Eye Cancer Research Articles

Commentary: Seeing the light

Cedric and Frank Garland 1 observed that metropolitan states in the south-west of the US had lower mortality rates from colon cancer in 1959–61, on average ~10 per 100 000 per year ageadjusted in white males, than metropolitan states in the northwest, on average ~15 per 100 000. They reported that the rank order coefficient of correlation between colon cancer mortality and solar irradiance across the metropolitan states was 0.7. It was 0.6 across non-metropolitan states and the same values were obtained when cancer mortality rates for US counties in 1950–69 were used instead of the whole-of-state values. They noted, from broad regional data, that the probably mainly south to north gradient in colon cancer mortality did not appear to correlate well with patterns of dietary meat, fruit, or vegetable intake but acknowledged that its correlationwith solar irradiance might still be due to confounding with some other dietary, behavioural, or, perhaps, genetic factor. Apperly 2 had reported an association between mortality from all cancers and solar irradiance across the states of the US 40 years earlier and suggested ‘it may be possible to reduce our cancer deaths by exposing suitable skin areas to sunlight . . . insufficient to cause skin cancer’. While the Garlands did not acknowledge this work they can be reasonably excused for not having uncovered it. Unsurprisingly, the Garlands advanced the possibility that photolytic production of vitamin D in the skin might explain the correlation between colorectal cancer mortality and solar irradiance. This is the major source of vitamin D for most human populations. They advanced an argument about antiinflammatory effects of calcium (the absorption of which is promoted by vitamin D) in the bowel mucosa and evidence of a protective effect of milk against colon cancer in one US study (milk was and is mandatorily fortified with vitamin D in the US) in support of this possibility. The Garlands and others published papers reporting on correlations in the US between solar irradiance and cancers of the breast, 3 prostate, 4 and ovary 5 over the subsequent decade or so. None of these, or the original paper on colon cancer, initially attracted much attention. Indeed, the International Agency for Research on Cancer’s 1992 monograph on the carcinogenic risk of solar and ultraviolet radiation to humans stated that ‘no adequate data were available to the Working Group’ when referring to all cancers other than skin, lip, and ocular cancers. 6

The inhibition of angiogenesis by antisense oligonucleotides to clusterin

Angiogenesis is a primary disease target in ocular retinopathy and a secondary target in numerous other angiogenic diseases such as cancer, rheumatoid arthritis and psoriasis. Clinical trials using antiangiogenic antisense oligonucleotides (aso's) for the treatment of ocular disorders or cancer are well advanced. Clusterin aso's are currently under investigation for the treatment of prostate cancer. We have investigated the antiangiogenic properties of clusterin aso's using a capillary cell (HUVEC) viability assay. In this study we included aso's to known apoptosis modulators (bcl-2, bcl-xl and survivin) which were previously identified in HUVEC's. We have also studied the effect of clusterin aso's on angiogenesis using an in vitro, matrigel assay and on HUVEC apoptosis using an ELISA DNA fragmentation assay. Clusterin, bcl-2, bcl-xl and survivin aso's were all found to inhibit HUVEC growth. The apoptosis-inducing drugs paclitaxel, camptothecin and doxorubicin were also found to inhibit HUVEC proliferation. Combinations of aso's with these drugs demonstrated a minor additive but not synergistic inhibitory effect on HUVEC proliferation. Clusterin aso's were found to strongly inhibit angiogenesis and induce high levels of apoptosis in HUVECs. In cancer cells the prosurvival protein clusterin may protect the cells from apoptosis-inducing agents so that the clusterin aso's may act as chemosensitization agents. These data demonstrate a strong antiangiogenic action of clusterin aso's, that is not necessarily related to any chemosensitization effect of this agent.

