Trial Of Therapy Research Articles

Abstract 4841: DNA methylation status classifies pleural mesothelioma cells according to their immune profile: implication for precision epigenetic therapy

Background: co-targeting of immune checkpoint inhibitors (ICI) CTLA-4 and PD-1 has recently become the new first-line standard of care therapy of pleural mesothelioma (PM) patients, with a significant improvement of overall survival (OS) over conventional chemotherapy. The analysis by tumor histotype demonstrated a greater efficacy of ICI therapy, compared to standard chemotherapy, in non-epithelioid (non-E) vs. epithelioid (E) PM, although some E PM patients also benefit from treatment. This evidence suggests that molecular tumor features, beyond histotype, could be relevant to improve the efficacy of ICI therapy in PM. Among these, tumor DNA methylation emerges as a promising factor to explore, due to its potential role in driving the immune phenotype of cancer cells. Therefore, we utilized a panel of cultured PM cells of different histotype to provide preclinical evidence supporting the role of the tumor methylation landscape and of its pharmacologic modulation, to prospectively improve the efficacy of ICI therapy of PM patients. Methods: the methylome profile (EPIC array) of distinct E (n=5) and non-E (n=9) PM cell lines was analyzed, followed by integrated analysis with their associated transcriptomic profile (Clariom S array), before and after in vitro treatment with the DNA hypomethylating agent (DHA) guadecitabine. The most variable methylated probes were selected to calculate the methylation score (CIMP index) for each cell line at baseline. Genes that were differentially expressed and methylated were then selected for gene ontology analysis. Results: the CIMP index stratified PM cell lines into two distinct classes, CIMP (hypermethylated; n=7) and LOW (hypomethylated; n=7), regardless of their E or non-E histotype. Integrated methylome and transcriptome analyses revealed that CIMP PM cells exhibited a substantial number of hypermethylated, silenced genes, which negatively impacted their immune phenotype compared to LOW PM cells. Treatment with DHA reverted the methylation-driven immune-compromised profile of CIMP PM cells and enhanced the constitutive immune-favorable profile of LOW PM cells. Conclusion: the study highlighted the relevance of DNA methylation in shaping the constitutive immune classification of PM cells, independent of their histological subtypes. The identified role of DHA in shifting the phenotype of PM cells towards an immune-favorable state supports its potential role in clinical trials of precision epigenetic therapy combined with ICI. Citation Format: Maria Fortunata Lofiego, Rossella Tufano, Emma Bello, Laura Solmonese, Francesco Marzani, Francesca Piazzini, Fabrizio Celesti, Francesca Pia Caruso, Teresa Maria Rosaria Noviello, Roberta Mortarini, Andrea Anichini, Michele Ceccarelli, Luana Calabrò, Michele Maio, Sandra Coral, Anna Maria Di Giacomo, Alessia Covre. DNA methylation status classifies pleural mesothelioma cells according to their immune profile: implication for precision epigenetic therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4841.

