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A J Foss

Publications and source records attributed to A J Foss.

At least 19 recordsLinked to original sources
PubMed2000

Relationship between expression of topoisomerase II isoforms and chemosensitivity in choroidal melanoma.

Choroidal melanoma has a high mortality rate and responds poorly to existing chemotherapy, but unexpected ex vivo sensitivity of a subset of these tumours to topoisomerase II inhibitors has been noted. Since chemoresistance may be mediated by the molecular phenotype of tumours, immunohistochemistry has been used to study the expression of both isoforms of topoisomerase II (alpha and beta) in 29 choroidal melanomas for which chemosensitivity assay data for doxorubicin or mitoxantrone are also available. Of these, eight tumours were topoisomerase II beta-positive and 11 were topoisomerase II alpha-positive. Recent studies showing genetic abnormality (often monosomy of chromosome 3) in choroidal melanoma suggest that loss of immunostaining could be due to genomic loss rather than down-regulation of topoisomerase II beta in these tumours. There was no convincing excess of anthracycline resistance in the topoisomerase II beta-negative group. Addition of topoisomerase II alpha, MDR1 (11/17 positive), LRP (16/28 positive), and MRP (5/29 positive) data in multivariate analysis did not reliably predict sensitivity or resistance. Vincristine chemosensitivity showed no relation to MDR1, LRP or MRP in 18 tumours tested. While it is possible that some tumours which do express topoisomerase II beta may respond to anthracyclines, the molecular basis of resistance or sensitivity to anthracyclines or vincristine in uveal melanoma is complex and remains incompletely understood.

Adult↗
PubMed2000

Abnormalities of the transforming growth factor-beta pathway in ocular melanoma.

The majority of ocular melanomas occur in the uveal tract. Chemotherapy is generally ineffective and large tumours requiring enucleation have a greater than 50% mortality at 5 years. Monosomy for chromosome 3 is common in uveal melanoma and it is known that there is loss of responsiveness to transforming growth factor beta (TGFbeta) in melanoma cell lines. Since the gene for TGFbeta receptor II (TGFbetaR2) is located on chromosome 3p22, this study investigates the possibility that the TGFbeta pathway, and TGFbetaR2 in particular, might be involved in the pathogenesis of this rare eye tumour. To this end, the expression of molecules in the pathway has been examined by immunocytochemistry (TGFbeta, TGFbetaR2, SMAD2, SMAD3, SMAD4, and p27), backed up by a cell culture assay of TGFbeta-mediated growth suppression, RT-PCR for SMAD4, and loss of heterozygosity (LOH) on 3p22. There was LOH at 3p22 in 6/19 tumours and loss of TGFbetaR2 expression in 10/27 tumours. Immunohistochemistry for SMADs 2, 3, and 4 showed potential loss of signal transduction in 14/27 tumours. The results indicate abnormality of the TGFbeta pathway in 61% of tumours for which unequivocal results were obtained and suggest that abrogation of control of melanocyte growth by the TGFbeta pathway may be important in the formation of uveal melanoma.

Adult↗
PubMed2000

Endothelial cells of tumor vessels: abnormal but not absent.

The question of whether some blood vessels in tumors of non-vascular origin are lined by cancer cells has been discussed for many years because of the relevance to metastasis, access of drugs to tumor cells, and the effectiveness of angiogenesis inhibitors. Most evidence favoring the existence of tumor cell-lined vessels has come from observations of standard histopathological tissue sections or from transmission and scanning electron microscopic studies. However, it has been difficult to determine convincingly just how abundant these vessels are in tumors. On the one hand, virtually the entire microvasculature is supposedly lined by tumor cells in aggressive uveal melanomas, assuming the presence of vasculogenic mimicry where tumor cells masquerading as endothelial cells create the channels for blood flow. On the other hand, morphometric studies using immunohistochemistry and green fluorescent protein-transfected tumor cells suggest that human colon cancer cells constitute only 3% of the vessel surface in tumors grown orthotopically in mice. This commentary weighs evidence that cancer cells are located in the wall of tumor vessels and discusses the pitfalls in identifying such vessels. Published data along with new observations illustrate the challenges of making an unequivocal identification of tumor cells in vessel walls. Taken together, current evidence suggests that cancer cells contribute at most only a small proportion of the lining of blood vessels in tumors and may be migrating through vessel walls or exposed by defects in the endothelium. Even in aggressive uveal melanomas, blood flow probably occurs mainly through channels lined by endothelial cells, not tumor cells, and most existing data do not support a functionally significant contribution of vasculogenic mimicry. Innovative new approaches that distinguish pleomorphic tumor cells from abnormal endothelial cells in vessel walls will help to define the incidence and importance of tumor cell-lined blood vessels in drug delivery and metastasis via the bloodstream.

