Conjunctival Melanoma: Features Based on the Fitzpatrick Skin Type (FST) in 540 Patients at a Single Ocular Oncology Center

Background: The Fitzpatrick skin type (FST) is a classification system for skin pigmentation that has been used to stratify risk for cutaneous melanoma; however, it has not yet been explored in the context of conjunctival melanoma. Herein, we examine FST and its association with the clinical features of conjunctival melanoma. Methods: A retrospective review was conducted on 540 medical records of patients with pathologic diagnosis of conjunctival melanoma. The patients were categorized according to the FST classification based on their external facial photographs at presentation. This includes: Type I (white skin color), Type II (fair skin color), Type III (average skin color), Type IV (light-brown skin color), Type V (brown skin color), and Type VI (black skin color). Other clinical features (namely tumor characteristics, tumor location, and tumor color) were also noted. Results: The FST included Types I (n=126, 23%), II (n=337, 62%), III (n=56, 10%), IV (n=8, 2%), V (n=12, 2%), and VI (n=1, \u3c1%). Statistical analysis (FST I vs. FST II vs. FST III, IV, V, and VI) revealed FST I and II tumors had smaller tumor thickness (2.1 vs. 2.8 vs. 3.6 mm, p=0.01) and less eyelid involvement (13% vs. 13% vs. 28%, p=0.02). Discussion: In this analysis, we found that the majority of patients with conjunctival melanoma are FST I or II; they also had smaller tumor thickness and less eyelid involvement than FST III, IV, V, and VI. Thus, patients with FST I and II should be considered a phenotype at risk for conjunctival melanoma and be observed accordingly

Conditional Metastasis of Uveal Melanoma in 8091 Patients over Half-Century (51 Years) by Age Group: Assessing the Entire Population and the Extremes of Age

PURPOSE: To evaluate cumulative incidence of metastasis at specific timepoints after treatment of uveal melanoma in a large cohort of patients and to provide comparison of conditional outcomes in the youngest and oldest cohorts (extremes of age). METHODS: Retrospective analysis of 8091 consecutive patients with uveal melanoma at a single center over a 51-year period. The patients were categorized by age at presentation (0-29 years [n = 348, 4%], 30-59 years [n = 3859, 48%], 60-79 years [n = 3425, 42%], 80 to 99 years [n = 459, 6%]) and evaluated for nonconditional (from presentation date) and conditional (from specific timepoints after presentation) cumulative incidence of metastasis at five, 10, 20, and 30 years. RESULTS: For the entire population of 8091 patients, five-year/10-year/20-year/30-year nonconditional cumulative incidence of metastasis was 15%/23%/32%/36%, and the conditional incidence improved to 6%/15%/25%/30% for patients who did not develop metastasis in the first three years. For the extremes of age (0-29 years and 80-99 years), the nonconditional cumulative incidence of metastasis revealed the younger cohort with superior outcomes at 8%/15%/19%/27% and 21%/29%/29%/29%, respectively (P \u3c 0.001). The conditional incidence (at one-year and two-year timepoints with metastasis-free survival) showed persistent superior younger cohort survival (P \u3c 0.001, P = 0.001), but no further benefit for patients with three-year metastasis-free survival at 4%/12%/16%/24% and 7%/18%/18%/18%, respectively (P = 0.09). CONCLUSIONS: Non-conditional metastasis-free survival analysis for patients with uveal melanoma revealed the youngest cohort to have significantly better survival than the oldest cohort, and this persisted into one-year and two-year conditional metastasis-free survival but diminished at the three-year conditional timepoint

High Local Control and Low Ocular Toxicity Using Ultra-Low-Dose “Boom-Boom” Radiotherapy for Indolent Orbital Lymphoma

Background: The first line definitive treatment for early-stage indolent B-cell lymphoma is radiation therapy (RT). Due to the sensitivity of orbital structures to radiation, ultra-low-dose RT (4 Gy in 2 fractions, boom-boom ) has and been utilized as an attractive option for orbital lymphoma. In this retrospective study, we evaluated the outcome and toxicity of boom-boom RT for indolent orbital lymphoma with an emphasis on ophthalmologic toxicity. Methods: This is a retrospective case series with 17 patients with orbital lymphoma who received boom-boom RT at a single tertiary referral center between January 2017 and June 2022. Medical records, imaging and radiation treatment plans were reviewed. Endpoints included response rate, progression, and ocular toxicity per oncologist and ophthalmology reports. Results: A total of 17 patients (12 female and 5 male) with 19 indolent orbital lymphomas were included. Median follow-up was 39 months. Complete, partial, and stable response was achieved in 65%, 24%, and 12% of patients, respectively. Only 1 patient developed local recurrent 47 month after radiation treatment, and was successfully salvaged with standard dose radiation (24 Gy). Five-year distant progression rate is 18%. Oncologist-reported Common Terminology Criteria for Adverse Events (CTCAE) toxicity rates were 6% grade 1 and 0% grade 2+. Ophthalmologist reported 33.3% new post-RT toxicities including dry eye, cataract, and chorioretinal atrophy. There is no significant vision acuity change after RT. Conclusions: Boom-Boom RT (4 Gy in 2 fractions) provides excellent control for indolent orbital lymphoma. While minimal toxicity was documented by radiation oncologists, higher rates were noted by ophthalmologists, highlighting the radiosensitivity of orbital structures and potentially underreported ocular toxicity in boom-boom and standard regimens. Further prospective randomized studies are needed to better define the outcome and toxicity of ultra-low-dose (4 Gy) RT for ocular lymphoma

