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Marine-derived fungi have emerged as a source for novel metabolites with a broad range of bioactivities. However, accessing the full potential of fungi under standard laboratory conditions remains challenging. LC-MS-based metabolomics in combination with varied culture conditions is a fast and powerful tool to detect new metabolites. Here, three developmental forms of the marine-derived fungus Aspergillus alliaceus were analyzed and 14 fungal metabolites, including new brominated polyketides (11-14) were isolated. Structure elucidation relied mainly on 1D and 2D NMR techniques and was supported by low- and high-resolution mass spectrometry and DFT-based computations. We sequenced the A. alliaceus genome, identified the bianthrone-producing biosynthetic gene cluster, and conducted expression analysis on genes involved in sexual development and biosynthesis. The NCI-60 cell line panel revealed selective in vitro activity against triple-negative breast cancer (TNBC) for the halogenated allianthrones and their full antiproliferative and cytotoxic effects were evaluated in five TNBC cell lines., (© 2024 Wiley-VCH GmbH.)

Purpose: This study evaluates the performance of a multitrait polygenic risk score (PRS) in an independent cohort to predict incident or progression of keratoconus., Design: Prospective cross-sectional and cohort study METHODS: Setting: Single-center; Study population: 1478 community-based young adults (18-30 years; 51% female), including 609 (52% female) who returned for an 8-year follow-up; Observation procedures: Scheimpflug imaging (Pentacam, Oculus), genotyping and development of a multitrait PRS previously validated to predict keratoconus in older adults.; Main outcome measure: Belin/Ambrόsio enhanced ectasia display (BAD-D) score and keratoconus, defined as BAD-D ≥2.6, were each analyzed against the PRS using linear and logistic regression, respectively., Results: Prevalence of keratoconus was 2.5% (95% confidence interval [CI] = 1.9-3.6) in the cross-sectional cohort. Each z-score increase in PRS was associated with worse BAD-D z-score by 0.13 (95%CI = 0.08-0.18) and 1.6 increased odds of keratoconus. The 8-year keratoconus incidence was 2.6% (95%CI = 1.3-4.0). Participants in the highest PRS decile were more likely to have incident keratoconus compared to the rest of the cohort (odds ratio = 3.85, 95%CI = 1.21-12.22). For each z-score increase in PRS, 8-year change in BAD-D z-score worsened by 0.11 (95%CI = 0.04-0.17)., Conclusions: A PRS for keratoconus could be useful in predicting incident keratoconus and progression, demonstrating its potential utility in clinical settings to identify patients at high risk of postsurgery ectasia or those who may benefit most from keratoconus intervention., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Optical coherence tomography (OCT) is a non-invasive technique to measure retinal layer thickness, providing insights into retinal ganglion cell integrity. Studies have shown reduced retinal nerve fibre layer (RNFL) and ganglion cell inner plexiform layer (GCIPL) thickness in Parkinson's disease (PD) patients. However, it is unclear if there is a common genetic overlap between the macula and peripapillary estimates with PD and if the genetic risk of PD is associated with changes in ganglion cell integrity estimates in young adults., Method: Western Australian young adults underwent OCT imaging. Their pRNFL, GCIPL, and overall retinal thicknesses were recorded, as well as their longitudinal changes between ages 20 and 28. Polygenic risk scores (PRS) were estimated for each participant based on genome-wide summary data from the largest PD genome-wide association study conducted to date. We further evaluated whether PD PRS was associated with changes in thickness at a younger age. To evaluate the overlap between retinal integrity estimates and PD, we annotated and prioritised genes using mBAT-combo and performed colocalisation through the GWAS pairwise method and HyPrColoc. We used a multi-omic approach and single-cell expression data of the retina and brain through a Mendelian randomisation framework to evaluate the most likely causal genes. Genes prioritised were analysed for missense variants that could have a pathogenic effect using AlphaMissense., Results: We found a significant association between the Parkinson's disease polygenic risk score (PD PRS) and changes in retinal thickness in the macula of young adults assessed at 20 and 28 years of age. Gene-based analysis identified 27 genes common to PD and retinal integrity, with a notable region on chromosome 17. Expression analyses highlighted NSF, CRHR1, and KANSL1 as potential causal genes shared between PD and ganglion cell integrity measures. CRHR1 showed consistent results across multiple omics levels., Interpretation: Our findings suggest that retinal measurements, particularly in young adults, could be a potential marker for PD risk, indicating a genetic overlap between retinal structural integrity and PD. The study highlights specific genes and loci, mainly on chromosome 17, as potential shared etiological factors for PD and retinal changes. Our results highlight the importance of further longitudinal studies to validate retinal structural metrics as early indicators of PD predisposition., (© 2024. The Author(s).)

Purpose: Few studies have explored choroidal changes after cessation of myopia control. This study evaluated the choroidal thickness (ChT) and choroidal vascularity index (CVI) during and after discontinuing long-term low-concentration atropine eye drops use for myopia control., Methods: Children with progressive myopia (6-16 years; n = 153) were randomized to receive 0.01% atropine eye drops or a placebo (2:1 ratio) instilled daily over 2 years, followed by a 1-year washout (no eye drop use). Optical coherence tomography imaging of the choroid was conducted at the baseline, 2-year (end of treatment phase), and 3-year (end of washout phase) visits. The main outcome measure was the subfoveal ChT. Secondary measures include the CVI., Results: During the treatment phase, the subfoveal choroids in both treatment and control groups thickened by 12-14 µm (group difference P = 0.56). During the washout phase, the subfoveal choroids in the placebo group continued to thicken by 6.6 µm (95% confidence interval [CI] = 1.7 to 11.6), but those in the atropine group did not change (estimate = -0.04 µm; 95% CI = -3.2 to 3.1). Participants with good axial eye growth control had greater choroidal thickening than the fast-progressors during the treatment phase regardless of the treatment group (P < 0.001), but choroidal thickening in the atropine group's fast-progressors was not sustained after stopping eye drops. CVI decreased in both groups during the treatment phase, but increased in the placebo group after treatment cessation., Conclusions: On average, compared to placebo, 0.01% atropine eye drop treatment did not cause a differential rate of change in ChT during treatment, but abrupt cessation of long-term 0.01% atropine eye drops may disrupt normal choroidal thickening in children.

While high circulating tumor DNA (ctDNA) levels are associated with poor survival for multiple cancers, variant-specific differences in the association of ctDNA levels and survival have not been examined. Here we investigate KRAS ctDNA (ctKRAS) variant-specific associations with overall and progression-free survival (OS/PFS) in first-line metastatic pancreatic ductal adenocarcinoma (mPDAC) for patients receiving chemoimmunotherapy ("PRINCE", NCT03214250), and an independent cohort receiving standard of care (SOC) chemotherapy. For PRINCE, higher baseline plasma levels are associated with worse OS for ctKRAS G12D (log-rank p = 0.0010) but not G12V (p = 0.7101), even with adjustment for clinical covariates. Early, on-therapy clearance of G12D (p = 0.0002), but not G12V (p = 0.4058), strongly associates with OS for PRINCE. Similar results are obtained for the SOC cohort, and for PFS in both cohorts. These results suggest ctKRAS G12D but not G12V as a promising prognostic biomarker for mPDAC and that G12D clearance could also serve as an early biomarker of response., (© 2024. The Author(s).)

Background: A rebound in myopia progression following cessation of atropine eyedrops has been reported, yet there is limited data on the effects of stopping 0.01% atropine compared to placebo control. This study tested the hypothesis that there is minimal rebound myopia progression after cessation of 0.01% atropine eyedrops, compared to a placebo., Methods: Children with myopia (n = 153) were randomised to receive 0.01% atropine eyedrops or a placebo (2:1 ratio) daily at bedtime during the 2-year treatment phase of the study. In the third year (wash-out phase), all participants ceased eyedrop instillation. Participants underwent an eye examination every 6 months, including measurements of spherical equivalent (SphE) after cycloplegia and axial length (AL). Changes in the SphE and AL during the wash-out phase and throughout the 3 years of the study (treatment + wash-out phase) were compared between the treatment and control groups., Results: During the 1-year wash-out phase, SphE and AL progressed by -0.41D (95% CI = -0.33 to -0.22) and +0.20 mm (95% CI = -0.46 to -0.36) in the treatment group compared to -0.28D (95% CI = 0.11 to 0.16) and +0.13 mm (95% CI = 0.18 to 0.21) in the control group. Progression in the treatment group was significantly faster than in the control group (p = 0.016 for SphE and <0.001 for AL). Over the 3-year study period, the cumulative myopia progression was similar between the atropine and the control groups., Conclusions: These findings showed evidence of rapid myopia progression following cessation of 0.01% atropine. Further investigations are warranted to ascertain the long-term effects of atropine eyedrops., (© 2024 The Authors. Clinical & Experimental Ophthalmology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of Ophthalmologists.)