Abstract 3430: FP008, a novel anti-PD-1×IL-10M fusion protein for cancer therapy

Abstract Immune checkpoint inhibitors (ICI) such as anti-PD-1/PD-L1 antibodies have achieved remarkable clinical successes in cancer therapy. However, over 70 % of patients receiving ICI treatments are not responsive or experience disease progression after an initial period of response. Terminal exhaustion of CD8+ T cell was supposed to contribute to this low responsiveness. On the other hand, IL-10 could enhance the anti-tumor activity of ICI by reinvigorating and expanding terminally exhausted CD8+ T cells. Encouraging efficacies have been observed in phase 1 clinical trials of IL-10 therapy, but severe hematologic toxicity and low dosage greatly hindered its efficacy in further clinical trials. We therefore developed FP008, a novel anti-PD-1 × IL-10M (IL-10 monomer) fusion protein, and demonstrated its promising potential for cancer therapy. FP008 exhibited strong anti-PD-1 blocking performance and activity comparable to its parental anti-PD-1 antibody. More importantly, FP008 significantly decreased CD8+ T cells apoptosis and promoted IFN-γ secretion when co-cultured with exhausted CD8+ T cells induced in vitro. This function was mainly caused by the IL-10M moiety, which was modified into a monomer to reduce downstream signaling and the resulting hematologic toxicity. Compared with wild-type (wt) IL-10, IL-10M significantly decreased the phagocytosis of erythrocytes by macrophages in vitro. The result was consistent with the observation in the toxicity study in monkeys. FP008 induced less STAT3 phosphorylation without PD-1 crosslinking in activated CD8+ T cells or reporter cells than wt IL-10. Furthermore, the STAT3 signaling was greatly enhanced after PD-1 crosslinking, indicating FP008 may have strong activity on TILs where PD-1 is highly expressed. In both CT26 and MC38 tumor models in hPD-1 knock-in mice, FP008 dose dependently inhibited tumor growth, with stronger anti-tumor efficacy and longer survival than Keytruda. In a CT26 rechallenge model after FP008 treatment and complete tumor regression, mice were re-challenged with CT26 tumor cells but remained tumor-free without further treatment, indicating that FP008 treatment could induce immunological memory. TILs analysis showed that the number of tumor-infiltrating CD8+ T cells increased, while Treg cells decreased after FP008 treatment. In a GLP toxicology study in cynomolgus monkeys, FP008 was well tolerated at the dose of 10 mg/kg, and produced minimal decrease of erythrocyte and no tissue damage. In conclusion, FP008 showed novel characteristics such as the synergistic function of anti-PD-1 and IL-10M, cis-activation of IL-10M by PD-1 enrichment and improved safety profiles. It demonstrated promising potential for clinical therapy for the anti-PD-1 naïve or resistant patients. Citation Format: Ce Gu, Jiaojiao Ding, Baiguang Ren, Mengying Liang, Linhui Ye, Yingye Ou, Chang Zhou, Bingquan Shen, Jian Guo, Xiaodong Wu, Ke Chen, Yongting Huo, Di Lu. FP008, a novel anti-PD-1×IL-10M fusion protein for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3430.

Abstract 5858: Prognostic and predictive role of T cell infiltration in stage III colon cancer (CC) treated with celecoxib: CALGB/SWOG 80702

Observational studies have demonstrated that aspirin and/or PTSG2 inhibitor (e.g., celecoxib) use, before or after colon cancer (CC) diagnosis, is associated with a lower risk of recurrence. However, a randomized trial of adjuvant celecoxib therapy in stage III CC did not show improved survival compared to placebo treatment. We therefore hypothesized that immune microenvironment features may identify patient subgroups with stronger survival benefits from anti-inflammatory celecoxib treatment. Drawing from an NCI-Intergroup trial (Cancer and Leukemia Group B [now Alliance for Clinical Trials in Oncology]/SWOG 80702) for patients with stage III resected CC that compared 3 versus 6 months of adjuvant fluorouracil, leucovorin, and oxaliplatin ± 3 years of celecoxib, we conducted tissue-based tumor microenvironment profiling on 1,098 resected tumors using a custom 9-plex, T-cell multiplex immunofluorescence assay coupled with digital image analysis and supervised machine learning. The Kaplan-Meier method was used to describe disease-free survival, based on T cell density, and log-rank testing was performed. Cox proportional hazards models were used to examine unadjusted and adjusted associations between T cell density and disease-free survival (DFS). Two-sided P values ≤0.05 were considered statistically significant. We found that higher CD3+ T cell density was associated with longer DFS with an adjusted hazard ratio (HR) of 0.69 (95% confidence interval [CI] 0.52-0.91) for patients with densities in the highest tertile as compared the lowest tertile (P=0.01). T cell subset analysis showed that stromal regulatory T helper cells (HR 0.42 comparing highest to lowest tertile, CI 0.31-0.58, P<0.001) and stromal memory cytotoxic T cells (HR 0.55 comparing highest to lowest tertile, CI 0.42-0.74, P<0.001) were most strongly associated with longer DFS. Compared to the placebo group, adjuvant celecoxib use associated with improved DFS for patients with low but not high stromal CD3+ T cell density (adjusted HRs of 0.45 [CI 0.31-0.65] for lowest tertile and 1.13 [CI 0.73-1.74] for highest tertile; Pinteraction=0.01). This association was also seen when the analysis was restricted to microsatellite stable tumors (HR 0.50 [CI 0.32-0.80] for lowest density tertile and 1.50 [CI 0.87-2.59] for highest density tertile; Pinteraction=0.01). T cell subset analysis showed that DFS benefit for celecoxib use most strongly associated with stromal memory helper T cell density (HR 0.38 [CI 0.26-0.56] for lowest density tertile and 1.26 [CI 0.80-1.97] for highest density tertile; Pinteraction<0.001). Together, these results show that while higher T cell infiltration is associated with improved DFS, lower T cell infiltration is associated with improved DFS for patients treated with celecoxib. This unexpected finding may inform immunomodulatory treatment strategies for CC. Citation Format: Yasutoshi Takashima, Chao Ma, Qian Shi, Andressa Dias Costa, Tyler Twombly, Juha P. Väyrynen, Melissa Zhao, Ardaman Shergill, Pankaj Kumar, Felix Couture, Philip Kuebler, Smitha Krishnamurthi, Benjamin Tan, Eileen M. O'Reilly, Anthony F. Shields, Shuji Ogino, Charles S. Fuchs, Jeffrey A. Meyerhardt, Jonathan A. Nowak. Prognostic and predictive role of T cell infiltration in stage III colon cancer (CC) treated with celecoxib: CALGB/SWOG 80702 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5858.

