Retinoblastoma (RB) management has evolved over the last three decades. Goals of modern RB treatment are first to protect life and prevent metastatic disease, then preservation of the globe and useful vision. With modern treatment protocols and early disease detection success rates can reach up to 100% of disease-free-globe and eye preservation. Treatment of advanced cases remains complex, requiring aggressive chemotherapy or/and external beam radiation. Treatment protocols are extremely diverse and dependent on local resources thus success rates are variable. Here we review narratively current treatment protocols and failure rates based on a PubMed search using keywords of retinoblastoma, retinoblastoma seed, retinoblastoma treatment, enucleation.
Therapy Resistance and Failure in Uveal Melanoma
Uveal Melanoma (UM), a common malignant intraocular tumor, is currently lacking a standard therapy. Traditional surgical approaches can result in patients losing organs or having difficult surgical procedures resulting in poor postoperative outcomes. Either way, there is no improvement in patients’ quality of life after surgery compared to radiotherapy. As a first-line treatment with radiotherapy, this therapy is limited by the size and location of the tumor. The risk of postoperative vision loss and second surgery for enucleation remains. UM is a special type of melanoma that is resistant to chemotherapy, and although the treatment is not effective, research has been investigated on this topic, suggesting new ideas for the treatment of UM - immunotherapy and targeted therapy. The current nivolumab plus ipilimumab treatment regimen has yielded relatively successful results, with some very encouraging case reports, but not as good as their efficacy in skin cancer. Despite the current unsatisfactory results of these new therapies, it is still the most attractive answer for UM that is highly metastatic and has a very poor prognosis. This review supports clinical decision-making and new treatment development by compiling the strengths and weaknesses of common treatments currently available in the clinic.
- Citations: 0
- Aug 10, 2022
Interventional Radiotherapy (Brachytherapy) in Eyelid and Ocular Surface Tumors: A Review for Treatment of Naïve and Recurrent Malignancies
The goal of radiotherapy in the treatment of eyelid and ocular surface tumors is to eradicate tumor burden in a manner that maintains visual function and preserve surrounding sensitive ocular tissue. Interventional radiotherapy (IRT-brachytherapy) is a radiotherapy technique associated with a highly focal dose distribution, with the advantage of boosting limited size target volumes to very high dose while sparing normal tissue. The reduction in the ocular and adnexal complications that result from this form of therapy, has led in recent years, to an increase in the use of IRT for the treatment of eyelid and ocular surface tumors. For eyelid malignancies, IRT is used as an independent treatment in small eyelids tumors, in postoperative treatment of high-risk patients and as well as salvage therapy in local recurrences. In the treatment of conjunctival malignancies, due to the high risk of local recurrence, the use of adjuvant therapies as IRT has shown to improve outcomes. In this review, we focus on eyelid and ocular surface IRT techniques and provide an overview of indication, outcomes and toxicity of IRT for the treatment of naïve and recurrent eyelid and conjunctival tumors.
- Citations: 2
- Mar 25, 2022
Increase of Kynurenic Acid after Encephalomyocarditis Virus Infection and Its Significances
The moust symptoms of piglets infected with Encephalomyocarditis virus (EMCV) are related to breeding difficulty, circulation insufficiency, depression and occurrence of high lethality. An increase of tryptophan metabolism in the periphery and in the central nervous system (CNS) in human and non-human subjects with inflammatory diseases has been suggested. We investigated an alterations of tryptophan metabolite i.e. kynurenic acid (KYNA) level in the serum of piglets after EMC virus infection. In addition, we investigated the markers of immune stimulation i.e. neopterin and β2-microglobulin. KYNA was determined by high performance liquid chromatography method, while neopterin and β2-microglobulin by ELISA method. Piglets with an age of 8 weeks were infected intranasal and orally with the EMC virus. Blood samples were collected before virus inoculation at day 0 (control) and at 1, 2, 3 and 4 days post inoculation (DPI) and piglets as control subjects were used, too. In EMCV infected piglets we observed a time dependent alteration of investigated parameters. KYNA level increased significantly and at 3 DPI was 341% of CO, p<0.001 and at 4 DPI an enhancement was 242% of CO, p<0.001, respectively. Neopterin increased moderately after EMCV infection and at 4 DPI was 130% of CO, p<0.05. Serum β2-microglobulin was slightly lowered and at 4 DPI was 86% of CO, p<0.05. Present data indicate an marked increase of kynurenine metabolism in the periphery after EMCV infection and an moderate activation of immune system. A marked increase of KYNA and a moderate enhancement of neopterin indicate sensibility of kynurenine metabolism to EMCV infection. Lowering of ß2-microgobulin might relate to development of events leading to the lethality. We suggest that due to viral infection an increase of KYNA might contribute to the inpairment of organs in the periphery and CNS function and might participate by sudden death.