This study explored the impact of short-term coronavirus disease 2019 (COVID-19) restrictions on the efficacy of atropine 0.01% eyedrops on myopia control in a multiethnic cohort of Australian children. In the Western Australia Atropine for the Treatment of Myopia study, 104 and 49 children were randomized to receive atropine 0.01% eyedrops and a placebo, respectively. We compared the 1-year myopia progression and axial elongation following the 2-month lockdown in 2020 to the same months in 2019 and 2021, i.e., the 1-year myopia progression up to May 2019-October 2019 (non-COVID-19) versus the 1-year progression up to May 2020-October 2020 (COVID-19 period), and the 1-year progression up to May 2021-October 2021 (non-COVID-19) versus the 1-year progression up to the same months in 2020. After excluding participants who withdrew, completed their treatment phase prior May 2020, or those whose study visits did not fall between May 2020 and October 2020, 65 participants (mean age at baseline = 11.8 ± 2.5 years) were included in the final analysis (49 in the treatment group; 16 in the placebo group). After correcting for age, sex, and ethnicity, there was no significant main effect of the short-term lockdown on the rate of spherical equivalent or axial length change. However, there was a lockdown × treatment interaction effect on the rate of axial elongation ( P = 0.007). This was such that in the treatment group, the 1-year axial elongation was faster during lockdown by 0.056 mm compared to the nonlockdown periods ( P = 0.009), while the rate of axial elongation in those on the placebo eye drops was similar during lockdown and nonlockdown. Our findings suggest that there is a decreased efficacy of low-concentration atropine even with relatively lenient restrictions lasting for a few months., Competing Interests: Dr Lingham is employed by Ocumetra; Dr Mackey consults for Novartis., (Copyright: © 2024 Taiwan J Ophthalmol.)

Purpose: Changes in refractive error during young adulthood is common yet risk factors at this age are largely unexplored. This study explored risk factors for these changes, including gene-environmental interactions., Methods: Spherical equivalent refraction (SER) and axial length (AL) for 624 community-based adults were measured at 20 (baseline) and 28 years old. Participants were genotyped and their polygenic scores (PGS) for refractive error calculated. Self-reported screen time (computer, television, and mobile devices) from 20 to 28 years old were collected prospectively and longitudinal trajectories were generated. Past sun exposure was quantified using conjunctival ultraviolet autofluorescence (CUVAF) area., Results: Median change in SER and AL were -0.023 diopters (D)/year (interquartile range [IQR] = -0.062 to -0.008) and +0.01 mm/year (IQR = 0.000 to 0.026), respectively. Sex, baseline myopia, parental myopia, screen time, CUVAF, and PGS were significantly associated with myopic shift. Collectively, these factors accounted for approximately 20% of the variance in refractive error change, with screen time, CUVAF, and PGS each explaining approximately 1% of the variance. Four trajectories for total screen time were found: "consistently low" (n = 148), "consistently high" (n = 250), "consistently very high" (n = 76), and "increasing" (n = 150). Myopic shift was faster in those with "consistently high" or "consistently very high" screen time compared to "consistently-low" (P ≤ 0.031). For each z-score increase in PGS, changes in SER and AL increased by -0.005 D/year and 0.002 mm/year (P ≤ 0.045). Of the three types of screen time, only computer time was associated with myopic shift (P ≤ 0.040). There was no two- or three-way interaction effect between PGS, CUVAF, or screen time (P ≥ 0.26)., Conclusions: Higher total or computer screen time, less sun exposure, and genetic predisposition are each independently associated with greater myopic shifts during young adulthood. Given that these factors explained only a small amount of the variance, there are likely other factors driving refractive error change during young adulthood.

One unexploited family of cancer biomarkers comprise glycoproteins, carbohydrates, and glycolipids (the Tumor Glycocode).A class of glycolipid cancer biomarkers, the tumor-marker gangliosides (TMGs) are presented here as potential diagnostics for detecting cancer, especially at early stages, as the biological function of TMGs makes them etiological. We propose that a quantitative matrix of the Cancer Biomarker Glycocode and artificial intelligence-driven algorithms will expand the menu of validated cancer biomarkers as a step to resolve some of the challenges in cancer diagnosis, and yield a combination that can identify a specific cancer, in a tissue-agnostic manner especially at early stages, to enable early intervention. Diagnosis is critical to reducing cancer mortality but many cancers lack efficient and effective diagnostic tests, especially for early stage disease. Ideal diagnostic biomarkers are etiological, samples are preferably obtained via non-invasive methods (e.g. liquid biopsy of blood or urine), and are quantitated using assays that yield high diagnostic sensitivity and specificity for efficient diagnosis, prognosis, or predicting response to therapy. Validated biomarkers with these features are rare. While the advent of proteomics and genomics has led to the identification of a multitude of proteins and nucleic acid sequences as cancer biomarkers, relatively few have been approved for clinical use. The use of multiplex arrays and artificial intelligence-driven algorithms offer the option of combining data of known biomarkers; however, for most, the sensitivity and the specificity are below acceptable criteria, and clinical validation has proven difficult. One strategic solution to this problem is to expand the biomarker families beyond those currently exploited. One unexploited family of cancer biomarkers comprise glycoproteins, carbohydrates, and glycolipids (the Tumor Glycocode). Here, we focus on a family of glycolipid cancer biomarkers, the tumor-marker gangliosides (TMGs). We discuss the diagnostic potential of TMGs for detecting cancer, especially at early stages. We include prior studies from the literature to summarize findings for ganglioside quantification, expression, detection, and biological function and its role in various cancers. We highlight the examples of TMGs exhibiting ideal properties of cancer diagnostic biomarkers, and the application of GD2 and GD3 for diagnosis of early stage cancers with high sensitivity and specificity. We propose that a quantitative matrix of the Cancer Biomarker Glycocode and artificial intelligence-driven algorithms will expand the menu of validated cancer biomarkers as a step to resolve some of the challenges in cancer diagnosis, and yield a combination that can identify a specific cancer, in a tissue-agnostic manner especially at early stages, to enable early intervention., Competing Interests: Author HS discloses patent filings protecting claims of intellectual property, under License to AOA Dx where author AJ works and where HS serves as consultant. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Nejatie, Yee, Jeter and Saragovi.)

Purpose: Treatments are available to slow myopic axial elongation. Understanding normal axial length (AL) distributions will assist clinicians in choosing appropriate treatment for myopia. We report the distribution of AL in Australians of different age groups and refractive errors., Methods: Retrospectively collected spherical equivalent refraction (SER) and AL data of 5938 individuals aged 5 to 89 years from 8 Australian studies were included. Based on the SER, participants were classified as emmetropes, myopes, and hyperopes. Two regression model parameterizations (piece-wise and restricted cubic splines [RCS]) were applied to the cross-sectional data to analyze the association between age and AL. These results were compared with longitudinal data from the Raine Study where the AL was measured at age 20 (baseline) and 28 years., Results: A piece-wise regression model (with 1 knot) showed that myopes had a greater increase in AL before 18 years by 0.119 mm/year (P < 0.001) and after 18 years by 0.011 mm/year (P < 0.001) compared to emmetropes and hyperopes, with the RCS model (with 3 knots) showing similar results. The longitudinal data from the Raine Study revealed that, when compared to emmetropes, only myopes showed a significant change in the AL in young adulthood (by 0.016 mm/year, P < 0.001)., Conclusions: The AL of myopic eyes increases more rapidly in childhood and slightly in early adulthood. Further studies of longitudinal changes in AL, particularly in childhood, are required to guide myopia interventions., Translational Relevance: The axial length of myopic eyes increases rapidly in childhood, and there is a minimal increase in the axial length in non-myopic eyes after 18 years of age.

