseases. However, miRNA-disease associations identified by previous computational methods are far from completeness and more effort is needed. Results We developed a computational framework to identify miRNA-disease associations by performing random walk analysis, and focused on the functional link between miRNA targets and disease genes in protein-protein interaction (PPI) networks. Furthermore, a bipartite miRNA-disease network was constructed, from which several miRNA-disease co-regulated modules were identified by hierarchical clustering analysis. Our approach achieved satisfactory performance in identifying known cancer-related miRNAs for nine human cancers with an area under the ROC curve (AUC) ranging from 71.3% to 91.3%. By systematically analyzing the global properties of the miRNA-disease network, we found that only a small number of miRNAs regulated genes involved in various diseases, genes associated with neurological diseases were preferentially regulated by miRNAs and some immunological diseases were associated with several specific miRNAs. We also observed that most diseases in the same co-regulated module tended to belong to the same disease category, indicating that these diseases might share similar miRNA regulatory mechanisms. Conclusions In this study, we present a computational framework to identify miRNA-disease associations, and further construct a bipartite miRNA-disease network for systematically analyzing the global properties of miRNA regulation of disease genes. Our findings provide a broad perspective on the relationships between miRNAs and diseases and could potentially aid future research efforts concerning miRNA involvement in disease pathogenesis. PMID:24103777

Solid Waste/Disease Relationships, A Literature Survey.

ERIC Educational Resources Information Center

Hanks, Thrift G.

Presented is a comprehensive survey of the literature on the relationships between disease and solid wastes. Diseases are grouped on the basis of waste type or disease vector, such as chemical waste, human fecal waste, animal fecal waste, rodent-borne disease, mosquito-borne disease and miscellaneous communicable disease. The following format is…

Celiac Disease: Symptoms, Diagnosis & Treatment

MedlinePlus

... for refractory celiac disease. Read More "Celiac Disease" Articles Celiac Disease Changes Everything / What is Celiac Disease? / Symptoms, Diagnosis & Treatment / Four Inches and Seven Pounds… / Learning to Live Well with Celiac Disease / Living Gluten- ...

GLADIATOR: a global approach for elucidating disease modules.

PubMed

Silberberg, Yael; Kupiec, Martin; Sharan, Roded

2017-05-26

Understanding the genetic basis of disease is an important challenge in biology and medicine. The observation that disease-related proteins often interact with one another has motivated numerous network-based approaches for deciphering disease mechanisms. In particular, protein-protein interaction networks were successfully used to illuminate disease modules, i.e., interacting proteins working in concert to drive a disease. The identification of these modules can further our understanding of disease mechanisms. We devised a global method for the prediction of multiple disease modules simultaneously named GLADIATOR (GLobal Approach for DIsease AssociaTed mOdule Reconstruction). GLADIATOR relies on a gold-standard disease phenotypic similarity to obtain a pan-disease view of the underlying modules. To traverse the search space of potential disease modules, we applied a simulated annealing algorithm aimed at maximizing the correlation between module similarity and the gold-standard phenotypic similarity. Importantly, this optimization is employed over hundreds of diseases simultaneously. GLADIATOR's predicted modules highly agree with current knowledge about disease-related proteins. Furthermore, the modules exhibit high coherence with respect to functional annotations and are highly enriched with known curated pathways, outperforming previous methods. Examination of the predicted proteins shared by similar diseases demonstrates the diverse role of these proteins in mediating related processes across similar diseases. Last, we provide a detailed analysis of the suggested molecular mechanism predicted by GLADIATOR for hyperinsulinism, suggesting novel proteins involved in its pathology. GLADIATOR predicts disease modules by integrating knowledge of disease-related proteins and phenotypes across multiple diseases. The predicted modules are functionally coherent and are more in line with current biological knowledge compared to modules obtained using previous disease-centric methods. The source code for GLADIATOR can be downloaded from http://www.cs.tau.ac.il/~roded/GLADIATOR.zip .

Perianal disease, small bowel disease, smoking, prior steroid or early azathioprine/biological therapy are predictors of disease behavior change in patients with Crohn’s disease

PubMed Central

Lakatos, Peter Laszlo; Czegledi, Zsofia; Szamosi, Tamas; Banai, Janos; David, Gyula; Zsigmond, Ferenc; Pandur, Tunde; Erdelyi, Zsuzsanna; Gemela, Orsolya; Papp, Janos; Lakatos, Laszlo

2009-01-01

AIM: To assess the combined effect of disease phenotype, smoking and medical therapy [steroid, azathioprine (AZA), AZA/biological therapy] on the probability of disease behavior change in a Caucasian cohort of patients with Crohn’s disease (CD). METHODS: Three hundred and forty well-characterized, unrelated, consecutive CD patients were analyzed (M/F: 155/185, duration: 9.4 ± 7.5 years) with a complete clinical follow-up. Medical records including disease phenotype according to the Montreal classification, extraintestinal manifestations, use of medications and surgical events were analyzed retrospectively. Patients were interviewed on their smoking habits at the time of diagnosis and during the regular follow-up visits. RESULTS: A change in disease behavior was observed in 30.8% of patients with an initially non-stricturing, non-penetrating disease behavior after a mean disease duration of 9.0 ± 7.2 years. In a logistic regression analysis corrected for disease duration, perianal disease, smoking, steroid use, early AZA or AZA/biological therapy use were independent predictors of disease behavior change. In a subsequent Kaplan-Meier survival analysis and a proportional Cox regression analysis, disease location (P = 0.001), presence of perianal disease (P < 0.001), prior steroid use (P = 0.006), early AZA (P = 0.005) or AZA/biological therapy (P = 0.002), or smoking (P = 0.032) were independent predictors of disease behavior change. CONCLUSION: Our data suggest that perianal disease, small bowel disease, smoking, prior steroid use, early AZA or AZA/biological therapy are all predictors of disease behavior change in CD patients. PMID:19630105

Triple burden of disease and out of pocket healthcare expenditure of women in India

PubMed Central

Ladusingh, Laishram; Mohanty, Sanjay Kumar

2018-01-01

Aim Women, unlike men, are subjected to triple burden of disease, namely, non-communicable and communicable diseases and reproductive health related diseases. To assess prevalence of triple burden of disease of currently married women and to contrast out of pocket maternal care expenditure of these diseases in India. Subject and methods This study uses nationally representative unit level data from the 71st round (2014) of the National Sample Survey Organisation. Descriptive statistics and bivariate analysis are employed to assess triple burden of diseases by background of currently married women. Mean out of pocket (OOP) expenditure for healthcare care by demographic and household characteristics of women are also compared by type of diseases. Two parts model is adopted for assessment of determents of out of pocket healthcare expenditure of women. Results Overall medical and non-medical expenses of non–communicable disease are much higher than those of other disease and disability, reproductive health related and communicable diseases. OOP expenditure for treatment of non-communicable diseases, reproductive health and related diseases and other disease and disability are significantly higher than the inpatient treatment of communicable diseases and the differences are statistically significant. Conclusion Out of pocket expenditure for treatment of non-communicable diseases is the highest, followed by that of other diseases & disability, then reproductive health related diseases and the least is for communicable diseases. OOP expenditures for maternal healthcare in private health facilities are much higher than in public health facilities regardless of types of disease. Women from households having insurance of any member spent less than that of women from households not having health insurance. There is an urgent need to expand the outreach of the public health system in India to rural areas. PMID:29746506

A comparative study of disease genes and drug targets in the human protein interactome

PubMed Central

2015-01-01

Background Disease genes cause or contribute genetically to the development of the most complex diseases. Drugs are the major approaches to treat the complex disease through interacting with their targets. Thus, drug targets are critical for treatment efficacy. However, the interrelationship between the disease genes and drug targets is not clear. Results In this study, we comprehensively compared the network properties of disease genes and drug targets for five major disease categories (cancer, cardiovascular disease, immune system disease, metabolic disease, and nervous system disease). We first collected disease genes from genome-wide association studies (GWAS) for five disease categories and collected their corresponding drugs based on drugs' Anatomical Therapeutic Chemical (ATC) classification. Then, we obtained the drug targets for these five different disease categories. We found that, though the intersections between disease genes and drug targets were small, disease genes were significantly enriched in targets compared to their enrichment in human protein-coding genes. We further compared network properties of the proteins encoded by disease genes and drug targets in human protein-protein interaction networks (interactome). The results showed that the drug targets tended to have higher degree, higher betweenness, and lower clustering coefficient in cancer Furthermore, we observed a clear fraction increase of disease proteins or drug targets in the near neighborhood compared with the randomized genes. Conclusions The study presents the first comprehensive comparison of the disease genes and drug targets in the context of interactome. The results provide some foundational network characteristics for further designing computational strategies to predict novel drug targets and drug repurposing. PMID:25861037

A comparative study of disease genes and drug targets in the human protein interactome.

PubMed

Sun, Jingchun; Zhu, Kevin; Zheng, W; Xu, Hua

2015-01-01

Disease genes cause or contribute genetically to the development of the most complex diseases. Drugs are the major approaches to treat the complex disease through interacting with their targets. Thus, drug targets are critical for treatment efficacy. However, the interrelationship between the disease genes and drug targets is not clear. In this study, we comprehensively compared the network properties of disease genes and drug targets for five major disease categories (cancer, cardiovascular disease, immune system disease, metabolic disease, and nervous system disease). We first collected disease genes from genome-wide association studies (GWAS) for five disease categories and collected their corresponding drugs based on drugs' Anatomical Therapeutic Chemical (ATC) classification. Then, we obtained the drug targets for these five different disease categories. We found that, though the intersections between disease genes and drug targets were small, disease genes were significantly enriched in targets compared to their enrichment in human protein-coding genes. We further compared network properties of the proteins encoded by disease genes and drug targets in human protein-protein interaction networks (interactome). The results showed that the drug targets tended to have higher degree, higher betweenness, and lower clustering coefficient in cancer Furthermore, we observed a clear fraction increase of disease proteins or drug targets in the near neighborhood compared with the randomized genes. The study presents the first comprehensive comparison of the disease genes and drug targets in the context of interactome. The results provide some foundational network characteristics for further designing computational strategies to predict novel drug targets and drug repurposing.

Genetics Home Reference: Alexander disease

MedlinePlus

... the prognosis of a genetic condition? Genetic and Rare Diseases Information Center Frequency The prevalence of Alexander disease ... Degenerative Nerve Diseases Health Topic: Leukodystrophies Genetic and Rare Diseases Information Center (1 link) Alexander disease Additional NIH ...

Parkinson's Disease

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... Staying Safe Videos for Educators Search English Español Parkinson's Disease KidsHealth / For Kids / Parkinson's Disease What's in this ... symptoms of something called Parkinson's disease. What Is Parkinson's Disease? Parkinson's disease is a disorder of the central ...

Avoiding Ticks

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Learning to Live Well with Celiac Disease

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... Foundation Celiac Disease Foundation Read More "Celiac Disease" Articles Celiac Disease Changes Everything / What is Celiac Disease? / Symptoms, Diagnosis & Treatment / Four Inches and Seven Pounds… / Learning to Live Well with Celiac Disease / Living Gluten- ...

Meeting the Challenge of Crohn's Disease

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... page please turn JavaScript on. Feature: Crohn's Disease Meeting the Challenge of Crohn's Disease Past Issues / Winter ... Living with Crohn's Disease / What Is Crohn's Disease / Meeting the Challenge of Crohn's Disease Winter 2016 Issue: ...

Universal etiology, multifactorial diseases and the constitutive model of disease classification.