Abstract 2445: Extending ENPP3 expression inference from tissue microarrays to whole tissue sections: building a case for automated patient enrichment and IHC scoring

Abstract Enrollment of patients with target-positive tumors is thought to be a factor of success in CD3-redirection targeted therapy trials. This process can incur significant testing costs for assays like immunohistochemistry (IHC) target expression assessment and requires laborious pathologist scoring. An ongoing Phase I study (NCT06178614) is evaluating the safety and preliminary anti-tumor activity of ENPP3xCD3 (JNJ-87890387) in ENPP3-unselected, advanced-stage solid tumors with a high prevalence of ENPP3 expression. This includes lung adenocarcinoma (LUAD) and colon adenocarcinoma (COAD) where ENPP3 cell surface expression is seen in >50% of patients. To help mitigate potential future IHC testing costs, we propose (1) an AI-based patient enrichment model that uses hematoxylin and eosin (H&E)-stained whole tissue sections (WTS) to infer ENPP3 expression and rule out LUAD and COAD patients likely to be ENPP3 negative. We also propose (2) a complementary model to infer H-scores from ENPP3 IHC-stained tissues as an alternative to pathologist scoring to help reduce workload. Training such models typically requires a large collection of WTS, which can be challenging to score, and may not be available in early clinical studies. Alternatively, tissue microarrays (TMAs) can incorporate hundreds of cases on a single slide and are readily available through commercial vendors, reducing the number of slides needed for model development. As TMA cores are typically orders of magnitude smaller than WTS, we (3) test the hypothesis that models trained on TMA cores can be deployed on WTS. To enable model training we developed a TMA preprocessing workflow that aligns paired serial H&E and IHC core images with their ground truth pathologist-derived H-scores. For our model backbone we use a vision transformer foundation model pre-trained on 55, 000 H&E WTS spanning tissue types, which conditions the model for tasks in histopathology. We then train separate fully supervised models to achieve two goals: (1) infer whether an H&E core’s paired ENPP3 H-score is greater than zero, i.e., H-score > 0 classification for patient enrichment, and (2) infer an IHC core’s H-score directly, i.e., H-score regression for automated H-scoring. The H&E-based COAD H-score > 0 classification model achieved AUC=0.79 on a held-out test set of 29 WTS. The IHC-based H-score regression models for COAD and LUAD achieved intraclass correlation coefficients of 0.76 and 0.88 on their respective held-out test sets (n=29 WTS for COAD and n=46 cores for LUAD). This approach could (1) help reduce the number of patients requiring IHC assessment and (2) minimize pathologists’ scoring workload, thus reducing trial costs and expediting patient enrollment. Our results suggest that (3) TMA cores may contain sufficient signal to train models for deployment on WTS for some tasks, which could help minimize modeling costs. Citation Format: Erik A. Burlingame, Fatemeh Koochaki, Tsun-wen Sheena Yao, Shajo Kunnath-Velayudhan, Chaitanya Parmar, Laurie Lenox, Tommaso Mansi, Joel Greshock, Kristopher Standish, Albert Juan Ramon. Extending ENPP3 expression inference from tissue microarrays to whole tissue sections: building a case for automated patient enrichment and IHC scoring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2445.

