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

Cross-Species Genome-Wide Analysis Reveals Molecular and Functional Diversity of the Unconventional Interferon-ω Subtype

Innate immune interferons (IFNs), particularly type I IFNs, are primary mediators regulating animal antiviral, antitumor, and cell-proliferative activity. These antiviral cytokines have evolved remarkable molecular and functional diversity to confront ever-evolving viral threats and physiological regulation. We have annotated IFN gene families across 110 animal genomes, and showed that IFN genes, after originating in jawed fishes, had several significant evolutionary surges in vertebrate species of amphibians, bats and ungulates, particularly pigs and cattle. For example, pigs have the largest but still expanding type I IFN family consisting of nearly 60 IFN-coding genes that encode seven IFN subtypes including multigene subtypes of IFN-α, -δ, and -ω. Whereas, subtypes such as IFN-α and -β have been widely studied in many species, the unconventional subtypes such as IFN-ω have barely been investigated. We have cross-species defined the IFN evolution, and shown that unconventional IFN subtypes particularly the IFN-ω subtype have evolved several novel features including: (1) being a signature multi-gene subtype expanding primarily in mammals such as bats and ungulates, (2) emerging isoforms that have superior antiviral potency than typical IFN-α, (3) highly cross-species antiviral (but little anti-proliferative) activity exerted in cells of humans and other mammalian species, and (4) demonstrating potential novel molecular and functional properties. This study focused on IFN-ω to investigate the immunogenetic evolution and functional diversity of unconventional IFN subtypes, which may further IFN-based novel antiviral design pertinent to their cross-species high antiviral and novel activities

Efficacy of group exercise–based cancer rehabilitation delivered via telehealth (TeleCaRe) : protocol for a randomized controlled trial

Background: Access to rehabilitation to support cancer survivors to exercise is poor. Group exercise–based rehabilitation may be delivered remotely, but no trials have currently evaluated their efficacy. Objective: We aimed to evaluate the efficacy of a group exercise–based cancer rehabilitation program delivered via telehealth compared to usual care for improving the quality of life of cancer survivors. Methods: A parallel, assessor-blinded, pragmatic randomized controlled trial with embedded cost and qualitative analysis will be completed. In total, 116 cancer survivors will be recruited from a metropolitan health network in Melbourne, Victoria, Australia. The experimental group will attend an 8-week, twice-weekly, 60-minute exercise group session supervised via videoconferencing supplemented by a web-based home exercise program and information portal. The comparison group will receive usual care including standardized exercise advice and written information. Assessments will be completed at weeks 0 (baseline), 9 (post intervention), and 26 (follow-up). The primary outcome will be health-related quality of life measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire at week 9. Secondary measures include walking capacity (6-minute walk test), physical activity (activPAL accelerometer), self-efficacy (Health Action Process Approach Questionnaire), and adverse events. Health service data including hospital length of stay, hospital readmissions, and emergency department presentations will be recorded. Semistructured interviews will be completed within an interpretive description framework to explore the patient experience. The primary outcome will be analyzed using linear mixed effects models. A cost-effectiveness analysis will also be performed. Results: The trial commenced in April 2022. As of June 2022, we enrolled 14 participants. Conclusions: This trial will inform the future implementation of cancer rehabilitation by providing important data about efficacy, safety, cost, and patient experience. Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12621001417875; https://tinyurl.com/yc5crwtr International Registered Report Identifier (IRRID): PRR1-10.2196/3855