PubMed

Fuller, Jonathan

2018-02-01

Infectious diseases are often said to have a universal etiology, while chronic and noncommunicable diseases are said to be multifactorial in their etiology. It has been argued that the universal etiology of an infectious disease results from its classification using a monocausal disease model. In this article, I will reconstruct the monocausal model and argue that modern 'multifactorial diseases' are not monocausal by definition. 'Multifactorial diseases' are instead defined according to a constitutive disease model. On closer analysis, infectious diseases are also defined using the constitutive model rather than the monocausal model. As a result, our classification models alone cannot explain why infectious diseases have a universal etiology while chronic and noncommunicable diseases lack one. The explanation is instead provided by the Nineteenth Century germ theorists. Copyright © 2017 Elsevier Ltd. All rights reserved.

The integrated disease network.

PubMed

Sun, Kai; Buchan, Natalie; Larminie, Chris; Pržulj, Nataša

2014-11-01

The growing body of transcriptomic, proteomic, metabolomic and genomic data generated from disease states provides a great opportunity to improve our current understanding of the molecular mechanisms driving diseases and shared between diseases. The use of both clinical and molecular phenotypes will lead to better disease understanding and classification. In this study, we set out to gain novel insights into diseases and their relationships by utilising knowledge gained from system-level molecular data. We integrated different types of biological data including genome-wide association studies data, disease-chemical associations, biological pathways and Gene Ontology annotations into an Integrated Disease Network (IDN), a heterogeneous network where nodes are bio-entities and edges between nodes represent their associations. We also introduced a novel disease similarity measure to infer disease-disease associations from the IDN. Our predicted associations were systemically evaluated against the Medical Subject Heading classification and a statistical measure of disease co-occurrence in PubMed. The strong correlation between our predictions and co-occurrence associations indicated the ability of our approach to recover known disease associations. Furthermore, we presented a case study of Crohn's disease. We demonstrated that our approach not only identified well-established connections between Crohn's disease and other diseases, but also revealed new, interesting connections consistent with emerging literature. Our approach also enabled ready access to the knowledge supporting these new connections, making this a powerful approach for exploring connections between diseases.

Two adolescent patients with coexistent Graves' disease and Moyamoya disease in Korea.

PubMed

Cheon, Chong Kun; Kim, Su Yung; Yoo, Jae-Ho

2014-06-01

Moyamoya disease is a cerebrovascular condition that results in the narrowing of the vessels of the circle of Willis and collateral vessel formation at the base of the brain. Although relationships between Graves' disease and cerebrovascular accidents in Moyamoya disease are obscure, the coexistence of the two diseases is noteworthy. Moyamoya disease has been rarely reported in adolescent patients with thyrotoxicosis. Recently, we encountered two adolescent Korean patients with Moyamoya disease associated with Graves' disease who presented with episodic right-sided hemiparesis and syncope. These two girls who had Graves' disease had no history of other diseases or head trauma. A thyroid function test revealed a euthyroid state and a high thyroid-stimulating hormone (TSH) receptor antibody titer at that time. The patients were diagnosed with Moyamoya disease based on brain magnetic resonance angiography and cerebral four-vessel angiography. The patients underwent cranial revascularization by encephalo-duroarterio-synangiosis as soon as a diagnosis was made, which resulted in successful symptom resolution. They fared well and had no additional neurological symptoms as of their last follow-up visits. Here, we report these two cases of confirmed Moyamoya disease complicated by Graves' disease with a review of the literature, and discuss the possible association between the two diseases. To our knowledge, this is the first report in South Korea on Moyamoya disease associated with Graves' disease in adolescents with a euthyroid.

Chagas disease and systemic autoimmune diseases among Bolivian patients in Switzerland.

PubMed

Jackson, Yves; Pula, Drenusha Vieira de Mello; Finckh, Axel; Chizzolini, Carlo; Chappuis, François

2018-02-05

Chronic cardiomyopathy occurs in 20-40% of the patients with Chagas disease. Autoimmune mechanisms may contribute to its pathogenesis. We diagnosed several cases of systemic autoimmune diseases among Bolivian migrants in Geneva with a high prevalence of Chagas disease. We tested the hypothesis of a clinical association between systemic autoimmune diseases and Chagas disease, particularly with the development of cardiomyopathy. We retrospectively searched the medical records of all Bolivian patients visiting Geneva University Hospitals between 2012 and 2015 for diagnosis of Chagas disease or systemic autoimmune diseases. Of the 2,189 eligible patients, 28 [1.3%; 95% confidence interval (CI) = 0.9-1.9%] presented with systemic autoimmune disease. The Chagas status was known in 903 (41.3%) patient, of whom 244 (27.0%; 95% CI = 24.2-30.0%) were positive. Eight (28.6%; 95% CI = 15.3-47.1%) of the 28 cases of systemic autoimmune disease had Chagas disease. We found no association between both entities (p = 1.000) or with Chagasic cardiomyopathy (p = 0.729). Moreover, there was no evidence of a temporal relationship between antiparasitic chemotherapy and the development of systemic autoimmune diseases. Our results do not support a clinical association between chronic Chagas disease and systemic autoimmune diseases. However, prospective studies in areas endemic for Chagas disease should better assess the prevalence of systemic autoimmune diseases and thus a possible relationship with this infection.

[Coexistence of coeliac disease and inflammatory bowel disease in children].

PubMed

Krawiec, Paulina; Pawłowska-Kamieniak, Agnieszka; Pac-Kożuchowska, Elżbieta; Mroczkowska-Juchkiewcz, Agnieszka; Kominek, Katarzyna

2016-01-01

Coeliac disease and inflammatory bowel disease are chronic inflammatory conditions of gastrointestinal tract with complex aetiology with genetic, environmental and immunological factors contributing to its pathogenesis. It was noted that immune-mediated disorders often coexist. There is well-known association between coeliac disease and type 1 diabetes and ulcerative colitis and primary sclerosing cholangitis. However, growing body of literature suggests the association between coeliac disease and inflammatory bowel disease, particularly ulcerative colitis. This is an extremely rare problem in paediatric gastroenterology. To date there have been reported several cases of children with coexisting coeliac disease and inflammatory bowel disease. Herewith we present review of current literature on coexistence of coeliac disease and inflammatory bowel disease in children. © 2016 MEDPRESS.

Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated.

PubMed

Robinson, John L; Lee, Edward B; Xie, Sharon X; Rennert, Lior; Suh, EunRan; Bredenberg, Colin; Caswell, Carrie; Van Deerlin, Vivianna M; Yan, Ning; Yousef, Ahmed; Hurtig, Howard I; Siderowf, Andrew; Grossman, Murray; McMillan, Corey T; Miller, Bruce; Duda, John E; Irwin, David J; Wolk, David; Elman, Lauren; McCluskey, Leo; Chen-Plotkin, Alice; Weintraub, Daniel; Arnold, Steven E; Brettschneider, Johannes; Lee, Virginia M-Y; Trojanowski, John Q

2018-06-05

Lewy bodies commonly occur in Alzheimer's disease, and Alzheimer's disease pathology is frequent in Lewy body diseases, but the burden of co-pathologies across neurodegenerative diseases is unknown. We assessed the extent of tau, amyloid-β, α-synuclein and TDP-43 proteinopathies in 766 autopsied individuals representing a broad spectrum of clinical neurodegenerative disease. We interrogated pathological Alzheimer's disease (n = 247); other tauopathies (n = 95) including Pick's disease, corticobasal disease and progressive supranuclear palsy; the synucleinopathies (n = 164) including multiple system atrophy and Lewy body disease; the TDP-43 proteinopathies (n = 188) including frontotemporal lobar degeneration with TDP-43 inclusions and amyotrophic lateral sclerosis; and a minimal pathology group (n = 72). Each group was divided into subgroups without or with co-pathologies. Age and sex matched logistic regression models compared co-pathology prevalence between groups. Co-pathology prevalence was similar between the minimal pathology group and most neurodegenerative diseases for each proteinopathy: tau was nearly universal (92-100%), amyloid-β common (20-57%); α-synuclein less common (4-16%); and TDP-43 the rarest (0-16%). In several neurodegenerative diseases, co-pathology increased: in Alzheimer's disease, α-synuclein (41-55%) and TDP-43 (33-40%) increased; in progressive supranuclear palsy, α-synuclein increased (22%); in corticobasal disease, TDP-43 increased (24%); and in neocortical Lewy body disease, amyloid-β (80%) and TDP-43 (22%) increased. Total co-pathology prevalence varied across groups (27-68%), and was increased in high Alzheimer's disease, progressive supranuclear palsy, and neocortical Lewy body disease (70-81%). Increased age at death was observed in the minimal pathology group, amyotrophic lateral sclerosis, and multiple system atrophy cases with co-pathologies. In amyotrophic lateral sclerosis and neocortical Lewy body disease, co-pathologies associated with APOE ɛ4. Lewy body disease cases with Alzheimer's disease co-pathology had substantially lower Mini-Mental State Examination scores than pure Lewy body disease. Our data imply that increased age and APOE ɛ4 status are risk factors for co-pathologies independent of neurodegenerative disease; that neurodegenerative disease severity influences co-pathology as evidenced by the prevalence of co-pathology in high Alzheimer's disease and neocortical Lewy body disease, but not intermediate Alzheimer's disease or limbic Lewy body disease; and that tau and α-synuclein strains may also modify co-pathologies since tauopathies and synucleinopathies had differing co-pathologies and burdens. These findings have implications for clinical trials that focus on monotherapies targeting tau, amyloid-β, α-synuclein and TDP-43.

Disease and Non-Battle Injury Rates For Marine Corps Enlisted Personnel during Peacetime

DTIC Science & Technology

1990-05-30

Infective and Parasitic Diseases, Diseases of the Respiratory System, and Injury and Poisoning. Although these rates were consistently lower than those...rates were 6 Diseases of the Digestive System, Infective and Parasitic Diseases, Diseases of the Respiratory System, and Injury and Poisoning. The...Diseases of the Digestive System in Europe and Northeast Asia, and Diseases of the Respiratory System in Southwest Asia. Conclusions Although these results

Lyme Disease in West Virginia: An Assessment of Distribution and Clinicians' Knowledge of Disease and Surveillance.

PubMed

Singh, Sarah; Parker, David; Mark-Carew, Miguella; White, Robert; Fisher, Melanie

2016-01-01

Lyme disease case misclassification, a top public health concern, may be attributed to the current disconnect between clinical diagnosis and surveillance. This study examines Lyme disease distribution in West Virginia (WV) and determines clinicians' knowledge of both disease and surveillance. Lyme disease surveillance data for 2013 were obtained from the WV Bureau for Public Health. A validated survey, distributed to clinicians at an academic medical center, assessed clinicians' knowledge of disease diagnosis and surveillance. There were 297 adult Lyme disease cases of which 83 were confirmed. Clinician survey responses resulted in a correct response rate of 70% for Lyme disease knowledge questions. Fewer than half of all clinicians were aware of the surveillance criteria for confirming Lyme disease cases. Neither medical specialty nor previous treatment of patients with Lyme disease were significantly associated with clinicians' knowledge of the disease. Clinicians in WV are familiar with symptoms and clinical management of Lyme disease. However, they are less knowledgeable about diagnosis and public health surveillance comprising reporting and confirming cases of the disease. Clinicians and public health authorities should collaborate more closely to promote education and awareness as a key step to successfully reducing the burden of Lymne disease.

[Treatment of Crohn's disease].

PubMed

Vavricka, St R; Rogler, G

2009-01-21

The therapy of Crohn's disease depends on its disease activity. For those different disease activities (such as flare, chronic active disease, remission) varying treatment concepts are followed. This overview presents important concepts in the treatment of Crohn's disease.