Chronotherapy for Hypertension: A Meta-Analysis and Systematic Review of RCTs.

The aim of this study was to evaluate the efficacy of chronotherapy for patients with essential hypertension with a range of clinical characteristics. We searched the PubMed, EMBASE, and Cochrane Library databases for randomized controlled trials of antihypertensive therapies in which patients were randomized to morning or evening administration. The primary outcomes of the included studies were ambulatory blood pressure (BP) parameters and patient characteristics, including age, body mass index, percentage of female participants, and drug ingestion, which were described in subgroup analyses. In total, 56 studies were included in the analyses. Meta-analyses and subgroup analyses revealed that specific populations of patients benefited more from bedtime dosing than from morning dosing in both 24-h or 48-h ambulatory systolic BP (SBP) and nighttime SBP, including (1) groups aged < 60 years, (2) those with body mass index ≥ 30 kg/m2, (3) studies with ≥ 50% female participants, and (4) patients receiving antihypertensive calcium channel blockers. However, when controversial data by Hermida et al. were omitted, the effects of BP controls were observed in patients with overweight, particularly obesity. Furthermore, calcium channel blockers contributed to an obvious reduction in nighttime SBP with chronotherapy. Chronotherapy for hypertension may not be completely ineffective, and the clinical program and timing of medication administration can be selected according to the patient's clinical characteristics. Registration PROSPERO identifier number CRD42021292795.

A Systematic Review of Novel Intravesical Approaches for the Treatment of Patients with Non-muscle-invasive Bladder Cancer.

A Systematic Review of Novel Intravesical Approaches for the Treatment of Patients with Non-muscle-invasive Bladder Cancer.

Atezolizumab with carboplatin plus nab-paclitaxel combination therapy for advanced nonsquamous non-small cell lung cancer with impaired renal function: A multicenter, single-arm phase 2 trial (RESTART, LOGiK 2002).

Atezolizumab with carboplatin plus nab-paclitaxel combination therapy for advanced nonsquamous non-small cell lung cancer with impaired renal function: A multicenter, single-arm phase 2 trial (RESTART, LOGiK 2002).

Machine learning prediction of HER2-low expression in breast cancers based on hematoxylin–eosin-stained slides

