Clear evidence that long-term, low-dose tamoxifen treatment can induce ocular toxicity. A prospective study of 63 patients.

The current study has prospectively investigated the incidence and course of ocular toxicity after low-dose tamoxifen treatment. Sixty-three patients with cancer who could be examined were analyzed. Tamoxifen was administered on a 20-mg daily dose. Median duration of treatment was 25 months. Median total tamoxifen dose was 14.4 gr. Four patients had retinopathy and/or keratopathy 10, 27, 31, and 35 months, respectively, after tamoxifen initiation (an incidence of 6.3%). Ophthalmologic findings consisted of decreased visual acuity, bilateral macular edema, yellow-white dots in the paramacular and fovea areas in all patients as well as corneal opacities in one patient. After tamoxifen withdrawal almost all ocular abnormalities were found to be reversible, except for the retinal opacities. This is the first prospective study in the literature indicating that even conventional low-dose tamoxifen treatment can induce ocular toxicity. In addition, the authors review and discuss the literature of the last decades.     

MEK inhibitor-associated retinopathy (MEKAR) in metastatic melanoma: Long-term ophthalmic effects

BackgroundMitogen-activated protein kinase kinase (MEK) inhibitors have aroused considerable interest in oncology. Activity has been demonstrated in various types of cancer, especially melanoma. MEK inhibitors induce a transient retinopathy, considered to be a class effect. At present, only sparse data are available on retinal effects with long-term MEK inhibition.Patients and methodsIn this prospective, observational study, patients with advanced melanoma participating in different phase 1/2 or phase 3 clinical trials were treated with the MEK inhibitor binimetinib, with a v-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibitor, or with combination therapy. They underwent regular ophthalmological examinations including determination of visual function, biomicroscopy, dilated fundoscopy and optical coherence tomography (OCT) for a period of up to 2 years. Retinopathy was diagnosed on defined OCT criteria.ResultsSixty-two patients were investigated between 1st October 2011 and 31st July 2015: 13 were treated with the MEK inhibitor binimetinib alone, 10 with a selective BRAF inhibitor, and 39 with combination therapy. In 92% of patients on monotherapy and 100% of those on combination treatment, binimetinib caused dose-related lesions with serous neuroretinal detachments and oedema, strongly dependent on the time after medication. With continued treatment, retinal volume and thickness decreased to levels below baseline, without any apparent functional deficits or changes in structural integrity.ConclusionsBinimetinib induces a specific retinopathy with daily fluctuations depending on the time interval after medication. The retinopathy partially recovers, but can still be detected many months later. Retinal thinning, possible first signs of retinal atrophy have been observed after long-term treatment, but, so far, without functional relevance.     

Usefulness of 22-oxa-1,25-dihydroxyvitamin D-3 (OCT) as a single agent or combined therapy with aromatase inhibitor (CGS 16949A) on 7,12-dimethylbenz[a]anthracene-induced rat mammary tumors

The antitumor effects of 22-oxa-1,25-dihydroxy-vitamin D-3 (OCT), a vitamin D-3 analogue, were evaluated on 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumors. The combined effects of OCT (0.3 mu g/kg) with tamoxifen (0.5 mg/kg) medroxyprogesterone acetate (MPA) 2.5 mg/kg), or a new aromatase inhibitor, CGS 16949A (0.8 mg/kg) were also evaluated. OCT significantly suppressed the growth of tumors without hypercalcemia in a dose dependent manner at the fourth week from the start of treatment. Tumor size in the OCT+CGS 16949A group was significantly decreased compared with that in the OCT or CGS 16949A alone. However, there was no significant difference in tumor size between OCT alone and combined therapy with tamoxifen or MPA. We conclude that a single administration of OCT, which does not cause hypercalcemia, is effective for breast cancer and that a combination of OCT and aromatase inhibitor, CGS 16949A augments the antitumor effect on tumors compared to each single agent.     

