Clinical Trials Research Articles

Deciphering the Role of ASPM in Breast Cancer: A Comprehensive Multicohort Study

Background: Assembly factor for spindle microtubules (ASPM) has gained significant attention in cancer research due to its association with tumor growth and progression. Through the analysis of large-scale genomic datasets, ASPM has been identified as the top upregulated gene in breast cancer (BC), characterized by high proliferation. This multicohort study aimed to investigate the clinicopathological and prognostic significance of ASPM mRNA and protein expression in BC. Methods: ASPM mRNA expression was assessed using the Cancer Genome Atlas (TCGA) BC cohort and has been further validated in the Molecular Taxonomy of BC International Consortium (METABRIC) (n = 1980), The Uppsala cohort (n = 249), in addition to the combined multicentric cohort (n = 7252). ASPM protein expression was evaluated in a large BC cohort (n = 1300) using immunohistochemistry. The correlations between ASPM expression, clinicopathological parameters, molecular subtypes and outcome were assessed. The response to taxane treatment was compared to the clinical prognosis of ASPM using the ROC plotter. Results: High ASPM mRNA and protein expression were significantly associated with aggressive BC features and poor survival across all cohorts. The association with poor outcomes was maintained in the adjuvant chemotherapy and radio-therapy-treated patients. Responders to taxane treatment showed significantly elevated ASPM levels compared to non-responders. Conclusions: High ASPM expression predicts poor prognosis in BC. It may play a role in treatment resistance within a specific subgroup of patients. Further clinical trials are warranted to explore the potential of ASPM as a target for therapeutic interventions in cancer.

Multi-center study on the application potential of Siaα-2,6Gal in early and differential diagnosis of lung cancer.

This study aimed to investigate the application potential of the abnormal glycan structure Siaα-2,6Gal in the early and differential diagnosis of lung cancer. Clinical data and serum samples from 730 patients and 120 healthy individuals participating in clinical trials on Siaα-2,6Gal were collected at three medical centers between January 2022 and June 2023. The levels of Siaα-2,6Gal, carcinoembryonic antigen (CEA), cytokeratin 19 fragment antigen (CYFRA21-1), squamous cell carcinoma antigen (SCC), neuron-specific enolase (NSE), and pro-gastrin-releasing peptide (ProGRP) in serum were measured. The application potentials of these markers in the early and differential diagnosis, classification, and staging of lung cancer were explored. (1) Serum Siaα-2,6Gal levels in the lung cancer group were 2,606 (1,970-3,458) U/mL, significantly higher than those in the benign lung disease, miscellaneous malignant tumor, miscellaneous benign disease, and healthy individual groups at 1,359 (950-1,528), 1,252 (903-1,532), 1,196 (850-1,490), and 1,210 (1,100-1,287) U/mL (P < 0.0001). (2) Serum Siaα-2,6Gal levels in the early-stage lung cancer (stages 0-II) group were 2,576 (1,929-3,338) U/mL, significantly higher than those in the benign pulmonary nodule group at 1,419 (1,105-1,820) U/mL (P < 0.0001). (3) Receiver operating characteristic curves showed that Siaα-2,6Gal had a high diagnostic efficiency for lung cancer (area under the curve (AUC) = 0.9217), significantly superior to CEA, CYFRA21-1, SCC, NSE, and ProGRP (AUCs of 0.6618, 0.6605, 0.5783, 0.5985, and 0.6381). Siaα-2,6Gal is a promising biomarker for lung cancer diagnosis and may offer superior differential diagnosis of early-stage lung cancer from benign pulmonary nodules compared to traditional tumor markers.

Anti-diabetic effects of marine natural products through redox modulation via Nrf2/HO-1 cytoprotective pathways

Diabetes mellitus (DM), a major global health concern, is a chronic metabolic disorder. Bioactive compounds sourced from numerous marine natural products recently have drawn attention as novel therapeutic approaches. Considering these chemicals and their role in cellular redox modulation by involving the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway, the current study attempts to highlight their anti-diabetic effects and the molecular mechanisms involved. Reactive oxygen species (ROS)-mediated oxidative stress, inflammation, and cellular damage are linked to most human pathologies specifically DM. The Nrf2/HO-1 pathway is a key defense mechanism developed by the cells to combat ROS burst. Marine natural compounds have strong pharmacological potential in triggering cellular antioxidant defense mechanisms by declining oxidative damage and inflammation linked to DM. How marine natural products potentially alleviate DM specifically type 2 diabetes (T2D) and its related issues is especially focused on. The literature was thoroughly analyzed to open a discussion about specific marine compounds and their well-established anti-diabetic effects to elucidate possible therapeutic applications. Furthermore, opportunities and the pros and cons of using these marine bioactive compounds as complementary treatment for DM are also discussed. The diverse characteristics of marine natural products, specifically with regard to redox control, offer promising opportunities for drug discovery and therapeutic interventions in clinical trials.