Background: High myopia (HM), defined as a spherical equivalent refractive error (SER) ≤ -6.00 diopters (D), is a leading cause of sight impairment, through myopic macular degeneration (MMD). We aimed to derive an improved polygenic score (PGS) for predicting children at risk of HM and to test if a PGS is predictive of MMD after accounting for SER., Methods: The PGS was derived from genome-wide association studies in participants of UK Biobank, CREAM Consortium, and Genetic Epidemiology Research on Adult Health and Aging. MMD severity was quantified by a deep learning algorithm. Prediction of HM was quantified as the area under the receiver operating curve (AUROC). Prediction of severe MMD was assessed by logistic regression., Findings: In independent samples of European, African, South Asian and East Asian ancestry, the PGS explained 19% (95% confidence interval 17-21%), 2% (1-3%), 8% (7-10%) and 6% (3-9%) of the variation in SER, respectively. The AUROC for HM in these samples was 0.78 (0.75-0.81), 0.58 (0.53-0.64), 0.71 (0.69-0.74) and 0.67 (0.62-0.72), respectively. The PGS was not associated with the risk of MMD after accounting for SER: OR = 1.07 (0.92-1.24)., Interpretation: Performance of the PGS approached the level required for clinical utility in Europeans but not in other ancestries. A PGS for refractive error was not predictive of MMD risk once SER was accounted for., Funding: Supported by the Welsh Government and Fight for Sight (24WG201)., Competing Interests: Declaration of interests The authors declare no potential conflicts of interests relevant to this manuscript. Outside this manuscript, KOM reports consultancy service for Santen and CooperVision; JAG reports membership of the Data Safety Monitoring Board for ‘CHAMPS-UK’ trial of atropine eyedrops for myopia (unpaid) and editorial board service for IOVS, TVST and OPO (unpaid)., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Myopia typically starts and progresses during childhood, but onset and progression can occur during adulthood. The goals of this review are to summarize published data on myopia onset and progression in young adults, aged 18 to 40 years, to characterize myopia in this age group, to assess what is currently known, and to highlight the gaps in the current understanding. Specifically, the peer-reviewed literature was reviewed to: characterize the timeline and age of stabilization of juvenile-onset myopia; estimate the frequency of adult-onset myopia; evaluate the rate of myopia progression in adults, regardless of age of onset, both during the college years and later; describe the rate of axial elongation in myopic adults; identify risk factors for adult onset and progression; report myopia progression and axial elongation in adults who have undergone refractive surgery; and discuss myopia management and research study design. Adult-onset myopia is common, representing a third or more of all myopia in western populations, but less in East Asia, where onset during childhood is high. Clinically meaningful myopia progression continues in early adulthood and may average 1.00 diopters (D) between 20 and 30 years. Higher levels of myopia are associated with greater absolute risk of myopia-related ocular disease and visual impairment, and thus myopia in this age group requires ongoing management. Modalities established for myopia control in children would be options for adults, but it is difficult to predict their efficacy. The feasibility of studies of myopia control in adults is limited by the long duration required.

Competing Interests: The authors have no conflicts of interest to disclose.

Purpose: Disseminated tumor cells (DTCs) expressing epithelial markers in the bone marrow are associated with recurrence and death, but little is known about risk factors predicting their occurrence. We detected EPCAM+/CD45- cells in bone marrow from early stage breast cancer patients after neoadjuvant chemotherapy (NAC) in the I-SPY 2 Trial and examined clinicopathologic factors and outcomes., Methods: Patients who signed consent for SURMOUNT, a sub-study of the I-SPY 2 Trial (NCT01042379), had bone marrow collected after NAC at the time of surgery. EPCAM+CD45- cells in 4 mLs of bone marrow aspirate were enumerated using immunomagnetic enrichment/flow cytometry (IE/FC). Patients with > 4.16 EPCAM+CD45- cells per mL of bone marrow were classified as DTC-positive. Tumor response was assessed using the residual cancer burden (RCB), a standardized approach to quantitate the extent of residual invasive cancer present in the breast and the axillary lymph nodes after NAC. Association of DTC-positivity with clinicopathologic variables and survival was examined., Results: A total of 73 patients were enrolled, 51 of whom had successful EPCAM+CD45- cell enumeration. Twenty-four of 51 (47.1%) were DTC-positive. The DTC-positivity rate was similar across receptor subtypes, but DTC-positive patients were significantly younger (p = 0.0239) and had larger pretreatment tumors compared to DTC-negative patients (p = 0.0319). Twenty of 51 (39.2%) achieved a pathologic complete response (pCR). While DTC-positivity was not associated with achieving pCR, it was significantly associated with higher RCB class (RCB-II/III, 62.5% vs. RCB-0/I; 33.3%; Chi-squared p = 0.0373). No significant correlation was observed between DTC-positivity and distant recurrence-free survival (p = 0.38, median follow-up = 3.2 years)., Conclusion: DTC-positivity at surgery after NAC was higher in younger patients, those with larger tumors, and those with residual disease at surgery., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: To test the hypothesis that 0.01% atropine eyedrops are a safe and effective myopia-control approach in Australian children., Methods: Children (6-16 years; 49% Europeans, 18% East Asian, 22% South Asian, and 12% other/mixed ancestry) with documented myopia progression were enrolled into this single-centre randomised, parallel, double-masked, placebo-controlled trial and randomised to receive 0.01% atropine (n = 104) or placebo (n = 49) eyedrops (2:1 ratio) instilled nightly over 24 months (mean index age = 12.2 ± 2.5 and 11.2 ± 2.8 years, respectively). Outcome measures were the changes in spherical equivalent (SE) and axial length (AL) from baseline., Results: At 12 months, the mean SE and AL change from baseline were -0.31D (95% confidence interval [CI] = -0.39 to -0.22) and 0.16 mm (95%CI = 0.13-0.20) in the atropine group and -0.53D (95%CI = -0.66 to -0.40) and 0.25 mm (95%CI = 0.20-0.30) in the placebo group (group difference p ≤ 0.01). At 24 months, the mean SE and AL change from baseline was -0.64D (95%CI = -0.73 to -0.56) and 0.34 mm (95%CI = 0.30-0.37) in the atropine group, and -0.78D (95%CI = -0.91 to -0.65) and 0.38 mm (95%CI = 0.33-0.43) in the placebo group. Group difference at 24 months was not statistically significant (p = 0.10). At 24 months, the atropine group had reduced accommodative amplitude and pupillary light response compared to the placebo group., Conclusions: In Australian children, 0.01% atropine eyedrops were safe, well-tolerated, and had a modest myopia-control effect, although there was an apparent decrease in efficacy between 18 and 24 months, which is likely driven by a higher dropout rate in the placebo group., (© 2022 The Authors. Clinical & Experimental Ophthalmology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of Ophthalmologists.)

Purpose: In utero exposure to cigarette smoke has been suggested to result in thinner retinal nerve fibre layer (RNFL). However, the potential cofounding effects of in utero alcohol exposure and passive smoking during childhood had not been considered. We explored RNFL thickness in young adults in relation to these early life factors., Methods: In 1989-1991, pregnant women completed questionnaires on their current smoking and alcohol drinking patterns. Following the birth of their offspring, information on household smokers was obtained between the 1- and 13-year follow-ups. At the 20-year follow-up, these offspring underwent an eye examination including optical coherence tomography imaging of the RNFL., Results: Participants (n = 1,287) were 19-22 years old at time of eye examination. Most participants (77%) had no in utero exposure to cigarette smoke; 1.3% were initially exposed but not after 18 weeks' gestation, while 21% had continual in utero smoking exposure. Half of the mothers never consumed alcohol or only consumed alcohol once during their pregnancies. After correcting for potential confounders, including in utero alcohel exposure and childhood passive smoking, participants who had continued in utero exposure to >10 cigarettes/day and ≤10 cigarettes/day had thinner RNFLs by 6.6 (95% confidence interval [CI] = 4.4-8.7) and 3.7 µm (95%[CI] = 2.3-5.5), respectively, than those with no exposure ( p < .001). In utero alcohol exposure and childhood passive smoking were not significantly associated with RNFL thickness after accounting for in utero exposure to smoking., Conclusions: In utero exposure to cigarette smoke is associated with thinner RFNL in young adulthood, independent of other early life environmental factors.

Worldwide, glaucoma affects about 3% of the population over the age of 50 years and is a leading cause of irreversible visual impairment among older people. Because glaucoma is asymptomatic in its early stages and can be challenging to diagnose clinically, it often remains undiagnosed until substantial vision loss has occurred. Efficient methods of glaucoma screening are therefore warranted for early detection of disease. Identification of risk factors for glaucoma - family history of glaucoma, older age, African or Asian ethnicities, raised intraocular pressure, and thin corneas - have helped inform guidelines on the recommended age at commencement and frequency of glaucoma screenings. A genetic predisposition or family history of glaucoma is one of the most important risk factors for the disease. However, an accurate family history cannot always be ascertained. Genetic testing for genes such as myocilin could help to identify high-risk individuals and, with further research, could even provide insight into individual patients' response to treatment. With the ongoing discovery of glaucoma-associated genes and the advent of polygenic risk scores to identify individuals at high risk of glaucoma, gene-based screening for glaucoma is becoming closer to realisation. In the meantime, regularly screening family members of people with existing glaucoma is an efficient way of detecting early glaucoma. Raising public awareness of glaucoma is also necessary to educate the general public on the key role of routine eye examinations and early disease detection. Future studies should be undertaken to explore efficient public health campaign methods for improving glaucoma awareness., Competing Interests: The authors declare that they have no competing interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is associated with a poor prognosis. Multianalyte signatures, including liquid biopsy and traditional clinical variables, have shown promise for improving prognostication in other solid tumors but have not yet been rigorously assessed for PDAC., Materials and Methods: We performed a prospective cohort study of patients with newly diagnosed locally advanced pancreatic cancer (LAPC) or metastatic PDAC (mPDAC) who were planned to undergo systemic therapy. We collected peripheral blood before systemic therapy and assessed circulating tumor cells (CTCs), cell-free DNA concentration (cfDNA), and circulating tumor KRAS (ctKRAS)-variant allele fraction (VAF). Association of variables with overall survival (OS) was assessed in univariate and multivariate survival analysis, and comparisons were made between models containing liquid biopsy variables combined with traditional clinical prognostic variables versus models containing traditional clinical prognostic variables alone., Results: One hundred four patients, 40 with LAPC and 64 with mPDAC, were enrolled. CTCs, cfDNA concentration, and ctKRAS VAF were all significantly higher in patients with mPDAC than patients with LAPC. ctKRAS VAF (cube root; 0.05 unit increments; hazard ratio, 1.11; 95% CI, 1.03 to 1.21; P = .01), and CTCs ≥ 1/mL (hazard ratio, 2.22; 95% CI, 1.34 to 3.69; P = .002) were significantly associated with worse OS in multivariate analysis while cfDNA concentration was not. A model selected by backward selection containing traditional clinical variables plus liquid biopsy variables had better discrimination of OS compared with a model containing traditional clinical variables alone (optimism-corrected Harrell's C-statistic 0.725 v 0.681)., Conclusion: A multianalyte prognostic signature containing CTCs, ctKRAS, and cfDNA concentration outperformed a model containing traditional clinical variables alone suggesting that CTCs, ctKRAS, and cfDNA provide prognostic information complementary to traditional clinical variables in advanced PDAC.

