Lesion Growth Rate Research Articles

Pharmacokinetic/pharmacodynamic analysis of geographic atrophy lesion area in patients receiving pegcetacoplan treatment or sham.

Pegcetacoplan is a complement C3/C3b inhibitor indicated for the treatment of geographic atrophy (GA). A population pharmacokinetic (PK)/pharmacodynamic (PD) analysis of pegcetacoplan used GA lesion area measurements from three clinical studies to determine the effect of pegcetacoplan exposure on GA progression. A base disease progression model was developed using data from sham-treated eyes and untreated fellow eyes, followed by treatment effect assessment in dose-response and PK/PD models. In total, 1501 patients from FILLY (NCT02503332), OAKS (NCT03525613), and DERBY (NCT03525600) received intravitreal pegcetacoplan 15 mg monthly or every other month (EOM) or sham treatment monthly or EOM and were included in the population analysis of lesion area. Disease progression over time was adequately described as linear-with-time over the 24-month maximal study duration. Disease-specific covariates associated with slower lesion growth were unilateral, unifocal, and subfoveal GA lesions and >20 intermediate or large drusen groups (≥63 μm) at baseline. The dose-response model estimated 0.80-fold (95% CI: 0.75, 0.84) and 0.83-fold (95% CI: 0.78, 0.87) reductions in GA lesion growth rate with pegcetacoplan monthly and EOM, respectively, versus sham. A relationship between vitreous humor concentration and GA lesion growth rate was quantified as 2.6% per unit of log-transformed vitreous pegcetacoplan concentration in the PK/PD model. PK/PD predictions of treatment effect based on exposure (pegcetacoplan monthly: 0.80 [90% CI: 0.77, 0.84]; pegcetacoplan EOM: 0.83 [90% CI: 0.80, 0.86]) were consistent with predictions based on dose response. These results support the benefit of pegcetacoplan administered monthly or EOM in slowing GA lesion growth.

Deep Learning to Predict the Future Growth of Geographic Atrophy from Fundus Autofluorescence

PurposeThe region of growth (ROG) of geographic atrophy (GA) throughout the macular area has an impact on visual outcomes. Here, we developed multiple deep learning (DL) models to predict the 1-year ROG of GA lesions using fundus autofluorescence (FAF) images. DesignIn this retrospective analysis, 3 types of models were developed using FAF images collected 6 months after baseline to predict the GA lesion area (segmented lesion mask) at 1.5 years, FAF images collected at baseline and 6 months to predict the GA lesion at 1.5 years, and FAF images collected 6 months after baseline to predict the GA lesion at 1 and 1.5 years. The 1-year ROG from the 6-month visit was derived by taking the difference between the GA lesion area (segmented lesion mask) at the 1.5-year and 6-month visits. ParticipantsPatients enrolled in the following lampalizumab clinical trials and prospective observational studies: NCT02247479, NCT02247531, NCT02479386, and NCT02399072. MethodsDatasets of study eyes from 597 patients were split into model training (310), validation (78), and test sets (209), stratified by baseline or initial lesion area, lesion growth rate, foveal involvement, and focality. DL experiments were performed using the 2-dimensional U-Net, whole-lesion and multiclass models were developed. Main Outcome MeasuresThe performance of the models was evaluated by calculating the Dice score, coefficient of determination (R2), and the squared Pearson correlation coefficient (r2) between the true and derived GA lesion 1-year ROG. ResultsThe model using baseline and 6-month FAF images to predict GA lesion enlargement at 1.5 years had the best performance for the derived 1-year ROG. Mean Dice scores were 0.73, 0.68, and 0.70, respectively, in the training, validation, and test sets. The R2 (0.77, 0.53, and 0.79) and r2 (0.83, 0.61, and 0.79) showed similar trends across the 3 sets. ConclusionsThese findings show the potential of using baseline and/or 6-month visit FAF images to predict 1-year GA ROG using a DL approach. This work could potentially help support decision making in clinical trials and more informed treatment decisions in clinical practice.

Phase 1 Study of JNJ-81201887 Gene Therapy in Geographic Atrophy Secondary to Age-Related Macular Degeneration