Abstract A006: Development of a circulating tumor cell-derived cancer organoid platform for drug screening against metastatic tumors and longitudinal monitoring of drug resistance

Abstract Metastatic disease remains the primary cause of cancer-related deaths, presenting a significant challenge in oncology drug development. Current drug screening efforts often rely on cell lines or primary tumor-derived models, which may not adequately mimic the behavior of metastatic tumors. To address this, we aimed to develop a system that more accurately reflects metastatic tumors for improved drug screening. We leveraged a specialized culture platform featuring patented coated plates and proprietary media developed by AcroCyte (Taiwan) to cultivate circulating tumor cells (CTCs) into cancer organoids without pre-selection or enrichment. Building on our previous work, where we successfully cultivated CTCs from fresh blood and cryopreserved peripheral blood mononuclear cells (PBMCs) from renal, colon, and lung cancer patients into cancer organoids, we have now demonstrated the ability to freeze these CTC- derived organoids and thaw them for new culture when needed. We also present new data extending this success to breast and prostate cancers. CTCs from five frozen PBMC samples from breast cancer patients and three from prostate cancer patients formed visible colonies, with positive immunostaining for EpCAM, cytokeratin, and CD44. The immune cells in the PBMC samples gradually died off within three weeks of culture, as confirmed by the absence of CD45- positive cells. Interestingly, CTC-derived organoids from breast and prostate cancers did not form the spheroids observed in renal, colon, and lung cancer models. Instead, they appeared as colonies or clusters of CTCs. After 6-8 weeks of active growth, these clusters exhibited a slower growth rate, although they remained viable in the proprietary culture system. We are actively evaluating various culture media supplements, tailored to breast and prostate cancers, to extend the active growth period of these CTC-derived organoids for longer durations. Importantly, these CTC-derived colonies retained drug sensitivity, demonstrating the system's potential for effective drug screening against metastatic tumors. Our platform now supports organoid development from renal, colon, lung, breast, and prostate cancers, and we are actively expanding to include all major solid tumors. Since this technology uses blood, which can be obtained non-invasively, it enables longitudinal monitoring of CTCs as a functional liquid biopsy. Additionally, frozen PBMCs can be used as a source material for CTCs, and the resulting organoids can be utilized for drug sensitivity testing. This platform could be instrumental in oncology drug development and holds promise for monitoring emerging drug resistance in clinical trials by analyzing PBMC samples collected before and after treatment, offering a functional liquid biopsy-based approach to aid in developing therapies targeting metastatic disease. Citation Format: Yi-chun Han, David Hsieh, Ruobo Zhang, Emily Miyashita-Lin, Shian-Jiun Shih. Development of a circulating tumor cell-derived cancer organoid platform for drug screening against metastatic tumors and longitudinal monitoring of drug resistance [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A006.

BN SO01 - Fluorescent Precision: Advancing Laparoscopic Cholecystectomy with Indocyanine Green ( ICG )

Abstract Background Laparoscopic cholecystectomy represents a significant advancement in surgical techniques for gallbladder disease. However, challenges persist in accurately identifying critical structures such as the bile ducts, leading to complications. Indocyanine Green (ICG), a fluorescent dye with unique properties, has emerged as a promising tool to enhance precision and safety in laparoscopic cholecystectomy. Originally developed for infrared photography, ICG's fluorescence capabilities have been harnessed in various medical applications, including ophthalmology and surgical procedures. Its ability to provide real-time visualization of the biliary anatomy facilitates better surgical navigation, reducing the risk of inadvertent injury and improving overall outcomes. Method Comprehensive review of existing literature and research on laparoscopic cholecystectomy, with a focus on the role of Indocyanine Green (ICG) in enhancing surgical precision and safety. Relevant articles, clinical trials, and meta-analyses were identified through databases such as PubMed, Google Scholar, and Scopus. Search terms included "laparoscopic cholecystectomy," "Indocyanine Green," "fluorescence imaging," and related terms. Results The results of this study highlight the significant role of Indocyanine Green (ICG) in laparoscopic cholecystectomy. Through a comprehensive review of existing literature and research, it was found that ICG integration enhances surgical precision and safety by providing real-time visualization of the biliary anatomy. The use of ICG reduces the risk of inadvertent injury and improves overall surgical outcomes. Despite challenges such as technical complexities and safety considerations, the evidence strongly supports the transformative potential of ICG in modern surgery. Conclusion In conclusion, the integration of Indocyanine Green (ICG) into laparoscopic cholecystectomy represents a pivotal advancement in surgical practice. The findings of this study underscore the importance of cautious navigation and collaboration in maximizing the benefits of ICG. By addressing challenges through innovation and evidence-based guidelines, ICG has the potential to revolutionize the landscape of minimally invasive surgery, offering patients safer procedures and better outcomes. As research continues to evolve, the journey of ICG in laparoscopic cholecystectomy holds promise for a future where precision and safety converge, ultimately shaping the standard of surgical excellence.

