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Abstract Cataract is a leading cause of blindness worldwide, necessitating a deeper understanding of its risk factors. We analyzed two cohorts: 1000 individuals from the general Swedish population and 933 patients who received plaque brachytherapy for uveal melanoma. Using Kaplan-Meier and cumulative incidence analyses, as well as Cox and competing risk regressions, we assessed whether there is a relationship between sex and cataract surgery. In the general population, female sex was a significant risk factor for cataract surgery, with a 10-year incidence of 16% compared to 10% for males (subdistribution hazard ratio adjusted for age, 1.35, P

Abstract Background Uveal melanoma is the most common primary intraocular tumor in adults. In Sweden, at least 100 patients are diagnosed with the disease each year. Almost half of the patients develop metastases, with a median survival time of 1 year once metastases are detected. The primary ocular tumor is typically treated with either enucleation or brachytherapy, and no adjuvant treatment is added. Melatonin is an indolamine hormone that has improved survival in previous trials with patients diagnosed with various cancers, including advanced cutaneous melanoma. Side effects have been mild. We aim to investigate if adjuvant treatment with melatonin for 5 years following diagnosis of non-metastasized uveal melanoma can decrease the occurrence of metastases. Methods An open-label, prospective, 5-year randomized clinical trial (RCT) will be conducted at St. Erik Eye Hospital. One hundred patients recently diagnosed with non-metastatic uveal melanoma will be randomized to either treatment with adjuvant melatonin 20 mg (4 tablets of 5 mg) at 10 pm for 5 years, or to standard follow-up (control group). The primary outcome measurement is the relative risk for having developed metastases 5 years after randomization. The secondary outcomes are overall survival, risk of developing other cancers, overall survival after detection of metastases, and differences in the occurrence of adverse events (AE) and serious adverse events (SAE) between the groups. Discussion Melatonin has been found to positively impact our immune system, inhibit angiogenesis, stimulate apoptosis in malignant cells, and act as a potent antioxidant. Previous clinical trials have used similar doses of melatonin with positive results, particularly in advanced stages of cancer. Previous animal and human studies have found the toxicity of the hormone to be low. Considering the potential benefits and limited risks of melatonin, as well as its global availability, it may be a suitable candidate for an adjuvant treatment in patients with uveal melanoma. Trial registration Our trial protocol has been approved and registered by the Swedish Medical Products Agency on June 22, 2022 (EudraCT 2022–500,307-49–00). Our trial registration number is NCT05502900, and the date of registration is August 16, 2022.

Abstract Glaucoma is the leading cause of irreversible blindness and is a major health and economic burden. Current treatments do not address the neurodegenerative component of glaucoma. In animal models of glaucoma, the capacity to maintain retinal nicotinamide adenine dinucleotide (NAD) pools declines early during disease pathogenesis. Treatment with nicotinamide, an NAD precursor through the NAD salvage pathway, robustly protects against neurodegeneration in a number of glaucoma models and improves vision in existing glaucoma patients. However, it remains unknown in humans what retinal cell types are able to process nicotinamide to NAD and how these are affected in glaucoma. To address this, we utilized publicly available RNA-sequencing data (bulk, single cell, and single nucleus) and antibody labelling in highly preserved enucleated human eyes to identify expression of NAD synthesizing enzyme machinery. This identifies that the neural retina favors expression of the NAD salvage pathway, and that retinal ganglion cells are particularly enriched for these enzymes. NMNAT2, a key terminal enzyme in the salvage pathway, is predominantly expressed in retinal ganglion cell relevant layers of the retina and declines in glaucoma. These findings suggest that human retinal ganglion cells can directly utilize nicotinamide and could maintain a capacity to do so in glaucoma, showing promise for ongoing clinical trials.

Abstract Neuroinflammation is recognized as a key component of neurodegenerative disease. In glaucoma, a common neurodegenerative disease and the leading cause of irreversible blindness, the evidence for neuroinflammation in patients is lacking. Animal models have demonstrated significant pro-inflammatory activation of resident glia in the retina, as well as influx of blood-derived monocytes and pro-inflammatory factors. Confirmation of this in human donor tissue has been challenging due to a lack of well-preserved and well-characterized post-mortem tissue. To address this we utilize archived, wax embedded eyes fixed immediately following enucleation from living glaucoma patients. We compared glaucoma to control eyes (enucleated for uveal melanoma where the tumor did not impact the central retina or optic nerve). We performed immunolabelling for neurodegenerative and glial markers (CD45, CD163, IBA1, GFAP, Vimentin) which were quantified by high-resolution light microscopy and image analysis in FIJI. Glaucoma eyes demonstrated significant neural loss consistent with advanced neurodegeneration. IBA1 and GFAP were significantly increased in the retina and optic nerve head of the glaucomatous eyes indicating that significant neuroinflammation had occurred which support findings in animal models. Inflammation is a treatable symptom of many diseases and as such, identification of earlier inflammatory processes in glaucoma could be important for potential future treatment options.