White paper on ophthalmic imaging for choroidal nevus identification and transformation into Melanoma

Purpose: To discuss the evolution of noninvasive diagnostic methods in the identification of choroidal nevus and determination of risk factors for malignant transformation as well as introduce the novel role that artificial intelligence (AI) can play in the diagnostic process. Methods: White paper. Results: Longstanding diagnostic methods to stratify benign choroidal nevus from choroidal melanoma and to further determine the risk for nevus transformation into melanoma have been dependent on recognition of key clinical features by ophthalmic examination. These risk factors have been derived from multiple large cohort research studies over the past several decades and have garnered widespread use throughout the world. More recent publications have applied ocular diagnostic testing (fundus photog-raphy, ultrasound examination, autofluorescence, and optical coherence tomography) to identify risk factors for the malignant transformation of choroidal nevus based on multimodal imaging features. The widespread usage of ophthalmic imaging systems to identify and follow choroidal nevus, in conjunction with the characterization of malignant transformation risk factors via diagnostic imaging, presents a novel path to apply AI. Conclusions: AI applied to existing ophthalmic imaging systems could be used for both identification of choroidal nevus and as a tool to aid in earlier detection of transformation to malignant melanoma. Translational Relevance: Advances in AI models applied to ophthalmic imaging systems have the potential to improve patient care, because earlier detection and treatment of melanoma has been proven to improve long-term clinical outcomes

Hyperprolactinaemia in first episode psychosis - a longitudinal assessment

Little is known about hyperprolactinaemia (HPL) in first episode psychosis (FEP) patients. We investigated longitudinal changes in serum prolactin in FEP, and the relationship between HPL, and antipsychotic medication and stress. Serum prolactin was recorded in FEP patients at recruitment and again, 3 and 12 months later. HPL was defined as a serum prolactin level greater than 410 mIU/L (~19.3ng/ml) for males, and a serum prolactin level greater than 510 mIU/L (~24.1ng/ml) for females. From a total of 174 people with serum prolactin measurements at study recruitment, 43% (n=74) had HPL, whilst 27% (n=21/78) and 27% (n=26/95) had HPL at 3 and 12 months respectively. We observed higher serum prolactin levels in females versus males (p<0.001), and in antipsychotic treated (n=68) versus antipsychotic naïve patients (p<0.0001). Prolactin levels were consistently raised in FEP patients taking risperidone, amisulpride and FGAs compared to other antipsychotics. No significant relationship was observed between perceived 3 stress scores (β=7.13, t =0.21, df=11, p=0.0.84 95% CI -72.91-87.16), or objective life stressors (β=-21.74, t=-0.31, df=8, p=0.77 95% CI -218.57-175.09) and serum prolactin. Our study found elevated rates of HPL over the course of the first 12 months of illness. We found no evidence to support the notion that stress is related to elevated serum prolactin at the onset of psychosis

GDF15 promotes weight loss by enhancing energy expenditure in muscle

Funding Information: We thank R. Seeley for sharing GFRAL-null mice; B. Lowell for sharing β-less mice; and J. Wu for shipping β-less mice to us. G.R.S. was supported by a Diabetes Canada Investigator Award (DI-5-17-5302-GS), a Canadian Institutes of Health Research Foundation Grant (201709FDN-CEBA-116200), a Tier 1 Canada Research Chair in Metabolic Diseases and a J. Bruce Duncan Endowed Chair in Metabolic Diseases; D.W. by Fellowship Grants from the McMaster Institute for Research on Aging (MIRA) at McMaster University; S.R. by a postdoctoral fellowship supported by MITACS and Novo Nordisk; L.K.T. by a CIHR Post-Doctoral Fellowship Award and Michael DeGroote Fellowship Award in Basic Biomedical Science; E.M.D. by a Vanier Canada Graduate Scholarship; G.P.H. by the Natural Sciences and Engineering Research Council of Canada (NSERC: 400362); G.J.D. and S.M.F. by NSERC-CGSM scholarships; L.D. by the Fonds de Recherche du Québec-Santé doctoral training award; D.P.B. by the GSK Chair in Diabetes of Université de Sherbrooke and a FRQS J1 salary award. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by the NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS. Funding Information: S.B.J. and R.E.K. are employees of Novo Nordisk, a pharmaceutical company producing and selling medicine for the treatment of diabetes and obesity. G.R.S. is a co-founder and shareholder of Espervita Therapeutics. McMaster University has received funding from Espervita Therapeutics, Esperion Therapeutics, Poxel Pharmaceuticals and Nestle for research conducted in the laboratory of G.R.S. S.R. is supported by a MITACS postdoctoral fellowship sponsored by Novo Nordisk. H.C.G. holds the McMaster-Sanofi Population Health Institute Chair in Diabetes Research and Care. G.R.S., G.P. and H.C.G. are inventors listed on a patent for identifying GDF15 as a biomarker for metformin. G.R.S. has received consulting/speaking fees from Astra Zeneca, Eli Lilly, Esperion Therapeutics, Merck, Poxel Pharmaceuticals and Cambrian Biosciences. The other authors declare no competing interests. Publisher Copyright: © 2023, The Author(s).Peer reviewedPublisher PD