The MSc in clinical trials at the University of Oxford: training the next generation of clinical trialists.

The MSc in clinical trials at the University of Oxford: training the next generation of clinical trialists.

Ocular Pharmacodynamics of Intravitreal Faricimab in Patients With Neovascular Age-Related Macular Degeneration or Diabetic Macular Edema.

Evaluate the ocular pharmacodynamics (PD) of intravitreal faricimab, a bispecific inhibitor of angiopoietin-2 (Ang-2) and vascular endothelial growth factor-A (VEGF-A), in patients with neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME). Aqueous humor (AH) samples (1025 free Ang-2 concentrations and 1345 free VEGF-A concentrations) were collected from approximately 300 faricimab-treated patients with nAMD or DME in phase2/3 trials. A population pharmacokinetic pharmacodynamic (popPKPD) model was developed to describe the dynamic effect of faricimab on free AH Ang-2 and VEGF-A. Mean baseline Ang-2 concentrations were 8.1 and 13.4pg/mL in patients with nAMD and DME, respectively. The corresponding mean baseline VEGF-A concentrations were 58 and 135pg/mL, respectively. Overall, approximately 79% of Ang-2 (84% within 8 weeks postdose and 55% beyond 12 weeks postdose) and 7% of VEGF-A postdose observations were below the lower limit of quantification. Model-derived Ang-2 and VEGF-A concentration-time profiles for patients on every 4-week/every 8-week dosing were predicted to maintain greater than 50% suppression of Ang-2 concentrations for the entire dosing period. Patients on every 12-week/16-week dosing were predicted to have greater than 50% Ang-2 suppression for 12 or more weeks, whereas 50% VEGF-A suppression was maintained for 9 to 10 weeks. At 8 weeks postdose, the median Ang-2 concentrations remained suppressed by approximately 80%. At 16 weeks postdose, the median VEGF-A concentrations returned to baseline, but median Ang-2 levels remained below baseline. A popPKPD analysis demonstrated faricimab's rapid and sustained suppression of AH Ang-2 and VEGF-A. A popPKPD analysis suggested that sustained suppression of ocular Ang-2 contributes to faricimab's extended durability, observed in clinical trials.

Abstract B026: Glioblastoma multiforme disseminates outside the central nervous system

Abstract Introduction: The liquid biopsy (LB) concept has gained significant attention in the last decade and has the potential to revolutionize cancer care. However, more validation in clinical trials is required on the value of LB in medical settings. Here, we focus on glioblastoma multiforme (GBM), a highly invasive and fatal subtype of the central nervous system malignant tumors. Circulating tumor cells (CTCs) are primary tumor cells released into the peripheral blood and migrating to distant organs. CTC presence is related to tumor spread and recurrence. In GBM, factors like short patient survival, the blood-brain barrier (BBB), and lack of lymphatic drainage in brain tissue make systemic dissemination rare but possible. Thus, noninvasive CTC detection can hold potential for diagnostic, predictive, and prognostic applications. Material and Methods: For cell stability preservation before sample processing, the peripheral blood samples from curatively resected GBM patients were collected preoperatively in Cell-Free DNA BCT® tubes (Streck, Inc.). CTCs were identified using CytoTrack CT11TM (2/C), a semi-automated immunofluorescence microscopy using glial fibrillary acidic protein, vimentin, and CD45 immunostaining, and DAPI counterstaining. The preliminary Kaplan-Maier survival analysis based on CTC positivity was performed in 39 patients with a follow-up longer than two years. Results: We analyzed the CTC presence in 100 GBM patient peripheral blood samples. The CTCs or cancer cell clusters were found in 35% of GBM patients. The Kaplan-Maier survival analysis did not show a correlation between CTC presence and survival. This phenomenon may be associated with the generally short survival of these patients, which is expected to increase with advances in oncology and palliative care and/or a possible suppression of tumor cell growth outside the CNS. Conclusions: We have observed the CTCs in the peripheral blood of GBM patients. The patient enrollment and clinical data recording are still ongoing. Citation Format: Pavel Stejskal, Josef Srovnal, Alona Rehulkova, Ondrej Kalita, Marek Slachta, Marian Hajduch. Glioblastoma multiforme disseminates outside the central nervous system [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B026.