- Citations: 0
- Sep 30, 2021
Primary Vitreoretinal Lymphoma Therapy Monitoring: Significant Vitreous Haze Reduction After Intravitreal Rituximab
Intravitreal rituximab is an off-label treatment option for primary vitreoretinal lymphoma (PVRL). The objective of this study was to monitor the therapeutic response and safety profile of intravitreal rituximab in a cohort of PVRL patients. In this retrospective, uncontrolled, open label, multicentre study, 20 eyes from 15 consecutive patients diagnosed with PRVL received at least one intravitreal injection of 1mg in 0.1ml rituximab. Biodata of the PVRL patients was recorded as well as visual acuity and vitreous haze score immediately before rituximab intravitreal injection and at follow-up examinations. Intravitreal rituximab safety data was also recorded. Additional rituximab injections were made during control visits on a pro re nata (PRN) regime using increased vitreous haze to indicate recurrence. There was significant vitreous haze reduction (p=0.0002) followed by significant improvement of visual acuity (mean best visual acuity before therapy 0.57 logMAR, after therapy 0.20 logMAR (p=0.0228) during the follow-up time up to 4 years. Only mild ocular side effects were reported. Median follow-up time was 565 days (range, 7-1253 days). Intravitreal rituximab therapy shows promising PVRL regression without any severe side effects. Although our clinical data support rituximab as intravitreal therapy in PVRL disease, further study is warranted.
- Citations: 4
- May 5, 2021
Klotho-Dependent Role of 1,25(OH)2D3 in the Brain
The antiaging protein Klotho is encoded by the Klotho gene first identified as an 'aging suppressor', in mice. Klotho deficiency is involved in premature aging and early death, while its overexpression is related to longevity. Klotho is mostly expressed in the kidney, but also in the brain, and in otherorgans. Two forms of Klotho, the cell membrane and secreted form, have pleiotropic activities that include regulation of general metabolism, oxidative stress, and mineral metabolism that correlates with its effect on accelerating aging. Membrane Klotho serves as an obligate co-receptor for the fibroblast growth factor (FGF), while secreted Klotho plays its role as a humoral factor. Klotho protein participates in the regulation of several biological activities, including regulation of calcium-phosphate homeostasis and PTH as well as vitamin D metabolism. The active form of vitamin D, 1,25(OH)2D3 (1,25-dihydroxy-vitamin D3 = calcitriol), acts as a neurosteroid that participates in the regulation of multiplebrain functions. It provides neuroprotection and suppresses oxidative stress, inhibits inflammation and inflammatory mediators, and stimulates various neurotrophins. Calcitriol is involved in many brain-related diseases, including multiple sclerosis, Alzheimer´s disease, Parkinson´s disease, and schizophrenia. This review covers the most recent advances in Klotho research and discusses Klotho-dependent roles of calcitriolin neuro-psycho-pathophysiology.