Frameless Image-Guided Radiosurgery for Trigeminal Neuralgia

Background: Frameless image-guided radiosurgery (IGRS) is a safe and effective noninvasive treatment for trigeminal neuralgia (TN). This study evaluates the use of frameless IGRS to treat patients with refractory TN. Methods: We reviewed the records of 20 patients diagnosed with TN who underwent frameless IGRS treatments between March 2012 and December 2013. Facial pain was graded using the Barrow Neurological Institute (BNI) scoring system. The initial setup uncertainty from simulation to treatment and the patient intrafraction uncertainty were measured. The median follow-up was 32 months. Results: All patients\u27 pain was BNI Grade IV or V before the frameless IGRS treatment. The mean intrafraction shift was 0.43 mm (0.28-0.76 mm), and the maximum intrafraction shift was 0.95 mm (0.53-1.99 mm). At last follow-up, 8 (40%) patients no longer required medications (BNI 1 or 2), 11 (55%) patients were pain free but required medication (BNI 3), and 1 (5%) patient had no pain relief (BNI 5). Patients who did not have prior surgery had a higher odds ratio for pain relief compared to patients who had prior surgery (14.9, P = 0.0408). Conclusions: Frameless IGRS provides comparable dosimetric and clinical outcomes to frame-based SRS in a noninvasive fashion for patients with medically refractory TN

Cytokine signature of inflammation mediated by autoreactive Th-cells, in calf muscle of claudicating patients with Fontaine stage II peripheral artery disease

Peripheral artery disease (PAD), a severe atherosclerotic condition primarily of the elderly, afflicts 200 million individuals, worldwide, and is associated with lower extremity myopathy. Circulating markers of inflammation have been linked to risk and severity of PAD but the contribution of local inflammation to myopathy remains unknown. We evaluated, by ELISA, calf muscle of PAD patients (N = 23) and control subjects (N = 18) for local expression of inflammatory cytokines including Granulocyte/Monocyte Colony-Stimulating Factor (GM-CSF), Interleukin 17A (IL-17A), Interferon ϒ (IFN-ϒ), tumor necrosis factor α (TNF-α), and Interleukin 6 (IL-6). One or more of these cytokines were expressed in nineteen patients and 2 controls and coordinated expression of GM-CSF, IL-17A, IFN-ϒ, and TNF-α, a signature of activated, MHC Class II dependent autoreactive Th-cells, was unique to 11 patients. GM-CSF is the central driver of tissue-damaging myeloid macrophages. Patients with this cytokine signature had a shorter (P= 0.017) Claudication Onset Distance (17 m) compared with patients lacking the signature (102 m). Transforming Growth Factor β1 (TGFβ1) and Chemokine Ligand 5 (CCL5) were expressed coordinately in all PAD and control muscles, independently of GM-CSF, IL-17A, IFN-ϒ, TNF-α, or IL-6. TGFβ1 and CCL5 and their gene transcripts were increased in PAD muscle, consistent with increased age-associated inflammation in these patients. Serum cytokines were not informative of muscle cytokine expression. We have identified a cytokine profile of autoimmune inflammation in calf muscles of a significant proportion of claudicating PAD patients, in association with decreased limb function, and a second independent profile consistent with increased “inflammaging” in all PAD patients

Sitting time and obesity in a sample of adults from Europe and the USA

This is an Accepted Manuscript of an article published by Taylor & Francis in Annals of Human Biology on 25 Sep 2016, available online: http://www.tandfonline.com/10.1080/03014460.2016.1232749.Obesity is a risk factor for many chronic diseases and the prevalence is increasing worldwide. Research suggests that sedentary behaviour (sitting) may be related to obesity.To examine the association between sitting time and obesity, while controlling for physical activity, in a large international sample.5338 adults from the UK, USA, Germany, Spain, Italy, France, Portugal, Austria and Switzerland self-reported their total daily sitting time, physical activity, age, height and weight. BMI (kg/m(2)), total physical activity (MET-minutes/week) and sitting time (hours/day) were derived. Participants were grouped into quartiles based on their daily sitting time (<4, 4 - ≤6, 6 - ≤8, and >8 hours/day) and logistic regression models explored the odds of being obese versus normal weight for each sitting time quartile.Participants in the highest sitting time quartile (≥8 hours/day) had 62% higher odds of obesity compared to participants in the lowest quartile (<4 hours/day) after adjustment for physical activity and other confounding variables (OR = 1.62, 95% CI = 1.24-2.12, p<0.01).Sitting time is associated with obesity in adults, independent of physical activity. Future research should clarify this association using objective measures of sitting time and physical activity to further inform health guidelines

Risk factors for genital infections in people initiating SGLT2 inhibitors and their impact on discontinuation