BackgroundTreatment with HER2-targeted therapies is recommended for HER2-positive breast cancer patients with HER2 gene amplification or protein overexpression. Interestingly, recent clinical trials of novel HER2-targeted therapies demonstrated promising efficacy in HER2-low breast cancers, raising the prospect of including a HER2-low category (immunohistochemistry, IHC) score of 1 + or 2 + with non-amplified in-situ hybridization for HER2-targeted treatments, which necessitated the accurate detection and evaluation of HER2 expression in tumors. Traditionally, HER2 protein levels are routinely assessed by IHC in clinical practice, which not only requires significant time consumption and financial investment but is also technically challenging for many basic hospitals in developing countries. Therefore, directly predicting HER2 expression by hematoxylin-eosin (HE) staining should be of significant clinical values, and machine learning may be a potent technology to achieve this goal.MethodsIn this study, we developed an artificial intelligence (AI) classification model using whole slide image of HE-stained slides to automatically assess HER2 status.ResultsA publicly available TCGA-BRCA dataset and an in-house USTC-BC dataset were applied to evaluate our AI model and the state-of-the-art method SlideGraph + in terms of accuracy (ACC), the area under the receiver operating characteristic curve (AUC), and F1 score. Overall, our AI model achieved the superior performance in HER2 scoring in both datasets with AUC of 0.795 ± 0.028 and 0.688 ± 0.008 on the USCT-BC and TCGA-BRCA datasets, respectively. In addition, we visualized the results generated from our AI model by attention heatmaps, which proved that our AI model had strong interpretability.ConclusionOur AI model is able to directly predict HER2 expression through HE images with strong interpretability, and has a better ACC particularly in HER2-low breast cancers, which provides a method for AI evaluation of HER2 status and helps to perform HER2 evaluation economically and efficiently. It has the potential to assist pathologists to improve diagnosis and assess biomarkers for companion diagnostics.

Investigating the trustworthiness of randomised controlled trials in osteopathic research: a systematic review with meta-analysis.

Investigating the trustworthiness of randomised controlled trials in osteopathic research: a systematic review with meta-analysis.

Combination Therapy With 177Lu-FAPI-2286 and Tyrosine Kinase Inhibitor: A Novel Approach for Treating Metastatic Medullary Thyroid Carcinoma.

A 48-year-old man diagnosed with symptomatic metastatic medullary thyroid carcinoma (MTC) presented with dyspnea and a right neck mass which was identified as a metastatic lymph node. Despite initial treatments with sorafenib and chemotherapy, his condition continued to worsen. Evaluation using 99mTc-FAPI-46 scintigraphy showed favorable uptake in both primary tumor and its metastases, leading to enrollment in a clinical trial for a combination therapy involving sorafenib and 177Lu-FAPI-2286. After four cycles of this treatment, the patient experienced significant improvement in symptoms, along with notable reductions in serum calcitonin and carcinoembryonic antigen (CEA) levels. This case underscores the potential effectiveness of 177Lu-FAPI-2286 in managing advanced MTC when conventional therapies prove ineffective.

The response to individualized treatment after a standardized treatment protocol among neck pain sufferers: a secondary analysis of a randomized controlled trial

BackgroundManual therapy and exercise are recommended for patients with neck pain. In a recent randomized controlled trial, home stretching exercises with or without manual therapy were offered to subjects with persistent or recurrent neck pain. No difference in pain or disability between the treatment groups were found after the two-week intervention period. We aimed to investigate whether these patients had a better outcome after individual tailoring of the treatment content two months after the initial structured intervention period.MethodsThis manuscript is a secondary analysis of a previous clinical trial where 131 patients with persistent or recurrent neck pain received treatments over two weeks (the intervention period). Pain and disability were assessed for two months following the intervention period. During this period, the treating therapists could recommend further individualized tailored treatment, including any treatment modality, regardless of the intervention group and whether the participants responded to the intervention (responders) or not (non-responders). Responders from the intervention period were defined as reporting a minimal clinical improvement on the numeric rating scale (NRS-11) at a 20-percentage points improvement (2 increments), regardless of group belonging in the original trial. All other participants were considered non-responders. We also evaluated the number of treatments, differences in disability, quality and affective component of pain, and quality of life during the individualized care period.ResultsFor responders to a randomized trial of manual therapy and stretching exercises, a significant worsening in pain was associated with an increasing number of treatments during a two-month individualized care period. Among non-responders to the initial intervention period, improvement in neck pain disability was observed with individually tailored treatments.ConclusionsFor responders to a randomized trial of manual therapy and stretching, worsening pain in the individualized care period was associated with increasing numbers of individually tailored treatments. Among non-responders to the initial intervention period, improvement in neck pain disability was observed with individually tailored treatments.Trial registration: The trial was registered at ClinicalTrials.gov, registration number NCT03576846, on 23rd of June 2018.