- Citations: 5
- Mar 31, 2021
Intervention of Tyrosine Hydroxylase Expression Alters Joint Inflammation and Th17/Treg Imbalance in Collagen-Induced Arthritis
Neuroendocrine dysregulation has been associated with rheumatoid arthritis (RA). Tyrosine hydroxylase (TH), a rate-limiting enzyme for synthesis of neuroendocrine hormones such as epinephrine, is also expressed in T lymphocytes and regulates balance between helper T (Th) 17 cells and regulatory T (Treg) cells. Herein, we aimed to show that TH expression in joints alleviates joint inflammation and Th17/Treg imbalance in collagen-induced arthritis (CIA), an animal model of RA, and these effects may be implemented by the mechanism of epinephrine action on α1-adrenoreceptor (α1-AR) in T cells. CIA was prepared by intradermal injection of collagen type II in tail base of DBA1/J mice. On the 33rd day post-immunization, lentiviral vectors encoding TH or TH shRNA were injected into ankle joints of CIA mice. Limb inflammation of the mice was assessed beginning from day 21 until day 69 post-immunization by measurement of limb swelling, erythema and rigidity. Th17 and Treg differentiation and function in ankle joints were assessed on day 69 post-immunization by test of the expression of Th17 transcriptional factor ROR-γt and the levels of proinflammatory cytokines interleukin (IL)-17 and IL-22 as well as the expression of Treg transcriptional factor Foxp3 and the levels of antiinflammatory cytokines transforming growth factor (TGF)-β1 and IL-10. T cells were obtained from the spleen of mice that had been immunized with collagen type II 41 day earlier and treated with epinephrine or α1-AR agonist phenylephrine in vitro. Flow cytometry was used to analyze the percentages of CD25-IL-17+ cells and CD25+Foxp3+ cells in CD4+ T cells. TH gene overexpression in ankle joints of CIA mice reduced limb inflammation and Th17-related transcription factor expression and inflammatory cytokine production but increased Treg-related antiinflammatory cytokine production in the joints. In contrast, TH gene silence in ankle joints of CIA mice enhanced limb inflammation and Th17 cell activity but decreased Treg cell function in the joints. Epinephrine upregulated α1-AR expression in T cells derived from CIA mice. Both epinephrine and phenylephrine reduced CIA-induced Th17 transcription factor expression and inflammatory cytokine production but enhanced Treg antiinflammatory cytokine production in vitro. Upregulating TH expression in joints alleviates joint inflammation and Th17/Treg imbalance in CIA at least partially by enhancing epinephrine action on α1-AR in T cells.
- Citations: 0
- Feb 6, 2021
The Putative Role of 1,25(OH)2D3 in the Association of Milk Consumption and Parkinson’s Disease
The consumption of dairy products, particularly of low fat milk, has been shown to be associated with the occurrence of Parkinson's disease. This association does not necessarily reflect a pathophysiological role of milk intake in the development of Parkinson's disease. Nevertheless, the present review discusses a potential mechanism possibly mediating an effect of milk consumption on Parkinson's disease. The case is made that milk is tailored in part to support bone mineralization of the suckling offspring and is thus rich in calcium and phosphate. Milk intake is thus expected to enhance intestinal calcium phosphate uptake. As binding to fatty acids impedes Ca2+ absorption, low fat milk is particularly effective. Calcium and phosphate uptake inhibit the formation of 1,25(OH)2D3 (1,25-dihydroxy-vitamin D3 = calcitriol), the active form of vitamin D. Calcium inhibits 1,25(OH)2D3 production in part by suppressing the release of parathyroid hormone, a powerful stimulator of 1,25(OH)2D3 formation. Phosphate excess stimulates the release of fibroblast growth factor FGF23, which suppresses 1,25(OH)2D3 formation, an effect requiring Klotho. 1,25(OH)2D3 is a main regulator of mineral metabolism, but has powerful effects apparently unrelated to mineral metabolism, including suppression of inflammation and influence of multiple brain functions. In mice, lack of 1,25(OH)2D3 and excessive 1,25(OH)2D3 formation have profound effects on several types of behavior, such as explorative behavior, anxiety, grooming and social behavior. 1,25(OH)2D3 is produced in human brain and influences the function of various structures including substantia nigra. In neurons 1,25(OH)2D3 suppresses oxidative stress, inhibits inflammation and stimulates neurotrophin formation thus providing neuroprotection. As a result, 1,25(OH)2D3 is considered to favorably influence the clinical course of Parkinson's disease. In conclusion, consumption of milk could in theory accelerate the downhill course of neuronal function in Parkinson's disease. However, substantial additional experimentation is required to define the putative causal role of 1,25(OH)2D3 in the pathophysiology of Parkinson's disease and its sensitivity to milk consumption.