Animals↗
PubMed2000

Development and validation of a patient based measure of outcome in ocular melanoma.

BACKGROUND: Patients with uveal melanoma can be treated by a number of modalities. As none of the different treatments offer a survival advantage, a key factor in choosing among treatments is their differential impact on patients' quality of life. A short, patient based questionnaire was developed and validated for evaluating outcomes following treatment for uveal melanoma. METHODS: The 21 item measure of outcome in ocular disease (MOOD) assesses the patient's view of outcome in terms of visual function and the impact of treatment. The reliability and validity of the three MOOD scores (total, vision, impact) were evaluated in 176 patients who had been treated for uveal melanoma (75 brachytherapy, 78 proton beam radiotherapy, 23 enucleation). Of these, 165 patients also completed the SF-36. RESULTS: All three MOOD scales met standard criteria for acceptability, reliability, and validity. The proportion of missing data was low, and responses to all items were well distributed across response categories. Internal consistency, assessed by Cronbach's alpha coefficients, exceeded the standard criterion of 0. 70 for all three summary scores. Item total correlations ranged from 0.22 to 0.77 (mean item total correlation 0.58), indicating good homogeneity. Test-retest correlations for all three summary scores exceeded 0.85. Scaling assumptions, assessed by item convergent and discriminant validity correlations, were met for the vision and impact scores. The MOOD showed good content validity, as assessed by review by ophthalmologists and patients. Construct validity was demonstrated by high intercorrelations between the vision and impact scores and the total scale; higher scores for patients who reported being very satisfied compared with those who were not very satisfied and for those who reported persistent red eye compared with those who did not have this complication (known group differences/hypothesis testing); moderate correlations between the MOOD and the SF-36 and visual acuity (convergent validity); and low correlations between the MOOD and age and sex (discriminant validity). CONCLUSIONS: The MOOD is a practical and scientifically sound patient based measure which can be used in research and audit to evaluate outcomes following treatment for uveal melanoma. It takes 5 minutes to complete and meets standard psychometric criteria for reliability and validity.

Activities of Daily Living↗
PubMed1999

Combination chemotherapy for choroidal melanoma: ex vivo sensitivity to treosulfan with gemcitabine or cytosine arabinoside.

Treatment of choroidal melanoma by chemotherapy is usually unsuccessful, with response rates of less than 1% reported for dacarbazine (DTIC)-containing regimens which show 20% or more response rates in skin melanoma. Recently, we reported the activity of several cytotoxic agents against primary choroidal melanoma in an ATP-based tumour chemosensitivity assay (ATP-TCA). In this study, we have used the same method to examine the sensitivity of choroidal melanoma to combinations suggested by our earlier study. Tumour material from 36 enucleated eyes was tested against a battery of single agents and combinations which showed some activity in the previous study. The combination of treosulfan with gemcitabine or cytosine arabinoside showed consistent activity in 70% and 86% of cases, respectively. Paclitaxel was also active, particularly in combination with treosulfan (47%) or mitoxantrone (33%). Addition of paclitaxel to the combination of treosulfan + cytosine analogue added little increased sensitivity. For treosulfan + cytosine arabinoside, further sequence and timing experiments showed that simultaneous administration gave the greatest suppression, with minor loss of inhibition if the cytosine analogue was given 24 h after the treosulfan. Administration of cytosine analogue 24 h before treosulfan produced considerably less inhibition at any concentration. While we have so far been unable to study metastatic tumour from choroidal melanoma patients, the combination of treosulfan with gemcitabine or cytosine arabinoside shows activity ex vivo against primary tumour tissue. Clinical trials are in progress.

Adenosine Triphosphate↗
PubMed1999

c-myc, p53, and Bcl-2 expression and clinical outcome in uveal melanoma.

AIMS: Overexpression of c-myc protein has independent prognostic significance in a variety of primary and metastatic cutaneous melanomas which suggests a possible role for this gene in melanomagenesis. We have therefore examined the importance of this oncogene in uveal melanoma and studied the coexpression of two other gene products, Bcl-2 and p53, which might contribute to its effect. METHODS: The percentage of cells positive for nuclear c-myc expression was estimated by flow cytometric analysis of nuclei extracted from paraffin blocks. The expression of Bcl-2 and p53 protein was assessed by immunohistochemistry. A total of 71 tumours were studied and the results compared with survival with a mean follow up period of 6 years. RESULTS: c-myc was expressed in > 50% of the cells by 70% of the tumours, and was independently associated with improved survival in a Cox multiple regression-model. Although Bcl-2 was expressed by the majority of the cells in 67% tumours, it was without effect on prognosis. None of the cases studied showed convincing positivity for p53. Analysis of coexpression showed that the best survival was seen in c-myc+/Bcl-2+ tumours and the worst in c-myc-/Bcl-2-tumours. CONCLUSION: The finding of improved rather than reduced survival in c-myc positive tumours is at variance with skin melanoma. There was no evidence to suggest that c-myc was modulated by upregulation of Bcl-2 or p53 inactivation/mutation. Although Bcl-2 is unlikely to have any effect on tumour growth or metastasis, it could contribute to the general lack of susceptibility to apoptosis in these tumours.