Hemoglobin C, S-C, and E Diseases

MedlinePlus

... quickly than others, resulting in chronic anemia. Hemoglobin C disease Hemoglobin C disease occurs mostly in blacks. ... a common complication of hemoglobin C disease. Hemoglobin S-C disease Hemoglobin S-C disease occurs in people who ...

21 CFR 101.77 - Health claims: fruits, vegetables, and grain products that contain fiber, particularly soluble...

Code of Federal Regulations, 2010 CFR

2010-04-01

... coronary heart disease. (1) Cardiovascular disease means diseases of the heart and circulatory system. Coronary heart disease is the most common and serious form of cardiovascular disease and refers to diseases... products that contain fiber, particularly soluble fiber, and risk of coronary heart disease. 101.77 Section...

Cerebral Small Vessel Disease and Chronic Kidney Disease

PubMed Central

2015-01-01

Chronic kidney disease, defined by a decreased glomerular filtration rate or albuminuria, is recognized as a major global health burden, mainly because it is an established risk factor for cardiovascular and cerebrovascular diseases. The magnitude of the effect of chronic kidney disease on incident stroke seems to be higher in persons of Asian ethnicity. Since the kidney and brain share unique susceptibilities to vascular injury due to similar anatomical and functional features of small artery diseases, kidney impairment can be predictive of the presence and severity of cerebral small vessel diseases. Chronic kidney disease has been reported to be associated with silent brain infarcts, cerebral white matter lesions, and cerebral microbleeds, independently of vascular risk factors. In addition, chronic kidney disease affects cognitive function, partly via the high prevalence of cerebral small vessel diseases. Retinal artery disease also has an independent relationship with chronic kidney disease and cognitive impairment. Stroke experts are no longer allowed to be ignorant of chronic kidney disease. Close liaison between neurologists and nephrologists can improve the management of cerebral small vessel diseases in kidney patients. PMID:25692105

Identifying patterns of immune-related disease: use in disease prevention and management.

PubMed

Dietert, Rodney R; Zelikoff, Judith T

2010-05-01

Childhood susceptibility to diseases linked with immune dysfunction affects over a quarter of the pediatric population in some countries. While this alone is a significant health issue, the actual impact of immune-related diseases extends over a lifetime and involves additional secondary conditions. Some comorbidities are well known (e.g., allergic rhinitis and asthma). However, no systematic approach has been used to identify life-long patterns of immune-based disease where the primary condition arises in childhood. Such information is useful for both disease prevention and treatment approaches. Recent primary research papers as well as review articles were obtained from PubMed, Chem Abstracts, Biosis and from the personal files of the authors. Search words used were: the diseases and conditions shown Figs. 1 and 2 in conjunction with comorbid, comorbidities, pediatric, childhood, adult, immune, immune dysfunction, allergy, autoimmune, inflammatory, infectious, health risks, environment, risk factors. Childhood diseases such as asthma, type-1 diabetes, inflammatory bowel disease, respiratory infections /rhinitis, recurrent otitis media, pediatric celiac, juvenile arthritis and Kawasaki disease are examples of significant childhood health problems where immune dysfunction plays a significant role. Each of these pediatric diseases is associated with increased risk of several secondary conditions, many of which appear only later in life. To illustrate, four prototypes of immune-related disease patterns (i.e., allergy, autoimmunity, inflammation and infectious disease) are shown as tools for: 1) enhanced disease prevention; 2) improved management of immune-based pediatric diseases; and 3) better recognition of underlying pediatric immune dysfunction. Identification of immune-related disease patterns beginning in childhood provides the framework for examining the underlying immune dysfunctions that can contribute to additional diseases in later life. Many pediatric diseases associated with dysfunctional immune responses have been linked with an elevated risk of other diseases or conditions as the child ages. Diseases within a pattern may be interlinked based on underlying immune dysfunctions and/or current therapeutic approaches for managing the entryway diseases. It may be beneficial to consider treatment options for the earliest presenting diseases that will concomitantly reduce the risk of immune-linked secondary conditions. Additionally, improved disease prevention is possible with more relevant and age-specific immune safety testing.

Insights from Genome-Wide Association Analyses of Nonalcoholic Fatty Liver Disease

PubMed Central

Kahali, Bratati; Halligan, Brian; Speliotes, Elizabeth K.

2016-01-01

Nonalcoholic fatty liver disease (NAFLD) is caused by hepatic steatosis, which can progress to nonalcoholic steatohepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma in the absence of excessive alcohol consumption. Nonalcoholic fatty liver disease will become the number one cause of liver disease worldwide by 2020. Nonalcoholic fatty liver disease is correlated albeit imperfectly with obesity and other metabolic diseases such as diabetes, hyperlipidemia, and cardiovascular disease, but exactly how having one of these diseases contributes to the development of other metabolic diseases is only now being elucidated. Development of NAFLD and related metabolic diseases is genetically influenced in the population, and recent genome-wide association studies (GWASs) have discovered genetic variants that associate with these diseases. These GWAS-associated variants cannot only help us to identify individuals at high risk of developing NAFLD, but also to better understand its pathophysiology so that we can develop more effective treatments for this disease and related metabolic diseases in the future. PMID:26676813

Gaucher Disease

MedlinePlus

... of the disease, but the procedure carries a high risk and is rarely performed in individuals with Gaucher disease. People with Gaucher disease type 1 are at increased risk for Parkinson's disease and Lewy Body Dementia. Gaucher disease type 2 is usually fatal ...

Matters of the heart: cardiovascular disease in U.S. women.

PubMed

Bybee, Kevin A; Stevens, Tracy L

2013-01-01

Cardiovascular disease is the leading cause of death in United States women and accounts for approximately 500,000 deaths annually. Over half of cardiovascular disease-related deaths in women result from coronary artery disease including acute coronary syndromes. This paper reviews gender specific issues in women as they relate to current cardiovascular disease epidemiology, trends in cardiovascular disease epidemiology, coronary artery disease detection, risk factor modification, and prevention of cardiovascular disease-related events.

Periodontal Disease and Systemic Diseases: An Update for the Clinician.

PubMed

John, Vanchit; Alqallaf, Hawra; De Bedout, Tatiana

2016-01-01

A link between periodontal disease and various systemic diseases has been investigated for several years. Interest in unearthing such a link has grown as the health care profession is looking for a better understanding of disease processes and their relationships to periodontal and other oral diseases. The article aims to provide recent information on the relationship between periodontal disease and systemic diseases such as; cardiovascular, respiratory, endocrine, musculoskeletal, and reproductive system related abnormalities.

Disease phobia and disease conviction are separate dimensions underlying hypochondriasis.

PubMed

Fergus, Thomas A; Valentiner, David P

2010-12-01

The current study uses data from a large nonclinical college student sample (N = 503) to examine a structural model of hypochondriasis (HC). This model predicts the distinctiveness of two dimensions (disease phobia and disease conviction) purported to underlie the disorder, and that these two dimensions are differentially related to variables important to health anxiety and somatoform disorders, respectively. Results were generally consistent with the hypothesized model. Specifically, (a) body perception variables (somatosensory amplification and anxiety sensitivity - physical) emerged as significant predictors of disease phobia, but not disease conviction; (b) emotion dysregulation variables (cognitive avoidance and cognitive reappraisal) emerged as significant predictors of disease conviction, but not disease phobia; and (c) both disease phobia and disease conviction independently predicted medical utilization. Further, collapsing disease phobia and disease conviction onto a single latent factor provided an inadequate fit to the data. Conceptual and therapeutic implications of these results are discussed. 2010 Elsevier Ltd. All rights reserved.

Insights into Mechanisms of Chronic Neurodegeneration

PubMed Central

Diack, Abigail B.; Alibhai, James D.; Barron, Rona; Bradford, Barry; Piccardo, Pedro; Manson, Jean C.

2016-01-01

Chronic neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and prion diseases are characterised by the accumulation of abnormal conformers of a host encoded protein in the central nervous system. The process leading to neurodegeneration is still poorly defined and thus development of early intervention strategies is challenging. Unique amongst these diseases are Transmissible Spongiform Encephalopathies (TSEs) or prion diseases, which have the ability to transmit between individuals. The infectious nature of these diseases has permitted in vivo and in vitro modelling of the time course of the disease process in a highly reproducible manner, thus early events can be defined. Recent evidence has demonstrated that the cell-to-cell spread of protein aggregates by a “prion-like mechanism” is common among the protein misfolding diseases. Thus, the TSE models may provide insights into disease mechanisms and testable hypotheses for disease intervention, applicable to a number of these chronic neurodegenerative diseases. PMID:26771599

Knowledge of Alzheimer's disease among Vietnamese Americans and correlates of their knowledge about Alzheimer's disease.

PubMed

Lee, Sang E; Casado, Banghwa Lee

2017-01-01

The present study examined the knowledge of Alzheimer's disease and correlates of the disease knowledge among Vietnamese Americans. Cross-sectional survey interviews were conducted with 95 middle-aged and older Vietnamese Americans. Vietnamese Americans showed limited knowledge about Alzheimer's disease. Normalization of Alzheimer's disease in old age was prevalent. They lacked knowledge about treatment and cure of Alzheimer's disease. Those who reside longer in the U.S. and are more exposed to Alzheimer's disease are likely to have higher levels of Alzheimer's disease knowledge. Our study identified current Alzheimer's disease knowledge level and status, and areas of misconceptions and knowledge gaps among Vietnamese Americans, calling for urgent needs for educational outreach to improve knowledge about Alzheimer's disease among Vietnamese Americans. Information about who can be more or less knowledgeable about Alzheimer's disease can be used to strategize and tailor outreach efforts for different segments of the Vietnamese American population.

TESTING PRACTICES AND VOLUME OF NON-LYME TICKBORNE DISEASES IN THE UNITED STATES

PubMed Central

Connally, Neeta P.; Hinckley, Alison F.; Feldman, Katherine A.; Kemperman, Melissa; Neitzel, David; Wee, Siok-Bi; White, Jennifer L.; Mead, Paul S.; Meek, James I.

2015-01-01

Large commercial laboratories in the United States were surveyed regarding the number of specimens tested for eight tickborne diseases in 2008. Seven large commercial laboratories reported testing a total of 2,927,881 specimens nationally (including Lyme disease). Of these, 495,585 specimens (17 percent) were tested for tickborne diseases other than Lyme disease. In addition to large commercial laboratories, another 1,051 smaller commercial, hospital, and government laboratories in four states (CT, MD, MN, and NY) were surveyed regarding tickborne disease testing frequency, practices, and results. Ninety-two of these reported testing a total of 10,091 specimens for four tickborne diseases other than Lyme disease. We estimate the cost of laboratory diagnostic testing for non-Lyme disease tickborne diseases in 2008 to be $9.6 million. These data provide a baseline to evaluate trends in tickborne disease test utilization and insight into the burden of these diseases. PMID:26565931

Defining the Role of Essential Genes in Human Disease

PubMed Central

Robertson, David L.; Hentges, Kathryn E.