ObjectiveTo evaluate the safety and tolerability of a single intravitreal injection of JNJ-81201887 (JNJ-1887) in patients with geographic atrophy (GA) secondary to advanced dry age-related macular degeneration (AMD). DesignPhase 1, open-label, single-center, first-in-human clinical study. SubjectsAdult patients (aged ≥50 years) with GA secondary to AMD in the study-treated eye (treated eye) with a best corrected visual acuity (BCVA) Snellen equivalent of 20/200 or worse in the treated eye (20/80 or worse after the first 3 patients), a total GA lesion size between 5 and 20 mm2 (2-8 disc area), and BCVA of 20/800 or better in fellow, non-treated eye were included. MethodsPatients (N=17) were sequentially enrolled into low (3.56×1010 viral genome [vg]/eye; n=3), intermediate (1.07×1011 vg/eye; n=3), and high (3.56×1011 vg/eye; n=11) dose cohorts without steroid prophylaxis and assessed for safety and tolerability over 24 months. Main Outcome MeasuresSafety and tolerability outcomes included assessment of ocular and non-ocular treatment-emergent adverse events (AEs) over 24 months. Secondary outcomes included GA lesion size and growth rate. ResultsBaseline patient characteristics were consistent with the disease under study, and all enrolled patients had foveal center–involved GA. JNJ-1887 was well tolerated across all cohorts, with no dose-limiting AEs. There were no serious or systemic AEs related to study intervention. Overall, 5/17 (29%) patients experienced 6 events of mild ocular inflammation related to study treatment; exam findings in all resolved, and AEs resolved in 4 of 5 patients following topical steroids or observation. One unresolved vitritis event, managed with observation, occurred in a patient with an unrelated fatal AE. No endophthalmitis or new-onset choroidal neovascularization was reported. GA lesion growth rate was similar among all cohorts over 24 months. For treated eyes in the high-dose cohort, GA lesion growth rate showed continued decline through 24 months, with a reduction in mean square root lesion growth from 0.211 mm at months 0-6 to 0.056 mm at months 18-24. ConclusionsAll 3 studied doses of JNJ-1887 had a manageable safety profile through 24 months of follow-up. Further investigation of JNJ-1887 for the treatment of GA is warranted.

Outer Retinal Tubulation in Geographic Atrophy.

Outer retinal tubulation (ORT) is observed on optical coherence tomography images from patients with geographic atrophy (GA), but its clinical implications are unclear. The objective of this study was to investigate the prevalence of ORT and its association with GA lesion growth rates. This post hoc longitudinal analysis assessed 62 eyes randomized to sham treatment in the phase 2 FILLY trial. ORT prevalence was estimated at baseline, month 12, and month 18 and change in GA lesion growth from baseline to month 18 was calculated. ORT prevalence rates were 24%, 43%, and 43% at baseline, month 12, and month 18, respectively. Slower mean GA lesion growth was observed in eyes with ORT present at baseline in the overall population as well as the subfoveal and nonsubfoveal GA subgroups. ORT presence may indicate a slower-growing GA lesion phenotype, independent of foveal involvement. [Ophthalmic Surg Lasers Imaging Retina 2024;55:448-451.].

Abstract 2391: Towards better prediction of treatment resistance: Directly modeling progression from multiple lesions

Abstract Late-stage cancers in the clinic present as a set of dispersed tumors, each with distinct growth kinetics. As most patients enrolled in trials of experimental anticancer therapeutics have late-stage malignancies, it is important to understand the impact of data analysis methodologies on the ability to detect treatment effect. In particular, we are interested in the potential risk posed by aggregating individual tumor measurements from multiple-lesion clinical data into a single tumor burden measurement, as this may cause a loss of information. In this work, we use quantitative modeling to assess how analyzing multiple lesions separately versus using an aggregated readout affects tumor response and detection of progression free survival and relapse. To assess the impact of data aggregation, we built a two-population clonal dynamics model consisting of sensitive and resistant tumor cells undergoing growth in the presence or absence of treatment. We performed parameter sweeps to assess the impact of individual model parameters on progression free survival and relapse. We then extended these sweeps to the multi-lesion situation, using nonlinear regression to compare parameter values of aggregated models and the parameter values of the individual models that comprised it. From our simulations, the most influential parameters in determining rebound are the growth rate of the resistant cells and the fraction of these cells, while growth rate of sensitive cells and growth rate inhibition affect effectiveness of treatment. In analyzing the multiple lesion model in different situations, we found that estimates for progression free survival were significantly more sensitive when the lesions were analyzed separately, rather than being aggregated. Our work suggests that aggregating the lesions into a single readout loses impact of individual lesion growth rate inhibitions, impairing early detection as the ability to detect fast growing, small, resistant lesions (despite overall tumor burden decreasing) is lost. Taken together, our findings suggest that data aggregation causes a loss of information. Relapse can be predicted at earlier times when using the multiple lesion model compared to an aggregated model. Citation Format: Samuel Protich, Madison Stoddard, Lin Yuan, Douglas White, Dean Bottino, Arijit Chakravarty. Towards better prediction of treatment resistance: Directly modeling progression from multiple lesions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2391.