乳腺癌相关性视网膜病变研究进展

乳腺癌相关性视网膜病变(breast cancer-associated retinopathy, BCAR)是一种较为罕见的疾病, 需要与肿瘤转移所致的视网膜病变相区别, BCAR在乳腺癌患者中的发病率较低。有关BCAR的定义、临床表现、治疗等均无统一定论, 当部分乳腺癌患者诊治过程中出现眼部症状时往往将其归为化疗副作用, 或误诊为糖尿病视网膜病变、老年性白内障等, 而未考虑到BCAR。早期诊治将有助于提高BCAR患者的生存质量, 本文综述了BCAR的发病机制、发病率、临床表现及诊断、治疗和预后。      

Molecular mechanisms of antiestrogen action in breast cancer

The success of antiestrogen therapy to treat all stages of breast cancer, and the evaluation of tamoxifen as a preventive for breast cancer in normal women, have focused attention on the molecular mechanisms of antiestrogen action and mechanisms of drug resistance. The overall goal of research is to enhance current therapies and to develop new approaches for breast cancer treatment and prevention. Recent studies show that tamoxifen and the new pure antiestrogens appear to have different mechanisms of action: tamoxifen and related compounds cause a change in the folding of the steroid binding domain that prevents gene activation whereas the pure antiestrogens cause a reduced interaction at response elements and cause a rapid loss of receptor complexes. Tamoxifen treatment produces changes in the cellular and circulating levels of growth factors that could influence both receptor negative or receptor positive tumor growth and the metastatic potential of a tumor. These events may explain the survival advantage observed with tamoxifen therapy. However, the current therapeutic challenge is to avoid drug resistance during long-term tamoxifen therapy. Numerous explanations for drug resistance to tamoxifen have been suggested, including elevated estrogen levels, increased tumor antiestrogen binding sites, receptor mutations, and impaired signal transduction. However, it is probable that multiple mechanisms evolve to facilitate tumor survival. Most importantly, current research is examining mechanisms responsible for the beneficial actions of tamoxifen on bones and lipids as well as the potentially deleterious effects of tamoxifen on liver and endometrial carcinogenesis and retinopathy. The urgent need to understand antiestrogenic drug mechanisms and toxicity is being facilitated by the application of the technology developed for basic molecular biology.     

Reversible ocular toxicity related to tamoxifen therapy

A 42-year-old woman with metastatic breast cancer developed bilateral optic disc swelling, retinal hemorrhages, and visual impairment three weeks after starting treatment with low doses of tamoxifen. Neurologic evaluation failed to provide an explanation for the ocular findings which resolved completely after cessation of tamoxifen therapy. This case suggests that tamoxifen has the potential for causing serious ophthalmologic toxicity which may be reversible if recognized early.     

糖尿病视网膜Muller细胞的研究进展

Muller细胞是脊椎动物视网膜内最主要的神经胶质细胞。它贯穿整个视网膜，与视网膜神经细胞及视网膜血管发生多种功能的交互作用。糖尿病视网膜病变（diabetic retinopathy，DR）的发病机制至今尚未明，近年来的临床和基础研究发现DR患者和动物模型中Muller细胞超微结构和生理功能发生了变化，这种变化早于视网膜血管损伤。本文就近几年有关糖尿病视网膜Muller细胞形态结构及生理变化的研究进展作一综述。     