Ustekinumab Biosimilars

Ustekinumab is a fully human IgG1k monoclonal antibody that binds with high affinity and specificity to the p40 subunit of interleukins (IL-) 12 and 23, inhibiting their activity by preventing binding to their receptors. The European extension of the patent (Supplementary Protection Certificate) of ustekinumab expired on 20 July 2024. Biosimilar alternatives to ustekinumab are now an additional option for treating patients. The efficacy data for this drug in moderate-to-severe psoriasis obtained both from clinical trials and indirect comparisons through meta-analyses, are superior to those of etanercept and adalimumab, and its safety profile is more favorable than that of tumor necrosis factor (TNF) inhibitors. Several ustekinumab biosimilars have already been approved by regulatory agencies: between October 2023 and October 2024, Wezlana® (Amgen ABP 654), Uzpruvo® (Alvotech AVT04) and Pyzchiva® (Samsung/Bioepis SB17) have been approved by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). SteQeyma® (Celltrion Healthcare CT-P43) was approved by the EMA in August 2024. Otulfi® (Fresenius Kabi/Formycon) was approved by the FDA in October 2024. Several other potential biosimilar candidates are under development, including BAT2206 (Bio-Thera), DMB-3115 (Dong-A ST), QX001S (Qyuns Therapeutic), BFI-751 (BioFactura), NeuLara (Neuclone), ONS3040 (Oncobiologics), and BOW090 (Epirus Biopharmaceuticals). In most cases, these monoclonal antibodies are expressed in cell lines (e.g., Chinese Hamster Ovary, CHO) different from those used for the originator (Sp2/0 spleen cell murine myeloma); of note, the cell line of origin is not a requirement for biosimilarity in the totality-of-evidence comparison exercise and may facilitate the production and reduce the immunogenicity of biosimilars originated in CHO cultures. This narrative review summarizes the available data on characteristics of the full comparability exercises and comparative clinical trials of these drugs.

Phytochemicals in Parkinson's Disease: a Pathway to Neuroprotection and Personalized Medicine.

Parkinson's disease (PD) is a complex neurodegenerative disorder marked by the progressive loss of dopaminergic neurons in the substantia nigra. While current treatments primarily manage symptoms, there is increasing interest in alternative approaches, particularly the use of phytochemicals from medicinal plants. These natural compounds have demonstrated promising neuroprotective potential in preclinical studies by targeting key pathological mechanisms such as oxidative stress, neuroinflammation, and protein aggregation. However, the clinical translation of these phytochemicals is limited due to a lack of robust clinical trials evaluating their safety, efficacy, and pharmacokinetics. This review provides a comprehensive overview of the neuroprotective potential of phytochemicals in PD management, examining the mechanisms underlying PD pathogenesis and emphasizing neuroprotection. It explores the historical and current research on medicinal plants like Mucuna pruriens, Curcuma longa, and Ginkgo biloba, and discusses the challenges in clinical translation, including ethical and practical considerations and the integration with conventional therapies. It further underscores the need for future research to elucidate mechanisms of action, optimize drug delivery, and conduct rigorous clinical trials to establish the safety and efficacy of phytochemicals, aiming to shape future neuroprotective strategies and develop more effective, personalized treatments for PD.

Disseminated intravascular coagulation is an underestimated but fatal adverse event associated with blinatumomab therapy: A pharmacovigilance analysis of FAERS.

Hematologic adverse events (AEs) are common and serious toxicities in patients with hematologic malignancies undergoing blinatumomab therapy. However, restrictive selection criteria in pivotal clinical trials can lead to an underestimation of rare but fatal toxicities. In this study, we systematically analyzed hematologic AEs associated with blinatumomab using the Food and Drug Administration Adverse Event Reporting System (FAERS) from October 2014 to December 2023. Disproportionate analysis was performed to identify overreported AEs, with a reporting odds ratio (ROR), and a lower bound of the 95% confidence interval (ROR025) exceeding one considered significant. Additionally, adjusted mortality rates and risk ratios (RR) of the top 10 reported hematologic AEs were calculated using a logistic regression model. Among 4745 blinatumomab-related cases, 418 (8.81%) involved hematologic AEs. We identified 22 significantly overreporting hematologic AEs compared to the full database, with myelosuppression (n = 39 [9.33%], ROR025 = 8.04), disseminated intravascular coagulation (DIC, n = 31 [7.42%], ROR025 = 15.14), and bone marrow failure (n = 14 [3.35%], ROR025 = 3.41) notably underestimated in clinical trials. DIC resulted in a substantial mortality rate of 45.16%. Finally, DIC was found to be independently associated with death in a multivariable logistic regression analysis (RR = 2.47 [95% CI: 1.11-3.83]). These findings could aid clinicians in the early detection of these rarely reported but fatal hematologic AEs, thereby reducing the risk of severe toxicities in blinatumomab recipients.