Modelling the displacement and coexistence of clonal lineages of Phytophthora infestans through revisiting past outbreaks

AbstractThe continuous changes in the lineage proportions of populations in the clonal plant pathogen Phytophthora infestans on potato and tomato crops have been perplexing to researchers and disease managers. Sudden outbreaks of newly emergent genotypes are often associated with these rapid composition changes. Modelling can predict the persistence and displacement of pathogen genotypes with differential fitness among hosts. Building upon previous models, we combined analytical and simulation methods to model the outcome of interactions between competing lineages on different hosts. Model inputs include pathogenesis parameters, and the outputs are fitness and lineage proportions within each host. Analytical solutions yielding complete displacement, partial coexistence‐displacement and complete coexistence were described. In a retrospective study, the lesion growth rate and sporulation density of P. infestans lineages on potato and tomato from pathogenicity trials were used as inputs. Output lineage frequencies were compared with historical epidemiological situations to check model accuracy. The results showed that pathogenesis traits measured from empirical trials could simulate lineage constituents on potato and tomato and estimate genotypic fitness with reasonable accuracy. The model also showed promise in predicting ongoing lineage displacements in the subsequent year or few years, even when the displaced lineage was still highly prevalent during the time of isolation. However, large uncertainties remain at temporal–spatial scales owing to complex meta‐population dynamics in some regions and adaptation to local environmental factors. This simulation model provides a new tool for forecasting pathogen compositions and can be used to identify potentially problematic genotypes based on pathogen life‐history traits.

High-Resolution Disease Phenotyping Reveals Distinct Resistance Mechanisms of Tomato Crop Wild Relatives against Sclerotinia sclerotiorum.

Besides the well-understood qualitative disease resistance, plants possess a more complex quantitative form of resistance: quantitative disease resistance (QDR). QDR is commonly defined as a partial but more durable form of resistance and, therefore, might display a valuable target for resistance breeding. The characterization of QDR phenotypes, especially of wild crop relatives, displays a bottleneck in deciphering QDR's genomic and regulatory background. Moreover, the relationship between QDR parameters, such as infection frequency, lag-phase duration, and lesion growth rate, remains elusive. High hurdles for applying modern phenotyping technology, such as the low availability of phenotyping facilities or complex data analysis, further dampen progress in understanding QDR. Here, we applied a low-cost (<1.000 €) phenotyping system to measure lesion growth dynamics of wild tomato species (e.g., Solanum pennellii or Solanum pimpinellifolium). We provide insight into QDR diversity of wild populations and derive specific QDR mechanisms and their cross-talk. We show how temporally continuous observations are required to dissect end-point severity into functional resistance mechanisms. The results of our study show how QDR can be maintained by facilitating different defense mechanisms during host-parasite interaction and that the capacity of the QDR toolbox highly depends on the host's genetic context. We anticipate that the present findings display a valuable resource for more targeted functional characterization of the processes involved in QDR. Moreover, we show how modest phenotyping technology can be leveraged to help answer highly relevant biological questions.

Beyond the three P's: adrenal involvement in MEN1.

Adrenal lesions (ALs) are often detected in patients with multiple endocrine neoplasia type 1 (MEN1). However, they are not well described in MEN1, making their clinical management unclear. This study examined the prevalence and outcomes of ALs found in MEN1. We performed a retrospective chart review of patients diagnosed with MEN1 from 1990 to 2021. ALs were diagnosed using abdominal or thoracic imaging and classified as being unilateral or bilateral, having single or multiple nodules, and as having diffuse enlargement or not. Measurable nodular lesions were analyzed for their size and growth over time. Patients' clinical and radiographic characteristics were collected. We identified 382 patients with MEN1, 89 (23.3%) of whom had ALs. The mean age at detection was 47 ± 11.9 years. We documented 101 measurable nodular lesions (mean size, 17.5 mm; range, 3-123 mm). Twenty-seven nodules (26.7%) were smaller than 1 cm. Watchful waiting was indicated in 79 (78.2%) patients, of whom 28 (35.4%) had growing lesions. Functional lesions were diagnosed in 6 (15.8%) of 38 that had functional work-up (diagnoses: pheochromocytoma (n = 2), adrenocorticotropic hormone-dependent hypercortisolism (n = 2), hyperandrogenism (n = 1), hyperaldosteronism (n = 1)); surgery was indicated for 5 (83.3%; n = 12 nodules), 2 of whom had bilateral, diffuse adrenal enlargement. Two patients were diagnosed with adrenocortical carcinoma and two with neoplasms of uncertain malignant potential. Radiographic or clinical progression of ALs is uncommon. Malignancy should be suspected on the basis of a lesion's growth rate and size. A baseline hormonal work-up is recommended, and no further biochemical work-up is suggested when the initial assessment shows nonfunctioning lesions.

Effects of Host and Weather Factors on the Growth Rate of Septoria nodorum Blotch Lesions on Winter Wheat.