Studies on the production and quality assurance of miniature 125I radioactive sources suitable for treatment of ocular and prostate cancers

125I sources were prepared by adsorption of 125I on palladium-coated silver wires. The effect of reducing agent on percentage adsorption of 125I was studied and the amount of adsorbed activity on source core was studied by repeated adsorption cycles. The activity per source in the sources produced from the same batch varied with coefficient of variation (i.e. the ratio of standard deviation to mean multiplied by 100) less than 10%. The unencapsulated source exhibited low leachability (< 0.01%). The laser parameters were optimized to obtain quality welds with negligible leak rate. The sources were laser-encapsulated in titanium capsules of 0.8 mm (OD)×4.5 mm (l). The release of radioactivity from encapsulated sources in an immersion test at 50 °C for 5 h was <5 nCi (185 Bq). The surface contamination on the sealed capsules was found to be<0.05 nCi or 1.85 Bq per source. The sources were used in the treatment of a child having retinoblastoma.

Risk of cancer at sites other than the breast in Swedish families eligible for BRCA1 or BRCA2 mutation testing

Population-based data on the risk of cancer in families eligible for BRCA1/2 mutation testing may help to reach a consensus about the association of BRCA1/2 mutations with cancer at sites other than the breast and may reveal new, non-BRCA1/2 related components of the familial clustering of cancer in those families. The families of the Swedish Family-Cancer Database with at least three generations (n = 944,723) were classified according to the criteria proposed by the German Consortium for Hereditary Breast and Ovarian Cancer. The cancer incidences in the classified families were compared with the incidences in the general population. The percentages of individuals with cancer in families eligible for BRCA1/2 mutation testing were compared with data in the literature to estimate the proportion of malignancies related to BRCA1/2 mutations. Families with two breast cancers before the age of 50 years showed increased risk of early onset pancreatic, prostate and ovarian cancers; families with ovarian and breast cancers presented increased incidences for ovarian and ocular cancers; families with two breast cancers, at least one of them under the age of 50 years, showed increased risks of prostate and primary liver cancers. Stomach cancer before age 70 years was twice as frequent in families with breast and ovarian cancers as in the general population. BRCA1/2 mutations probably explain most of the aggregation of ovarian cancer in families with male breast cancer, and in families with at least two breast cancers diagnosed before age 50 years. The association of BRCA1/2 mutations with ovarian, pancreatic, prostate and stomach cancers was confirmed at a population level. However, the clustering of early pancreatic cancer in families with two breast cancers under age 50 years, the aggregation of ovarian cancer in families with breast and ovarian cancers, and the increased incidence of early onset prostate cancer in families with male breast cancer seem to be due to other effects unrelated to BRCA1/2 mutations.

Diagnostic and therapeutic applications of recombinant antibodies: targeting the extra-domain B of fibronectin, a marker of tumor angiogenesis.

Angiogenesis, the sprouting of new blood vessels from preexisting ones, is a phenomenon associated to several human pathologies, including different potentially blinding ocular disorders, rheumatoid arthritis, and cancer. Indeed, ongoing angiogenesis is a characteristic feature of the majority of aggressive solid tumors, and is also a pre-requisite for the progression towards the metastatic phenotype. One established marker of angiogenesis is represented by an isoform of the oncofoetal fibronectin (FN), containing an additional domain inserted by alternative splicing of the FN pre-mRNA and called extra-domain B (ED-B). This isoform has been found to be present almost exclusively in the modified extra-cellular matrix surrounding newly-formed blood vessels in tumors (and other animal models of ocular pathologies), being completely absent from the normal vasculature in adult organs. This article reviews the recombinant antibodies raised against ED-B and the different methodologies used for the generation of these antibodies. Moreover, new diagnostic and therapeutic applications based on the delivery of bioactive molecules to tumor blood vessels by means of ED-B targeting will be discussed.

Ocular effects of radiofrequency energy.