Skin Cancer Diagnosis by Lesion, Physician, and Examination Type: A Systematic Review and Meta-Analysis.

Skin cancer is the most common cancer in the US; accurate detection can minimize morbidity and mortality. To assess the accuracy of skin cancer diagnosis by lesion type, physician specialty and experience, and physical examination method. PubMed, Embase, and Web of Science. Cross-sectional and case-control studies, randomized clinical trials, and nonrandomized controlled trials that used dermatologists or primary care physicians (PCPs) to examine keratinocytic and/or melanocytic skin lesions were included. Search terms, study objectives, and protocol methods were defined before study initiation. Data extraction was performed by a reviewer, with verification by a second reviewer. A mixed-effects model was used in the data analysis. Data analyses were performed from May 2022 to December 2023. Meta-analysis of diagnostic accuracy comprised sensitivity and specificity by physician type (primary care physician or dermatologist; experienced or inexperienced) and examination method (in-person clinical examination and/or clinical images vs dermoscopy and/or dermoscopic images). In all, 100 studies were included in the analysis. With experienced dermatologists using clinical examination and clinical images, the sensitivity and specificity for diagnosing keratinocytic carcinomas were 79.0% and 89.1%, respectively; using dermoscopy and dermoscopic images, sensitivity and specificity were 83.7% and 87.4%, and for PCPs, 81.4% and 80.1%. Experienced dermatologists had 2.5-fold higher odds of accurate diagnosis of keratinocytic carcinomas using in-person dermoscopy and dermoscopic images compared with in-person clinical examination and images. When examining for melanoma using clinical examination and images, sensitivity and specificity were 76.9% and 89.1% for experienced dermatologists, 78.3% and 66.2% for inexperienced dermatologists, and 37.5% and 84.6% for PCPs, respectively; whereas when using dermoscopy and dermoscopic images, sensitivity and specificity were 85.7% and 81.3%, 78.0% and 69.5%, and 49.5% and 91.3%, respectively. Experienced dermatologists had 5.7-fold higher odds of accurate diagnosis of melanoma using dermoscopy compared with clinical examination. Compared with PCPs, experienced dermatologists had 13.3-fold higher odds of accurate diagnosis of melanoma using dermoscopic images. The findings of this systematic review and meta-analysis indicate that there are significant differences in diagnostic accuracy for skin cancer when comparing physician specialty and experience, and examination methods. These summary metrics of clinician diagnostic accuracy could be useful benchmarks for clinical trials, practitioner training, and the performance of emerging technologies.

Demographics and Immunotherapy Efficacy for Advanced Hepatocellular carcinoma: A Systematic Review and Meta-Analysis of Phase III Clinical Trials

Introduction: Immune checkpoint inhibitors (ICIs) are fundamental in treating advanced hepatocellular carcinoma (HCC). Considering previous reports implied varied responses among patient subgroups, such as patients with different hepatitis etiologies, we planned this meta-analysis to identify specific populations that might derive greater survival benefits from ICIs as a first-line treatment. Methods: We conducted a comprehensive search in PubMed and the Cochrane Library for phase III clinical trials comparing ICIs and multikinase inhibitors (MKIs) as first-line therapies for advanced HCC. We extracted and synthesized hazard ratios (HRs) for overall survival (OS) across different patient subgroups mainly using the random effect model. Results: Our analysis included nine phase III trials involving ICIs, either alone or in combination with other treatments, compared with MKIs. The synthesized HRs for patients with hepatitis B virus, hepatitis C virus, and nonviral etiologies were 0.74, 0.77, and 0.86, respectively, showing no significant differences (p = 0.13). Such finding remained when we only analyzed clinical trials with positive results. HRs consistently favored ICIs across various demographics such as age, sex, geographic region, performance status, alpha-fetoprotein levels, and disease stage or extent. Notably, patients with extrahepatic spread showed a trend towards better outcomes (HR 0.73) compared to those without (HR 0.85, p = 0.07). Conclusion: The efficacy of ICIs as a first-line treatment for advanced HCC was consistent across diverse patient subgroups, regardless of hepatitis etiology or other demographic factors. These findings do not support using these characteristics to determine the use of ICI therapy in advanced HCC.

Systemic antimicrobials as an adjunct in the management of periodontitis - which drug is best?