Septoria nodorum blotch (SNB), caused by Parastagonospora nodorum, is a major disease of winter wheat that occurs frequently in the central and southeastern United States. Quantitative resistance to SNB in wheat is determined by various disease resistance components and their interaction with environmental factors. A study was conducted in North Carolina from 2018 to 2020 to characterize SNB lesion size and growth rate and to quantify the effects of temperature and relative humidity on lesion expansion in winter wheat cultivars with different levels of resistance. Disease was initiated in the field by spreading P. nodorum-infected wheat straw in experimental plots. Cohorts (groups of foliar lesions arbitrarily selected and tagged as an observational unit) were sequentially selected and monitored throughout each season. Lesion area was measured at regular intervals, and weather data were collected using in-field data loggers and the nearest weather stations. Final mean lesion area was approximately seven times greater on susceptible than on moderately resistant cultivars, and lesion growth rate was approximately four times higher on susceptible than on moderately resistant cultivars. Across trials and cultivars, temperature had a strong effect of increasing lesion growth rates (P < 0.001), while relative humidity had no significant effect (P = 0.34). Lesion growth rate declined slightly and steadily over the duration of cohort assessment. Our results demonstrate that restricting lesion growth is an important component of SNB resistance in the field and suggest that the ability to limit lesion size may be a useful breeding goal.

Evaluating novel imaging-based mathematical modeling prediction of immunotherapy response by individual melanoma brain metastasis and patient prognosis.

e14013 Background: Ipilimumab/Nivolumab (Ipi/Nivo) significantly transformed outcomes for patients with melanoma brain metastases (MBM), however inter- and intra-patient responses can vary widely. The purpose of this study is to develop and calibrate an imaging-based mathematical model to predict lesion-specific immune response to Ipi/Nivo in patients with MBM to guide early local treatments such as radiotherapy and evaluate the prognostic value of identifying treatment resistant lesions. Methods: Baseline and follow-up 3D T1-W contrast MRIs of patients who solely received Ipi/Nivo after diagnosis with MBM were used to segment individual brain metastases and track serial volumetric data for each lesion to develop a mechanistic model (eq 1). After applying appropriate assumptions to our model, tumor burden ( ρ), intrinsic lesion growth rate ( α 0), Ipi/Nivo-induced kill rate ( μ) and immune response strength ( Λ) were quantified for each lesion. Growth rate shortly after the start of treatment ( α 1 ) was calculated using the short-term model solution (eq 2). dρ/dt= (α0- μ+μ.Λ).ρ - μ.Λ.ρ2 (eq 1) ρ(t)≈eα1.t (eq 2) Change in BM volume between baseline and last follow-up was used to classify each lesion as either ‘responder’ or ‘non-responder’; these were compared with the Wilcoxon-rank-sum test. The highest α1 value for any one BM within a patient tumor was evaluated for its potential to sort patient overall survival (OS). Because the median survival was not reached for this cohort, we determined the α1 threshold of 0.005 to sort patients using an optimization routine that generates the maximum AUC to separate the cohort into 2 groups on an ROC curve. Kaplan-Meier (KM) curves were compared between these 2 groups. Results: In 23 patients, we evaluated 61 lesions. At the lesion level, model parameters representing μ and Λ were significantly different between responder and non-responder lesions (p-values &lt;0.0001 and 0.0004, respectively). The highest α1value for any one BM within a patient tumor was used to sort patient overall survival (OS) into prognostically ‘favorable’ or ‘unfavorable’ groups based on patient survival to ±1,200 days. In this limited cohort, OS KM curves by most aggressive lesion for favorable (α1 &lt; 0.005) vs. unfavorable (α1 &gt; 0.005) were not significant by log-rank test (p = 0.3263). Conclusions: In this limited cohort, we demonstrate feasibility to leverage serial conventional imaging and tumor volumetric data to calibrate a mechanistic model to predict per-lesion treatment response of MBM to Ipi/Nivo. Although the p-value between groups was found to be insignificant when predicting survival using α1, this is likely because of the small number of patients included in this study (n=23). Furthermore, when taken together with the notable AUC (=0.7917) observed in the ROC curve, this promising result supports further investigation in a larger cohort.

Use of internal thoracic artery as a conduit protects coronary artery in the long-term period after coronary artery bypass graft surgery

Aim. To assess whether the internal thoracic artery (ITA) is able to protect coronary artery (CA) after coronary artery bypass graft (CABG) surgery.Material and Methods. Having performed coronary angiography in the long term after CABG surgery, we evaluated 102 angiograms by visual analysis and using Gensini score and SYNTAX score. Using these parameters, we investigated the association of internal thoracic artery and saphenous vein grafts with anatomy and pathology of the coronary artery.Results. Calculation of Gensini score revealed that use of ITA grafts was associated with mild coronary atherosclerosis [4 (0; 17)] as compared with SV grafts [32 (2 ; 32)]. Relative increase of atherosclerotic burden in the coronary artery was 21.05% for the ITA grafts and 102.87% for the SV grafts. Lesion growth rate was significantly higher after using SV grafts than in case with ITA grafts (p = 0.0002)Conclusion. ITA grafts reduce progression of atherosclerosis in bypassed coronary arteries in comparison with SV grafts.

PD38-12 NATURAL HISTORY OF SMALL INDEX LESIONS ON MULTIPARAMETRIC MRI: IMPLICATIONS FOR ACTIVE SURVEILLANCE

You have accessJournal of UrologyCME1 Apr 2023PD38-12 NATURAL HISTORY OF SMALL INDEX LESIONS ON MULTIPARAMETRIC MRI: IMPLICATIONS FOR ACTIVE SURVEILLANCE Anjali Pillai, Zoe Blake, Daniel R. Nemirovsky, Jacob J. Enders, Neil Mendhiratta, Alexander P. Kenigsberg, Michael B. Rothberg, Jibriel Noun, Daniel Nethala, Sandeep Gurram, Bradford J. Wood, Baris Turkbey, and Peter A. Pinto Anjali PillaiAnjali Pillai More articles by this author , Zoe BlakeZoe Blake More articles by this author , Daniel R. NemirovskyDaniel R. Nemirovsky More articles by this author , Jacob J. EndersJacob J. Enders More articles by this author , Neil MendhirattaNeil Mendhiratta More articles by this author , Alexander P. KenigsbergAlexander P. Kenigsberg More articles by this author , Michael B. RothbergMichael B. Rothberg More articles by this author , Jibriel NounJibriel Noun More articles by this author , Daniel NethalaDaniel Nethala More articles by this author , Sandeep GurramSandeep Gurram More articles by this author , Bradford J. WoodBradford J. Wood More articles by this author , Baris TurkbeyBaris Turkbey More articles by this author , and Peter A. PintoPeter A. Pinto More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003336.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Multiparametric magnetic resonance imaging (mpMRI) has demonstrated utility as an adjunct to active surveillance (AS). However, the optimal time interval between sequential MRIs is not standardized. This aims to analyze index lesion growth rates to potentially inform modern AS imaging practice. METHODS: A prospectively maintained database of patients on AS at our institution was queried for patients with ≥2 mpMRIs with no index lesion or index lesions ≤7 mm, as well as a subset of patients with no index lesion or index lesions ≤5 mm. Both cohorts were limited to patients with paired MRI-targeted biopsy showing benign or Gleason grade group (GG) 1 disease. For MRIs preceding PI-RADS scoring, an internal Likert suspicion scoring system was converted into PI-RADS scores. Imaging intervals were calculated between serial mpMRIs and growth rate was calculated with two-tailed t-tests to assess differences between initial and most recent lesion sizes measured on mpMRI. RESULTS: Between 2003-2021, patients on AS with ≥2 mpMRIs with small index lesions measuring ≤7 mm (n=123) or <5 mm (n=65) were identified (Table 1). Lesions in both the ≤7 mm (p=.015) and ≤5 mm (p=.003) cohorts demonstrated a significant change between first and last mpMRI. For the ≤7 mm cohort, average overall growth rate was 0.44±2.4 mm/year over a mean imaging interval of 1.27±0.09 years. For the ≤5 mm cohort, the average overall growth rate was 0.70±3.05 mm/year over a mean imaging interval of 1.31±0.13 years. There were 11 lesions that grew over 5 mm in the first year after initial mpMRI, however, univariate analysis of age, PSA, PI-RADS, and GG did not identify these variables as significant predictors of growth. The majority of lesions (84.6%) grew <1 mm/year (Figure 1). CONCLUSIONS: Small MRI lesions in patients on AS demonstrate minimal growth between follow up mpMRIs. This may indicate that these lesions can be followed longer surveillance intervals. Further studies are needed to prospectively identify the small subset of lesions that demonstrate more rapid growth. Source of Funding: N/A © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e998 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Anjali Pillai More articles by this author Zoe Blake More articles by this author Daniel R. Nemirovsky More articles by this author Jacob J. Enders More articles by this author Neil Mendhiratta More articles by this author Alexander P. Kenigsberg More articles by this author Michael B. Rothberg More articles by this author Jibriel Noun More articles by this author Daniel Nethala More articles by this author Sandeep Gurram More articles by this author Bradford J. Wood More articles by this author Baris Turkbey More articles by this author Peter A. Pinto More articles by this author Expand All Advertisement PDF downloadLoading ...