Radiofrequency (RF) energy has been reported to cause a variety of ocular effects, primarily cataracts but also effects on the retina, cornea, and other ocular systems. Cataracts have been observed in experimental animals when one eye was exposed to a localized, very high RF field and the other eye was the unexposed control. The results show that 2450 MHz exposures for >or=30 min at power densities causing extremely high dose rates (>or=150 W/kg) and temperatures (>or=41 degrees C) in or near the lens caused cataracts in the rabbit eye. However, cataracts were not observed in the monkey eye exposed to similar exposure conditions, reflecting the different patterns of energy absorption (SAR, specific absorption rate) distribution, due to their different facial structure. Since the monkey head is similar in structure to the human head, the nonhuman primate study showed that the incident power density levels causing cataracts in rabbits and other laboratory animals cannot be directly extrapolated to primates, including human beings. It is reasonable to assume that an SAR that would induce temperatures >or=41 degrees C in or near the lens in the human eye would produce cataracts by the same mechanism (heating) that caused cataracts in the rabbit lens; however, such an exposure would greatly exceed the currently allowable limits for human exposure and would be expected to cause unacceptable effects in other parts of the eye and face. Other ocular effects including corneal lesions, retinal effects, and changes in vascular permeability, have been observed after localized exposure of the eye of laboratory animals to both continuous wave (CW) and pulsed wave (PW) exposures, but the inconsistencies in these results, the failure to independently confirm corneal lesions after CW exposure, the failure to independently confirm retinal effects after PW exposure, and the absence of functional changes in vision are reasons why these ocular effects are not useful in defining an adverse effect level for RF exposure. While cataracts develop after localized exposure of the eye at SARs >or= 150 W/kg, whole body exposure at much lower levels (14-42 W/kg) is lethal to rabbits. Two studies reported cataracts in this animal after 30 daily exposures at SARs at the upper end of the lethal range, e.g., 38-42 W/kg; however, long term exposure of rabbits (23 h/day, 6 months) at 1.5 W/kg (17 W/kg in the rabbit head) did not cause cataracts or other ocular effects. A long term (1-4 years) investigation of monkeys exposed at high SARs (20 and 40 W/kg to the monkey face) found no cataracts or other ocular effects or change in visual capability. The results of these long term studies support the conclusion that clinically significant ocular effects, including cataracts, have not been confirmed in human populations exposed for long periods of time to low level RF energy. The results of four recent human studies show that there is no clear evidence of an association between RF exposure and ocular cancer.

TGF-beta in uveal melanoma.

Uveal melanoma is the most common primary ocular cancer among adults and patients with distant metastases seldom survive longer than a year. Melanomas of the eye have the advantage of growing in the special environment of an immune privileged site and it has long been shown, that the special immunosuppressive properties of the intraocular microenvironment are strongly mediated by cytokines, especially transforming growth factor-beta (TGF-beta). Here, we sought to investigate the presence of TGF-beta in surgically removed uveal melanoma specimens using immunohistochemical methods to verify possible autocrine mechanisms. Immunocytochemistry for pan-TGF-beta and TGF-beta(2) was performed on 13 melanoma specimens using an alkaline phosphatase labeling procedure. Melanocytic origin of the tumors was confirmed by HMB-45 staining. All tissue samples exhibited positive staining using either pan-TGF-beta or TGF-beta(2) antibody regardless of cell-type, size of the tumor, or tumor location. The intensity of staining did not vary significantly within a given tumor. All tumors stained positive against the HMB-45 antibody. Many cytokines have been found to act on melanoma tumors. The presence of the TGF-beta(2) isoform in all specimens points to progressive tumor-growth as has been shown for melanomas of the skin. Based on our immunohistochemical findings and the immunosuppressive properties of TGF-beta, we suppose that ocular melanomas should be able to create their own immunosuppressive environment even in the uvea, which might be a non-privileged site.

Validation of self-reported complications by bone marrow transplantation survivors.

Self-administered questionnaires are commonly used to measure exposures and outcomes in epidemiological research and thus need good validity. With increasing numbers of cancer survivors, there is interest in the ongoing assessment of therapy-related complications. A medical record validation of patient-reported complications following bone marrow transplantation (BMT) was performed using a self-administered questionnaire. The study population consisted of 100 patients who had undergone BMT at the City of Hope. The following self-reported complications were validated using medical records: ocular, endocrine, cardiovascular, musculoskeletal, pulmonary, gastrointestinal, neurological, graft-versus-host disease, and subsequent cancers. Using information from medical records as the standard, sensitivities ranged from 52.9% for subsequent cancers to 100% for avascular necrosis and hypothyroidism. Specificities ranged from 75.4% for ocular complications to 100% for avascular necrosis. There was intermediate to excellent agreement (kappa = 0. 4-1.0) for all complications evaluated. Thus, the agreement between self-reporting and medical records was good for complications with clear diagnostic criteria that are easily communicated to the patient, but was diminished for complications with non-established diagnostic criteria (xerophthalmia) or a fluctuating course (peripheral neuropathies and hypertension). Overall these results suggest that cancer survivors can self-report serious complications with an acceptable level of accuracy in epidemiological research.