2011-01-01

A greater understanding of the causes of human disease can come from identifying characteristics that are specific to disease genes. However, a full understanding of the contribution of essential genes to human disease is lacking, due to the premise that these genes tend to cause developmental abnormalities rather than adult disease. We tested the hypothesis that human orthologs of mouse essential genes are associated with a variety of human diseases, rather than only those related to miscarriage and birth defects. We segregated human disease genes according to whether the knockout phenotype of their mouse ortholog was lethal or viable, defining those with orthologs producing lethal knockouts as essential disease genes. We show that the human orthologs of mouse essential genes are associated with a wide spectrum of diseases affecting diverse physiological systems. Notably, human disease genes with essential mouse orthologs are over-represented among disease genes associated with cancer, suggesting links between adult cellular abnormalities and developmental functions. The proteins encoded by essential genes are highly connected in protein-protein interaction networks, which we find correlates with an over-representation of nuclear proteins amongst essential disease genes. Disease genes associated with essential orthologs also are more likely than those with non-essential orthologs to contribute to disease through an autosomal dominant inheritance pattern, suggesting that these diseases may actually result from semi-dominant mutant alleles. Overall, we have described attributes found in disease genes according to the essentiality status of their mouse orthologs. These findings demonstrate that disease genes do occupy highly connected positions in protein-protein interaction networks, and that due to the complexity of disease-associated alleles, essential genes cannot be ignored as candidates for causing diverse human diseases. PMID:22096564

The Converged Experience of Risk and Disease

PubMed Central

Aronowitz, Robert A

2009-01-01

Context: One underappreciated consequence of modern clinical and public health practices is that the experience of being at risk for disease has been converging with the experience of disease itself. This is especially true for certain chronic diseases, in which early diagnosis and aggressive treatment have led to symptom-less and sign-less disease and in which treatments have largely been aimed at altering the disease's future course. Methods: This article reviews the historical scholarship and medical literature pertinent to transformations in the chronic disease and risk experiences. Findings: The experience of chronic disease increasingly resembles or has become indistinguishable from risk because of (1) new clinical interventions that have directly changed the natural history of disease; (2) increased biological, clinical, and epidemiological knowledge about the risk of chronic disease; (3) the recruitment of larger numbers into chronic disease diagnoses via new screening and diagnostic technology and disease definitions; (4) new ways of conceptualizing efficacy; and (5) intense diagnostic testing and medical interventions. Conclusions: The converged experience of risk and disease has led to some unsettling and generally underappreciated consequences that might be subjected to more clinical and policy reflection and response: (1) some puzzling trends in medical decision making, such as the steep and uniform increase in the numbers of women across a broad spectrum of risk/disease in breast cancer who have opted for prophylactic mastectomies; (2) a larger and highly mobilized disease/risk population, resulting in an expanded market for interventions and greater clout for disease advocates; (3) shifts in the perceived severity of the disease, with ripple effects on how people experience and understand their illness and risk of disease; and (4) interventions that promise both to reduce the risk of disease and to treat its symptoms. PMID:19523124

Mining disease state converters for medical intervention of diseases.

PubMed

Dong, Guozhu; Duan, Lei; Tang, Changjie

2010-02-01

In applications such as gene therapy and drug design, a key goal is to convert the disease state of diseased objects from an undesirable state into a desirable one. Such conversions may be achieved by changing the values of some attributes of the objects. For example, in gene therapy one may convert cancerous cells to normal ones by changing some genes' expression level from low to high or from high to low. In this paper, we define the disease state conversion problem as the discovery of disease state converters; a disease state converter is a small set of attribute value changes that may change an object's disease state from undesirable into desirable. We consider two variants of this problem: personalized disease state converter mining mines disease state converters for a given individual patient with a given disease, and universal disease state converter mining mines disease state converters for all samples with a given disease. We propose a DSCMiner algorithm to discover small and highly effective disease state converters. Since real-life medical experiments on living diseased instances are expensive and time consuming, we use classifiers trained from the datasets of given diseases to evaluate the quality of discovered converter sets. The effectiveness of a disease state converter is measured by the percentage of objects that are successfully converted from undesirable state into desirable state as deemed by state-of-the-art classifiers. We use experiments to evaluate the effectiveness of our algorithm and to show its effectiveness. We also discuss possible research directions for extensions and improvements. We note that the disease state conversion problem also has applications in customer retention, criminal rehabilitation, and company turn-around, where the goal is to convert class membership of objects whose class is an undesirable class.

Effect of Benralizumab in Atopic Dermatitis

ClinicalTrials.gov

2018-06-22

Dermatitis, Atopic; Dermatitis; Eczema; Skin Diseases; Skin Diseases, Genetic; Genetic Diseases, Inborn; Skin Diseases, Eczematous; Hypersensitivity; Hypersensitivity, Immediate; Immune System Diseases

The behavioural/dysexecutive variant of Alzheimer’s disease: clinical, neuroimaging and pathological features

PubMed Central

Pijnenburg, Yolande A. L.; Perry, David C.; Cohn-Sheehy, Brendan I.; Scheltens, Nienke M. E.; Vogel, Jacob W.; Kramer, Joel H.; van der Vlies, Annelies E.; Joie, Renaud La; Rosen, Howard J.; van der Flier, Wiesje M.; Grinberg, Lea T.; Rozemuller, Annemieke J.; Huang, Eric J.; van Berckel, Bart N. M.; Miller, Bruce L.; Barkhof, Frederik; Jagust, William J.; Scheltens, Philip; Seeley, William W.; Rabinovici, Gil D.

2015-01-01

A ‘frontal variant of Alzheimer’s disease’ has been described in patients with predominant behavioural or dysexecutive deficits caused by Alzheimer’s disease pathology. The description of this rare Alzheimer’s disease phenotype has been limited to case reports and small series, and many clinical, neuroimaging and neuropathological characteristics are not well understood. In this retrospective study, we included 55 patients with Alzheimer’s disease with a behavioural-predominant presentation (behavioural Alzheimer’s disease) and a neuropathological diagnosis of high-likelihood Alzheimer’s disease (n = 17) and/or biomarker evidence of Alzheimer’s disease pathology (n = 44). In addition, we included 29 patients with autopsy/biomarker-defined Alzheimer’s disease with a dysexecutive-predominant syndrome (dysexecutive Alzheimer’s disease). We performed structured chart reviews to ascertain clinical features. First symptoms were more often cognitive (behavioural Alzheimer’s disease: 53%; dysexecutive Alzheimer’s disease: 83%) than behavioural (behavioural Alzheimer’s disease: 25%; dysexecutive Alzheimer’s disease: 3%). Apathy was the most common behavioural feature, while hyperorality and perseverative/compulsive behaviours were less prevalent. Fifty-two per cent of patients with behavioural Alzheimer’s disease met diagnostic criteria for possible behavioural-variant frontotemporal dementia. Overlap between behavioural and dysexecutive Alzheimer’s disease was modest (9/75 patients). Sixty per cent of patients with behavioural Alzheimer’s disease and 40% of those with the dysexecutive syndrome carried at least one APOE ε4 allele. We also compared neuropsychological test performance and brain atrophy (applying voxel-based morphometry) with matched autopsy/biomarker-defined typical (amnestic-predominant) Alzheimer’s disease (typical Alzheimer’s disease, n = 58), autopsy-confirmed/Alzheimer’s disease biomarker-negative behavioural variant frontotemporal dementia (n = 59), and controls (n = 61). Patients with behavioural Alzheimer’s disease showed worse memory scores than behavioural variant frontotemporal dementia and did not differ from typical Alzheimer’s disease, while executive function composite scores were lower compared to behavioural variant frontotemporal dementia and typical Alzheimer’s disease. Voxel-wise contrasts between behavioural and dysexecutive Alzheimer’s disease patients and controls revealed marked atrophy in bilateral temporoparietal regions and only limited atrophy in the frontal cortex. In direct comparison with behavioural and those with dysexecutive Alzheimer’s disease, patients with behavioural variant frontotemporal dementia showed more frontal atrophy and less posterior involvement, whereas patients with typical Alzheimer’s disease were slightly more affected posteriorly and showed less frontal atrophy (P < 0.001 uncorrected). Among 24 autopsied behavioural Alzheimer’s disease/dysexecutive Alzheimer’s disease patients, only two had primary co-morbid FTD-spectrum pathology (progressive supranuclear palsy). In conclusion, behavioural Alzheimer’s disease presentations are characterized by a milder and more restricted behavioural profile than in behavioural variant frontotemporal dementia, co-occurrence of memory dysfunction and high APOE ε4 prevalence. Dysexecutive Alzheimer’s disease presented as a primarily cognitive phenotype with minimal behavioural abnormalities and intermediate APOE ε4 prevalence. Both behavioural Alzheimer’s disease and dysexecutive Alzheimer’s disease presentations are distinguished by temporoparietal-predominant atrophy. Based on the relative sparing of frontal grey matter, we propose to redefine these clinical syndromes as ‘the behavioural/dysexecutive variant of Alzheimer’s disease’ rather than frontal variant Alzheimer’s disease. Further work is needed to determine whether behavioural and dysexecutive-predominant presentations of Alzheimer’s disease represent distinct phenotypes or a single continuum. PMID:26141491

Crohn Disease: Epidemiology, Diagnosis, and Management.

PubMed

Feuerstein, Joseph D; Cheifetz, Adam S

2017-07-01

Crohn disease is a chronic idiopathic inflammatory bowel disease condition characterized by skip lesions and transmural inflammation that can affect the entire gastrointestinal tract from the mouth to the anus. For this review article, we performed a review of articles in PubMed through February 1, 2017, by using the following Medical Subject Heading terms: crohns disease, crohn's disease, crohn disease, inflammatory bowel disease, and inflammatory bowel diseases. Presenting symptoms are often variable and may include diarrhea, abdominal pain, weight loss, nausea, vomiting, and in certain cases fevers or chills. There are 3 main disease phenotypes: inflammatory, structuring, and penetrating. In addition to the underlying disease phenotype, up to a third of patients will develop perianal involvement of their disease. In addition, in some cases, extraintestinal manifestations may develop. The diagnosis is typically made with endoscopic and/or radiologic findings. Disease management is usually with pharmacologic therapy, which is determined on the basis of disease severity and underlying disease phenotype. Although the goal of management is to control the inflammation and induce a clinical remission with pharmacologic therapy, most patients will eventually require surgery for their disease. Unfortunately, surgery is not curative and patients still require ongoing therapy even after surgery for disease recurrence. Importantly, given the risks of complications from both Crohn disease and the medications used to treat the disease process, primary care physicians play an important role in optimizing the preventative care management to reduce the risk of complications. Copyright © 2017 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

[Infectious diseases that people should be informed: a Delphi survey of clinicians engaged in practice of infectious diseases in Japan].

PubMed

Kashiwagi, Tomoko; Horiguchi, Itsuko; Ishikawa, Naoko; Marui, Eiji

2009-01-01

To identify specific infectious diseases about which the Japanese public should be informed. A Delphi survey was conducted, recruiting 26 physicians who are engaged in clinical practice of infectious diseases and working at designated medical institutions of infectious diseases in Japan. Following HIV/AIDS (first ranked), tuberculosis (second) and influenza (third), 24 diseases in total were identified based on "knowledge, awareness and behavior of inhabitants" or "social and clinico-epidemiological circumstances". Scores for the top three ranked diseases were more than two-folds of those for following diseases. Among the top 10 ranked diseases, 9 were in common with the previous survey result among public health physicians and veterinarians working for governmental agencies. Our findings of scores for specific diseases most likely reflect an importance of performing preventions and early diagnoses of severe diseases and promoting prophylaxis for travelers' diseases which tend to be factors for prioritizing infectious diseases among clinicians. The top-scored diseases among clinicians were consistent with those among public health officers, indicating the critical need to inform the public about these diseases. Nevertheless, both clinicians and public health experts have already attempted to promote preventions and/or treatment for these diseases in the previous time, and thus, the previous experience must be critically reviewed and reconsidered for improvements. In future, the similar surveys to ours should target specific subjects of experts and investigate more specific types of infectious diseases. Following such an expert survey, concrete action plans to inform the public about prioritized diseases are also called for.

Lysosomal storage diseases

PubMed Central

Ferreira, Carlos R.; Gahl, William A.