The Role of the Complement Pathway in Clinical Progression of Geographic Atrophy: Analysis of the Phase III Chroma and Spectri Trials

To investigate the relationship between complement pathway activities and progression of geographic atrophy (GA) secondary to age-related macular degeneration in samples collected from patients enrolled in the Chroma and Spectri trials. Chroma and Spectri were phase III, double-masked, and sham-controlled, 96-week trials. Aqueous humor (AH) samples collected at baseline and week 24 visits from 81 patients with bilateral GA across all 3 treatment groups (intravitreal lampalizumab 10 mg every 6 weeks, every 4 weeks, or corresponding sham procedures) were tested, along with patient-matched plasma samples collected at baseline. Antibody capture assays using the Simoa platform were used to measure the levels of complement factor B, the Bb fragment of complement factor B, intact complement component 3 (C3), processed C3, intact complement C4, and processed C4. Complement factor D levels were measured using enzyme-linked immunosorbent assay. Correlations of complement levels and activities (i.e., processed:intact ratio of complement component) in AH and plasma with baseline GA lesion size and growth rate. In baseline AH, there were strong correlations (Spearman's rho ≥ 0.80) between intact complement proteins, between processed complement proteins, and between linked processed and intact complement proteins; weak correlations (rho ≤ 0.24) were found between complement pathway activities. There were no strong correlations between complement protein levels and activities measured in AH and plasma at baseline (rho ≤ 0.37). Baseline complement levels and activities in AH and plasma did not correlate with baseline GA lesion size or change from baseline in GA lesion area at week 48 (i.e., annualized growth rate). There were no strong correlations between changes in complement levels/activities in the AH from baseline to week 24 and annualized GA lesion growth rate. Genotype analysis did not reveal a meaningful correlation between complement-related, age-related macular degeneration risk single-nucleotide polymorphisms and complement levels and activities. Complement levels or activities in AH and plasma did not correlate with GA lesion size or growth rate. This suggests that local complement activation as measured in AH does not appear to be related to GA lesion progression. Proprietary or commercial disclosure may be found after the references.

Parametric mapping of QTL for resistance to European canker in apple in ‘Aroma’ × ‘Discovery’

Resistance to European canker (Neonectria ditissima) in apple is currently one of the most important breeding targets for commercial production in Sweden. Previous research has identified significant genetic variation in susceptibility to the disease, with the local Swedish cultivar ‘Aroma’ considered as one of the most resistant cultivars. Identification of genetic regions underlying the resistance of this cultivar would be a valuable tool for future breeding. Thus, we performed Bayesian quantitative trait loci (QTL) mapping for resistance to European canker in a full-sib family of ‘Aroma’ × ‘Discovery’. Mapping was performed with the area under the disease progression curves (AUDPCs) from all seven (AUDPC_All7) and the first four assessments (AUDPC_First4), and three parameters of a sigmoid growth model for lesion length. As a scale for the effect of the different parameters, historic phenotypic data from screenings of a genetically diverse germplasm was compiled and re-analyzed. The parametrization of the data on lesion growth increased the number of QTL that could be identified with high statistical power, and provided some insight into their roles during different stages of disease development in the current experimental setup. Five QTL regions with strong or decisive evidence were identified on linkage groups 1, 8, 15, and 16. The QTL regions could be assigned to either of the parameters lesion length at the first assessment (‘LL_A1’), the maximal lesion growth rate (lesion length doubling time, ‘t_gen’), and the lesion length at girdling (‘LL_G’). Three of these QTL were traced along the pedigrees of some known relatives of the FS family, and discussed in relation to future crosses for breeding and genetic research.

Geographic Atrophy Phenotypes in Subjects of Different Ethnicity: Asia–Pacific Ocular Imaging Society Work Group Report 3

To characterize geographic atrophy (GA) and evaluate differences between Asians and non-Asians. Multicenter, retrospective case series. Subjects aged ≥ 50 years with GA secondary to age-related macular degeneration in the absence of neovascularization in the study eye and follow-up of ≥ 2 years. The GA lesion characterized at baseline and last follow-up based on multimodal imaging (fundus autofluorescence [FAF], near infrared [NIR], and spectral domain-OCT). Patients were grouped as either Asian or non-Asian. Comparison of (1) phenotypes of GA lesions (size, foveal involvement, number of foci, drusen background, and choroid background) and (2) growth rates of GA. A total of 144 patients (169 eyes) with distribution of 50.9% Asians and 49.1% non-Asians. The age and sex were similar between Asians and non-Asians (Asians: mean age, 77.2 ± 10.1 years, 47.9% female; non-Asians: mean age, 79.7 ± 8.4 years, 58.7% female). Asians exhibited thicker choroids (167 ± 74 versus [vs.] 134 ± 56 μm; P < 0.01) and lower prevalence of drusen (40.7% vs. 66.3%; P < 0.01). At baseline, the GA area was smaller in Asians vs. non-Asians (NIR, 3.7 ± 4.6 vs. 6.3 ± 6.8 mm2; P= 0.01: FAF, 2.4 ± 3.4 vs. 8.4 ± 9.6 mm2; P< 0.01). Asians had fewer GA foci (1.7 ± 1.3 vs. 2.7 ± 2.2; P < 0.01) compared to non-Asians. The proportion with diffused or banded FAF junctional zone pattern was similar between Asians and non-Asians (44.2% vs. 60.2%; P= 0.20). Asians had a slower GA lesion growth rate than non-Asians (NIR, 0.7 vs. 1.9 mm2/year; P<0.01: FAF, 0.3 vs. 2.0 mm2/year; P < 0.01: NIR, 0.2 vs. 0.4 mm/year; P < 0.01 square root transformed: FAF, 0.1 vs. 0.3 mm/year; P < 0.01 square root transformed). The factors associated with GA lesion growth rate are (from the highest effect size) ethnicity, junctional zone FAF pattern, baseline GA area, and number of GA foci. Higher GA lesion growth rate was observed in both Asian and non-Asian subgroups, with drusen or lesion size and FAF patterns meeting inclusion criteria of recent therapeutic trials, but growth rate remained significantly slower in Asians. Eyes with baseline lesion ≥ 5 mm2 showed the highest growth rate, and the difference between ethnicities was no longer significant (2.6 vs. 3.3 mm2/year; P= 0.14). There are differences in GA lesion phenotype, associated features, and growth rate between Asians and non-Asian subjects. Proprietary or commercial disclosure may be found after the references.