生长抑素增强三苯氧胺抗乳腺癌作用的体外研究

Objective:To study the antineoplastic effects of tamoxifen(TAM) in combination with a somatostain analogue(octreotide,OCT) on breast cancer.Methods:Estrogen receptor(ER)-positive(MCF-7) and ER-negative(MDA-MB-435S)human breast carcinoma cell lines were treated with TAM or OCT,or combination of both agents in vitro.Cell proliferation was evaluated by MTT assay,distribu-tion of cell cycle and rate of apoptosis were detemined by flow cytometry.Results:The inhibitory effect of OCT or TAM on proliferation of MCF-7 cells was associated with cell arrest in G0/G1 phase and induction of apoptosis.The inhibitory effect on proliferation of MCF-7 cells enhanced when treatment of TAM combined with OCT.The increased rate of apoptosis induced by combination of TAM and OCT was much higher than use of either TAM or OCT alone.TAM or OCT also had weak inhibitory effect on MDA-MB435S cell.The cells were arrested at S phase by TAM and at G0/G1 phase by OCT, but the induction of apoptosis was not identified.However,the rate of apoptosis was 22.7% if combined treatment of TAM and OCT applied.Conclusion:TAM and OCT can synergistically inhibit proliferation and induce apoptosis of ER-positive and ER-negative breast cancer cells.The synergism of TAM and OCT may be of interest in the clinical treatment of breast carcinoma.     

Cancer-retina antigens as potential paraneoplastic antigens in melanoma-associated retinopathy

Melanoma-associated retinopathy is a rare paraneoplastic neurological syndrome characterized by retinopathy in melanoma patients. The main photoreceptor proteins have been found to be expressed as cancer-retina antigens in melanoma. Here we present evidence that these can function as paraneoplastic antigens in melanoma-associated retinopathy. Sera and one tumor cell line of such patients were studied and ret-transgenic mice spontaneously developing melanoma were used as a murine model for melanoma-associated retinopathy. Splenocytes and sera were used for adoptive transfer from tumor-bearing or control mice to wild-type mice. Retinopathy was investigated in mice by funduscopy, electroretinography and eye histology. Expression of photoreceptor proteins and autoantibodies against arrestin and transducin were detected in melanoma-associated retinopathy patients. In tumor-bearing ret-transgenic mice, retinopathy was frequently (13/15) detected by electroretinogram and eye histology. These pathological changes were manifested in degenerations of photoreceptors, bipolar cells and pigment epithelium as well as retinal detachment. Mostly these defects were combined. Cancer-retina antigens were expressed in tumors of these mice, and autoantibodies against arrestin were revealed in some of their sera. Adoptive transfer of splenocytes and sera from tumor-bearing into wild-type mice led to the induction of retinopathy in 4/16 animals. We suggest that melanoma-associated retinopathy can be mediated by humoral and/or cellular immune responses against a number of cancer-retina antigens which may function as paraneoplastic antigens in melanoma-associated retinopathy.     

Radiation-induced retinopathy]

Radiation retinopathy is a retinal microangiopathy, observed after irradiation of the eye. It can rarely lead to neovascular glaucoma and enucleation due to pain. It is due to a progressive retinal capillary then vascular occlusion. Total irradiation dose, dose fraction, and surface of the irradiated retina seem to be strong predictive factors for radiation retinopathy. Patients who underwent an irradiation near the eye (skull base tumors, nasal and paranasal tumors, or brain tumors) should be followed by periodic ophthalmologic examination to detect and treat when necessary the non perfusion areas.     

Large Cell Neuroendocrine Carcinoma of the Lung with Cancer-Associated Retinopathy

We report a rare case of large cell neuroendocrine carcinoma (LCNEC) of the lung with cancer-associated retinopathy (CAR). To our knowledge, only two cases of LCNEC with CAR have been reported, one in 1995 and another in 2013. CAR, typically associated with small cell lung cancer (SCLC), is one of the paraneoplastic syndromes with deterioration of visual acuity, visual field constriction, and photophobia. CAR is caused by an autoimmune system reaction against the same antigen in the tumor and retinal photoreceptor cells. To diagnose CAR, genetic retinal dystrophies or any other medical causes of retinopathy should be excluded, but there are no standard diagnostic criteria. Anti-retinal antibodies are known to be positive in CAR patients, and anti-recoverin antibodies are thought to be sensitive and specific to CAR. In our case, anti-recoverin antibodies were not detected by serum tests, but CAR could be diagnosed on the basis of ophthalmological findings including clinical symptoms, electroretinographic findings, and visual field tests. CAR with clinical features of rapid visual disorder should be considered in LCNEC patients as well as in SCLC patients.Key Words: Large cell neuroendocrine carcinoma, Cancer-associated retinopathy, Anti-recoverin antibodies     

Late retinal complications of radiation therapy for nasal and paranasal malignancies: relationship between irradiated-dose area and severity.