2016-01-01

Lysosomes are cytoplasmic organelles that contain a variety of different hydrolases. A genetic deficiency in the enzymatic activity of one of these hydrolases will lead to the accumulation of the material meant for lysosomal degradation. Examples include glycogen in the case of Pompe disease, glycosaminoglycans in the case of the mucopolysaccharidoses, glycoproteins in the cases of the oligosaccharidoses, and sphingolipids in the cases of Niemann-Pick disease types A and B, Gaucher disease, Tay-Sachs disease, Krabbe disease, and metachromatic leukodystrophy. Sometimes, the lysosomal storage can be caused not by the enzymatic deficiency of one of the hydrolases, but by the deficiency of an activator protein, as occurs in the AB variant of GM2 gangliosidosis. Still other times, the accumulated lysosomal material results from failed egress of a small molecule as a consequence of a deficient transporter, as in cystinosis or Salla disease. In the last couple of decades, enzyme replacement therapy has become available for a number of lysosomal storage diseases. Examples include imiglucerase, taliglucerase and velaglucerase for Gaucher disease, laronidase for Hurler disease, idursulfase for Hunter disease, elosulfase for Morquio disease, galsulfase for Maroteaux-Lamy disease, alglucosidase alfa for Pompe disease, and agalsidase alfa and beta for Fabry disease. In addition, substrate reduction therapy has been approved for certain disorders, such as eliglustat for Gaucher disease. The advent of treatment options for some of these disorders has led to newborn screening pilot studies, and ultimately to the addition of Pompe disease and Hurler disease to the Recommended Uniform Screening Panel (RUSP) in 2015 and 2016, respectively. PMID:29152458

21 CFR 101.75 - Health claims: dietary saturated fat and cholesterol and risk of coronary heart disease.

Code of Federal Regulations, 2010 CFR

2010-04-01

... of coronary heart disease. (1) Cardiovascular disease means diseases of the heart and circulatory system. Coronary heart disease is the most common and serious form of cardiovascular disease and refers... cholesterol and risk of coronary heart disease. 101.75 Section 101.75 Food and Drugs FOOD AND DRUG...

21 CFR 101.83 - Health claims: plant sterol/stanol esters and risk of coronary heart disease (CHD).

Code of Federal Regulations, 2010 CFR

2010-04-01

.... (1) Cardiovascular disease means diseases of the heart and circulatory system. Coronary heart disease (CHD) is one of the most common and serious forms of cardiovascular disease and refers to diseases of... of coronary heart disease (CHD). 101.83 Section 101.83 Food and Drugs FOOD AND DRUG ADMINISTRATION...

Coats' disease, Turner syndrome, and von Willebrand disease in a patient with Wildtype Norrie disease pseudoglioma.

PubMed

Desai, Rajen U; Saffra, Norman A; Krishna, Rati P; Rosenberg, Steven E

2011-01-01

The authors describe a girl diagnosed as having Coats' disease, Turner syndrome (45X karyotype), and type 1 von Willebrand disease. She tested negative for the Norrie disease pseudoglioma (NDP) gene located on the X-chromosome, which has been suspected of contributing to Coats' disease. Copyright 2010, SLACK Incorporated.

Hospital readmissions with acute infectious diseases in New Zealand children < 2 years of age.

PubMed

Seibt, Silvia; Gilchrist, Catherine A; Reed, Peter W; Best, Emma J; Harnden, Anthony; Camargo, Carlos A; Grant, Cameron C

2018-03-05

Infectious diseases are the leading cause of hospital admissions in young children. Hospitalisation with an infectious disease is a recurrent event for some children. Our objective was to describe risk factors for infectious disease readmission following hospital admission with an infectious disease in the first two years of life. We performed a national cohort study of New Zealand children, born 2005-2009, with an infectious disease admission before age 24 months. Children readmitted with an infectious disease within 12 months of the first infectious disease admission were identified. Every infectious disease admission was categorised as a respiratory, enteric, skin and soft tissue, urinary or other infection. Independent associations of demographic and child health factors with infectious disease readmission were determined using multiple variable logistic regression. From 2005 to 2011, there were 69,902 infectious disease admissions for 46,657 children less than two years old. Of these 46,657 children, 10,205 (22%) had at least one infectious disease readmission within 12 months of their first admission. The first infectious disease admission was respiratory (54%), enteric (15%), skin or soft tissue (7%), urinary (4%) or other (20%). Risk of infectious disease readmission was increased if the first infectious disease admission was respiratory (OR = 1.87, 95% CI 1.78-1.95) but not if it was in any other infectious disease category. Risk factors for respiratory infectious disease readmission were male gender, Pacific or Māori ethnicity, greater household deprivation, presence of a complex chronic condition, or a first respiratory infectious disease admission during autumn or of ≥3 days duration. Fewer factors (younger age, male gender, presence of a complex chronic condition) were associated with enteric infection readmission. The presence of a complex chronic condition was the only factor associated with urinary tract infection readmission and none of the factors were associated with skin or soft tissue infection readmission. In children less than two years old, infectious disease readmission risk is increased if the first infectious disease admission is a respiratory infectious disease but not if it is another infectious disease category. Risk factors for respiratory infectious disease readmission are different from those for other infectious disease readmissions.

Chagas disease and systemic autoimmune diseases among Bolivian patients in Switzerland

PubMed Central

Jackson, Yves; Pula, Drenusha Vieira de Mello; Finckh, Axel; Chizzolini, Carlo; Chappuis, François

2018-01-01

BACKGROUND Chronic cardiomyopathy occurs in 20-40% of the patients with Chagas disease. Autoimmune mechanisms may contribute to its pathogenesis. We diagnosed several cases of systemic autoimmune diseases among Bolivian migrants in Geneva with a high prevalence of Chagas disease. OBJECTIVES We tested the hypothesis of a clinical association between systemic autoimmune diseases and Chagas disease, particularly with the development of cardiomyopathy. METHODS We retrospectively searched the medical records of all Bolivian patients visiting Geneva University Hospitals between 2012 and 2015 for diagnosis of Chagas disease or systemic autoimmune diseases. FINDINGS Of the 2,189 eligible patients, 28 [1.3%; 95% confidence interval (CI) = 0.9-1.9%] presented with systemic autoimmune disease. The Chagas status was known in 903 (41.3%) patient, of whom 244 (27.0%; 95% CI = 24.2-30.0%) were positive. Eight (28.6%; 95% CI = 15.3-47.1%) of the 28 cases of systemic autoimmune disease had Chagas disease. We found no association between both entities (p = 1.000) or with Chagasic cardiomyopathy (p = 0.729). Moreover, there was no evidence of a temporal relationship between antiparasitic chemotherapy and the development of systemic autoimmune diseases. CONCLUSIONS Our results do not support a clinical association between chronic Chagas disease and systemic autoimmune diseases. However, prospective studies in areas endemic for Chagas disease should better assess the prevalence of systemic autoimmune diseases and thus a possible relationship with this infection. PMID:29412344

BioM2MetDisease: a manually curated database for associations between microRNAs, metabolites, small molecules and metabolic diseases

PubMed Central

Xu, Yanjun; Yang, Haixiu; Wu, Tan; Dong, Qun; Sun, Zeguo; Shang, Desi; Li, Feng; Xu, Yingqi; Su, Fei; Liu, Siyao

2017-01-01

Abstract BioM2MetDisease is a manually curated database that aims to provide a comprehensive and experimentally supported resource of associations between metabolic diseases and various biomolecules. Recently, metabolic diseases such as diabetes have become one of the leading threats to people’s health. Metabolic disease associated with alterations of multiple types of biomolecules such as miRNAs and metabolites. An integrated and high-quality data source that collection of metabolic disease associated biomolecules is essential for exploring the underlying molecular mechanisms and discovering novel therapeutics. Here, we developed the BioM2MetDisease database, which currently documents 2681 entries of relationships between 1147 biomolecules (miRNAs, metabolites and small molecules/drugs) and 78 metabolic diseases across 14 species. Each entry includes biomolecule category, species, biomolecule name, disease name, dysregulation pattern, experimental technique, a brief description of metabolic disease-biomolecule relationships, the reference, additional annotation information etc. BioM2MetDisease provides a user-friendly interface to explore and retrieve all data conveniently. A submission page was also offered for researchers to submit new associations between biomolecules and metabolic diseases. BioM2MetDisease provides a comprehensive resource for studying biology molecules act in metabolic diseases, and it is helpful for understanding the molecular mechanisms and developing novel therapeutics for metabolic diseases. Database URL: http://www.bio-bigdata.com/BioM2MetDisease/ PMID:28605773

BioM2MetDisease: a manually curated database for associations between microRNAs, metabolites, small molecules and metabolic diseases.

PubMed

Xu, Yanjun; Yang, Haixiu; Wu, Tan; Dong, Qun; Sun, Zeguo; Shang, Desi; Li, Feng; Xu, Yingqi; Su, Fei; Liu, Siyao; Zhang, Yunpeng; Li, Xia

2017-01-01

BioM2MetDisease is a manually curated database that aims to provide a comprehensive and experimentally supported resource of associations between metabolic diseases and various biomolecules. Recently, metabolic diseases such as diabetes have become one of the leading threats to people’s health. Metabolic disease associated with alterations of multiple types of biomolecules such as miRNAs and metabolites. An integrated and high-quality data source that collection of metabolic disease associated biomolecules is essential for exploring the underlying molecular mechanisms and discovering novel therapeutics. Here, we developed the BioM2MetDisease database, which currently documents 2681 entries of relationships between 1147 biomolecules (miRNAs, metabolites and small molecules/drugs) and 78 metabolic diseases across 14 species. Each entry includes biomolecule category, species, biomolecule name, disease name, dysregulation pattern, experimental technique, a brief description of metabolic disease-biomolecule relationships, the reference, additional annotation information etc. BioM2MetDisease provides a user-friendly interface to explore and retrieve all data conveniently. A submission page was also offered for researchers to submit new associations between biomolecules and metabolic diseases. BioM2MetDisease provides a comprehensive resource for studying biology molecules act in metabolic diseases, and it is helpful for understanding the molecular mechanisms and developing novel therapeutics for metabolic diseases. http://www.bio-bigdata.com/BioM2MetDisease/. © The Author(s) 2017. Published by Oxford University Press.

[Raise awareness of IgG4 relative ocular disease].

PubMed

Wei, Shihui; Li, Hongyang

2015-12-01

Purpose IgG4-related ocular disease is a chronic systemic disease with lymphocyte abnormal. The lacrimal glands, extraocular muscles and infraorbital nerve were often involved which was often the first symptom of systemic disease. While ophthalmologists did not know this disease well. They usually misdiagnosed it as idiopathic inflammatory pseudotumor, thyroid-associated ophthalmopathy etc, which resulted in delayed treatments. Here pathogenesis, clinical features and treatment methods of IgG4-relative ocular disease were described in order to improve awareness of this ocular disease, reduce clinical misdiagnosis, improve disease prognosis and standardized treatment. As the incidence of this disease increased in recent years, it is very necessary to improve awareness of the disease for ophthalmologists.

Chad: An Overview of a Country Plagued with Internal Strife and Regional Conflict

DTIC Science & Technology

2012-04-09

est.) Major infectious diseases degree of risk: very high food or waterborne diseases: bacterial and protozoal diarrhea, hepatitis A, and typhoid ... fever vectorborne disease: malaria water contact disease: schistosomiasis respiratory disease: meningococcal meningitis animal contact disease

Von Hippel-Lindau Disease

MedlinePlus

What is Von Hippel-Lindau disease (VHL)? Von Hippel-Lindau disease (VHL) is a rare disease that causes tumors and cysts to grow in your body. They ... can become cancerous. What causes Von Hippel-Lindau disease (VHL)? Von Hippel-Lindau disease (VHL) is a ...