Modelling uveal melanoma

BACKGROUND/AIMThere 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...

Is Angiopoietin-2 Necessary for the Initiation of Tumor Angiogenesis?

Almost all functional cells are located within 30 μm of a blood capillary. Acute changes in blood flow are regulated in response to tissue needs by changes in the constriction level of blood vessels, 1 whereas long-term regulation of tissue perfusion is achieved by growth of new blood vessels or by vascular regression. 2 Physiological angiogenesis is limited to wound healing and changes in female reproductive organs during the menstrual cycle and pregnancy but blood vessels maintain their ability to grow and regress throughout life. Changes in the vasculature occur in association with many pathological processes, such as ocular neovascularization, inflammatory diseases, and cancer. 3 The concept that solid tumor growth depends on angiogenesis is well established. 4 Indeed, tumor size is restricted to a few cubic millimeters if it is not able to attract new blood vessels. The primitive embryonic vasculature is laid down by vasculogenesis, 5 which involves in situ differentiation of endothelial cells (ECs) from mesodermal precursors and their organization into a primary vascular plexus. In adults, all new blood vessels appear to be formed by angiogenesis, which is based on sprouting of blood vessels from existing ones or on intussusceptive growth involving in situ remodeling of the vessels by protruding interstitial tissue columns. In embryos, some developing organs including the brain and kidneys are vascularized by angiogenesis. The initiation of blood vessel growth involves focal reduction of intercellular interactions and interactions between the cells of the blood vessel and the surrounding extracellular matrix (ECM). This is associated with a loss of pericytes (PCs) and possibly of smooth muscle cells (SMCs) from the existing vessels. 2 Many angiogenic factors have been shown to be mitogenic and chemoattractive for ECs. The ECs have been shown to distort malleable substrata in a process called traction 6,7 and the reorganized ECM may facilitate the formation of complex weblike EC structures. Formation of functional blood vessels requires remodeling of this EC meshwork. Initiation of blood flow enables adaptation to changing blood and oxygen pressure conditions and further remodeling of the vascular network. 8 The maturation of newly formed vessels involves the accumulation of a basal lamina and tightly associated PCs or SMCs on the abluminal side. Although many phases of vessel growth overlap, this classification shows that complex orchestration is required in order for angiogenesis to proceed. Numerous substances can trigger the angiogenic process by causing a reprogramming of cells in the blood vessels 9 and these responses are beginning to be elucidated. In this issue of The American Journal of Pathology, Stratmann et al 10 report their novel finding that the angiopoietin-2 (Ang-2) signaling molecule is up-regulated in a spotlike fashion in the endothelium of growing blood vessels in glioblastoma. The authors also show that angiopoietin-1 (Ang-1), a related signaling molecule, is secreted from tumor cells and that Tie-2, a receptor for both Ang-1 and Ang-2, is up-regulated in the endothelium of vessels undergoing angiogenesis.

Ocular toxicity and cancer chemotherapy. A review.

Systemic anticancer therapies can produce acute and chronic organ damage, but the eye is usually considered a protected site. Nonetheless, the oculo-visual system has a potentially high degree of sensitivity to toxic substances. Ocular toxicity induced by cancer chemotherapy includes a broad spectrum of disorders, reflecting the unique anatomic, physiologic, and biochemical features of this essential organ. A review of the literature regarding the ocular toxicity of chemotherapeutic agents, hormonal agents, biologic agents, and high dose chemotherapy with allogeneic and autologous bone marrow transplantation was conducted. Ocular toxicity induced by anticancer chemotherapy is not uncommon. The development of more aggressive regimens as well as new agents and combination chemotherapies have resulted in a significant increase of reported cases of chemotherapy-induced ocular side effects. In most instances, the mechanisms of ocular toxicity continue to be poorly understood. Ocular toxicities induced by chemotherapeutic agents are generally not preventable; therefore, clinicians must be aware of potential vision-threatening complications. Prompt consultation with an ophthalmologist can lead to early detection, proper diagnosis, and appropriate therapeutic measures. Dose reduction or discontinuation of incriminated drugs may help in reducing the severity and the duration of side effects.