Adolescent↗
PubMed1999

Modelling uveal melanoma.

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.

Adult↗
PubMed1998

Predictive power of screening tests for metastasis in uveal melanoma.

PURPOSE: Uveal melanoma undergoes haematogenous dissemination, particularly to the liver. It is routine practice to screen for metastatic disease. The purpose of this study was to evaluate such screening tests and to determine their value in detecting metastatic disease at presentation. METHODS: In this study of a series of 245 patients with uveal melanoma of whom 55 (22%) died, the sensitivity, specificity, positive and negative predictive powers and likelihood ratio of the blood tests, chest radiographs and liver ultrasound investigations performed at diagnosis were determined. RESULTS: All the screening investigations were found to have a low yield, but the most sensitive were those for gamma-glutamyl transpeptidase (gamma GT; sensitivity 21%) and alkaline phosphatase (sensitivity 25%), with gamma GT being more specific (specificity 92%). No blood test had a positive predictive power greater than 50%. The chest radiograph and liver ultrasonography were both 100% specific but had sensitivities of 2% and 14% respectively. CONCLUSIONS: Only the chest radiograph and liver ultrasonography had positive predictive powers greater than 50% and these tests had very poor sensitivity. We conclude that there is no good test available for screening for metastatic uveal melanoma.

Biomarkers, Tumor↗
PubMed1998

The prognostic significance of c-myc oncogene expression in uveal melanoma.

The role of the c-myc oncogene has been little investigated in uveal melanoma. In this study an analysis of c-myc oncoprotein expression was undertaken using flow cytometry in 71 patients with posterior uveal melanoma. Nuclear c-myc oncoprotein was detected in all of the tumours, and survival analysis revealed a significant association between high oncoprotein positivity and improved survival (log rank test: chi2 = 6.47, P = 0.01). Multifactorial analysis using Cox's proportional hazards model revealed nuclear c-myc oncoprotein to be an independent prognostic marker more accurate than other clinicopathological parameters (log rank test: chi2 = 6.61, P = 0.01). However, this result of high oncoprotein expression correlating with improved outcome is surprising and in contrast to our previous studies using the same method on cutaneous melanoma, where high levels of nuclear c-myc expression have been found to correlate with poor outcome both in primary and secondary disease. This study suggests that the pattern of oncogene expression in uveal melanoma is distinct from cutaneous melanoma and that the underlying biology of these tumours is different.

Adolescent↗
PubMed1998

Does raised intraocular pressure begin in utero?

AIM: To determine whether fetal and infant growth, as assessed by weight at birth and weight at 1 year, are related to intraocular pressure. METHODS: 717 men and women born in Hertfordshire between 1920 and 1930, for whom records of birth weight and weight at 1 year were available, were examined. Visual fields were assessed using the Takagi central 25 degrees 75 point static threshold screening program. Tonometry was performed using the Perkin's tonometer. The disc was assessed by direct ophthalmoscopy through dilated pupils. RESULTS: A significant inverse relation was found between systolic blood pressure and birth weight. However, no association was found between birth weight or weight at 1 year and intraocular pressure, cup/disc ratio, or visual field defects. CONCLUSIONS: There was no evidence to support fetal or infant growth as being important factors for the subsequent development of raised intraocular pressure.

Aged↗
PubMed1998

Axon deviation in the human lamina cribrosa.

AIMS: To examine the course taken by individual retinal ganglion cell axons through the human lamina cribrosa. METHODS: Retinal ganglion cell axons were labelled using the retrograde tracer horseradish peroxidase applied directly to the optic nerve in two normal human eyes removed during the course of treatment for extraocular disease. RESULTS: A majority of axons took a direct course through the lamina cribrosa but a significant minority, in the range 8-12%, deviated to pass between the cribrosal plates in both central and peripheral parts of the optic disc. CONCLUSIONS: It is postulated that these axons would be selectively vulnerable to compression of the lamina cribrosa in diseases such as glaucoma in which the intraocular pressure is increased.

Aged↗
PubMed1997

The ex vivo chemosensitivity profile of choroidal melanoma.