Effects of Temperature on Development of Canker-Causing Pathogens in Almond and Prune.

Between 2000 and 2020, canker diseases of nut and stone fruit trees have become very widespread and severe in California. This study determined the effects of temperature on the development of canker-causing pathogens of almond and prune. Five pathogen taxa, Botryosphaeria dothidea, Cytospora leucostoma, Diaporthe (Phomopsis) neotheicola, Lasiodiplodia citricola, and Neofusicoccum mediterraneum, were used. Colony growth on medium and canker lesion development on detached shoots were measured at 10, 15, 20, 25, 30, and 35°C. The effects of temperature on colony growth differed among different pathogen taxa, although 25°C was the optimal temperature for most of the pathogens tested. The patterns of lesion growth as response to temperature were different among the different pathogens and tree crops. On almond, the highest growth rates appeared at 30°C for B. dothidea and L. citricola, but at 20°C for N. mediterraneum. The growth rates for C. leucostoma were lower than those of the other three pathogen taxa, with the highest rates recorded at 25°C. However, on prune, C. leucostoma showed greater lesion growth rates at different temperatures than the other pathogen taxa and maximum growth at 30 to 35°C. Similar trends were observed for L. citricola. The growth rates of B. dothidea and N.mediterraneum were comparatively lower than those of C. leucostoma and L. citricola.

68Ga-DOTA-FAPI-04 PET/CT imaging in radioiodine-refractory differentiated thyroid cancer (RR-DTC) patients.

This study aimed to assess the potential of 68Ga-DOTA-FAPI-04 PET/CT for the detection of the radioiodine-refractory differentiated thyroid cancer (RR-DTC) lesions. We analyzed the 68Ga-DOTA-FAPI-04 PET/CT imaging data of 24 RR-DTC patients (7 men and 17 women; 49.6 ± 10.5 year). Clinical data were collected including history, last post-therapeutic radioiodine whole body scan, contemporary CT, thyroglobulin, and antithyroglobulin. Target lesions were selected and measured by the RECIST 1.1. The mean growth rates of the target lesions in the past 6months were recorded. Tumor uptake of lesions were quantified by SUVmax and the tumor-to-background ratios. The correlation between SUVmax and target lesion growth rate and thyroglobulin was analyzed. On patient-based analysis, positive metastases were detected in 87.5% (21/24) patients. Except for the lymph node (LN) metastasis of 3 patients (patient 6, 12 and 17#) and the lung metastasis of another 3 patients (patient 9, 13 and 21#), most of the lesions were positive on 68Ga-DOTA-FAPI-04 PET/CT images, including LN metastasis and distant metastasis such as lung, bone and pleura. There were altogether 33 target lesions including 30 lung metastases and 3LN metastases with the mean SUVmax and the growth rate were 4.25 and 6.51%, respectively. SUVmax was statistically associated with the growth rates of the target lesions (p = 0.047). No statistically significant correlation was found between the SUVmax and the serum thyroglobulin levels (p = 0.139). 68Ga-DOTA-FAPI-04 PET/CT has a promising detection rate for RR-DTC metastasis. The FAPI uptake of the tumor may provide a potential therapeutic target for RR-DTC. NIH Clinical Trials.gov (NCT04499365).

Residual effect of defeated stripe rust resistance genes/QTLs in bread wheat against prevalent pathotypes of Puccinia striiformis f. sp. tritici.