PURPOSE: Radiation-induced cataract, once a notorious ocular complication of radiation therapy, is no longer considered a severe complication, because visual acuity can be restored by surgical treatment without significant complications. Late retinal complications of retinopathy and glaucoma, for which there is no effective method of treatment, have become serious complications of radiotherapy of the head and neck. We retrospectively investigated the risk of late retinal complications of radiotherapy for nasal and paranasal malignancies according to the radiation dose and area of the retina irradiated. METHODS AND MATERIALS: Between October 1982 and May 1996, 43 eyes of 25 patients were exposed to fractionated external-beam irradiation for treatment of advanced nasal and paranasal cancer. None of the patients had tumor invasion into the eyes. The patients were followed ophthalmologically for a minimum of 2 years (range 2.0-11, mean 4.5, median 3.3). The radiation dose and area of the retina irradiated were estimated from the dose distribution figures calculated using the portal films and CT scan. RESULTS: Major late adverse effects of radiotherapy were observed in the retina in 9 of 43 eyes (in 8/25 patients). Radiation retinopathy was observed in 7 eyes, and the cumulative incidence was 25%. The median interval before the onset of symptoms attributable to retinopathy was 32 months (range 16-60). Neovascular glaucoma developed in 3 of the 43 eyes, with a cumulative incidence of 7%. The median period to the onset of symptoms attributable to glaucoma was 22 months (range 16-26). Obstruction of the central retinal artery was observed in 1 eye. The irradiation doses to the retinas that developed late complications ranged between 54-75 Gy (mean 61, median 61). No patients who received less than 50 Gy developed retinal complications. The retina in 21 eyes was exposed to a dose of 50 Gy or more. In 13 of the 21 eyes, 60% or more of the retina was irradiated, and 8 of the eyes (62%) in this group (> or = 50 Gy, > or = 60%) developed severe retinal complications, whereas such complications only developed in 1 of the 8 eyes (13%) in the other group (> or = 50 Gy, > or = 60%). The results suggest that the radiation dose and area irradiated are the most important factors in the development of severe complications. CONCLUSION: Radiation-induced retinopathy and glaucoma are more serious late complications than cataracts, which are easily treated with surgery. We investigated the risk of late retinal complications of radiotherapy, and our findings suggested that the radiation dose and area irradiated are the most important factors in the development of severe complications. We recommend that the radiation dose and area of the retina irradiated be minimized in patients at risk of eye complications, and the patients should be closely followed by periodic ophthalmologic testing after treatment.     

Characterization of a small-cell-lung-carcinoma cell line from a patient with cancer-associated retinopathy

We examined the biologic properties of a small-cell-lung-carcinoma (SCLC) cell line (designated MN-1112) established from a patient with SCLC who showed paraneoplastic retinopathy syndrome. Morphologic and immunocytochemical analyses showed that MN-1112 cells possess features of the classic type of SCLC. MN-1112 cells grew in suspension forming relatively large clumps of cells with a doubling time of 72 hr. By light-microscope examination, the cells were relatively small and had scanty cytoplasm. The cells produced NSE, ACTH and CK (BB isozyme); they also expressed recoverin, a novel photoreceptor protein, detected by Northern-blot and Western-immunoblot analysis using human-recoverin-specific DNA probe and anti-bovine-recoverin polyclonal antibody. This report shows that human recoverin is expressed in cultured SCLC cells. Our results support the hypothesis that, in cancer-associated retinopathy (CAR) patients, auto-immune antibody targeting for ectopic recoverin in SCLC is initially produced and cross-reacts with the retinal protein, resulting in the retinal degeneration that occurs in CAR patients. © 1996 Wiley-Liss, Inc.     