Environmental factors in the epidemiology and aetiology of malignant tumours of the eye

This review examines the scientific evidence for and against the role of environmental factors such as acute and accumulative ultraviolet radiation and visible light exposure as causative factors in the development of a spectrum of eye diseases. Displasia and neoplasia are more common in sunny areas and may be due to ultraviolet B radiation. Pale skin, pale iris and a history of squamous cell carcinoma or solar keratoses indicate at-risk patients. Ocular cancer may have an annual age-adjusted incidence between 0.6 per 100,000 and 0.9 per 100,000 for the male population and between 0.5 per 100,000 and 0.8 per 100,000 for the female population.

Inhibition of melanoma cell/matrix interaction by tamoxifen.

Following our recent finding that calmodulin antagonists can reduce cancer cell attachment to extracellular matrix proteins, we investigated the calmodulin antagonistic and anti-attachment properties of the non-steroidal anti-oestrogens tamoxifen and droloxifene. These drugs and four of their active metabolites were found to have calmodulin antagonist activity with IC50 values of 2-4 microM and to be capable of inhibiting attachment of murine B16 melanoma to extracellular matrix proteins in vitro. IC50 values for inhibition of attachment were 11 microM for tamoxifen and ranged from 5 to 40 microM for the other five compounds tested. (Poor reproducibility in drug potency between attachment experiments was almost certainly due to the low aqueous solubility of these drugs.) The effects of tamoxifen on cell/matrix adhesion were most evident between 15 min and 3 h of cell attachment. No effects of tamoxifen were evident in cells which had been allowed to attach for 6 h or more. Tamoxifen at concentrations between 0.1 and 30 microM was without effect on intracellular free calcium concentration. Tamoxifen also inhibited attachment of human ocular melanoma cells and human breast cancer (MCF7) cells to type I collagen. The concentration at which tamoxifen and its metabolites affect cell attachment in vitro (2-14 microM) is of the same order as the tissue concentrations of these drugs achieved clinically. The possibility exists that reduction of cell/matrix interactions may contribute to the clinical anti-metastatic efficacy of tamoxifen and some of its active metabolites.

Photodynamic therapy of human cancer

Photodynamic therapy (PDT) is currently an investigational therapy for human cancer. PDT is performed in two steps: (a) the injection of a photosensitizer, followed by a period of time during which it is cleared from most normal tissues; and (b) activation of the photosensitizer by exposure to light. Singlet oxygen is thought to be the agent produced by photoactivation most responsible for tumor destruction. Over 3000 patients have been treated with PDT and reported in the literature. The published results of clinical PDT in the treatment of superficial bladder cancer, gynecological cancer, endobronchial malignancies, gastrointestinal cancer, intracranial cancer, ocular cancer, and cutaneous and subcutaneous cancers are critically reviewed in the present work. The current laser types used for clinical PDT are reviewed, as well as light delivery devices which have been recently developed. In situ light dosimetry devices and their use in the treatment of superficial bladder cancer and for intraoperative therapy are discussed.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>

Epidemiologic aspects of intraocular malignant melanoma.

Although descriptions of ocular melanoma date to antiquity, interest in the disease as a specific clinical entity probably began with the Dane, Bendz, in 1833, who described the complete clinical course of a patient with this tumor. The invention of the ophthalmoscope in the mid-19th century gave further impetus to the interest in ocular melanoma, and by the first quarter of this century, a number of books dedicated solely to the topic of ocular cancer had been published. Clinical interest continues today at a high level, and recently there has been new interest in the etiology and epidemiology of the disease [1].