This study is a systematic review and meta-analysis that assesses systemic antimicrobials: azithromycin (AZT) and amoxicillin/metronidazole (AMX/MTZ), as adjuvants to subgingival instrumentation in the treatment of periodontitis. The aim is to establish if one antimicrobial is superior as an adjuvant therapy in the management of periodontal disease. This systematic review and meta-analysis included randomised controlled trials (RCTs), controlled clinical trials, and prospective and retrospective human studies. Participants had to be adults (≥18 years of age) with a diagnosis of periodontitis in the categories: chronic/aggressive, stages II/III, grades B/C. All participants completed full mouth subgingival instrumentation (SI) with the use of adjunct systemic antimicrobial therapy: the intervention group: AZT and the control group: AMX/MTZ. A total of 779 studies were retrieved from the data search; following the application of selection criteria and independent review duplicated by two authors, seven studies were eligible for review. Two studies were subsequently excluded due to insufficient information. Therefore five studies were included in the review, all were self-funded and four were conducted in recognised universities. The primary outcome measure was probing pocket depth changes at 1-12 months. Secondary outcome measures were: the number of residual sites with pocket depths ≥5 mm, clinical attachment levels, bleeding on probing, plaque indices (at 1-12 months), and occurrence of adverse events. Review Manager Software (The Cochrane Collaboration, Copenhagen, Denmark) was used to conduct meta-analysis. Heterogeneity between studies was expected, therefore the random-effects model was utilised to pool results from multiple studies. Statistical heterogeneity was assessed by I2 and Cochrane's test for heterogeneity. The certainty of evidence was assessed and a summary of GRADE criteria: risk of bias, inconsistency, imprecision, indirectness and publication bias. Bias was graded for the five studies included in this meta-analysis and systematic review. Two studies were low risk, two were moderate risk and one was high risk. The study rated high for risk of bias was due to an incomplete description of blinding. Three of the studies were rated low bias for outcome measurement as they reported blinding of data assessors. No studies had deviations from the intended interventions and all outcomes were detected; therefore, all studies were rated as low bias for these domains. All five of the studies demonstrated changing in probing pocket depths at 1-3 months, however, the intervention and control cohorts showed no significant difference. One study showed a statistically significant difference in probing pocket depths at 12 months, in favour of AZT. This systematic review and meta-analysis demonstrates no statistically significant difference between the two cohorts: AZT and AMX/MTZ for mean changes in clinical attachment level, probing pocket depths or bleeding on probing at 1-3 months; when used as an adjunct to mechanical intervention in the treatment of periodontitis. It was recorded, evidence of low to moderate certainty, that for the AZT cohort: fewer adverse events were evident and fewer sites with residual probing pocket depths of ≥5 mm at 1-3 months were recorded. Based on this systematic review and meta-analysis, there is no statistically significant superior drug therapy, comparing the use of AZT versus AMX/MTZ as an adjunct in the treatment of periodontists. However, evidence of low to moderate certainty demonstrates fewer adverse events and fewer sites with residual pocket depths ≥5 mm at 1-3 months in the AZT cohort, compared to the AMX/MTZ cohort. A greater number of clinical trials and a stronger evidence base in the future will allow for authentication of current findings.

Translating insights into therapies for Long Covid.

Long Covid is defined by a wide range of symptoms that persist after the acute phase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Commonly reported symptoms include fatigue, weakness, postexertional malaise, and cognitive dysfunction, with many other symptoms reported. Symptom range, duration, and severity are highly variable and partially overlap with symptoms of myalgic encephalomyelitis/chronic fatigue syndrome and other post-acute infectious syndromes, highlighting opportunities to define shared mechanisms of pathogenesis. Potential mechanisms of Long Covid are diverse, including persistence of viral reservoirs, dysregulated immune responses, direct viral damage of tissues targeted by SARS-CoV-2, inflammation driven by reactivation of latent viral infections, vascular endothelium activation or dysfunction, and subsequent thromboinflammation, autoimmunity, metabolic derangements, microglial activation, and microbiota dysbiosis. The heterogeneity of symptoms and baseline characteristics of people with Long Covid, as well as the varying states of immunity and therapies given at the time of acute infection, have made etiologies of Long Covid difficult to determine. Here, we examine progress on preclinical models for Long Covid and review progress being made in clinical trials, highlighting the need for large human studies and further development of models to better understand Long Covid. Such studies will inform clinical trials that will define treatments to benefit those living with this condition.