Purpose: To develop a prognostic score that correlates to a low, medium, and high incidence of treatment failure after plaque brachytherapy of uveal melanoma (UM). Methods and Materials: All patients who have received plaque brachytherapy for posterior UM at St. Erik Eye Hospital in Stockholm, Sweden from 1995 through 2019 were included (n = 1636). Treatment failure was defined as tumor recurrence, lack of tumor regression, or any other condition requiring a secondary transpupillary thermotherapy (TTT), plaque brachytherapy, or enucleation. The total sample was randomized into 1 training and 1 validation cohort, and a prognostic score for the risk for treatment failure was developed. Results: In multivariate Cox regression, low visual acuity, tumor distance to the optic disc ≤2 mm, American Joint Committee on Cancer (AJCC) stage, and a tumor apical thickness of >4 (for Ruthenium-106) or >9 mm (for Iodine-125) were independent predictors of treatment failure. No reliable threshold could be identified for tumor diameter or cancer stage. In competing risk analyses of the validation cohort, the cumulative incidence of treatment failure, as well as of secondary enucleation, increased with the prognostic score: In the low, intermediate, and high-risk classes, the 10-year incidence of treatment failure was 19, 28, and 35% and of secondary enucleation 7, 19, and 25 %, respectively. Conclusions: Low visual acuity, American Joint Committee on Cancer stage, tumor thickness, and tumor distance to the optic disc are independent predictors of treatment failure after plaque brachytherapy for UM. A prognostic score was devised that identifies low, medium, and high risk for treatment failure.

Abstract Background Uveal melanoma is a rare form of cancer with high mortality. The incidence of metastases is attributed to early seeding of micrometastases from the eye to distant organs, primarily the liver. Once these seeded clusters of dormant tumor cells grow into larger radiologically detectable macrometastases, median patient survival is about 1 year. Melatonin is an important hormone for synchronizing circadian rhythms. It is also involved in other aspects of human physiology and may offer therapeutic benefits for a variety of diseases including cancer. Methods Articles involving the physiological effects of melatonin, pharmacokinetics, and previous use in cancer studies were acquired using a comprehensive literature search in the Medline (PubMed) and Web of Science databases. In total, 147 publications were selected and included in the review. Results Melatonin has been observed to suppress the growth of cancer cells, inhibit metastatic spread, enhance immune system functions, and act as an anti-inflammatory in both in vitro and in vivo models. Melatonin may also enhance the efficacy of cancer treatments such as immuno- and chemotherapy. Numerous studies have shown promising results for oral melatonin supplementation in patients with other forms of cancer including cutaneous malignant melanoma. Cell line and animal studies support a hypothesis in which similar benefits may exist for uveal melanoma. Conclusions Given its low cost, good safety profile, and limited side effects, there may be potential for the use of melatonin as an adjuvant oncostatic treatment. Future avenues of research could include clinical trials to evaluate the effect of melatonin in prevention of macrometastases of uveal melanoma.

Summary: Acute myeloid leukemia (AML) is defined by an accumulation of immature myeloid blasts in the bone marrow. To identify key dependencies of AML stem cells in vivo, here we use a CRISPR-Cas9 screen targeting cell surface genes in a syngeneic MLL-AF9 AML mouse model and show that CXCR4 is a top cell surface regulator of AML cell growth and survival. Deletion of Cxcr4 in AML cells eradicates leukemia cells in vivo without impairing their homing to the bone marrow. In contrast, the CXCR4 ligand CXCL12 is dispensable for leukemia development in recipient mice. Moreover, expression of mutated Cxcr4 variants reveals that CXCR4 signaling is essential for leukemia cells. Notably, loss of CXCR4 signaling in leukemia cells leads to oxidative stress and differentiation in vivo. Taken together, our results identify CXCR4 signaling as essential for AML stem cells by protecting them from differentiation independent of CXCL12 stimulation.

Dysregulation of cytokines in the bone marrow (BM) microenvironment promotes acute myeloid leukemia (AML) cell growth. Due to the complexity and low throughput of in vivo stem-cell based assays, studying the role of cytokines in the BM niche in a screening setting is challenging. Here, we developed an ex vivo cytokine screen using 11 arrayed molecular barcodes, allowing for a competitive in vivo readout of leukemia-initiating capacity. With this approach, we assessed the effect of 114 murine cytokines on MLL-AF9 AML mouse cells and identified the tumor necrosis factor ligand superfamily member 13 (TNFSF13) as a positive regulator of leukemia-initiating cells. By using Tnfsf13−/− recipient mice, we confirmed that TNFSF13 supports leukemia initiation also under physiological conditions. TNFSF13 was secreted by normal myeloid cells but not by leukemia mouse cells, suggesting that mature myeloid BM cells support leukemia cells by secreting TNFSF13. TNFSF13 supported leukemia cell proliferation in an NF-κB-dependent manner by binding TNFRSF17 and suppressed apoptosis. Moreover, TNFSF13 supported the growth and survival of several human myeloid leukemia cell lines, demonstrating that our findings translate to human disease. Taken together, using arrayed molecular barcoding, we identified a previously unrecognized role of TNFSF13 as a positive regulator of AML-initiating cells. The arrayed barcoded screening methodology is not limited to cytokines and leukemia, but can be extended to other types of ex vivo screens, where a multiplexed in vivo read-out of stem cell functionality is needed.