Retinopathy associated with adjuvant high-dose interferon-α2b in a patient with resected melanoma: a case report and review of the literature

Interferon is the only accepted adjuvant treatment for patients with melanoma; hence, oncologists should be aware of the possibility of retinal abnormalities resulting from its use. Interferon-associated retinopathy in patients being treated for resected melanoma is a rare phenomenon with a proposed immunological basis. Patients are usually asymptomatic or have mild visual impairments, with cotton wool infarcts and hemorrhages. These symptoms and signs usually resolve with the discontinuation of interferon, but in a few severe presentations the visual impairments and retinal changes can be irreversible.     

Radiation retinopathy is treatable with anti-vascular endothelial growth factor bevacizumab (Avastin)

PURPOSE: To report on bevacizumab treatment for radiation retinopathy affecting the macula. PATIENTS AND METHODS: Twenty-one patients with radiation retinopathy (edema, hemorrhages, capillary dropout, and neovascularization) and a subjective or objective loss of vision were treated. Treatment involved intravitreal injection of bevacizumab (1.25 mg in 0.05 mL) every 6-12 weeks. Treatment was discontinued at patient request or if there was no measurable response to therapy. Main outcome measures included best corrected visual acuity, ophthalmic examination, retinal photography, and angiography. RESULTS: Bevacizumab treatment was followed by reductions in retinal hemorrhage, exudation, and edema. Visual acuities were stable or improved in 86% (n=18). Three patients discontinued therapy. Each was legally blind before treatment (n=1), experienced little to no subjective improvement (n=2), or was poorly compliant (n=2). Three patients (14%) regained 2 or more lines of visual acuity. No ocular or systemic bevacizumab-related side effects were observed. CONCLUSIONS: Intravitreal bevacizumab can be used to treat radiation retinopathy. In most cases treatment was associated with decreased vascular leakage, stabilization, or improved vision. An anti-vascular endothelial growth factor strategy may reduce tissue damage associated with radiation vasculopathy and neuropathy.     

Ophthalmologic Techniques to Assess the Severity of Hyperviscosity Syndrome and the Effect of Plasmapheresis in Patients with Waldenström's Macroglobulinemia

BackgroundThe aim of this study is to determine the serum immunoglobulin (Ig) M and serum viscosity (SV) levels at which retinal changes associated with hyperviscosity syndrome (HVS) as a result of Waldenström's macroglobulinemia (WM) occur. In addition, the effect of plasmapheresis on HVS-related retinopathy was tested.Patients and MethodsA total of 46 patients with WM received indirect ophthalmoscopy, laser Doppler retinal blood flow measurements, serum IgM, and SV determinations. A total of 9 patients with HVS were studied before and after plasmapheresis.ResultsMean IgM and SV levels of patients with the earliest retinal changes were 5442 mg/dL and 3.1 cp, respectively. Plasmapheresis improved retinopathy, decreased serum IgM (46.5 ± 18%; P = .0009), SV (44.7 ± 17.3%; P = .002), retinal venous diameter (15.3 ± 5.8%; P = .0001), and increased venous blood speed by +55.2 ± 22.5% (P = .0004).ConclusionExamination of the retina is useful in identifying the symptomatic threshold of plasma viscosity levels in patients with HVS and can be used to gauge the effectiveness of plasmapheresis treatment.     