Heart Disease, Stroke, or Other Cardiovascular Disease and Adult Vaccination

MedlinePlus

... Adult Diseases Resources Heart Disease, Stroke, or Other Cardiovascular Disease and Adult Vaccination Language: English (US) Español (Spanish) ... important step in staying healthy. If you have cardiovascular disease, talk with your doctor about getting your vaccinations ...

Evaluation of Ocoxin-Viusid® in Advanced or Metastatic Ovarian Epithelial Cancer

ClinicalTrials.gov

2018-06-08

Carcinoma; Ovarian Neoplasm; Endocrine Gland Neoplasm; Urogenital Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Endocrine System Diseases; Gonadal Disorders; Genital Neoplasm, Female; Neoplasms, Glandular and Epithelial

Tick-borne Diseases: The Big Two | NIH MedlinePlus the Magazine

MedlinePlus

... been a tick bite. Photo: CDC/James Gathany Lyme disease Lyme disease is the most common tick-borne disease in ... nervous system can develop in patients with late Lyme disease. Lyme disease has different stages. The rash is ...

[Neurological complications of inflammatory bowel diseases].

PubMed

Cieplik, N; Stangel, M; Bachmann, O

2013-02-01

Inflammatory bowel diseases, such as Crohn's disease, ulcerative colitis, autoantibody driven celiac disease and infectious Whipple's disease can all be associated with neurological symptoms. The neurological manifestation may occur even before the gastrointestinal symptoms or the enteropathic symptoms can even be absent as in celiac disease. These diseases can be caused by malresorption and lack of vitamins due to enteral inflammation as well as (auto-)immunological mechanisms and drug-associated side effects. Thus, inflammatory bowel diseases have to be considered in the differential diagnosis. In this review the most common neurological manifestations of these diseases will be described as well as the diagnostic approach.

The Disease Portals, disease-gene annotation and the RGD disease ontology at the Rat Genome Database.

PubMed

Hayman, G Thomas; Laulederkind, Stanley J F; Smith, Jennifer R; Wang, Shur-Jen; Petri, Victoria; Nigam, Rajni; Tutaj, Marek; De Pons, Jeff; Dwinell, Melinda R; Shimoyama, Mary

2016-01-01

The Rat Genome Database (RGD;http://rgd.mcw.edu/) provides critical datasets and software tools to a diverse community of rat and non-rat researchers worldwide. To meet the needs of the many users whose research is disease oriented, RGD has created a series of Disease Portals and has prioritized its curation efforts on the datasets important to understanding the mechanisms of various diseases. Gene-disease relationships for three species, rat, human and mouse, are annotated to capture biomarkers, genetic associations, molecular mechanisms and therapeutic targets. To generate gene-disease annotations more effectively and in greater detail, RGD initially adopted the MEDIC disease vocabulary from the Comparative Toxicogenomics Database and adapted it for use by expanding this framework with the addition of over 1000 terms to create the RGD Disease Ontology (RDO). The RDO provides the foundation for, at present, 10 comprehensive disease area-related dataset and analysis platforms at RGD, the Disease Portals. Two major disease areas are the focus of data acquisition and curation efforts each year, leading to the release of the related Disease Portals. Collaborative efforts to realize a more robust disease ontology are underway. Database URL:http://rgd.mcw.edu. © The Author(s) 2016. Published by Oxford University Press.

Spectrum of disease outcomes in mice infected with YFV-17D

PubMed Central

Erickson, Andrea K.

2015-01-01

The host and viral factors that influence disease outcome during flavivirus infections are not fully understood. Using the live attenuated yellow fever virus (YFV) vaccine strain 17D as a model system we evaluated how viral dose, inoculation route and immunopathogenesis contributed to disease outcome in mice deficient in the type I IFN response. We found that YFV-17D infection of IFN-α/β receptor knockout mice resulted in three distinct disease outcomes: no clinical signs of disease, fatal viscerotropic disease or fatal neurotropic disease. Interestingly, viral load at disease onset did not correlate with disease outcome. However, we found increased immune infiltrates in the brain tissues of mice that developed neurotropic disease. Additionally, mice that developed viscerotropic disease, as characterized by liver and spleen pathology and/or intestinal haemorrhage, had significantly elevated levels of alanine aminotransferase, monocyte chemotactic protein and IFN-inducible protein (IP)-10 as compared with mice with no clinical signs of disease or neurotropic disease. Furthermore, mice treated with recombinant IP-10 throughout YFV-17D infection showed increased mortality and an increased percentage of mice with viscerotropic disease. Our results demonstrated that viral load did not correlate with pathogenesis, and the host immune response played a pivotal role in disease outcome and contributed to YFV-17D pathogenesis in mice. PMID:25646269

Assessing the Effects of Disease and Bleaching on Florida ...

EPA Pesticide Factsheets

Coral diseases have increased in frequency over the past few decades and have important influences on the structure and composition of coral reef communities. However, there is limited information on the etiologies of many coral diseases, and pathways via which coral diseases are acquired and transmitted are still in question. Furthermore, it is difficult to assess the impacts of disease on coral populations because outbreaks often co-occur with temperature-induced bleaching and anthropogenic stressors. We developed spatially-explicit population models of coral disease and bleaching dynamics to quantify the impact of six common diseases on Florida Keys corals, including aspergillosis, dark spots, white band, white plague, white patch, and yellow band. Models were fit to an 8-year data set of coral abundance, disease prevalence, and bleaching prevalence. Model selection was used to assess alternative pathways for disease transmission, and the influence of environmental stressors, including sea temperature and human population density, on disease prevalence and coral mortality. Classic disease transmission from contagious to susceptible colonies provided the best model only for aspergillosis. For other diseases, direct transmission from the external environment provided the best fit to observed data. Estimates of disease reproductive ratio values (R0) were less than one for each disease, indicating coral colonies were below densities required for diseases

Spectrum of disease outcomes in mice infected with YFV-17D.

PubMed

Erickson, Andrea K; Pfeiffer, Julie K

2015-06-01

The host and viral factors that influence disease outcome during flavivirus infections are not fully understood. Using the live attenuated yellow fever virus (YFV) vaccine strain 17D as a model system we evaluated how viral dose, inoculation route and immunopathogenesis contributed to disease outcome in mice deficient in the type I IFN response. We found that YFV-17D infection of IFN-α/β receptor knockout mice resulted in three distinct disease outcomes: no clinical signs of disease, fatal viscerotropic disease or fatal neurotropic disease. Interestingly, viral load at disease onset did not correlate with disease outcome. However, we found increased immune infiltrates in the brain tissues of mice that developed neurotropic disease. Additionally, mice that developed viscerotropic disease, as characterized by liver and spleen pathology and/or intestinal haemorrhage, had significantly elevated levels of alanine aminotransferase, monocyte chemotactic protein and IFN-inducible protein (IP)-10 as compared with mice with no clinical signs of disease or neurotropic disease. Furthermore, mice treated with recombinant IP-10 throughout YFV-17D infection showed increased mortality and an increased percentage of mice with viscerotropic disease. Our results demonstrated that viral load did not correlate with pathogenesis, and the host immune response played a pivotal role in disease outcome and contributed to YFV-17D pathogenesis in mice. © 2015 The Authors.

The Role of Reactive Oxygen Species in the Pathogenesis of Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease: A Mini Review

PubMed Central

Abiramasundari, Rajagopal Selladurai; Essa, Musthafa Mohamed; Akbar, Mohammed D.

2016-01-01

Neurodegenerative diseases affect not only the life quality of aging populations, but also their life spans. All forms of neurodegenerative diseases have a massive impact on the elderly. The major threat of these brain diseases includes progressive loss of memory, Alzheimer's disease (AD), impairments in the movement, Parkinson's disease (PD), and the inability to walk, talk, and think, Huntington's disease (HD). Oxidative stress and mitochondrial dysfunction are highlighted as a central feature of brain degenerative diseases. Oxidative stress, a condition that occurs due to imbalance in oxidant and antioxidant status, has been known to play a vital role in the pathophysiology of neurodegenerative diseases including AD, PD, and HD. A large number of studies have utilized oxidative stress biomarkers to investigate the severity of these neurodegenerative diseases and medications are available, but these only treat the symptoms. In traditional medicine, a large number of medicinal plants have been used to treat the symptoms of these neurodegenerative diseases. Extensive studies scientifically validated the beneficial effect of natural products against neurodegenerative diseases using suitable animal models. This short review focuses the role of oxidative stress in the pathogenesis of AD, PD, and HD and the protective efficacy of natural products against these diseases. PMID:28116038

[Analysis on death causes of residents in Anhui province, 2013].

PubMed

He, Qin; Chen, Yeji; Dai, Dan; Xu, Wei; Xing, Xiuya; Liu, Zhirong

2015-09-01

To analyze the demographic characteristics and the death causes of the residents in Anhui province, and provide evidence for the disease prevention and control. Using descriptive epidemiological analysis, the demographic characteristics and death data of the national disease surveillance points (DSPs) in Anhui province in 2013 were analyed by areas. The aging of the population was observed in all the areas in Anhui, which was most obvious in Jianghuai, followed by Wannan and Huaibei. The overall mortality was 627.10/100 000. The mortalities of diseases varied with sex, area and age. Among the 3 areas, the overall mortality, chronic disease mortality and injury mortality were highest in Huaibei and lowest in Wannan. The area specific difference in mortality of infectious diseases was small. Regardless of areas or the types of diseases, the mortality was higher in males than in females. Deaths caused by diseases with unknown origins were common in residents aged >65 years. The mortality of chronic diseases was higher in residents aged >45 years, especially in those aged 65-84 years. The mortality of injuries was higher in age groups >15 years and >45 years. The mortality of infectious diseases peaked at both young age group and old age group. The top five death causes were cerebrovascular diseases, malignant tumors, heart diseases, respiratory diseases and injuries. Regardless of sex or area, the major death causes were similar, but the ranks were slightly different. The major death causes varied in different age groups, but they were similar in same age group in different areas. The major death causes were diseases originated in perinatal period, and congenital malformations, deformations and chromosomal abnormalities in children aged <1 year. The major death causes in children aged 1-14 years were injuries, diseases originated in perinatal period, congenital malformations, deformations and chromosomal abnormalities. Injuries and malignant tumors were the first and second death causes in residents aged 15-44 years. Malignant tumors, injuries, cerebrovascular diseases and heart diseases were the major death causes in residents aged 45-64 years. The major death causes were cerebrovascular diseases, malignant tumors, heart diseases and respiratory diseases in residents aged 65-84 years and heart diseases, cerebrovascular diseases, respiratory diseases and malign tumors in residents aged≥85 years. The major death causes in residents in Anhui province were cerebrovascular diseases, malignant tumors and injuries. Close attention should be paid to the prevention and control of cerebrovascular diseases, malignant tumors and heart diseases in age group≥45 years. It is necessary to strengthen the prevention and control of injuries in age group 15-44 years. Huaibei is a key area of disease prevention and control in Anhui, especially chronic disease and injury preventions.

Evaluation of Ocoxin®-Viusid® in Metastatic Colorectal Adenocarcinoma

ClinicalTrials.gov

2018-06-15

Colorectal Neoplasm; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasm; Rectal Diseases; Colonic Diseases; Intestinal Disease; Gastrointestinal Disease; Digestive System Disease

Evaluation of Parkinson disease and Alzheimer disease with the use of neuromelanin MR imaging and (123)I-metaiodobenzylguanidine scintigraphy.