Likelihood of Germline Mutation with Solitary Unilateral Retinoblastoma Based on Patient Age at Presentation. A Real-World Analysis of 482 Consecutive Patients.

Introduction: Retinoblastoma due to germline mutation has a greater risk of bilateral presentation, and multifocal or extraocular involvement. In solitary unilateral retinoblastoma, the inheritance pattern is less understood and assumed to be somatic. We assessed the likelihood of germline inheritance in children with unilateral retinoblastoma and whether it varies based on age at presentation. Methods: This was a retrospective case study assessing 482 consecutive patients with solitary unilateral retinoblastoma at Wills Eye Hospital between 1972 and 2020 for the likelihood of germline inheritance based on age at presentation (≤1 year vs. \u3e1 year). Germline inheritance was deemed likely if there was a family history of retinoblastoma, positive genetic testing, and/or progression to bilateral retinoblastoma. Only patients with \u3e1-month follow-up were included. Chi-square test and Odds Ratio analyses were performed. Results: 465 of the 482 patients had sufficient follow-up data. 16% (n=72) of all patients, and 29% (n=37) of patients ≤1 year of age with unilateral retinoblastoma were likely to have germline disease (p=0.001). When compared to patients \u3e1 year of age (n=339), patients ≤1 year (n=126) demonstrated a greater likelihood of germline inheritance with a 2.96 odds ratio ([1.55 – 5.65]). Discussion: The inheritance of unilateral retinoblastoma is poorly understood. We found that 16% of children with unilateral retinoblastoma likely have germline inheritance, with a greater likelihood in children ≤1 year of age. Therefore, early assessment of inheritance and genetic testing of unilateral retinoblastoma may uncover germline disease and potential bilateral progression, for which a more conservative management approach to preserve vision should be considered

A Multicenter Analysis of Nucleic Acid Quantification Using Aqueous Humor Liquid Biopsy in Retinoblastoma: Implications for Clinical Testing

PURPOSE: Retinoblastoma (RB) is most often diagnosed with clinical features and not diagnosed with tumor biopsy. This study describes tumor-derived analyte concentrations from aqueous humor (AH) liquid biopsy and its use in clinical assays. DESIGN: Case series study. PARTICIPANTS: Sixty-two RB eyes from 55 children and 14 control eyes from 12 children from 4 medical centers. METHODS: This study included 128 RB AH samples including: diagnostic (DX) samples, samples from eyes undergoing treatment (TX), samples after completing treatment (END), and during bevacizumab injection for radiation therapy after completing RB treatment (BEV). Fourteen-control AH were analyzed for unprocessed analytes (double-stranded DNA [dsDNA], single-stranded DNA [ssDNA], micro-RNA [miRNA], RNA, and protein) with Qubit fluorescence assays. Double-stranded DNA from 2 RB AH samples underwent low-pass whole-genome sequencing to detect somatic copy number alterations. Logistic regression was used to predict disease burden given analyte concentrations. MAIN OUTCOME MEASURES: Unprocessed analyte (dsDNA, ssDNA, miRNA, RNA and protein) concentrations. RESULTS: Results revealed dsDNA, ssDNA, miRNA, and proteins, but not RNA, were quantifiable in most samples (up to 98%) with Qubit fluorescence assays. Median dsDNA concentration was significantly higher in DX (3.08 ng/μl) compared to TX (0.18 ng/μl; CONCLUSIONS: Aqueous humor liquid biopsy in RB is a high-yield source of dsDNA, ssDNA, miRNA, and protein. Diagnostic samples are most useful for RB 1 gene mutational analyses. Genomic analysis may be more informative of tumor activity status than quantification alone and can be performed even with smaller analyte concentrations obtained from TX samples. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found after the references

Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density.

The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease