Surrogate Marker Research Articles

Gender-specific inflammatory burden and headache risk in youth: a NHANES analysis

BackgroundHeadaches are a common and often debilitating condition among youth. The Inflammatory Burden Index (IBI), a simple surrogate marker of systemic inflammation, has been linked to various diseases. However, evidence for its relationship with headaches, particularly in youth, is lacking. This study aimed to investigate the association between IBI and persistent headache in youth, with a focus on evaluating gender-specific responses to IBI exposure.MethodsWe analyzed data from 2,210 young people in the 2001–2004 National Health and Nutrition Examination Survey (NHANES). The association between IBI and frequent or severe headaches in the past year was investigated using weighted logistic regression models. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated, and threshold effect analyses were performed.ResultsYouths in the highest IBI quartile (Q4) had a 46% higher risk of severe headaches compared to the lowest quartile (Q1) (OR: 1.46, 95% CI: 1.12–1.91, P = 0.0051). Gender-stratified analysis revealed a significant association between high IBI and headache risk in females (OR: 1.48; 95% CI: 1.03–2.11, P = 0.0324), but not in males. Threshold effect analysis identified an IBI breakpoint of 3.78, below which the headache risk increased significantly in females under 18 years (OR: 1.12, 95% CI: 1.01–1.25, P = 0.0385).ConclusionsOur findings demonstrate a significant association between elevated IBI and increased headache risk in youth, particularly in females. This gender-specific effect suggests that inflammatory processes may play a more prominent role in headache pathophysiology among female youth. These results underscore the importance of considering inflammatory markers in the early identification and prevention of youth headaches, especially in females.

Clinicopathologic Features of Breast Tumors in Germline TP53 Variant-Associated Li-Fraumeni Syndrome.

We present one of the largest cohorts of TP53-pathogenic germline variants (PGVs) associated with patients with Li-Fraumeni syndrome (n = 82) with breast tumors (19 to 76y; median age: 35). Most had missense variants (77%), followed by large gene rearrangements (LGRs; 12%), truncating (6%), and splice-site (5%) variants. Twenty-one unique germline missense variants were found, with hotspots at codons 175, 181, 245, 248, 273, 334, and 337. Of 100 total breast tumors, 63% were invasive (mostly ductal), 30% pure ductal carcinoma in situ, 4% fibroepithelial lesions, and 3% with unknown histology. Unlike BRCA-associated tumors, approximately half of the breast cancers exhibited HER2-positivity, of which ~50% showed estrogen receptor coexpression. Pathology slides were available for review for 61 tumors (44 patients), and no significant correlation between the type of TP53 PGVs and histologic features was noted. High p53 immunohistochemistry expression (>50%) was seen in 67% of tumors tested (mostly missense variant). Null pattern (<1% cells) was seen in 2 (LGR and splicing variants carriers). Surprisingly, 2 tumors from patients with an LGR and 1 tumor from a patient with a truncating variant showed p53 overexpression (>50%). The subset of patients with the Brazilian p.R337H variant presented at a higher age than those with non-p.R337H variant (46 vs 35y) though statistically insignificant (P = 0.071) due to an imbalance in the sample size, and were uniquely negative for HER2-overexpressing tumors. To conclude, breast cancer in carriers of TP53 PGVs has some unique clinicopathological features that suggest differential mechanisms of tumor formation. p53 immunohistochemistry cannot be used as a surrogate marker to identify germline TP53-mutated breast cancers.

Traditional Chinese medicine for cardiovascular disease: efficacy and safety

In China and other Asian nations, traditional medicine has long been utilized in the treatment of cardiovascular diseases (CVD). While Chinese authorities have incorporated traditional Chinese medicine (TCM) treatment experiences as a supplementary guide for CVD, its international recognition remains limited due to a scarcity of high-quality and reliable randomized controlled trials (RCTs) evidence. The purpose of this study was to examine the clinical outcomes with TCM for CVD after the recent publication of large trials adding &amp;gt;20,000 individuals to the published data. Here, we systematically reviewed 55 published RCTs (modified Jadad scores &amp;gt; 4) in the past 20 years, involving a total of 36,261 patients. In most studies, TCM has been associated with significant improvements in alternative endpoints such as hypertension, coronary heart disease, stroke and heart failure. A total of 19 trials reported on primary outcomes such as cardiovascular events and death events. During the follow-up period, some Chinese patent medicines can effectively reduce the “hard” endpoints of coronary heart disease, stroke, and heart failure, the overall trend of cardiovascular outcomes is lower. The risk of adverse effects was not significantly increased compared to the control group, suggesting its potential as an alternative approach for primary and secondary prevention of CVD based on the available evidence.

Hepatic real-world outcomes with obeticholic acid in primary biliary cholangitis (HEROES): A trial emulation study design.

Primary biliary cholangitis (PBC) is a rare, progressive liver disease. Obeticholic acid (OCA) received accelerated approval for treating patients with PBC in whom ursodeoxycholic acid (UDCA) failed, based on a surrogate endpoint of reduction in alkaline phosphatase. Analysis of the long-term safety extension with 2 external control groups demonstrated a significant increase in event-free survival in OCA-treated patients. This fully real-world evidence study assessed the effect of OCA treatment on the clinical outcomes. This trial emulation used data from the Komodo Healthcare Map™ claims database linked to US national laboratory, transplant, and death databases. Patients with compensated PBC and intolerance/inadequate response to UDCA who initiated OCA therapy were compared with patients who were OCA-eligible but not OCA-treated. The primary endpoint was time to first occurrence of death, liver transplant, or hospitalization for hepatic decompensation, analyzed using a propensity-score weighted Cox proportional hazards model. Baseline prognostic factors were balanced using standardized morbidity ratio weighting. For the primary analysis, 4174 patients contributed 11,246 control index dates; 403 patients contributed OCA indexes. Weighted groups were well balanced. Median (95% CI) follow-up in the OCA and non-OCA arms was 9.3 (8.4-10.6) months and 17.5 (16.2-18.6) months (weighted population; censored at discontinuation). Eight events occurred in the OCA arm, 32 in the weighted control (HR=0.37; 95% CI=0.14-0.75; p<0.001). Effects were consistent for each component of the composite endpoint. We identified a 63% reduced risk of hospitalization for hepatic decompensation, liver transplant, or death in OCA-treated versus non-OCA-treated individuals. HEROES; ClinicalTrials.gov NCT05292872.

Left atrial single-cell transcriptomics reveals amphiregulin as a surrogate marker for atrial fibrillation

Atrial fibrillation (AF) is strongly associated with strokes, heart failure, and increased mortality. This study aims to identify the monocyte–macrophage heterogeneity and interactions of these cells with non-immune cells, and to identify functional biomarkers in patients with AF. Therefore, we assess the single cell landscape of left atria (LA), using a combination of single cell and nucleus RNA-seq. Myeloid cells in LA tissue are categorized into five macrophage clusters, three monocyte clusters, and others. Cell-Chat analysis revealed that monocytes and IL1B+ macrophages send epidermal growth factor (EGF) signals to fibroblasts. Amphiregulin (AREG) is the most upregulated gene in monocytes and IL1B+ macrophages in the AF group, compared with healthy controls from other groups. Serum AREG levels are higher in patients with persistent AF. These data suggested that EGF signaling pathway could be a therapeutic target for AF and serum AREG levels provide an effective biomarker for predicting persistent AF.

Population-Based Evidence for the Use of Serum Neurofilaments as Individual Diagnostic and Prognostic Biomarkers in Amyotrophic Lateral Sclerosis.

Neurofilament light chains (NfL) and phosphorylated neurofilament heavy chains (pNfH), established as diagnostic and prognostic biomarkers in hospital-based amyotrophic lateral sclerosis (ALS) cohorts, are now surrogate markers in clinical trials. This study extends their evaluation to a population level, with the aim of advancing their full establishment and assessing the transferability of biomarker findings from controlled cohorts to real-world ALS populations. We measured serum NfL and pNfH levels in all ALS patients (n = 790) and general population controls (n = 570) with available baseline samples participating in the epidemiological ALS Registry Swabia, providing platform-specific (ELLA™) reference data and Z-scores for controls, as well as reference data, disease-specific Z-scores and longitudinal data in ALS. We evaluated the diagnostic and prognostic utility of neurofilaments and quantified the impact of ALS-related factors and non-ALS confounders. Neurofilaments showed high diagnostic and prognostic utility at the population level, with NfL superior to pNfH. The novel concept of a population-based ALS Z-score significantly improved the prognostic utility compared to absolute raw values. Both biomarkers increased more strongly with age in controls than in ALS, and age adjustment improved diagnostic accuracy. Our data show that disease progression rates, ALS phenotype, body mass index (BMI), and renal function need to be considered when interpreting neurofilament levels; longitudinal neurofilament levels were generally stable in individual patients, especially when adjusted for age and baseline levels. Population-based assessment enhances the utility of particularly serum NfL as a diagnostic and prognostic biomarker in ALS and improves the translation of findings from controlled cohorts to real-world populations. ANN NEUROL 2024;96:1040-1057.

Vascular Endothelial Effects of Sacubitril/Valsartan in Heart Failure With Reduced Ejection Fraction: Randomized Controlled Trial

BackgroundThe mechanism of how sacubitril/valsartan improves outcomes in heart failure with reduced ejection fraction (HFrEF) is still incompletely understood. ObjectivesThe aim of this trial was to delineate the effects of sacubitril/valsartan on endothelial function, retinal microvascular function, and arterial stiffness in HFrEF. MethodsThis double-blind controlled trial randomized 79 stable HFrEF patients with NYHA class II-IV on guideline-recommended therapy (mean age: 59.4 ± 12 years, left ventricular ejection fraction: 30% ± 7%) to sacubitril/valsartan or valsartan alone for 3 months. The primary endpoint was flow-mediated vasodilation (FMD). Secondary outcomes included flicker-induced dilatation of retinal arterioles and venules (FIDv), retinal arteriovenous ratio, and surrogate markers of arterial stiffness (pulse wave velocity and augmentation index). ResultsThe primary outcome FMD did not significantly differ between sacubitril/valsartan and valsartan alone (FMD 6.6% ± 3.9% vs 6.7% ± 2.8%; ANCOVA coefficient adjusted for baseline values 0.36, 95% CI: −0.78 to 1.51, P = 0.53). The secondary outcomes flicker-induced dilatation of retinal arterioles, arteriovenous ratio, pulse wave velocity, and augmentation index showed no significant differences. FIDv was lower after sacubitril/valsartan versus valsartan alone (FIDv 2.4% ± 1.3% vs 3.1% ± 2.1%; ANCOVA coefficient −0.7, 95% CI: −1.4 to −0.02, P = 0.04). Systolic blood pressure was lower after sacubitril/valsartan versus valsartan alone (ANCOVA coefficient −6.5 mm Hg, 95% CI: −12.7 to −0.3 mm Hg, P = 0.04). There were numerically fewer serious adverse events with sacubitril/valsartan versus valsartan alone. ConclusionsIn this randomized double-blind clinical trial addressing mechanisms, sacubitril/valsartan lowered blood pressure and flicker-induced dilatation of retinal venules in patients with symptomatic HFrEF but did not improve endothelial function, retinal microvascular function, or arterial stiffness compared to valsartan monotherapy. (Differential Vascular and Endocrine Effects of Valsartan/​Sacubitril in Heart Failure With Reduced Ejection Fraction [VASCEND]; NCT03168568)

Phase angle as a marker of muscle quality: A systematic review and meta-analysis

Background & aimsPhase angle (PhA) is a biomarker derived from raw bioelectrical impedance analysis (BIA) values: resistance (R) and reactance (Xc). PhA reflects cellular membrane integrity and, as a result, has been considered a marker of fluid distribution, making it a potential prognostic indicator. A growing body of research demonstrates independent associations between PhA and muscle strength, mass, and composition. In this context, PhA has the extra potential to serve as a marker of muscle quality. However, the evidence supporting its use for this purpose is not well established. This study aimed to investigate the relationship between PhA and markers of muscle quality. MethodsThis systematic review and meta-analysis (Internal Prospective Register of Systematic Reviews – PROSPERO on a registration code: CRD42024507853) focused on observational studies assessing the relationship between PhA and markers of both concepts of muscle quality: the muscle quality index (MQI: strength by a unit of mass) and the muscle composition (i.e., skeletal muscle radiodensity [SMD], muscle echogenicity, muscle fat fraction, inter- and intramuscular adiposity). Risk of bias was assessed using the Newcastle-Ottawa Scale (NOS) and Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2), while the certainty of evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Meta-analyses with a random-effects model were conducted. ResultsSeventeen studies were included in this systematic review, encompassing 2,710 participants. Meta-analyses demonstrated that PhA had a moderate positive correlation coefficient with SMD (4 studies, 924 participants; r = 0.54, 95% confidence interval (CI) 0.38 to 0.69, heterogeneity (I2) = 92%) and good accuracy (85%) for classifying low SMD (2 studies, 390 participants; Area Under the Curve – AUC pooled 0.85, 95% CI 0.78 to 0.92, I2 = 0%). PhA was inversely-moderately correlated with muscle echogenicity (8 studies, 1,401 participants; r = - 0.42, 95% CI - 0.57 to - 0.24, I2 = 82%) and positively-weakly correlated with MQI (2 studies, 191 participants; r = 0.36, 95% CI 0.21 to 0.49, I2 = 17%). All studies had a higher risk of bias. The certainty of evidence ranged from low to very low. ConclusionDespite technical challenges, this study demonstrates the potential of PhA as a surrogate marker for muscle quality, particularly expressing muscle composition (SMD). Future studies should utilize BIA with standardized protocols to potentially establish specific cutoff values for PhA, thereby enhancing its diagnostic accuracy and clinical applicability. These studies could additionally explore the mechanisms underlying the associations between PhA and muscle quality aspects. In cases where technical factors are not easily controlled, the use of standardized PhA (SPhA), which converts PhA into Z-scores, could be beneficial. Although this warrants investigation, this approach (SPhA) has the potential to account for variables such as age, sex, device differences, and health status.

Assessing parotid gland function through diffusion weighted MRI during and post-radiotherapy in head and neck cancer patients

ObjectivesThe purpose of this study was to evaluate the usefulness of apparent diffusion coefficient (ADC) variation in irradiated parotid glands during and after 3D conformal radiotherapy (3DCRT). Materials and methodsThis study enrolled 15 head and neck cancer (HNC) patients who were treated with 3DCRT underwent diffusion weighted imaging (DWI) at rest and after gustatory stimulation in three time points as follows: before, during (one day after receiving the mean dose 26 Gy) and 6 months after the end of radiotherapy (RT). Salivary Ejection Fraction (SEF) data was also obtained from salivary gland scintigraphy (SGS) at the same three time points as MRI. Mean ADC at rest and after stimulation (ADCr, ADCs) and SEF were extracted from parotid region for three time points. Finally, SEF and changes of ADC over time at rest and after stimulation and in each time point were compared. ResultsDifference between mean ADCr before RT and during RT was not significant (p = 0.12). The ADCr values were significantly higher after RT than before RT (p = 0.003) and during RT (after dose 26 Gy) (p = 0.001). The difference between ADCr and ADCs in each time point showed that there is significant difference between ADCr and ADCs before RT (p = 0.005). Difference between these parameters after RT was also significant (p = 0.05). Non-significant difference (p = 0.21) between ADCr and ADCs during RT was observed. The result of SEF also was significantly lower after RT than during (p = 0.008) and before RT (p = 0.001). ConclusionMean ADC values could be used as a surrogate marker to characterize the parotid function in different stages of RT.

The Prognostic Value of Single and Repeated ≥10% FEV1 Declines for Chronic Lung Allograft Dysfunction

There is a paucity of data reporting the positive and negative predictive values (PPV, NPV) of acute declines in lung function on chronic lung allograft dysfunction (CLAD). We sought to define the predictive ability of single or repeated FEV1 declines for at least 3 weeks on the development of CLAD or death by 1-year. We analyzed 340 subjects with at least 3 years of follow-up data from two lung transplant centers. A single ≥10% FEV1 decline had a PPV of 35% and NPV of 63%, and a repeated ≥10% FEV1 decline for at least 3 weeks had a PPV of 44% and NPV of 65%. Notably, the proportion of individuals with incipient CLAD at the time of a single or repeated ≥20% FEV1 decline was 50% and 71%, respectively. These estimates could inform the development of acute lung allograft dysfunction FEV1 thresholds as enrollment criteria or surrogate outcome measures.

Addressing the commercial determinants of mental health: an umbrella review of population-level interventions.

There is increasing evidence that commercial determinants impact mental health. Addressing the commercial determinants may therefore be a way of improving population-level mental health. This umbrella review aimed to provide an overview of evidence in this field and identify knowledge gaps. Five databases (MEDLINE, Embase, PsycINFO, Scopus and Cochrane Library) were searched on the 18/19 of July 2022. Eligible papers were systematic reviews published after 31 December 2011. No geographical limits were applied. Eligible interventions were those that targeted the behaviours or products of commercial actors. Ineligible interventions included individual behaviour change interventions, such as those seeking to educate consumers. Included mental health outcomes were anxiety, depression, self-harm and suicide, whilst surrogate outcomes included product consumption. Industry involvement and the quality of included reviews (critical components of A MeaSurementTool toAssess systematicReviews -AMSTAR 2) were assessed. A narrative synthesis was used to compare the findings by industry, and a typology of interventions was developed. Eight reviews with mental health outcomes were included, each with multiple methodological weaknesses. There is some evidence that reducing the availability of alcohol or pesticides may lower suicide rates. Despite the known links, no evidence on the mental health impacts of population-level interventions tackling the social media, tobacco, gambling and ultra-processed foods industries were located. All gambling reviews were identified as having links to industry. Future high-quality evaluations of commercial determinants interventions developed specifically with the aim of achieving positive mental health outcomes and/or that evaluate mental health outcomes and are free from industry links are needed. PROSPERO ref. number CRD42022346002.

Electroencephalography Longitudinal Markers of Central Neuropathic Pain Intensity in Spinal Cord Injury: A Home-Based Pilot Study

Background: It is well known from cross-sectional studies that pain intensity affects brain activity as measured by electroencephalography (EEG) in people with neuropathic pain (NP). However, quantitative characterisation is scarce. Methods: In this longitudinal study, ten people with spinal cord injury-related NP recorded their home EEG activity ten days before and after taking medications over a period of several weeks. Results: The reduction in pain due to medications was accompanied by changes in the resting state EEG and its reactivity to eyes opening (EO) and closing (EC). There was a significant positive correlation between the frontal theta band and the intensity of pain (visual numerical scale) pre-medication (p = 0.007, Pearson R = 0.29) and theta, alpha, and lower beta (6–15 Hz) band power and the intensity of pain after post-medication over the frontal, central, and parietal cortices. Reactivity had a negative correlation with pain intensity at all locations and frequency bands and showed similar behaviour in wider frequency bands like 8–15 Hz at the occipital cortex and 2–12 Hz at the frontal cortex. Conclusions: EEG could be used to detect the intensity of NP to serve as a surrogate or pharmacodynamic marker.

Detection of HHV-5 HHV-6a HHV-6b and HHV-7 in the urine: potential use as a non-invasive diagnostic tool for immune profiling

Decline in immune function with age has been studied extensively, but approaches to immune restoration have been hampered by the lack of simple methods of identifying individuals whose immune system is in decline. Our approach has been to identify individuals whose immune decline has led to a loss of control of common latent viral infections and their consequent reactivation. Viruses excreted in urine were detected and quantified and we believe this approach could provide a 'surrogate marker' for identifying immune compromised individuals. Here we report the detection of human herpes virus (HHV) 5, 6a, 6b and 7 in the urine of healthy individuals over a wide age range and their correlation with T cell receptor excision circle (TREC) data. The results did not show a clear correlation between TREC values and the detection of individual specific viruses or viral load values when measured singly. However, a correlation was found between low TREC values and the detection of several different human herpes viruses in the urine in males. We present evidence suggesting that for males, the detection of three or more different human herpes viruses in the urine could identify individuals with declining immune function as evidenced by their significantly lower TREC levels.

Giant Cell-Rich Tumors of the Skeleton.

The accurate diagnosis of giant cell-rich tumors of bone is challenging, especially in limited tissue samples. This diverse group of neoplasms have similar and often ambiguous clinical presentations, radiologic features, and morphologic characteristics. During the last decade, the discovery of pathogenic recurrent genetic alterations has allowed the development of immunohistochemical surrogate markers and FISH assays that can help differentiate the entities of this broad group from one another. The correct diagnosis of these neoplasms is essential in the management of the affected patients.

Bias-corrected group sequential design in the presence of surrogate endpoints with application to PALM trial

Surrogate endpoints are pivotal in clinical trials, replacing true endpoints that may be challenging to measure. However, their imprecise association with true endpoints can lead to biased results, necessitating validation through trials. This paper proposes a bias-corrected group sequential design in the presence of surrogate endpoints to address these challenges. We introduce bias-corrected test statistics tailored to scenarios where both true and surrogate endpoints are available or where true endpoints are limited. Our approach is exemplified through a simulation study and a case study redesign of the Pamoja Tulinde Maisha (PALM) trial, showcasing its practical implementation and benefits. The proposed design enhances the accuracy of interim analyses by mitigating biases associated with surrogate endpoints. Through rigorous evaluation and comparison with alternative designs, we demonstrate the effectiveness of the proposed methods.

Case–control Comparative Study of Porous Metal Augments versus Bone Graft in Management of Segmental Acetabular Defect in Hip Arthroplasty Procedures

Abstract Introduction: Acetabular bone loss represents a great challenge during hip arthroplasty procedures. This study aims at evaluating the efficacy and functional outcome of cost-friendly alternatives (autograft or allograft) when compared to the porous metal augments during reconstruction of acetabular defects in either complex primary or revision total hip replacement. Patients and Methods: This is a retrospective matched control study for evaluation of short and midterm results of metal augments versus bone graft during hip arthroplasty procedures. Inclusion criteria included adult patients who suffered from segmental acetabular defect and underwent hip arthroplasty procedure. The study included 34 cases divided into 2 groups. Group 1 cases were reconstructed with augment reconstruction. Group 2 was the control group which was reconstructed using graft reconstruction. Results: The mean age for Group 1 was 52.29 years (range: 30–68) and for Group 2 was 52.1 years, (range from 32 to 71 years). The mean follow-up period was 74.8 months in Group 1 (range: 66–85 months) and 71.5 months in Group 2 (range: 60–102 months). Both the groups included 13 males and 4 females. Group 1 had a mean postoperative Harris Hip Score (HHS) of 90.5 (range from 85 to 94), and Group 2 had a mean postoperative HHS of 88.7 (range from 80 to 94) with P = 0.236. Conclusion: Acetabular reconstruction using cost-friendly alternatives shows similar short-to-midterm results when compared to trabecular metal augments in a budget-conscious health setting.

Intracoronary administration of tenecteplase to prevent PCI-related myocardial infarction in patients with echo-attenuated coronary plaques: study protocol for a multicenter, prospective, randomized controlled trial

BackgroundPercutaneous coronary intervention (PCI)-related myocardial infarction (MI), especially the distal type associated with microvascular dysfunction, is not an uncommon complication of the procedure. Specific lesion features, the echo-attenuated plaques (EA) in particular, are well-established contributors to the pathogenesis of distal-type MI. These plaques are prone to disruption during PCI, leading to microvascular thrombosis and distal embolism. Tenecteplase (TNK), a 3rd-generation thrombolytic drug, has demonstrated effective thrombolytic capacity without significantly increasing the bleeding risk. Our study aims to evaluate whether a low-dose intracoronary TNK administration prior to PCI in patients with intravascular ultrasound (IVUS)-detected EA can reduce the occurrence of PCI-related MI and improve clinical outcomes.MethodsThis trial is designed as a multicenter, prospective randomized controlled trial with a 1-month follow-up. The primary outcome of the study is the incidence of PCI-related myocardial infarction (MI) occurring within 48 h after PCI, which serves as a valid surrogate endpoint for assessing the efficacy of tenecteplase-based PCI in preventing future major adverse cardiovascular events (MACE) in patients with EA (Bulluck, et. al, Eur Heart J 42:2630–42, 2021) {1b.1}. Secondary outcomes include the proportion of patients with elevated postoperative high-sensitivity cTnI exceeding 5, 10, 35, and 70 times of the normal baseline, incidence of coronary slow flow after stent implantation and post-dilation, frame count of angiographic flow after stent implantation and post-dilation, as well as the incidence of MACE during hospitalization and at the 1-month follow-up.DiscussionThis trial may demonstrate that an immediate intracoronary administration of low-dose TNK following PCI can effectively lower the incidence of PMI in patients with EA, while confirming the safety of this therapeutic approach.Trial registrationChinese Clinical Trial Registry (ChiCTR2400084840). Registered on May 27, 2024.

Sensitivity of unconstrained quantitative magnetization transfer MRI to amyloid burden in preclinical Alzheimer’s disease

Abstract Magnetization transfer MRI is sensitive to semisolid macromolecules, including amyloid beta, and has previously been used to discriminate Alzheimer’s disease (AD) patients from controls. Here, we fit an unconstrained 2-pool quantitative MT (qMT) model, that is, without constraints on the longitudinal relaxation rate R1s of semisolids, and investigate the sensitivity of the estimated parameters to amyloid accumulation in preclinical participants. We scanned 15 cognitively normal volunteers, of which 9 were amyloid positive by [18F]florbetaben PET. A 12 min hybrid-state qMT scan with an effective resolution of 1.24 mm isotropic and whole-brain coverage was acquired to estimate the unconstrained 2-pool qMT parameters. Group comparisons and correlations with florbetaben PET standardized uptake value ratios were analyzed at the lobar level. We find that the exchange rate and semisolid pool’s R1s were sensitive to the amyloid concentration, while morphometric measures of cortical thickness derived from structural MRI were not. Changes in the exchange rate are consistent with previous reports in clinical AD, while changes in R1s have not been reported previously as its value is typically constrained in the literature. Our results demonstrate that qMT MRI may be a promising surrogate marker of amyloid beta without the need for contrast agents or radiotracers.

Photoreceptor assessment in age-related macular degeneration.

Clinical trials investigating drugs for various stages of age-related macular degeneration (AMD) are actively underway and there is a strong interest in outcomes that demonstrate a structure-function-correlation. The ellipsoid zone (EZ), a crucial anatomical feature affected in this disease, has emerged as a strong contender. There is significant interest in evaluating EZ metrics on Optical Coherence Tomography (OCT), such as integrity and reflectivity, as disruption of this photoreceptor-rich layer may indicate disease progression. Loss of photoreceptor integrity in the junctional zone of geographic atrophy (GA) has been shown to exceed the areas of retinal pigment epithelial (RPE) atrophy, thus predicting future GA expansion. Furthermore, reduced visual acuity and retinal sensitivity have been correlated with loss of EZ integrity, underscoring a structure-function relationship. Photoreceptor integrity has also recently been acknowledged by the Food and Drug Administration (FDA), supporting its use as a primary endpoint in clinical trials investigating treatments for GA. However, the segmentation of this EZ still poses challenges. Continuous enhancements in OCT resolution and advancements in automated segmentation algorithms contribute to improved assessment of the EZ, strengthening its potential as an imaging biomarker for assessing photoreceptor function. It remains to be seen whether the EZ will serve as a surrogate marker for intermediate AMD. This article aims to provide an overview of the current understanding and knowledge of the EZ, while addressing ongoing challenges encountered in its assessment and interpretation.

166Ho-RadioEmbolizaTiOn Using personalized prediCtive dosimetry in patients with Hepatocellular carcinoma: A prospective, single-centre study (RETOUCH).

Holmium-166 (166Ho) radioembolization could offer a more individualized approach in terms of imaging and dosimetry. We aim to evaluate the feasibility and safety of 166Ho selective internal radiation therapy (SIRT) using a higher tumour dose than previously administered determined by 166Ho-scout as a surrogate marker in HCC patients. This is an open-label, prospective, non-randomized, single-centre pilot study that included patients with HCC that received 166Ho-SIRT if the work-up using 166Ho-scout showed a tumour-absorbed dose ≥150 Gy, a non-tumoural liver absorbed dose less than 60 Gy and a lung absorbed dose less than 30 Gy. Primary endpoints were feasibility and safety-toxicity profiles at 24-48 h and 1 month. Overall response rates (ORR) at 3 months (mRECIST, RECIST 1.1 and metabolic response by FDG and choline PET CT) and time to progression (TTP) represented the secondary endpoints. Fifteen patients with large tumours (mean diameter 55.67 ± 28.42 mm) received 17 166Ho-SIRT treatments between July 2020 and June 2022. All the attempted treatments were accomplished. Mean administered tumour dose was 183.18 ± 71.71 Gy, while non-tumour liver dose was 30.29 ± 14.56 Gy. Median time of follow-up was 12 months (IQR 9-16). Only grade 1-2 clinical and biological AEs were observed. There were no liver decompensations. At 3 months, objective response was achieved for all target lesions (CR 78.57%, PR 21.43% according to mRECIST). Median TTP was 18.8 (range 2.9; n.e.) months. Personalized 166Ho-SIRT with a tumour delivered dose ≥150 Gy was feasible and safe for HCC patients with promising response rates.