- Citations: 2
- Dec 31, 2020
Kynurenine Aminotransferases I, II and III Are Present in Saliva.
Fluids of the human body such as serum, cerebrospinal fluid and saliva contain a wide variety of proteins. Because kynurenic acid (KYNA) has been detected in human saliva, we wondered if KYNA could be produced in saliva by KYNA-synthesising enzymes, namely the kynurenine aminotransferases KAT I, KAT II and KAT III. Thirty samples of human saliva from control volunteers were investigated. KAT activity was measured in the presence of 1 mM pyruvate and 2 µM or 100 µM L-kynurenine and KYNA production was assessed by high-performance liquid chromatography. Saliva dose- and time-dependently produced KYNA. KAT activity ranged between 900 and 1050 pmol/mg protein/h: 900 for KAT I, 950 for KAT III and 1050 for KAT II. KYNA was synthesised in saliva at a physiological concentration of 2 µM L-kynurenine and at a higher concentration of 100 µM. Investigation of the distributions of the enzymes in saliva revealed that KAT I, KAT II and KAT III activity in a centrifuge-obtained pellet ranged from ~100% to 120%; in the supernatant, the percentage was between 0% and 20%. We observed a nonsignificant tendency for lower KAT activity in women's saliva than in men's. KATs present in saliva were sensitive to the GABA-transaminase inhibitor γ-acetylenic GABA, with a concentration of 100 µM γ-acetylenic GABA significantly blocking the formation of KYNA (50% of control, p < 0.05). Furthermore, KATs in saliva were sensitive to anti-dementia drugs, such as D-cycloserine and cerebrolysin, in an in vitro study. Our data revealed for the first time the presence of KAT I, KAT II and KAT III proteins in human saliva. KAT activity was found mostly in pelleted cells, suggesting their presence in salivary gland cells. KAT proteins in saliva are sensitive to drugs blocking KYNA formation. Our data indicate the presence of cells in saliva involved in the biochemical machinery of the kynurenine pathway. Their role in the digestive process remains to be clarified. We speculate that modulation of KYNA formation in the mouth by food and/or drugs might affect glutamate neurotransmission and cholinergic activity in the CNS and/or periphery and play a role under physiological as well as pathological conditions.
- Citations: 3
- Mar 11, 2020
Sphingomyelin Synthases in Neuropsychiatric Health and Disease
Sphingomyelin synthases (SMS) catalyze the conversion of ceramide and phosphatidylcholine to sphingomyelin and diacylglycerol and are thus crucial for the balance between synthesis and degradation of these structural and bioactive molecules. SMS thereby play an essential role in sphingolipid metabolism, cell signaling, proliferation and differentiation processes. Although tremendous progress has been made toward understanding the involvement of SMS in physiological and pathological processes, literature in the area of neuropsychiatry is still limited. In this review, we summarize the main features of SMS as well as the current methodologies and tools used for their study and provide an overview of SMS in the central nervous system and their implications in neurological as well as psychiatric disorders. This way, we aim at establishing a basis for future mechanistic as well as clinical investigations on SMS in neuropsychiatric health and diseases.
- Citations: 14
- Dec 27, 2019