Purpose: The purpose of this study was to explore the age-related change in choroidal thickness (ChT) and test the hypothesis that baseline ChT is predictive of refractive error change in healthy young adults., Methods: Participants underwent spectral-domain optical coherence tomography (SD-OCT) imaging and autorefraction at 20 (baseline) and 28 years old. The enhanced depth imaging mode on the SD-OCT was used to obtain images of the choroid. Scans were exported from the SD-OCT and analyzed with a custom software that automatically measures the central ChT. The longitudinal change in subfoveal ChT and association between baseline subfoveal ChT and 8-year change in refractive error (spherical equivalent) were determined using linear mixed models., Results: In total, 395 eyes of 198 participants (44% men; 18-22 years at baseline) were included. Over 8 years, mean spherical equivalent decreased by 0.25 diopters (D) and axial length increased by 0.09 mm. Subfoveal choroid thickened by 1.3 µm/year (95% confidence interval [CI] = 0.6-2.0), but this was reduced by 0.9 µm/year (95% CI = 1.6-0.2) for every 1 mm increase in axial length. For every 10 µm increase in baseline ChT, average annual change in spherical equivalent and axial length reduced by 0.006 D/year and 0.003 mm/year, respectively., Conclusions: In a community-based cohort of young adults, the choroid continued to change during early adulthood. Choroidal thickening was less in eyes that were longer at baseline, and the choroid thinned in eyes that showed myopia progression. The association between baseline ChT and longitudinal changes in spherical equivalent and axial length supports the hypothesis that ChT may be predictive of refractive error development and/or myopia progression.

Myopia tends to develop and progress fastest during childhood, and the age of stabilization has been reported to be 15-16 years old. Thus, most studies on myopia have centered on children. Data on the refractive error profile in young adulthood - a time in life when myopia is thought to have stabilized and refractive error is unaffected by age-related pathology such as cataract - are limited. The Raine Study has been following a community-based cohort of young adults representative of the general Western Australia population since their prenatal periods in 1989-1991, with eye examinations performed when participants were 20 and 28 years old. At 20 years old, prevalence of myopia in the cohort was 25.8%. Using long-term trajectory of serum vitamin D levels and conjunctival ultraviolet autofluorescence (CUVAF) area to objectively quantify sun exposure, the Raine Study confirmed a negative relationship between time spent outdoors and myopia prevalence. However, prospective studies are required to determine the amount of CUVAF area or serum vitamin D levels associated with time duration. Combining data from the Raine Study and several other cohorts, Mendelian randomization studies have confirmed a link between myopia and a genetic predisposition toward higher education. Several novel potential associations of myopia or ocular biometry were investigated, including fetal growth trajectory, which was found to be significantly associated with corneal curvature at 20 years. By age 28, myopia prevalence had increased to 33.2%. Between 20 and 28 years old, myopia progressed and axial length elongated, on average, by -0.041D/year and 0.02 mm/year, respectively. Smaller CUVAF area at follow-up, female sex, and parental myopia were significant risk factors for myopia incidence and progression between 20 and 28 years. Given the limited research in young adults, further investigations are warranted to confirm the Raine Study findings, as well as identify novel genetic or environmental factors of myopia incidence and progression in this age group., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lee and Mackey.)

We report a water-soluble poly(phenylene ethynylene) ( PPE-Pt(IV) ) that is functionalized with oxidized oxaliplatin Pt(IV) units and its use for photoactivated chemotherapy. The photoactivation strategy is based on photoinduced electron transfer from the PPE backbone to oxaliplatin Pt(IV) as an electron acceptor; this process triggers the release of oxaliplatin, which is a clinically used anticancer drug. Mechanistic studies carried out using steady-state and time-resolved fluorescence spectroscopy coupled with picosecond-nanosecond transient absorption support the hypothesis that electron transfer triggers the drug release. Photoactivation is effective, producing oxaliplatin with a good chemical yield in less than 1 h of photolysis (400 nm, 5 mW cm -2 ). Photorelease of oxaliplatin from PPE-Pt(IV) can also be effected with two-photon excitation by using 100 fs pulsed light at 725 nm. Cytotoxicity studies using SK-OV-3 human ovarian cancer cells demonstrate that without photoactivation PPE-Pt(IV) is not cytotoxic at concentrations up to 10 μM in polymer repeating unit (PRU) concentration. However, following a short period of 460 nm irradiation, oxaliplatin is released from PPE-Pt(IV) , resulting in cytotoxicity at concentrations as low as 2.5 μM PRU.

Purpose: Changes in retinal thickness are common in various ocular diseases. Transverse magnification due to differing ocular biometrics, in particular axial length, affects measurement of retinal thickness in different regions. This study evaluated the effect of axial length and refractive error on measured macular thickness in two community-based cohorts of healthy young adults., Methods: A total of 2160 eyes of 1247 community-based participants (18-30 years; 23.4% myopes, mean axial length = 23.6mm) were included in this analysis. Macular thickness measurements were obtained using a spectral-domain optical coherence tomography (which assumes an axial length of 24.385mm). Using a custom program, retinal thickness data were extracted at the 9 Early Treatment of Diabetic Retinopathy Study (ETDRS) regions with and without correction for transverse magnificent effects, with the corrected measurements adjusting according to the participant's axial length. Linear mixed models were used to analyse the effect of correction and its interaction with axial length or refractive group on retinal thickness., Results: The raw measures (uncorrected for axial length) underestimated the true retinal thickness at the central macula, while overestimating at most non-central macular regions. There was an axial length by correction interaction effect in all but the nasal regions (all p<0.05). For each 1mm increase in axial length, the central macular thickness is overestimated by 2.7-2.9μm while thicknesses at other regions were underestimated by 0.2-4.1μm. Based on the raw thickness measurements, myopes have thinner retinas than non-myopes at most non-central macular. However, this difference was no longer significant when the corrected data was used., Conclusion: In a community-based sample, the raw measurements underestimate the retinal thickness at the central macula and overestimate the retinal thickness at non-central regions of the ETDRS grid. The effect of axial length and refractive error on retinal thickness is reduced after correcting for transverse magnification effects resulting from axial length differences., Competing Interests: The authors have declared that no competing interests exist.