PubMed

Miyoshi, F; Ogawa, T; Kitao, S-i; Kitayama, M; Shinohara, Y; Takasugi, M; Fujii, S; Kaminou, T

2013-01-01

Progressive changes in the substantia nigra pars compacta and locus ceruleus of patients with Parkinson disease and Alzheimer disease visualized by neuromelanin MRI and cardiac postganglionic sympathetic nerve function on (123)I-metaiodobenzylguanidine scintigraphy have not been fully evaluated. We compared the diagnostic value of these modalities among patients with early Parkinson disease, late Parkinson disease, and Alzheimer disease. We compared contrast ratios of signal intensity in medial and lateral regions of the substantia nigra pars compacta and locus ceruleus with those of the tegmentum of the midbrain and the pons, respectively, by use of neuromelanin MRI in patients with early Parkinson disease (n = 13), late Parkinson disease (n = 31), Alzheimer disease (n = 6), and age-matched healthy control subjects (n = 20). We calculated heart-to-mediastinum ratios on (123)I-metaiodobenzylguanidine scintigrams after setting regions of interest on the left cardiac ventricle and upper mediastinum. The signal intensity of the lateral substantia nigra pars compacta on neuromelanin MRI was significantly reduced in early and late Parkinson disease, and that of the medial substantia nigra pars compacta was gradually and stage-dependently reduced in Parkinson disease. The signal intensity of the locus ceruleus was obviously reduced in late Parkinson disease. Signal reduction was not significant in the substantia nigra pars compacta and locus ceruleus of patients with Alzheimer disease. The heart-to-mediastinum ratio on (123)I-metaiodobenzylguanidine scintigrams was stage-dependently reduced in Parkinson disease and normal in Alzheimer disease. The signal intensity ratios in substantia nigra pars compacta and locus ceruleus on neuromelanin MRI positively correlated with the heart-to-mediastinum ratio on (123)I-metaiodobenzylguanidine scintigrams. Both neuromelanin MRI and (123)I-metaiodobenzylguanidine scintigraphy can help to evaluate disease progression in Parkinson disease and are useful for differentiating Parkinson disease from Alzheimer disease.

Clinical Investigation Program

DTIC Science & Technology

1992-10-01

Tick-Borne Disease Surveillance in Febrile, Hospitalized Patients KEYWORDS: tick-borne disease, Lyme disease, Rocky Mountain Spotted Fever PRINCIPAL...tick-borne diseases such as Lyme disease, Ehrlichiosis, Q fever, and Rocky Mountain Spotted Fever in the patients admitted to Womack Army Medical...several common tick-borne diseases such as Lyme disease, ehrlichiosis, Q fever, and Rocky Mountain Spotted Fever (RMSF) in a non-active duty military

Gut microbiota and liver diseases

PubMed Central

Minemura, Masami; Shimizu, Yukihiro

2015-01-01

Several studies revealed that gut microbiota are associated with various human diseases, e.g., metabolic diseases, allergies, gastroenterological diseases, and liver diseases. The liver can be greatly affected by changes in gut microbiota due to the entry of gut bacteria or their metabolites into the liver through the portal vein, and the liver-gut axis is important to understand the pathophysiology of several liver diseases, especially non-alcoholic fatty liver disease and hepatic encephalopathy. Moreover, gut microbiota play a significant role in the development of alcoholic liver disease and hepatocarcinogenesis. Based on these previous findings, trials using probiotics have been performed for the prevention or treatment of liver diseases. In this review, we summarize the current understanding of the changes in gut microbiota associated with various liver diseases, and we describe the therapeutic trials of probiotics for those diseases. PMID:25684933

Are diseases increasing in the ocean?

USGS Publications Warehouse

Lafferty, Kevin D.; Porter, James W.; Ford, Susan E.

2004-01-01

Many factors (climate warming, pollution, harvesting, introduced species) can contribute to disease outbreaks in marine life. Concomitant increases in each of these makes it difficult to attribute recent changes in disease occurrence or severity to any one factor. For example, the increase in disease of Caribbean coral is postulated to be a result of climate change and introduction of terrestrial pathogens. Indirect evidence exists that (a) warming increased disease in turtles; (b) protection, pollution, and terrestrial pathogens increased mammal disease; (c) aquaculture increased disease in mollusks; and (d) release from overfished predators increased sea urchin disease. In contrast, fishing and pollution may have reduced disease in fishes. In other taxa (e.g., sea grasses, crustaceans, sharks), there is little evidence that disease has changed over time. The diversity of patterns suggests there are many ways that environmental change can interact with disease in the ocean.

Mammary and extramammary Paget's disease

PubMed Central

Lloyd, J; Flanagan, A

2000-01-01

Mammary and extramammary Paget's disease are uncommon intraepithelial adenocarcinomas. Both conditions have similar clinical features, which mimic inflammatory and infective diseases. Histological diagnostic confusion can arise between Paget's disease and other neoplastic conditions affecting the skin, with the most common differential diagnoses being malignant melanoma and atypical squamous disease. The glandular differentiation of both mammary Paget's disease and extramammary Paget's disease is indicated by morphological appearances, the presence of intracellular mucin in many cases, and positive immunohistochemical staining for glandular cytokeratins, epithelial membrane antigen, and carcinoembryonic antigen. This article provides an overview of mammary and extramammary Paget's disease and discusses recent evidence regarding the cell of origin. The concepts of primary and secondary Paget's disease are presented and the differential diagnosis is discussed with reference to immunohistochemical markers that might be of diagnostic value. Key Words: mammary Paget's disease • extramammary Paget's disease PMID:11064666

77 FR 32975 - AHRQ Workgroups on ICD-10-CM/PCS Conversion of Quality Indicators (QIs)

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-04

... relevant clinical expertise (e.g., cardiovascular disease, neurologic disease, orthopedic and musculoskeletal disease, obstetrics and gynecologic disease, surgery, critical care and pulmonary disease... measurement using administrative data in specific, relevant clinical domains (e.g., cardiovascular disease...

Translations on USSR Science and Technology, Biomedical Sciences, No. 13

DTIC Science & Technology

1977-10-31

Diseases of female genital organs Diseases of urogenital organs Diseases of veins Diseases of skin and subcutaneous tissues Lumbosacral radiculitis ...the diseases of urogenital organs, lumbosacral radiculitis , diseases of the skin and subcutaneous cel- lular tissue, and tumors. This difference in

Functional genomics approaches to neurodegenerative diseases.

PubMed

Rubinsztein, David C

2008-09-01

Many of the neurodegenerative diseases that afflict humans are characterised by the protein aggregation in neurons. These include complex diseases like Alzheimer's disease and Parkinson's disease, and Mendelian diseases caused by polyglutamine expansion mutations [like Huntington's disease (HD) and various spinocerebellar ataxias (SCAs), like SCA3]. A range of functional genomic strategies have been used to try to elucidate pathways involved in these diseases. In this minireview, I focus on how modifier screens in organisms from yeast to mice may be of value in helping to elucidate pathogenic pathways.

[Inpatients days in patients with respiratory diseases and periodontal disease].

PubMed

Fernández-Plata, Rosario; Olmedo-Torres, Daniel; Martínez-Briseño, David; González-Cruz, Herminia; Casa-Medina, Guillermo; García-Sancho, Cecilia

2017-01-01

Periodontal disease is a chronic inflammatory gingival process that has been associated with the severity of respiratory diseases. In Mexico a prevalence of 78% was found in population with social security and > 60 years old. The aim of this study is to establish the association between periodontal disease and respiratory diseases according to the inpatient days. A cross-sectional study was conducted from January to December 2011. We included hospitalized patients, ≥ 18 years of age, without sedation or intubated. A dentist classified patients into two groups according to the severity of the periodontal disease: mild-to-moderate and severe. We estimated medians of inpatient days by disease and severity. Negative binomial models were adjusted to estimate incidence rate ratios and predicted inpatient days. 3,059 patients were enrolled. The median of observed and predicted inpatient days was higher in the group of severe periodontal disease (p < 0.05). Patients with chronic obstructive pulmonary disease, tuberculosis, and influenza had the highest incidence rates ratios of periodontal disease (p < 0.05). The severity of periodontal disease is positively -associated with inpatient days of patients with respiratory diseases.

Epidemiology of peptic ulcer disease in Wuhan area of China from 1997 to 2002

PubMed Central

Dong, Wei-Guo; Cheng, Chun-Sheng; Liu, Shao-Ping; Yu, Jie-Ping

2004-01-01

AIM: To describe the epidemiological features of peptic ulcer disease in Wuhan area during 1997-2002, to analyze the sex, age and occupation characteristics, as well as the geographic distribution of peptic ulcer disease, and to determine the effective methods of preventing and controlling peptic ulcer disease. METHODS: In the early 1980s, the peptic ulcer disease registry system was established to collect the data of peptic ulcer disease in Wuhan area. Here we performed a statistically detailed analysis of 4876 cases of peptic ulcer disease during 1997-2002. RESULTS: The morbidity of peptic ulcer disease between males and females was significantly different (χ2 = 337.9, P < 0.001). The majority of peptic ulcer diseases were found at the age of 20 to 50 years. Because of different occupations, the incidence of peptic ulcer disease was different in different areas. CONCLUSION: The incidence of peptic ulcer disease is highly associated with sex, age, occupation and geographic environmental factors. By analyzing the epidemiological features of peptic ulcer disease, we can provide the scientific data for prevention and control of peptic ulcer disease. PMID:15484323

Link Between Celiac Disease and Inflammatory Bowel Disease.

PubMed

Shah, Ayesha; Walker, Marjorie; Burger, Daniel; Martin, Neal; von Wulffen, Moritz; Koloski, Natasha; Jones, Mike; Talley, Nicholas J; Holtmann, Gerald J

2018-05-14

The aim of this analysis was to assess in patients with inflammatory bowel disease (IBD) the risk of celiac disease and in celiac disease patients the risk of IBD. Previous studies report a possible association between IBD and celiac disease; however, this link is controversial. Using the search terms "inflammatory bowel disease" and "celiac disease," we identified initially 1525 publications. In total 27 studies met inclusion criteria. Proportions and 95% confidence intervals (CIs) for the prevalence of IBD in celiac disease and vice versa were compared with published prevalence rates for the respective geographic regions. We included 41,482 adult IBD patients (20,357 with Crohn's disease; 19,791 with ulcerative colitis; and 459 patients with celiac disease). Overall, in IBD patients the prevalence of celiac disease was 1110/100,000 (95% CI, 1010-1210/100,000) as compared with a prevalence of 620/100,000 (95% CI, 610-630/100,000) in the respective populations (odds ratio, 2.23; 95% CI, 1.99-2.50). In contrast, in patients with celiac disease, 2130/100,000 had IBD (95% CI, 1590-2670/100,000) as compared with 260/100,000 (95% CI, 250/100,000-270/100,000) in the respective populations (odds ratio, 11.10; 95% CI, 8.55-14.40). This effect was not different for ulcerative colitis and Crohn's disease. Although there was no evidence for publication bias for celiac disease in IBD, the funnel plot suggested that the association between IBD in celiac disease might be influenced by publication bias. The data are consistent with the notion that celiac disease is a risk factor for IBD and to lesser degree patients with IBD have an increased risk of celiac disease.

Chronic comorbidity in patients with early rheumatoid arthritis: a descriptive study.