急性白血病眼底改变与血液学参数的关系

目的探讨初诊急性白血病患者视网膜病变的发病率,视网膜改变与血液学参数的关系。方法123例急性白血病中急性髓性白血病86例和急性淋巴细胞白血病37例,年龄14~77岁。由眼科医师用直接或间接检眼镜在白血病诊断的5 d内对视网膜变化进行检查。包括视网膜内出血（IRH）、白色中心出血（WCH）、棉絮状斑（CW S）。结果视网膜损害见于61例患者（49.6%）,高白细胞计数,低血小板数和红细胞压积减低与视网膜病变发生有显著相关（P〈0.001）。有网膜病变者血清乳酸脱氢酶（LDH）水平明显增高（527.79±125.20对218.70±87.31,P〈0.001）。结论红细胞压积减低和较高的白细胞计数在急性白血病的发病机制中是重要的因素。     

Impact of tamoxifen adjuvant therapy on symptoms, functioning, and quality of life.

This article reviews the symptoms and everyday problems associated with tamoxifen adjuvant therapy and their impact on patients' quality of life. In addition, the purported toxic effects of tamoxifen therapy (e.g., premature menopause, weight gain, and depression) are discussed, and data are presented that refute claims of the toxicity of tamoxifen therapy. From randomized controlled trials of adjuvant therapy, we know that tamoxifen therapy increases the rate of hot flashes, night sweats, and vaginal discharge; however, in observational studies these symptoms do not have a statistically significant impact on patients' quality of life as measured by standardized, self-report questionnaires. The Breast Cancer Prevention Trial found no evidence of excessive rates of depression or clinically significant differences in sexual functioning between women receiving placebo and those receiving tamoxifen therapy. Although several serious medical risks from tamoxifen therapy exist (e.g., uterine cancer, blood clots, stroke, and cataracts), there are additional benefits from tamoxifen therapy in addition to an increase in disease-free survival rates and overall survival rates, including a decrease in contralateral breast cancer and fractures. Ultimately, the decision to receive tamoxifen therapy is a personal choice for each woman to make on the basis of the evidence of tamoxifen therapy's benefits and risks, along with her own motivation to receive therapy. When the benefits of such therapy are small, some women may choose to avoid treatment, but others may wish to try therapy to determine whether possible side effects are relevant. For women in whom the absolute survival benefits are large, there may be less difficulty in making this decision.     

Ocular toxicity during adjuvant chemoendocrine therapy for early breast cancer: results from International Breast Cancer Study Group trials

BACKGROUND: Others have reported ocular toxicity after adjuvant chemoendocrine therapy, but this study looked at ocular toxicity in similarly treated patients from large randomized clinical trials. METHODS: Information was retrieved on incidence and timing of ocular toxicity from the International Breast Cancer Study Group (IBCSG) database of 4948 eligible patients randomized to receive tamoxifen or toremifene alone or in combination with chemotherapy (either concurrently or sequentially). Case reports of patients with ocular toxicity were evaluated to determine whether ocular toxicity occurred during chemotherapy and/or hormonal therapy. Additional information was obtained from participating institutions for patients in whom ocular toxicity occurred after chemotherapy but during administration of tamoxifen or toremifene. RESULTS: Ocular toxicity was reported in 538 of 4948 (10.9%) patients during adjuvant treatment, mainly during chemotherapy. Forty-five of 4948 (0.9%) patients had ocular toxicity during hormone therapy alone, but only 30 (0.6%) patients had ocular toxicity reported either without receiving any chemotherapy or beyond 3 months after completing chemotherapy and, thus, possibly related to tamoxifen or toremifene. In 3 cases, retinal alterations, without typical aspects of tamoxifen toxicity, were reported; 4 patients had cataract (2 bilateral), 12 impaired visual acuity, 10 ocular irritation, 1 optical neuritis, and the rest had other symptoms. CONCLUSION: Ocular toxicity during adjuvant therapy is a common side effect mainly represented by irritative symptoms due to chemotherapy. By contrast, ocular toxicity during hormonal therapy is rare and does not appear to justify a regular program of ocular examination. However, patients should be informed of this rare side effect so that they may seek prompt ophthalmic evaluation for ocular complaints.