Abstract PR005: Leveraging mass cytometry for phenotyping CTCs in SCLC liquid biopsies: Tracking therapy resistance at a personalized level

Abstract Liquid biopsies present a promising, minimally invasive procedure through which clinicians can assess and monitor disease status by interrogating circulating tumor cell (CTC) and immune cell phenotypes. In the case of Small-cell lung cancer (SCLC) – a type of lung cancer characterized by aggressive growth, dismal prognosis and limited treatment options - leveraging liquid biopsies and CTCs for evaluating disease status would be of great benefit, given that biopsies are scarce. Furthermore, SCLC CTC numbers are higher compared to other cancers, presenting a unique opportunity to utilize them for assessing SCLC therapy resistance and identifying new targetable markers. In this study, we leverage mass cytometry (i.e. CyTOF) to phenotype SCLC CTC phenotypes in longitudinal clinical specimens to assess therapy resistance at a personalized level. By using CyTOF - a multiplex cytometric approach that enables interrogation of 30-50 protein markers per single cell – we show that we are able to identify and analyze a significant number of CTCs and their heterogeneous expression profiles. To achieve this, we first optimized a CyTOF panel of ∼25-30 antibodies by using SCLC cell lines and blood specimens from healthy donors and SCLC patients. We show that by using this approach, we are able to identify and phenotype SCLC CTCs by using the combination of CD45 (negative expression) and CD56 positive expression with further validation achieved by TTF1 and SCLC subtype transcription factor expression (NEUROD1, POU2F3 and ASCL1). This approach avoids enriching for specific CTC epithelial phenotypes that express surface markers that fluctuate during epithelial- mesenchymal transition (EMT) (e.g. EpCAM, a common marker for isolating CTCs). For parallel immune profiling we assessed among others CD8/CD4 (T cells) and CD11b/HLA-DR (Myeloid-derived suppressor cells, MDSCs) expression. We then proceeded to interrogate CTC phenotypic differences in the naïve vs relapsed setting as well as dynamic changes in longitudinal blood specimens from SCLC patients by evaluating markers that describe immune suppression activity (PD-L1) and EMT status (E-Cadherin, Vimentin, MUC1, Twist and Slug). Importantly, we show that with our approach we can track in real time therapeutic targets that are currently being tested in clinical trials or have been recently FDA approved (e.g. pYAP and DLL3) and found that MUC1 and pYAP are significantly increased in CTCs detected in blood specimens of SCLC relapsed patients. Our immune profiling showed an increase of MDSC percentages and a decrease in the CD4/CD8 T cell ratio in the relapsed setting. Finally, when we used PHENOSTAMP, a previously developed reference EMT map for assessing EMT phenotypes in lung cancer clinical specimens, we observed an increase of EMT heterogeneity in CTCs in relapsed patients. Our study highlights the translational power of our approach in utilizing CyTOF for longitudinally tracking CTCs directly in SCLC patient liquid biopsies towards assessing therapy response and resistance at a personalized level. Citation Format: Loukia G Karacosta, Sayantan Bhattacharyya, Allison Stewart, Ashley Victorian, Ester F Lujan, Shafqat Ehsan, Subin Kim, Alberto Duarte, Runsheng Wang, Benedict Anchang, Jing Wang, Lauren Byers. Leveraging mass cytometry for phenotyping CTCs in SCLC liquid biopsies: Tracking therapy resistance at a personalized level [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr PR005.

Sequential Grafting of the Left Internal Thoracic Artery to the Left Anterior Descending Artery and Graft Failure.

There is concern that left internal thoracic artery (LITA) to diagonal to left anterior descending artery (LAD) grafts may be more susceptible to failure compared to single LITA-LAD grafts. Pooled individual patient data from eight clinical trials with systematic graft imaging were analyzed to assess the incidence of sequential LITA-Diagonal-LAD vs. single LITA-LAD grafts. Mixed-effects multivariable logistic regression, adjusting for patient characteristics and clustering within trials, was used. Of 3969 patients with LITA-LAD grafts, 283 (7.1%) patients received sequential LITA-Diagonal-LAD grafts. Patients with sequential LITA-Diagonal-LAD grafts were older (66 vs. 65 y, p=0.009) and more often male (88% vs. 83%, p=0.03). Overall, graft failure occurred in 9.3% of patients with LITA-LAD grafts, with more graft failure occurring in single (9.5%) than in sequential LITA-Diagonal-LAD grafts (6.4%, p=0.08) at a median (25th-75th percentile) time to imaging of 1.0 (1.0-1.1) years. After multivariable adjustment, sequential LITA-Diagonal-LAD grafting was not associated with graft failure (adjusted odds ratio: 1.22, 95% confidence interval: 0.68-2.18, p=0.55). There was no difference in mortality (2.8% vs. 5.3%, p=0.06), myocardial infarction (1.4% vs. 1.6%, p=0.90), revascularization (4.5% vs. 7.3%, p=0.08), or stroke (1.7% vs. 1.2%, p=0.40) between groups. In selected patients, LITA-Diagonal-LAD grafting was not associated with higher risk of graft failure or adverse clinical events at one year.