PubMed

Kroot, E J; van Gestel, A M; Swinkels, H L; Albers, M M; van de Putte, L B; van Riel, P L

2001-07-01

To study the presence of chronic coexisting diseases in patients with rheumatoid arthritis (RA) and its effect on RA treatment, disease course, and outcome during the first years of the disease. From January 1985 to December 1990, 186 patients with recent onset RA were enrolled in a prospective longitudinal study. Between January 1991 and November 1992 patients were interviewed on the basis of a comorbidity questionnaire. For analysis the diseases were coded according to the International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) medical diagnoses. Disease activity during the period of followup was measured by the Disease Activity Score. Outcome in terms of physical disability (Health Assessment Questionnaire) and radiological damage (Sharp's modified version) over 3 and 6 year periods was determined. In the group of 186 patients, with mean disease duration of 4.3 years at January 1991, 50 patients (27%) reported at least one chronic coexisting disease. The most frequently reported coexisting diseases were of cardiovascular (29%), respiratory (18%), or dermatological (11%) origin. For the major part (66%) chronic coexisting diseases were already present before onset of RA. No statistically significant differences in use of disease modifying antirheumatic drugs or corticosteroids were observed between RA patients with and without chronic coexisting diseases. No statistically significant differences were found in disease activity or in outcome in terms of physical disability and radiological damage over 3 and 6 year periods between the 2 groups with RA. The results showed that about 27% of patients with RA in this inception cohort had at least one chronic coexisting disease. Treatment, disease course, and outcome did not differ between patients with and without chronic coexisting diseases during the first years of the disease.

Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study.

PubMed

Cleynen, Isabelle; Boucher, Gabrielle; Jostins, Luke; Schumm, L Philip; Zeissig, Sebastian; Ahmad, Tariq; Andersen, Vibeke; Andrews, Jane M; Annese, Vito; Brand, Stephan; Brant, Steven R; Cho, Judy H; Daly, Mark J; Dubinsky, Marla; Duerr, Richard H; Ferguson, Lynnette R; Franke, Andre; Gearry, Richard B; Goyette, Philippe; Hakonarson, Hakon; Halfvarson, Jonas; Hov, Johannes R; Huang, Hailang; Kennedy, Nicholas A; Kupcinskas, Limas; Lawrance, Ian C; Lee, James C; Satsangi, Jack; Schreiber, Stephan; Théâtre, Emilie; van der Meulen-de Jong, Andrea E; Weersma, Rinse K; Wilson, David C; Parkes, Miles; Vermeire, Severine; Rioux, John D; Mansfield, John; Silverberg, Mark S; Radford-Smith, Graham; McGovern, Dermot P B; Barrett, Jeffrey C; Lees, Charlie W

2016-01-09

Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34,819 patients (19,713 with Crohn's disease, 14,683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype-phenotype associations across 156,154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. After quality control, the primary analysis included 29,838 patients (16,902 with Crohn's disease, 12,597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10(-78)), even after exclusion of NOD2, MHC, and 3p21 (p=9·23 × 10(-18)). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6·8 × 10(-4)). Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time. International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list). Copyright © 2016 Cleynen et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.

Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study

PubMed Central

Cleynen, Isabelle; Boucher, Gabrielle; Jostins, Luke; Schumm, L Philip; Zeissig, Sebastian; Ahmad, Tariq; Andersen, Vibeke; Andrews, Jane M; Annese, Vito; Brand, Stephan; Brant, Steven R; Cho, Judy H; Daly, Mark J; Dubinsky, Marla; Duerr, Richard H; Ferguson, Lynnette R; Franke, Andre; Gearry, Richard B; Goyette, Philippe; Hakonarson, Hakon; Halfvarson, Jonas; Hov, Johannes R; Huang, Hailang; Kennedy, Nicholas A; Kupcinskas, Limas; Lawrance, Ian C; Lee, James C; Satsangi, Jack; Schreiber, Stephan; Théâtre, Emilie; van der Meulen-de Jong, Andrea E; Weersma, Rinse K; Wilson, David C; Parkes, Miles; Vermeire, Severine; Rioux, John D; Mansfield, John; Silverberg, Mark S; Radford-Smith, Graham; McGovern, Dermot P B; Barrett, Jeffrey C; Lees, Charlie W

2016-01-01

Summary Background Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. Methods This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34 819 patients (19 713 with Crohn's disease, 14 683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype–phenotype associations across 156 154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. Findings After quality control, the primary analysis included 29 838 patients (16 902 with Crohn's disease, 12 597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10−78), even after exclusion of NOD2, MHC, and 3p21 (p=9·23 × 10−18). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6·8 × 10−4). Interpretation Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time. Funding International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list). PMID:26490195

Biliary Atresia

MedlinePlus

... Grants & Grant History Research Resources Research at NIDDK Technology Advancement & Transfer Meetings & Workshops Health Information Diabetes Digestive Diseases Kidney Disease Weight Management Liver Disease Urologic Diseases Endocrine Diseases Diet & Nutrition ...

A Clinical and Histological Analysis of Mesenchymal Stem Cells in Amputation

ClinicalTrials.gov

2017-08-08

Ischemia; Peripheral Arterial Disease; Peripheral Vascular Disease; Vascular Disease; Arterial Occlusive Disease; Arteriosclerosis; Atherosclerosis; Cardiovascular Disease; Pathologic Processes; Orthopedic Procedures; Amputation

Microbial origins of chronic diseases.

PubMed

Gargano, Lisa M; Hughes, James M

2014-01-01

Chronic diseases such as cardiovascular disease and cancer are among the leading causes of death worldwide and have been on the rise over the past decade. Associations between microbial agents and development of chronic diseases have been made in the past, and new connections are currently being assessed. Investigators are examining the relationship between infectious agents and chronic disease using new technologies with more rigor and specificity. This review examines microbial agents' links to and associations with cardiovascular diseases, cancer, neurodegenerative diseases, renal diseases, psychiatric disorders, and obesity and addresses the important role of the human microbiome in maintenance of health and its potential role in chronic diseases. These associations and relationships will impact future research priorities, surveillance approaches, treatment strategies, and prevention programs for chronic diseases.

Normal CAG and CCG repeats in the Huntington`s disease genes of Parkinson`s disease patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rubinsztein, D.C.; Leggo, J.; Barton, D.E.

1995-04-24

The clinical features of Parkinson`s disease, particularly rigidity and bradykinesia and occasionally tremor, are seen in juvenile-onset Huntington`s disease. Therefore, the CAG and CCG repeats in the Huntington`s disease gene were investigated in 45 Parkinson`s disease patients and compared to 40 control individuals. All of the Parkinson`s disease chromosomes fell within the normal size ranges. In addition, the distributions of the two repeats in the Parkinson`s disease patients did not differ significantly from those of the control population. Therefore, abnormalities of these trinucleotide repeats in the Huntington`s disease gene are not likely to contribute to the pathogenesis of Parkinson`s disease.more » 12 refs., 2 figs.« less

Graves' disease following subacute thyroiditis.

PubMed

Nakano, Yoshishige; Kurihara, Hideo; Sasaki, Jun

2011-12-01

Subacute thyroiditis is a painful, inflammatory disease frequently accompanied with fever. It is suspected to be a viral infectious disease, while Graves' disease is an autoimmune disease. Thus, there appears to be no etiological relationship between the two diseases. A total of 25,267 thyroid disease patients made their first visits to our thyroid clinic during a period of 24 years between 1985 and 2008. Among them, subacute thyroiditis and Graves' disease accounted for 918 patients (3.6%) and 4,617 patients (18.2%), respectively. We have encountered 7 patients (one male and six female) with subacute thyroiditis followed by Graves' disease in this period (0.15% of the 4,617 patients with Graves' disease and 0.76% of the 918 patients with subacute thyroiditis). The age ranges were 40~66 years (mean 48.7 years) at the onset of subacute thyroiditis. The intervals between the onsets of subacute thyroiditis and Graves' disease were 1~8 months (mean 4.7 months). Because Graves' disease was preceded by subacute thyroiditis, the signs and symptoms of both diseases were evident together in the intervening period. The diagnosis of Graves' disease in those patients is always difficult because of atypical signs and symptoms and an unclear onset time. The causes of the Graves'disease that followed subacute thyroiditis are still unknown. However, the inflammatory nature of subacute thyroiditis may lead to the activation of the autoimmune response in susceptible subjects, resulting in the onset of Graves' disease. Graves' disease should be suspected when a high blood level of thyroid hormone persists after subacute thyroiditis.

Taming wildlife disease: bridging the gap between science and management

USGS Publications Warehouse

Joseph, Maxwell B.; Mihaljevic, Joseph R.; Arellano, Ana Lisette; Kueneman, Jordan G.; Cross, Paul C.; Johnson, Pieter T.J.

2013-01-01

1.Parasites and pathogens of wildlife can threaten biodiversity, infect humans and domestic animals, and cause significant economic losses, providing incentives to manage wildlife diseases. Recent insights from disease ecology have helped transform our understanding of infectious disease dynamics and yielded new strategies to better manage wildlife diseases. Simultaneously, wildlife disease management (WDM) presents opportunities for large-scale empirical tests of disease ecology theory in diverse natural systems. 2.To assess whether the potential complementarity between WDM and disease ecology theory has been realized, we evaluate the extent to which specific concepts in disease ecology theory have been explicitly applied in peer-reviewed WDM literature. 3.While only half of WDM articles published in the past decade incorporated disease ecology theory, theory has been incorporated with increasing frequency over the past 40 years. Contrary to expectations, articles authored by academics were no more likely to apply disease ecology theory, but articles that explain unsuccessful management often do so in terms of theory. 4.Some theoretical concepts such as density-dependent transmission have been commonly applied, whereas emerging concepts such as pathogen evolutionary responses to management, biodiversity–disease relationships and within-host parasite interactions have not yet been fully integrated as management considerations. 5.Synthesis and applications. Theory-based disease management can meet the needs of both academics and managers by testing disease ecology theory and improving disease interventions. Theoretical concepts that have received limited attention to date in wildlife disease management could provide a basis for improving management and advancing disease ecology in the future.

Historical review of the List of Occupational Diseases recommended by the International Labour organization (ILO)

PubMed Central

2013-01-01

The list of occupational diseases established in the international and national legal system has played important roles in both prevention of and compensation for workers’ diseases. This report reviewed the historical development in the ILO list of occupational diseases and suggested implications of the trends. Since the first establishment of the ILO list of occupational diseases in 1925, the list has played a key role in harmonizing the development of policies on occupational diseases at the international level. The three occupational diseases (anthrax, lead poisoning, and mercury poisoning) in the first ILO list of occupational diseases, set up in 1925 as workmen’s compensation convention represented an increase of occupational diseases from the Industrial Revolution. Until the 1960s, 10 occupational diseases had been representative compensable occupational diseases listed in Convention No. 121, which implies that occupational diseases in this era were equated to industrial poisoning. Since 1980, with advancements in diagnostic techniques and medical science, noise-induced hearing loss, and several bronchopulmonary diseases have been incorporated into the ILO occupational list. Since 2002, changes in the structure of industries, emerging new chemicals, and advanced national worker’s compensation schemes have provoked the ILO to revise the occupational disease list. A new format of ILO list appended in Recommendation 194 (R194) was composed of two dimensions (causes and diseases) and subcategories. Among 50 member states that had provided their national lists of occupational diseases, until 2012 thirty countries were found to have the list occupational diseases having similar structure to ILO list in R194. PMID:24472440

Screening for Peripheral Artery Disease and Cardiovascular Disease Risk Assessment with Ankle Brachial Index in Adults

MedlinePlus

... Force Recommendations Screening for Peripheral Artery Disease and Cardiovascular Disease Risk Assessment with Ankle Brachial Index in Adults ... on Screening for Peripheral Artery Disease (PAD) and Cardiovascular Disease (CVD) Risk Assessment with Ankle Brachial Index (ABI) ...