Uveal melanoma has a high mortality rate and responds poorly to existing chemotherapy. We have therefore examined the sensitivity of uveal melanoma to cytotoxic agents using an ex vivo chemosensitivity assay to determine whether some agents which have not been used for this tumor might have activity. An ATP-based tumor chemosensitivity assay (ATP-TCA) was used to determine the effect of nine cytotoxic drugs at multiple dilutions in 28 primary uveal melanoma specimens. Evaluable assay results from up to 16 tumors with each drug showed variable sensitivity to alkylating agents (three of nine with mitomycin C, one of 15 with cisplatin and seven of 15 with treosulfan), cytosine arabinoside (seven of 16), paclitaxel (one of five) and doxorubicin (two of 16). No tumors were sensitive to temozolomide, or 5-fluorouracil, and only one of 14 to vincristine. The combination of treosulfan with cytosine arabinoside resulted in enhanced tumor cell inhibition in three of five tumors tested. Combinations containing paclitaxel combined with doxorubicin or cisplatin showed some activity, but none achieved 100% inhibition and the results were similar to those obtained with paclitaxel alone. Uveal melanoma shows considerable heterogeneity of sensitivity to cytotoxic drugs, with considerable resistance to most agents, matching clinical experience. The results suggest that cytosine arabinoside or gemcitabine plus treosulfan may be an active combination. Clinical trials will commence shortly. The use of the ATP-TCA provides a method of testing multiple agents and combinations in a way which would be otherwise impossible in rare tumors such as uveal melanoma.

Antineoplastic Agents↗
PubMed1997

Reassessment of the PAS patterns in uveal melanoma.

BACKGROUND: Previous work has highlighted the prognostic importance of patterns of periodic acid Schiff (PAS) staining (the Folberg patterns) in uveal melanoma. These patterns have been ascribed to blood vessels but the patterns are different from those seen with other staining techniques for blood vessels. It has recently been shown that microvessel density is the dominant prognostic factor in uveal melanoma. This study reinvestigates the nature and significance of the PAS patterns. METHODS: The PAS patterns were compared with the patterns seen with conventional connective tissue stains and with the patterns seen in sections stained for the presence of blood vessels (by immunohistochemistry for factor VIII related antigen). The PAS patterns were determined on a panel of 117 cases of uveal melanoma. The prognostic significance of each of these patterns was determined and, as more than one pattern can exist in a tumour, principal components analysis was performed to determine the number of underlying factors. RESULTS: Comparison of the PAS patterns with other stains demonstrates that they are based on connective tissue including fibrovascular tissue. Five of the nine PAS patterns carried prognostic significance on univariate analysis. Principal components analysis suggested that these patterns represented three underlying factors, which were tentatively identified as representing disordered growth (factor 1), emergence of rapidly growing subclones (factor 2), and section orientation (factor 3). CONCLUSIONS: The PAS patterns are based on fibrovascular tissue and can be ascribed to three underlying factors. The first two of these factors carried prognostic significance and the first (disordered growth) retained independent prognostic significance in a multivariate Cox model which included microvessel density and tumour size.

Biomarkers, Tumor↗
PubMed1997

Predictive factors for the development of rubeosis following proton beam radiotherapy for uveal melanoma.

AIMS/BACKGROUND: Proton beam radiotherapy can effectively treat primary uveal melanomas of any size. Some patients, however, develop adverse late effects following treatment and the purpose of this study was to determine which factors give rise to a poor local outcome. METHODS: The hospital records from a first cohort of 127 patients treated by protons from 1989 to 1992 were reviewed retrospectively. The presence of rubeosis was selected as a measure of significant ocular damage. Split file analysis was performed with 73 cases forming a test group with the remaining 54 cases acting as a validation group. RESULTS: Large tumour size and the presence of retinal detachment were significant, independent risk factors for developing rubeosis for both the test and validation groups. These factors also predicted subsequent enucleation for uncontrolled ocular pain. Patients with tumours too large to plaque and with an associated retinal detachment had a 90% chance of developing rubeosis within 4 years of proton beam radiotherapy. CONCLUSIONS: Patients with a uveal melanoma too large for plaque therapy and an associated retinal detachment run a very high risk of developing rubeosis after proton beam radiotherapy and one third of individuals developing rubeosis required enucleation for pain even if local tumour control was satisfactory.

Adult↗
PubMed1996

Microvessel count predicts survival in uveal melanoma.

Microvessel density has become established as an important prognostic indicator for many tumor types. This study investigates the microvessel density as a prognostic factor for survival in patients with uveal melanoma, which is the commonest intraocular tumor and has a clear tendency for metastatic spread to the liver. Factor VIII-related antigen was identified immunohistochemically in bleached sections from 123 tumors. Maximum blood vessel density in an area of 0.25 mm2 was recorded, along with other accepted prognostic information. Microvessel density was the single most important prognostic factor on univariate testing, and in a Cox proportional hazard model, tumor size was the only other variable to be entered. No other accepted prognostic factor entered the model. We conclude that microvessel density is an important prognostic factor for survival in patients with uveal melanoma and allows the identification of high-risk patients for whom adjuvant therapy should be considered.

Biomarkers, Tumor↗