The periodic breakdowns of stripe rust resistance due to emergence of new virulent and more aggressive pathotypes of Puccinia striiformis f. sp. tritici have resulted in severe epidemics in India. This necessitates the search for new and more durable resistance sources against stripe rust. The three bread wheat cultivars PBW 343 (carries Yr9 and Yr27), PBW 621 (carries Yr17) and HD 2967 (gene not known) were highly popular among the farmers after their release in 2011. But presently all three cultivars are highly susceptible to stripe rust at seedling as well as at adult plant stages as their resistance has been broken down due to emergence of new pathotypes of the pathogen (110S119, 238S119). In previous study, the crosses of PBW 621 with PBW 343 and HD 2967 and evaluation of further generations (up to F4) against pathotype 78S84 resulted in resistant segregants. In the present study, the F5 and F6 RIL populations have been evaluated against new pathotypes of Pst. The RILs categorized based on the disease severity on the P (Penultimate leaf) and F (flag) leaf into three categories i.e., high, moderate and low level of APR (adult plant resistance) having 1-200, 201-400 and >400 values of AUDPC, respectively, upon infection with stripe rust. The various APR components (latent period, lesion growth rate, spore production and uredial density) were studied on each category, i.e., resistant, moderately resistant and susceptible. The values of APR parameters decreased as the level of resistance increased. Based on molecular analysis, the lines (representing different categories of cross PBW 621 X PBW 343) containing the genes Yr9 and Yr17 due to their interactive effect provide resistance. Based on BSA using 35k SNPs and KASP markers association with phenotypic data of the RIL population (PBW 621 X HD 2967) showed the presence of two QTLs (Q.Pst.pau-6B, Q.Pst.pau-5B) responsible for the residual resistance and two SNPs AX-94891670 and AX-94454107 were found to be associated with the trait of interest on chromosome 6B and 5B respectively. The present study concludes that in the population of both the crosses (PBW 621 X PBW 343 and PBW 621 X HD 2967) major defeated gene contributed towards residual resistance by interacting with minor gene/QTLs.

Oncotic (Myxomatous) Aneurysms: A Review of Management

AbstractAtrial myxomas are the most common primary cardiac tumors and may manifest with neurological symptoms in ∼ 30% of cases. Cerebral ischemia, aneurysmal formation, and extravascular metastases are mechanisms that lead to these neurological manifestations. Perilesional changes on computed tomography (CT) and magnetic resonance imaging (MRI) may help in the diagnosis of myxomatous aneurysms, which are usually located in the distal middle cerebral artery (MCA) and in the posterior cerebral artery (PCA) circulation territories. Careful resection of the cardiac lesion is essential for preventing embolism. However, treatment of myxomatous aneurysms is controversial due to the limited understanding of the natural history of this condition. Treatment may include clinical observation in asymptomatic patients, surgical resection, endovascular approaches, adjuvant chemotherapy, and low-dose radiation therapy. We present one case of a female patient with myxomatous aneurysm secondary to an atrial myxoma who presented with neurological symptoms and another case of a female patient who developed neurological symptoms after initial surgical treatment of the primary lesion. Lesion growth rate, topography, morphology, and the patient's clinical condition must be considered when choosing a therapeutical method. Further clinical studies are needed to achieve a better understanding and treatment of this disease.

Adenosine A1R/A3R (Adenosine A1 and A3 Receptor) Agonist AST-004 Reduces Brain Infarction in a Nonhuman Primate Model of Stroke.

Treatment with A1R/A3R (adenosine A1 and A3 receptor) agonists in rodent models of acute ischemic stroke results in significantly reduced lesion volume, indicating activation of adenosine A1R or A3R is cerebroprotective. However, dosing and timing required for cerebroprotection has yet to be established, and whether adenosine A1R/A3R activation will lead to cerebroprotection in a gyrencephalic species has yet to be determined. The current study used clinical study intervention timelines in a nonhuman primate model of transient, 4-hour middle cerebral artery occlusion to investigate a potential cerebroprotective effect of the dual adenosine A1R/A3R agonist AST-004. Bolus and then 22 hours intravenous infusion of AST-004 was initiated 2 hours after transient middle cerebral artery occlusion. Primary outcome measures included lesion volume, lesion growth kinetics, penumbra volume as well as initial pharmacokinetic-pharmacodynamic relationships measured up to 5 days after transient middle cerebral artery occlusion. Secondary outcome measures included physiological parameters and neurological function. Administration of AST-004 resulted in rapid and statistically significant decreases in lesion growth rate and total lesion volume. In addition, penumbra volume decline over time was significantly less under AST-004 treatment compared with vehicle treatment. These changes correlated with unbound AST-004 concentrations in the plasma and cerebrospinal fluid as well as estimated brain A1R and A3R occupancy. No relevant changes in physiological parameters were observed during AST-004 treatment. These findings suggest that administration of AST-004 and combined A1R/A3R agonism in the brain are efficacious pharmacological interventions in acute ischemic stroke and warrant further clinical evaluation.