Chimeric antigen receptor (CAR) T cells have demonstrated promising efficacy, particularly in hematologic malignancies. One challenge regarding CAR T cells in solid tumors is the immunosuppressive tumor microenvironment (TME), characterized by high levels of multiple inhibitory factors, including transforming growth factor (TGF)-β. We report results from an in-human phase 1 trial of castration-resistant, prostate cancer-directed CAR T cells armored with a dominant-negative TGF-β receptor (NCT03089203). Primary endpoints were safety and feasibility, while secondary objectives included assessment of CAR T cell distribution, bioactivity and disease response. All prespecified endpoints were met. Eighteen patients enrolled, and 13 subjects received therapy across four dose levels. Five of the 13 patients developed grade ≥2 cytokine release syndrome (CRS), including one patient who experienced a marked clonal CAR T cell expansion, >98% reduction in prostate-specific antigen (PSA) and death following grade 4 CRS with concurrent sepsis. Acute increases in inflammatory cytokines correlated with manageable high-grade CRS events. Three additional patients achieved a PSA reduction of ≥30%, with CAR T cell failure accompanied by upregulation of multiple TME-localized inhibitory molecules following adoptive cell transfer. CAR T cell kinetics revealed expansion in blood and tumor trafficking. Thus, clinical application of TGF-β-resistant CAR T cells is feasible and generally safe. Future studies should use superior multipronged approaches against the TME to improve outcomes., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Importance: Myopia incidence and progression has been described extensively in children. However, few data exist regarding myopia incidence and progression in early adulthood., Objective: To describe the 8-year incidence of myopia and change in ocular biometry in young adults and their association with the known risk factors for childhood myopia., Design, Setting, and Participants: The Raine Study is a prospective single-center cohort study. Baseline and follow-up eye assessments were conducted from January 2010 to August 2012 and from March 2018 to March 2020. The data were analyzed from June to July 2021. A total of 1328 participants attended the baseline assessment, and 813 participants attended the follow-up assessment. Refractive information from both visits was available for 701 participants. Participants with keratoconus, previous corneal surgery, or recent orthokeratology wear were excluded., Exposures: Participants' eyes were examined at ages 20 years (baseline) and 28 years., Main Outcomes and Measures: Incidence of myopia and high myopia; change in spherical equivalent (SE) and axial length (AL)., Results: A total of 516 (261 male [50.6%]) and 698 (349 male [50.0%]) participants without myopia or high myopia at baseline, respectively, were included in the incidences analyses, while 691 participants (339 male [49%]) were included in the progression analysis. The 8-year myopia and high myopia incidence were 14.0% (95% CI, 11.5%-17.4%) and 0.7% (95% CI, 0.3%-1.2%), respectively. A myopic shift (of 0.50 diopters [D] or greater in at least 1 eye) occurred in 261 participants (37.8%). Statistical significance was found in longitudinal changes in SE (-0.04 D per year; P < .001), AL (0.02 mm per year; P <.001), and lens thickness (0.02 mm per year; P < .001). Incident myopia was associated with self-reported East Asian vs White race (odds ratio [OR], 6.13; 95% CI, 1.06-35.25; P = .04), female vs male sex (OR, 1.81; 95% CI, 1.02-3.22; P = .04), smaller conjunctival ultraviolet autofluorescence area (per 10-mm2 decrease, indicating less sun exposure; OR, 9.86; 95% CI, 9.76-9.97; P = <.009), and parental myopia (per parent; OR, 1.57; 95% CI, 1.03-2.38; P = <.05). Rates of myopia progression and axial elongation were faster in female participants (estimate: SE, 0.02 D per year; 95 % CI, 0.01-0.02 and AL, 0.007 mm per year, 95 % CI, 0.00.-0.011; P ≤ .001) and those with parental myopia (estimate per parent: SE, 0.01 D per year; 95% CI, 0.00-0.02 and AL, 95% CI, 0.002-0.008; P ≤ .001). Education level was not associated with myopia incidence or progression., Conclusions and Relevance: These findings suggest myopia progression continues for more than one-third of adults during the third decade of life, albeit at lower rates than during childhood. The protective effects of time outdoors against myopia may continue into young adulthood.

Purpose: Cross-sectional studies have variably reported that poor sleep quality may be associated with myopia in children. Longitudinal data, collected over the ages when myopia develops and progresses, could provide new insights into the sleep-myopia paradigm. This study tested the hypothesis that 12-year trajectories of sleep behaviour from childhood to adolescence is associated with myopia during young adulthood., Methods: At the 5-, 8-, 10-, 14- and 17-year follow-ups of the longitudinal Raine Study, which has been following a cohort since their birth in 1989-1992, participants' parents/guardians completed the Child Behaviour Checklist questionnaire (CBCL), which collected information on their child's sleep behaviour and quality. The CBCL includes six questions measuring sleep behaviour, which parents rated as 0 = not true, 1 = somewhat/sometimes true, or 2 = very/often true. Scores were summed at each follow-up to form a composite "sleep behaviour score". Latent Class Growth Analysis (LCGA) was used to classify participants according to their 12-year trajectory of sleep behaviour. At the 20-year follow-up, an eye examination was performed which included cycloplegic autorefraction and axial length measurement., Results: The LCGA identified three clusters of participants based on their trajectory of sleep behaviour: those with minimal' (43.6% of the total Raine Study sample), 'declining' (48.9%), or 'persistent' (7.5%) sleep problems. A total of 1194 participants had ophthalmic data and longitudinal sleep data available for analysis (47.2% female, 85.6% Caucasian). No significant differences were observed in regards to age, sex, ethnicity or ocular parameters between trajectory groups. Unadjusted and fully adjusted analyses demonstrated that sleep problem behaviour was not significantly associated with changes in refractive error, axial length or corneal radius., Conclusions: Our findings do not support the hypothesis that there is an association between sleep behaviour and myopia. Future longitudinal studies should explore sleep trajectory data pre- and post-myopia diagnosis to confirm our results., (© 2021 The Authors Ophthalmic and Physiological Optics © 2021 The College of Optometrists.)

Background: The prevalence of myopia is increasing globally including in Europe and parts of Asia but Australian data are lacking. This study aim described the change in myopia prevalence in middle-aged Australian adults over approximately a 20-year period., Methods: Two contemporary Western Australian studies (conducted in mid-late 2010s): the coastal-regional Busselton Healthy Ageing Study (BHAS) and the urban Gen1 of the Raine Study (G1RS) were compared to two earlier studies (early-mid 1990s) in Australia: the urban Blue Mountains Eye Study (BMES) and urban/regional Melbourne Visual Impairment Project (MVIP). Refractive error was measured by autorefraction, vertometry, or subjective refraction. Participants (49-70 years) of European descent without self-reported/diagnosed cataract, corneal disease, or refractive or corneal surgery were included., Results: After exclusions, data were available from 2217, 1760, 700, 2987 and 756 participants from BMES, urban MVIP, regional MVIP, BHAS, and G1RS, respectively. The mean age ranged from 57.1 ± 4.6 years in the G1RS to 60.1 ± 6.0 years in the BMES; 44-48% of participants were male. When stratified by location, the contemporary urban G1RS cohort had a higher age-standardised myopia prevalence than the urban MVIP and BMES cohorts (29.2%, 16.4%, and 23.9%, p < 0.001). The contemporary coastal-regional BHAS had a higher age-standardised myopia prevalence than the regional MVIP cohort (19.4% vs. 13.8%, p = 0.001)., Conclusions: We report an increase in myopia prevalence in older adults in Australia born after World War ll compared to cohorts born before, accounting for urban/regional location. The prevalence of myopia remains relatively low in middle-aged Australian adults., (© 2021 Royal Australian and New Zealand College of Ophthalmologists.)

Circulating cell-free DNA (ccfDNA) is used increasingly as a cancer biomarker for prognostication, as a correlate for tumor volume, or as input for downstream molecular analysis. Determining optimal blood processing and ccfDNA quantification are crucial for ccfDNA to serve as an accurate biomarker as it moves into the clinical realm. Whole blood was collected from 50 subjects, processed to plasma, and used immediately or frozen at -80°C. Plasma ccfDNA was extracted and concentration was assessed by real-time quantitative PCR (qPCR), fluorimetry, and droplet digital PCR (ddPCR). For the 24 plasma samples from metastatic pancreatic cancer patients, the variant allele fractions (VAF) of KRAS G12/13 pathogenic variants in circulating tumor DNA (ctDNA) were measured by ddPCR. Using a high-speed (16,000 × g) or slower-speed (4100 × g) second centrifugation step showed no difference in ccfDNA yield or ctDNA VAF. A two- versus three-spin centrifugation protocol also showed no difference in ccfDNA yield or ctDNA VAF. A higher yield was observed from fresh versus frozen plasma by qPCR and fluorimetry, whereas a higher yield was observed for frozen versus fresh plasma by ddPCR, however, no difference was observed in ctDNA VAF. Overall, our findings suggest factors to consider when implementing a ccfDNA extraction and quantification workflow in a research or clinical setting., (Copyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Patients newly diagnosed with metastatic pancreatic ductal adenocarcinoma generally have poor survival, with heterogeneous rates of progression. Biomarkers that could predict progression and/or survival would help inform patients and providers as they make care decisions. In a previous retrospective study, we discovered that circulating thrombospondin-2 (THBS2) could, in combination with CA19-9, better distinguish patients with PDAC versus healthy controls. Here we evaluated whether THBS2 levels, previously not known to be prognostic, were associated with outcome in 68 patients at time of diagnosis of metastatic PDAC. Specifically, we interrogated the association of THBS2 level, alone or in combination with CA19-9, with progression by 90 days and/or survival to 180 days. The results indicate that elevated THBS2 levels alone, at the time of a metastatic PDAC diagnosis, can identify patients with a shorter time to death and thus help patients and providers when planning treatment., Competing Interests: CONFLICTS OF INTEREST Authors have no conflicts of interest to declare., (Copyright: © 2021 Gimotty et al.)