Photodynamic Therapy of Human Ocular Cancer

Photodynamic therapy (PDT), also known as photoradiation therapy, was employed in five patients with ocular tumors that had been photosensitized to hematoporphyrin derivative (HPD). In each case more conventional treatment had failed to control the tumor, or the patient was considered a poor candidate for surgical intervention because of advanced age or general health. Intravenous administration of 2.5-3.0 mg/kg HPD was followed by PDT 2-4 days later, using a dye laser tuned to a wavelength of 632 nm. Laser light was delivered either by a fiber optic probe maintained at a fixed distance, or via a slit lamp system, for intervals of up to 20 minutes. The levels of energy applied were mainly below 420 Joules/cm2, but for tumors less than 1 mm diameter energy levels were as high as 3000 J/cm2 with a conservative power value as low as 20 mW/cm2. Tumor response to PDT was disappointing. Although substantial superficial tumor necrosis occurred in several cases, it did not extend to the deeper levels of tumor tissue. In each instance surgical intervention became necessary. Deficiencies in the procedure are discussed.

Ocular anatomy for nuclear medicine

The small size of the eye has precluded many efforts to image ophthalmologic disease processes. An understanding of those areas where nuclear medicine has been successful in ophthalmology requires a review of the appropriate anatomy. The accessibility of the nasolacrimal system and its pumping action have allowed for a unique physiologic appraisal with nuclear medicine techniques. The "magic bullet" that has eluded the search of oncology has left ophthalmologists without a practical diagnostic modality for ocular cancers. However, by placing detection devices in close proximity to these tumors, some useful information can be obtained. Unfortunately, this requires surgical dissection. New techniques have already been introduced into ophthalmology (fluorophotometry) in diabetic disease of the eye and nuclear medicine may have a considerable impact in this area. Understanding the anatomy of the retinal capillaries and larger vessels is essential to the reading of the pioneering work of Freeman and coworkers.

Capillary Endothelial Cell Migration: Stimulating Activity of Aqueous Humor From Patients With Ocular Cancers&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;

In double-masked studies, various concentrations of aqueous humor (AH) from 157 patients (208 samples) with ocular cancers, nonmalignant ocular lesions, and normal eyes were added to bovine capillary endothelial (BCE) cells plated onto gold-coated cover slips. The phagokinetic tracks made by 100 cells at each concentration were traced, and the mean area of migration plus or minus the standard error of the mean was determined. Data are expressed as the percentages of increase in mean track area made by 100 cells incubated in medium that contained AH samples beyond the mean area of 100 cells incubated in medium alone. The percentage increases in migration-stimulating activity were as follows: a) malignant ocular disease--retinoblastoma (30 samples), 34 +/- 2; malignant melanoma (55 samples), 37 +/- 3; b) nonmalignant ocular disease--cataracts, glaucoma, pseudoglioma, and diabetic retinopathy (36 samples), 14 +/- 2; c) control AH--no ocular disease (51 samples), 9 +/- 1; normal eyes and systemic cancer (36 samples), 38 +/- 6. The percentage increase in endothelial cell migration was as great in cases of systemic cancer as it was in cases of ocular cancer. The endothelial cell migration-stimulating activity in AH from patients with intraocular cancers was significantly higher than the levels in the other groups of patients having no systemic cancer (P much less than .001). In addition, when the results were compared in the control group and the group with benign ocular disease, no significant differences were detected (P greater than .01).

Occupation in Relation to Cancer of the Eye and Adnexa : With Practical Points for the Ophthalmologist

The medical literature of Great Britain, France, Germany, and, to a lesser extent, that of America contains articles dealing with occupational cancer. No specific ar­ ticles on cancer of the eye and adnexa have been found. Kenneway, in an article concerning the anatomical distribution of occupational cancer, found 11 cases of eye and eyelid epitheliomas among 100 pitch workers, and 2 cases among 33 tar work­ ers. Among 38 persons who had 75 can­ cers due to arsenic only one case in which the eyelid was involved was found. Among 21,510 patients suffering with neoplastic disease, seeking treatment at Memorial Hospital, New York City, dur­ ing a period of 13 years, Haagensen found 208 cases of ocular cancer (not all were verified by biopsy). At the 1936 meeting of the American College of Surgeons the writer presented a report on an occupational study of cancer of the eye, setting forth the results in 1,000 patients. The cases were equally divided between carcinomas and malig­ nant melanomas.