Production of Value-Added Arabinofuranosyl Nucleotide Analogues from Nucleoside by an In Vitro Enzymatic Synthetic Biosystem

Arabinofuranosyl nucleotide analogue (arabinoside) and the derived compounds, a family of nucleoside analogues, exhibit diverse, typically biological activities and are widely used as antibacterial, antiviral, anti-inflammatory, and antitumor drugs in both clinical and preclinical trials. Despite their long and rich history in medicinal chemistry, the biosynthesis of arabinoside has only been sporadically designed and studied and has remained a challenging task. In this study, an in vitro synthetic enzymatic biosystem was designed and constructed for the production of arabinoside from low-cost nucleoside, based on a phosphorolysis -isomerization-dephosphorylation enzymatic cascade conversion routes. The enzymatic system achieves the biosynthesis of arabinoside by isomerizing the ribose part of nucleoside to arabinose. The reaction conditions affecting the yield of arabinoside were investigated and optimized, including meticulous enzyme selection, key enzyme dosage, the concentration of orthophosphate, and reaction time. Under the optimized conditions, we achieved the production of 0.12 mM of arabinofuranosylguanine from 0.5 mM of guanosine, representing 24% of the theoretical yield. Furthermore, this biosystem also demonstrated the capability to produce other arabinosides, such as vidarabine, spongouridine, and hypoxanthine arabinofuranoside from corresponding nucleosides. Overall, our biosynthesis approach provides a pathway for the biosynthesis of arabinoside.

Bridging the Gap: A Systematic Review and Meta-Analysis of Interventions to Address Barriers in Migrant Mental Health Care Access

Despite their higher risk of mental health conditions, migrants often face barriers to accessing mental health care. This systematic review aims to synthesize the evidence on interventions to improve mental health care access for migrants (protocol CRD42024556575). PubMed, Embase, PsycINFO, and CINAHL were searched for experimental and observational studies on this topic. A narrative summary and a meta-analysis of the study findings are presented, along with a GRADE quality assessment. Eighteen reports, accounting for 3285 migrants, were included in the final selection. There were six randomized controlled trials, nine non-randomized clinical trials, and three observational studies. The interventions consisted of psychoeducation (27.8%), digital tools (22.2%), outreach programs, counseling, peer support (each 11.1%), and miscellaneous approaches (16.7%). There was marked heterogeneity in the intervention structure and outcome measure across the studies. Nevertheless, all studies reported a positive effect of the interventions on mental health care access. Still limited by few studies providing data suitable for the pooled estimate, the meta-analyses found a significant effect in reducing stigma and improving mental health literacy. Overall, this review identified promising interventions for improving migrant mental health care access. Future research is needed to validate interventions that can be applied sustainably across different contexts and migrant populations.

Methods for Identifying Epilepsy Surgery Targets Using Invasive EEG: A Systematic Review

Background: The pre-surgical evaluation for drug-resistant epilepsy achieves seizure freedom in only 50–60% of patients. Efforts to identify quantitative intracranial EEG (qEEG) biomarkers of epileptogenicity are needed. This review summarizes and evaluates the design of qEEG studies, discusses barriers to biomarker adoption, and proposes refinements of qEEG study protocols. Methods: We included exploratory and prediction prognostic studies from MEDLINE and Scopus published between 2017 and 2023 that investigated qEEG markers for identifying the epileptogenic network as the surgical target. Cohort parameters, ground truth references, and analytical approaches were extracted. Results: Out of 1789 search results, 128 studies were included. The study designs were highly heterogeneous. Half of the studies included a non-consecutive cohort, with sample sizes ranging from 2 to 166 patients (median of 16). The most common minimum follow-up was one year, and the seizure onset zone was the most common ground truth. Prediction studies were heterogeneous in their analytical approaches, and only 25 studies validated the marker through post-surgical outcome prediction. Outcome prediction performance decreased in larger cohorts. Conversely, longer follow-up periods correlated with higher prediction accuracy, and connectivity-based approaches yielded better predictions. The data and code were available in only 9% of studies. Conclusions: To enhance the validation qEEG markers, we propose standardizing study designs to resemble clinical trials. This includes using a consecutive cohort with long-term follow-up, validating against surgical resection as ground truth, and evaluating markers through post-surgical outcome prediction. These considerations would improve the reliability and clinical adoption of qEEG markers.