Precis: Higher physical working capacity (PWC) at age 17 was associated with thicker peripapillary retinal nerve fiber layer (pRNFL) at age 20, suggesting a mechanistic link between cardiovascular fitness and neuroretinal integrity., Purpose: Physical activity and cardiovascular fitness have been linked with lower odds of developing glaucoma. We tested the hypothesis that early beneficial effects of physical activity and cardiovascular fitness can be observed by measuring the pRNFL thickness in young healthy adults., Methods: The Raine Study is a longitudinal study that has followed a cohort since before their births in 1989-1992. Parent-reported physical activity was collected between 8 and 17 years, and latent class analysis was used to identify the participants' physical activity trajectories. At the 20-year follow-up (participants' mean age=20.1±0.4 y), participants' metabolic equivalent of task-minutes/week was determined using self-reported physical activity data. Participants' PWC was assessed at the 14- and 17-year follow-ups to estimate their level of cardiovascular fitness. An eye examination, which included spectral-domain optical coherence tomography imaging, was conducted at the 20-year follow-up for 1344 participants., Results: Parent-reported or participant-reported physical activity was not associated with pRNFL thickness. However, higher PWC at 17 years was associated with thicker pRNFL globally [by 0.3 µm; 95% confidence interval (CI)=0.2-0.6; P<0.001], superotemporally (by 0.4 µm; 95% CI=0.1-0.7; P=0.013), inferonasally (by 0.7 µm; 95% CI=0.1-0.9; P=0.002), and nasally (by 0.4 µm; 95% CI=0.1-0.7; P=0.006) per 10 Watt increase in PWC., Conclusions: The association between estimated cardiovascular fitness and pRNFL thickness suggests there may be overlapping mechanisms for cardiovascular health and retinal ganglion cell integrity. While the effect sizes were small, it is possible that larger effects and clinically significant associations may arise as we follow this cohort of participants through their later adulthood., Competing Interests: Disclosure: S.Y. is supported by a NHMRC Early Career Fellowship. A.W.H. and D.A.M. are each supported by a NHMRC Practitioner Fellowship. The remaining authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To report the distribution of peripapillary retinal nerve fiber layer (RNFL) thickness in healthy young adults, investigate factors associated with RNFL thickness, and report the percentage of outside normal limits (ONL) and borderline (BL) RNFL thickness classifications based on the optical coherence tomography (OCT) manufacturer reference database., Methods: Participants of the Raine Study Generation 2 cohort (aged 18-22 years) underwent spectral domain OCT imaging with an RNFL circle scan. Eyes with inadequate scans or optic nerve pathology were excluded. Linear mixed models were used to analyze associations., Results: Data were available for 1288 participants (mean age, 20.0 years). Mean RNFL thicknesses in right and left eyes, respectively, were global = 100.5 µm, 100.3 µm (P = 0.03); temporal = 73.1 µm, 68.9 µm (P < 0.001); superotemporal = 140.6 µm, 136.3 µm (P < 0.001); superonasal = 104.9 µm, 115.1 µm (P < 0.001); nasal = 79.7 µm, 79.1 µm (P = 0.09); inferonasal = 109.8 µm, 111.5 µm (P < 0.001); and inferotemporal = 143.2 µm, 143.6 µm (P = 0.51). Longer axial length was associated with thinner RNFL globally, nasally, inferotemporally, superotemporally, superonasally, and inferonasally, as well as thicker RNFL temporally. The prevalence of ONL and BL classifications was generally higher than the expected rates of 1% and 4%, respectively, in temporal sectors and lower than expected in nasal sectors. The prevalence of global BL classifications was lower than expected (right eye, 2.3%; left eye, 2.6%)., Conclusions: Measured RNFL thickness differs with axial length and between right and left eyes. More reference data are needed to better define the normal limits of RNFL variation in different populations., Translational Relevance: This study provides an improved understanding of normal variation in RNFL thickness in young adults.

Ovarian cancer often has a poor clinical prognosis because of late detection, frequently after metastatic progression, as well as acquired resistance to taxane-based therapy. Herein, we evaluate a novel class of covalent microtubule stabilizers, the C-22,23-epoxytaccalonolides, for their efficacy against taxane-resistant ovarian cancer models in vitro and in vivo. Taccalonolide AF, which covalently binds β-tubulin through its C-22,23-epoxide moiety, demonstrates efficacy against taxane-resistant models and shows superior persistence in clonogenic assays after drug washout due to irreversible target engagement. In vivo, intraperitoneal administration of taccalonolide AF demonstrated efficacy against the taxane-resistant NCI/ADR-RES ovarian cancer model both as a flank xenograft, as well as in a disseminated orthotopic disease model representing localized metastasis. Taccalonolide-treated animals had a significant decrease in micrometastasis of NCI/ADR-RES cells to the spleen, as detected by quantitative RT-PCR, without any evidence of systemic toxicity. Together, these findings demonstrate that taccalonolide AF retains efficacy in taxane-resistant ovarian cancer models in vitro and in vivo and that its irreversible mechanism of microtubule stabilization has the unique potential for intraperitoneal treatment of locally disseminated taxane-resistant disease, which represents a significant unmet clinical need in the treatment of ovarian cancer patients.

Background: Precision medicine approaches for managing patients with metastatic castrate-resistant prostate cancer (mCRPC) are lacking. Non-invasive approaches for molecular monitoring of disease are urgently needed, especially for patients suffering from bone metastases for whom tissue biopsy is challenging. Here we utilized baseline blood samples to identify mCRPC patients most likely to benefit from abiraterone plus prednisone (AAP) or enzalutamide., Methods: Baseline blood samples were collected for circulating tumor cell (CTC) enumeration and qPCR-based gene expression analysis from 51 men with mCRPC beginning treatment with abiraterone or enzalutamide., Results: Of 51 patients (median age 68 years [51-82]), 22 received AAP (abiraterone 1000 mg/day plus prednisone 10 mg/day) and 29 received enzalutamide (160 mg/day). The cohort was randomly divided into training (n = 37) and test (n = 14) sets. Baseline clinical variables (Gleason score, PSA, testosterone, and hemoglobin), CTC count, and qPCR-based gene expression data for 141 genes/isoforms in CTC-enriched blood were analyzed with respect to overall survival (OS). Genes with expression most associated with OS included MSLN, ARG2, FGF8, KLK3, ESRP2, NPR3, CCND1, and WNT5A. Using a Cox-elastic net model for our test set, the 8-gene expression signature had a c-index of 0.87 (95% CI [0.80, 0.94]) and was more strongly associated with OS than clinical variables or CTC count alone, or a combination of the three variables. For patients with a low-risk vs. high-risk gene expression signature, median OS was not reached vs. 18 months, respectively (HR 5.32 [1.91-14.80], p = 0.001). For the subset of 41 patients for whom progression-free survival (PFS) data was available, the median PFS for patients with a low-risk vs high-risk gene expression signature was 20 vs. 5 months, respectively (HR 2.95 [1.46-5.98], p = 0.003)., Conclusions: If validated in a larger prospective study, this test may predict patients most likely to benefit from second-generation antiandrogen therapy.

Competing Interests: Disclosure: The authors declare no conflict of interest.

Background: Sleep apnoea, a common sleep-disordered breathing condition, is characterised by upper airway collapse during sleep resulting in transient hypoxia, hypoperfusion of the optic nerve, and spike in intracranial pressure. Previous studies have reported conflicting findings on the association of sleep apnoea with glaucoma, and there are limited reports on the link between sleep apnoea and age-related macular degeneration (AMD)., Methods: Middle-aged and older participants from the longitudinal United Kingdom (UK) Biobank (n = 502,505) and the Canadian Longitudinal Study on Aging (CLSA; n = 24,073) were included in this analysis. Participants in the UK Biobank and the CLSA were followed for 8 and 3 years, respectively. Participants with diagnosed glaucoma or AMD at baseline were excluded from the analysis. In the UK Biobank, sleep apnoea and incident cases of glaucoma and AMD were identified through hospital inpatient admission, primary care records, and self-reported data. Multivariable Cox proportional hazards models were used to explore associations of sleep apnoea with incidence of glaucoma or AMD., Results: During the 8-year follow-up in the UK Biobank, glaucoma incidence rates per 1000 person-years were 2.46 and 1.59 for participants with and without sleep apnoea, and the AMD incidence rates per 1000 person-years were 2.27 and 1.42 for participants with and without sleep apnoea, respectively. Multivariable adjusted hazard ratios of glaucoma and AMD risk for sleep apnoea were 1.33 (95% confidence interval [CI] 1.10-1.60, P = 0.003) and 1.39 (95% CI 1.15-1.68, P <  0.001) relative to participants without sleep apnoea. In the CLSA cohort, disease information was collected through in-person interview questionnaires. During the 3-year follow-up, glaucoma incidence rates per 1000 person-years for those with and without sleep apnoea were 9.31 and 6.97, and the AMD incidence rates per 1000 person-years were 8.44 and 6.67, respectively. In the CLSA, similar associations were identified, with glaucoma and AMD odds ratios of 1.43 (95% CI 1.13-1.79) and 1.39 (95% CI 1.08-1.77), respectively, in participants with sleep apnoea compared to those without sleep apnoea (both P <  0.001)., Conclusions: In two large-scale prospective cohort studies, sleep apnoea is associated with a higher risk of both glaucoma and AMD. These findings indicate that patients with sleep apnoea might benefit from regular ophthalmologic examinations.