Introduction: To identify risk factors, absolute risk, and impact on treatment discontinuation of genital infections with sodium-glucose co-transporter-2 inhibitors (SGLT2i). Research design and methods: We assessed the relationship between baseline characteristics and genital infection in 21 004 people with type 2 diabetes initiating SGLT2i and 55 471 controls initiating dipeptidyl peptidase-4 inhibitors (DPP4i) in a UK primary care database. We assessed absolute risk of infection in those with key risk factors and the association between early genital infection and treatment discontinuation. Results: Genital infection was substantially more common in those treated with SGLT2i (8.1% within 1 year) than DPP4i (1.8%). Key predictors of infection with SGLT2i were female sex (HR 3.64; 95% CI 3.23 to 4.11) and history of genital infection; &lt;1 year before initiation (HR 4.38; 3.73 to 5.13), 1–5 years (HR 3.04; 2.64 to 3.51), and &gt;5 years (HR 1.79; 1.55 to 2.07). Baseline HbA1c was not associated with infection risk for SGLT2i, in contrast to DPP4i where risk increased with higher HbA1c. One-year absolute risk of genital infection with SGLT2i was highest for those with a history of prior infection (females 23.7%, males 12.1%), compared with those without (females 10.8%, males 2.7%). Early genital infection was associated with a similar discontinuation risk for SGLT2i (HR 1.48; 1.21–1.80) and DPP4i (HR 1.58; 1.21–2.07). Conclusions: Female sex and history of prior infection are simple features that can identify subgroups at greatly increased risk of genital infections with SGLT2i therapy. These data can be used to risk-stratify patients. High HbA1c is not a risk factor for genital infections with SGLT2i

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

CyberKnife Robotic-Assisted Stereotactic Radiosurgery for Advanced Stages of Ciliochoroidal Uveal Melanoma. Preliminary Results in Mexico

Objective: The objective of this study was to report the early results of CyberKnife® (CK®) stereotactic radiosurgery in advanced stages of ciliochoroidal (CBCh) melanoma in Mexican patients. Methods: A retrospective review of charts was performed to analyze the outcomes of patients who underwent CK® (Accuray Inc, Sunnyvale, CA, United States). Results: Four patients with CBCh melanoma were treated under this protocol. The mean age was 53.2 ± 5.3 years (range, 47-60). Median of follow-up was 9.5 ± 3.1 months (range, 5-12). Mean tumor diameter was 13.49 mm, mean thickness, 11.74 mm, and mean gross tumor volume was 1251.97 mm3. Tumors were dome- (50%) and mushroom-shaped (50%) in medium-to-large sizes. Three patients had T3b tumors, and one had a T4d tumor at the early tumor staging according to the American Joint Committee on Cancer. A mean dose of 2763 ± 181.3 cGy was prescribed to the 90% isodose line. All patients achieved local tumor control after single-session radiosurgery at the latest follow-up. One patient presented with acute toxicity (extensive serous retinal detachment associated with radiation induced tumor vasculopathy) that was promptly managed. None of the patients required secondary enucleation. Conclusions: CK® appears to be an effective therapy for medium to large-sized CBCh melanoma. A prospective comparative study with longer follow-up is needed to confirm these findings and to evaluate long-term morbidity

A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma

Therapy of advanced melanoma is changing dramatically. Following mutational and biological subclassification of this heterogeneous cancer, several targeted and immune therapies were approved and increased survival significantly. To facilitate further advancements through pre-clinical in vivo modeling, we have established 459 patient-derived xenografts (PDX) and live tissue samples from 384 patients representing the full spectrum of clinical, therapeutic, mutational, and biological heterogeneity of melanoma. PDX have been characterized using targeted sequencing and protein arrays and are clinically annotated. This exhaustive live tissue resource includes PDX from 57 samples resistant to targeted therapy, 61 samples from responders and non-responders to immune checkpoint blockade, and 31 samples from brain metastasis. Uveal, mucosal, and acral subtypes are represented as well. We show examples of pre-clinical trials that highlight how the PDX collection can be used to develop and optimize precision therapies, biomarkers of response, and the targeting of rare genetic subgroups