Among non-small cell lung cancer (NSCLC) patients with therapeutically targetable tumor mutations in epidermal growth factor receptor (EGFR), not all patients respond to targeted therapy. Combining circulating-tumor DNA (ctDNA), clinical variables, and radiomic phenotypes may improve prediction of EGFR-targeted therapy outcomes for NSCLC. This single-center retrospective study included 40 EGFR-mutant advanced NSCLC patients treated with EGFR-targeted therapy. ctDNA data included number of mutations and detection of EGFR T790M. Clinical data included age, smoking status, and ECOG performance status. Baseline chest CT scans were analyzed to extract 429 radiomic features from each primary tumor. Unsupervised hierarchical clustering was used to group tumors into phenotypes. Kaplan-Meier (K-M) curves and Cox proportional hazards regression were modeled for progression-free survival (PFS) and overall survival (OS). Likelihood ratio test (LRT) was used to compare fit between models. Among 40 patients (73% women, median age 62 years), consensus clustering identified two radiomic phenotypes. For PFS, the model combining radiomic phenotypes with ctDNA and clinical variables had c-statistic of 0.77 and a better fit (LRT p = 0.01) than the model with clinical and ctDNA variables alone with a c-statistic of 0.73. For OS, adding radiomic phenotypes resulted in c-statistic of 0.83 versus 0.80 when using clinical and ctDNA variables (LRT p = 0.08). Both models showed separation of K-M curves dichotomized by median prognostic score (p < 0.005). Combining radiomic phenotypes, ctDNA, and clinical variables may enhance precision oncology approaches to managing advanced non-small cell lung cancer with EGFR mutations.

Although the majority of patients with metastatic non-small-cell lung cancer (mNSCLC) lacking a detectable targetable mutation will receive pembrolizumab-based therapy in the frontline setting, predicting which patients will experience a durable clinical benefit (DCB) remains challenging., Materials and Methods: Patients with mNSCLC receiving pembrolizumab monotherapy or in combination with chemotherapy underwent a 74-gene next-generation sequencing panel on blood samples obtained at baseline and at 9 weeks. The change in circulating tumor DNA levels on-therapy (molecular response) was quantified using a ratio calculation with response defined by a > 50% decrease in mean variant allele fraction. Patient response was assessed using RECIST 1.1; DCB was defined as complete or partial response or stable disease that lasted > 6 months. Progression-free survival and overall survival were recorded., Results: Among 67 patients, 51 (76.1%) had > 1 variant detected at a variant allele fraction > 0.3% and thus were eligible for calculation of molecular response from paired baseline and 9-week samples. Molecular response values were significantly lower in patients with an objective radiologic response (log mean 1.25% v 27.7%, P < .001). Patients achieving a DCB had significantly lower molecular response values compared to patients with no durable benefit (log mean 3.5% v 49.4%, P < .001). Molecular responders had significantly longer progression-free survival (hazard ratio, 0.25; 95% CI, 0.13 to 0.50) and overall survival (hazard ratio, 0.27; 95% CI, 0.12 to 0.64) compared with molecular nonresponders., Conclusion: Molecular response assessment using circulating tumor DNA may serve as a noninvasive, on-therapy predictor of response to pembrolizumab-based therapy in addition to standard of care imaging in mNSCLC. This strategy requires validation in independent prospective studies., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Jeffrey C. ThompsonConsulting or Advisory Role: OncoCyte, AstraZeneca, Guardant HealthErica L. CarpenterHonoraria: AstraZeneca Consulting or Advisory Role: Bristol-Myers Squibb Research Funding: Merck, Janssen, Becton Dickinson, United Health Group Patents, Royalties, Other Intellectual Property: Invention disclosure titled "Methods and Compositions for Treating Neuroblastoma", and invention disclosure titled "Methods and Compositions for Identifying, Diagnosing and Treating Neuroblastoma" Travel, Accommodations, Expenses: AstraZeneca, Foundation Medicine,Katie QuinnEmployment: Guardant Health Stock and Other Ownership Interests: Guardant HealthCarin R. EspenschiedEmployment: Guardant Health Stock and Other Ownership Interests: Guardant HealthAllysia MakEmployment: Guardant Health Stock and Other Ownership Interests: Guardant HealthLesli A. KiedrowskiEmployment: Guardant Health Stock and Other Ownership Interests: Guardant HealthMartina LefterovaEmployment: Guardant Health Stock and Other Ownership Interests: Guardant Health Consulting or Advisory Role: PersonalisRebecca J. NagyEmployment: Guardant Health Stock and Other Ownership Interests: Guardant HealthSharyn I. KatzConsulting or Advisory Role: Trizell Research Funding: NovartisChristine A. CiunciHonoraria: Imedex Research Funding: Celgene, Merck, Bristol-Myers Squibb, MacroGenicsJoshua M. BaumlConsulting or Advisory Role: Bristol-Myers Squibb, Merck, AstraZeneca, Genentech, Celgene, Boehringer Ingelheim, Guardant Health, Takeda, Novartis, Janssen, Ayala Pharmaceuticals, Regeneron, Inivata, Foundation Medicine Research Funding: Merck, Carevive Systems, Novartis, Incyte, Bayer, Janssen, AstraZeneca, Takeda, Amgen, Pfizer, Mirati TherapeuticsRoger B. CohenConsulting or Advisory Role: Heat Biologics, Innate Pharma, Cantargia AB, Genocea Biosciences, AstraZeneca Research Funding: Heat Biologics, Merck, Celldex, Innate Pharma, Kyn therapeutics, Xencor, Genocea Biosciences Travel, Accommodations, Expenses: Heat Biologics, Innate Pharma, Genocea BiosciencesCorey J. LangerHonoraria: Bristol-Myers Squibb, Genentech/Roche, Lilly/ImClone, AstraZeneca, Takeda Science Foundation, Merck Consulting or Advisory Role: Genentech/Roche, Lilly/ImClone, Merck, Abbott Biotherapeutics, Bayer/Onyx, Clarient, Clovis Oncology, Celgene, Cancer Support Community, Bristol-Myers Squibb, ARIAD, Takeda, AstraZeneca, Pfizer, Novocure, Gilead Sciences Research Funding: Merck, Advantagene, Clovis Oncology, Celgene, Inovio Pharmaceuticals, Ariad, GlaxoSmithKline, Genentech/Roche, Stem CentRx, Lilly, Trizell Other Relationship: Lilly, Amgen, Peregrine Pharmaceuticals, SyntaCharu AggarwalConsulting or Advisory Role: Genentech, Lilly, Celgene, Merck, AstraZeneca Speakers' Bureau: AstraZeneca, Roche/Genentech, An Immediate Family Member Research Funding: Genentech/Roche, Incyte, Macrogenics, Merck Sharp & Dohme, AstraZeneca/MedImmune No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Inflammation and cigarette smoking predispose to macular diseases, and choroidal and retinal thinning. We explored the choroidal and retinal thicknesses in young adults against their 7-year C-reactive protein (CRP) level trajectory and pack-years smoked. Participants from the Raine study, a longitudinal cohort study, had serum CRP levels analysed at the 14-, 17-, and 20-year follow-ups. Group-based trajectory modelling was used to classify participants according to their 7-year CRP levels. At the 20-year follow-up (at 18-22 years old), participants completed questionnaires on their smoking history, and underwent optical coherence tomography imaging to obtain their choroidal and retinal thicknesses at the macula. Three CRP trajectories were identified: consistently low CRP levels (78% of sample), increasing (11%), or consistently high (11%). 340 and 1035 participants were included in the choroidal and retinal thickness analyses, respectively. Compared to those in the "Low" trajectory group, participants in the "Increasing" and "High" groups had 14-21 μm thinner choroids at most macular regions. Every additional pack-year smoked was linked with a 0.06-0.10 μm thinner retina at the inner and outer macular rings, suggesting a dose-dependent relationship between smoking and thinner retinas. These associations may suggest that an increased risk of future visual impairment or eye disease associated with these risk factors may be present since young adulthood.

Purpose: To describe the thickness profiles of the full retinal and outer retinal layers (ORL) at the macula in healthy young adults, and associations with best-corrected visual acuity (BCVA)., Methods: In total, 1604 participants (19-30 years) underwent an eye examination that included measurements of their BCVA, axial length, and autorefraction. The retinal thickness at the foveal pit and at the nine Early Treatment of Diabetic Retinopathy Study macular regions (0.5-mm radius around the fovea, and superior, inferior, temporal, and nasal quadrants of the inner and outer rings of the macula) were obtained using spectral-domain optical coherence tomography imaging. A custom program was used to correct for transverse magnification effects because of different axial lengths., Results: The median full retinal and ORL thicknesses at the central macula were 285 µm and 92 µm. The full retina was thinnest centrally and thickest at the inner macula ring, whereas the ORL was thickest centrally and gradually decreased in thickness with increasing eccentricity. There was no association between axial length and the full retinal or ORL thickness. Increased thicknesses of the full retina at the central macula was associated with better BCVA; however, the effect size was small and not clinically significant., Conclusions: This article mapped the full retinal and ORL thickness profile in a population-based sample of young healthy adults., Translational Relevance: Thickness values presented in this article could be used as a normative reference for future studies on young adults and in clinical practice.

Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed too late for effective therapy. The classic strategy for early detection biomarker advancement consists of initial retrospective phases of discovery and validation with tissue samples taken from individuals diagnosed with disease, compared with controls. Using this approach, we previously reported the discovery of a blood biomarker panel consisting of thrombospondin-2 (THBS2) and CA19-9 that together could discriminate resectable stage I and IIa PDAC as well as stages III and IV PDAC, with c-statistic values in the range of 0.96 to 0.97 in two phase II studies. We now report that in two studies of blood samples prospectively collected from 1 to 15 years prior to a PDAC diagnosis (Mayo Clinic and PLCO cohorts), THBS2 and/or CA19-9 failed to discriminate cases from healthy controls at the AUC = 0.8 needed. We conclude that PDAC progression may be heterogeneous and for some individuals can be more rapid than generally appreciated. It is important that PDAC early-detection studies incorporate high-risk, prospective prediagnostic cohorts into discovery and validation studies. Prevention Relevance: A blood biomarker panel of THBS2 and CA19-9 detects early stages of pancreatic ductal adenocarcinoma at diagnosis, but not when tested across a population up to 1 year earlier. Our findings suggest serial sampling over time, using prospectively collected samples for biomarker discovery, and more frequent screening of high-risk individuals., (©2020 American Association for Cancer Research.)

Background: We aimed to determine whether plasma cell-free DNA (cfDNA) concentration is associated with survival in patients with isocitrate dehydrogenase ( IDH ) wild-type glioblastoma (GBM)., Methods: Pre-operative and post-chemoradiotherapy blood samples were prospectively collected from patients with newly diagnosed IDH wild-type GBM. Patients underwent surgical resection or biopsy and received adjuvant radiotherapy with concomitant temozolomide. Cell-free DNA (cfDNA) was isolated from plasma and quantified using SYBR Green-based q polymerase chain reaction (qPCR)., Results: Sixty-two patients were enrolled and categorized into high vs. low cfDNA groups relative to the pre-operative median value (25.2 ng/mL, range 5.7-153.0 ng/mL). High pre-operative cfDNA concentration was associated with inferior PFS (median progression-free survival (PFS), 3.4 vs. 7.7 months; log-rank P = .004; hazard ratio [HR], 2.19; 95% CI, 1.26-3.81) and overall survival (OS) (median OS, 8.0 vs. 13.9 months; log-rank P = .01; HR, 2.43; 95% CI, 1.19-4.95). After adjusting for risk factors, including O 6 -methylguanine-DNA methyltransferase ( MGMT ) promoter methylation status, pre-operative cfDNA remained independently associated with PFS (HR, 2.70; 95% CI, 1.50-4.83; P = .001) and OS (HR, 2.65; 95% CI, 1.25-5.59; P = .01). Post-hoc analysis of change in cfDNA post-chemoradiotherapy compared to pre-surgery ( n = 24) showed increasing cfDNA concentration was associated with worse PFS (median, 2.7 vs. 6.0 months; log-rank P = .003; HR, 4.92; 95% CI, 1.53-15.84) and OS (median, 3.9 vs. 19.4 months; log-rank P < .001; HR, 7.77; 95% CI, 2.17-27.76)., Conclusions: cfDNA concentration is a promising prognostic biomarker for patients with IDH wild-type GBM. Plasma cfDNA can be obtained noninvasively and may enable more accurate estimates of survival and effective clinical trial stratification., (© The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: The cost-effectiveness of letermovir as cytomegalovirus (CMV) prophylaxis in adult seropositive patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT), compared with the conventional strategy of preemptive treatment, has not been evaluated in Asia., Methods: A decision analytical model, simulating the clinical progression of CMV infection on a lifetime horizon, was developed to compare prophylactic strategy with letermovir with preemptive therapy alone as anti-CMV strategies. Prophylaxis comprised administering letermovir for 14 weeks, with clinical outcomes measured at 24 weeks, followed by preemptive therapy if CMV infection occurred. This approach was modeled on outcomes of the letermovir phase 3 clinical study. The model enumerated the cost of letermovir prophylaxis, quality-adjusted life years (QALYs), and incremental cost per QALYs gained with prophylaxis. The opposite arm involved regular monitoring and preemptive therapy for CMV reactivation. Real-world costs from the adult HSCT center at Queen Mary Hospital, Hong Kong, were adopted for analysis. Costs and clinical benefits, expressed as QALYs, were discounted at 3% per year., Results: Letermovir prophylaxis compared with preemptive therapy only would lead to an increase of life-year and QALYs at increased costs. Incremental cost-effectiveness analysis showed that letermovir prophylaxis had an associated cost of HKD 193,580 for each life-year gained, and HKD 234,675 for each QALY gained. Probabilistic sensitivity analysis showed that the majority of incremental cost-effectiveness ratio fell below the cost-effectiveness threshold of HKD 382,046 (one gross domestic product per capita) per QALY gained., Conclusions: Letermovir prophylaxis would be cost-effective for preventing CMV infection in adult seropositive allogeneic HSCT recipients in Hong Kong.

Natural products have served as inspirational scaffolds for the design and synthesis of novel antineoplastic agents. Here we present our preliminary efforts on the synthesis and biological evaluation of a new class of electrophilic steroids inspired by the naturally occurring taccalonolides. We demonstrate that these simplified analogs exhibit highly persistent antiproliferative properties similar to the taccalonolides and retain activity against resistant cancer cell lines that warrants further preclinical development., Competing Interests: The authors declare no competing financial interest., (© 2020 American Chemical Society.)

Precis: Although mental or emotional stress may result raise in intraocular pressure (IOP) we found weak associations between endogenous stress markers concentrations and retinal nerve fiber layer (RNFL) thickness, thus limited evidence that stress affects retinal ganglion cells integrity., Purpose: Increased exposure to glucocorticoids is linked to elevated IOP, which is a risk factor for glaucoma. We explored the RNFL thickness for changes that may mimic preclinical glaucomatous changes, in relation to the hormonal stress response., Materials and Methods: Young healthy adults (n=863) underwent a Trier Social Stress Test. Endogenous plasma adrenocorticotropic hormone (ACTH) and cortisol were measured for those who provided biological samples, and adrenal sensitivity was calculated. On the basis of cortisol levels before and after the Trier Social Stress Test, participants were categorized into one of 3 stress response types: anticipatory-responders, reactive-responders, and nonresponders. Participants underwent an eye examination that included spectral-domain optical coherence tomography to measure peripapillary RNFL thickness., Results: Higher levels of ACTH were associated with thinner RNFL globally (P=0.009), and at the inferotemporal (P=0.015), superotemporal (P=0.044), and temporal sectors (P=0.046). Lower adrenal sensitivity was associated with thinner RNFL inferotemporally (P<0.001) and temporally (P=0.037). However, these effect sizes were small; for example, a 10 pg/mL increase in baseline ACTH was associated with only a 3 µm thinner RNFL. RNFL thickness was not associated with plasma cortisol levels and or significantly different between groups of acute stress response patterns., Conclusions: Although there was a link between ACTH or adrenal sensitivity and RNFL thickness, this association was weak and its clinical significance is unclear. Despite the close associations between levels of endogenous stress markers and IOP, we found limited evidence of a link to RNFL integrity.

Purpose: To determine whether a multianalyte liquid biopsy can improve the detection and staging of pancreatic ductal adenocarcinoma (PDAC)., Experimental Design: We analyzed plasma from 204 subjects (71 healthy, 44 non-PDAC pancreatic disease, and 89 PDAC) for the following biomarkers: tumor-associated extracellular vesicle miRNA and mRNA isolated on a nanomagnetic platform that we developed and measured by next-generation sequencing or qPCR, circulating cell-free DNA (ccfDNA) concentration measured by qPCR, ccfDNA KRAS G12D/V/R mutations detected by droplet digital PCR, and CA19-9 measured by electrochemiluminescence immunoassay. We applied machine learning to training sets and subsequently evaluated model performance in independent, user-blinded test sets., Results: To identify patients with PDAC versus those without, we generated a classification model using a training set of 47 subjects (20 PDAC and 27 noncancer). When applied to a blinded test set ( N = 136), the model achieved an AUC of 0.95 and accuracy of 92%, superior to the best individual biomarker, CA19-9 (89%). We next used a cohort of 20 patients with PDAC to train our model for disease staging and applied it to a blinded test set of 25 patients clinically staged by imaging as metastasis-free, including 9 subsequently determined to have had occult metastasis. Our workflow achieved significantly higher accuracy for disease staging (84%) than imaging alone (accuracy = 64%; P < 0.05)., Conclusions: Algorithmically combining blood-based biomarkers may improve PDAC diagnostic accuracy and preoperative identification of nonmetastatic patients best suited for surgery, although larger validation studies are necessary., (©2020 American Association for Cancer Research.)