Should animal studies precede human trials for novel myopia control therapies?

Should animal studies precede human trials for novel myopia control therapies?

Randomised Crossover Trial of Home-Based Neuromuscular Electrical Stimulation Therapy as an Adjunct to Cardiac Rehabilitation in Frail Older Adult Patients With Chronic Heart Failure.

Neuromuscular electrical stimulation (NMES) is an alternative therapy for patients unable to perform sufficient voluntary exercises. This randomised crossover study aimed to evaluate the safety and efficacy of home-based NMES as an adjunct to cardiac rehabilitation (CR) for improving physical function in frail older adult patients with chronic heart failure (CHF). 8 frail older adult patients with CHF underwent 8 weeks of CR supplemented with home-based NMES and 8 weeks of CR alone in random order, separated with a 4-week washout period. NMES at 50-Hz frequency was administered for 50 min/day, 5 times per week, with electrodes placed on the legs. Changes in the short physical performance battery (SPPB) score, leg strength, and the Barthel index were assessed between patients with CR with and without home-based NMES. No NMES-related adverse events were observed. CR with home-based NMES had a higher total SPPB score and 5-repetition sit-to-stand test time of 2.67 points and -10.67 s, respectively, than CR alone (95% confidence interval [CI] 0.3-5.0, P<0.05 and 95% CI -19.5 to -1.3, P<0.05, respectively). No significant leg strength or Barthel index changes were observed between CR with and without home-based NMES. Home-based NMES safely improved physical function in frail older adult patients with CHF.

Clinical observational studies of potential participants’ current negative affect status for a clinical study of stem cell therapy for ischemic stroke: study protocol

IntroductionThe number of clinical research projects on stem cell therapy for stroke has increased annually with the rapid development of stem cells and regenerative medicine technologies. Some evidence indicates that negative emotions can affect the recruitment, compliance, retention, satisfaction, and even treatment outcomes of participants in clinical research. However, knowledge is insufficient regarding patients’ negative emotions associated with their participation in potential stem cell clinical research studies. Therefore, the study aims to investigate the negative emotions and main influencing factors for potential participants in clinical research on stem cell therapy for stroke.MethodsThis study protocol follows the Strengthening the Reporting of Observational Studies in Epidemiology Good Practice for Reporting Observational Studies. The questionnaire for this study will include 59 questions for potential participants regarding (1) their demographic characteristics, and (2) their levels of anxiety, depression, social support, general self-efficacy, and self-perceived burden.DiscussionThis study’s main strength is that it will contribute evidence on key predictors of negative affectivity in potential participants undergoing clinical trials of stem cell therapy for stroke. The results will support stem cell clinical center researchers in intervening in potential participants’ negative emotions, which is important for clinical research managers and policymakers worldwide.ConclusionThe study protocol developed in this study was validated through a rigorous development process, demonstrating scientific validity for negative affect evaluation in stem cell clinical research. This instrument provides clinicians with a standardized assessment protocol to monitor treatment-emergent emotional distress during experimental interventions, showing particular promise in identifying early psychological risks associated with novel biological therapies.

Efficacy of acupuncture-related therapy for postmenopausal osteoporosis: a systematic review and network meta-analysis based on randomized controlled trials

IntroductionTo compare and analyze the clinical effects of acupuncture-related therapies for postmenopausal osteoporosis (PMOP) and propose the optimal scheme, we utilized a network meta-analysis to evaluate the therapeutic effects of various commonly used acupuncture methods for PMOP.MethodsRandomized controlled trials of acupuncture-related therapies for PMOP were searched in eight databases (PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, China Science and Technology Journal Database, China Biomedical Literature Database, and Wanfang database) from January 1, 2002 to December 31, 2023. Our primary outcomes included overall clinical effectiveness rate, bone mineral density (BMD), and visual analog scale scores (VAS). The secondary outcome is adverse events. The entire process of literature screening and data analysis was conducted by 2 independent investigators.ResultsA total of 30 studies with 2,342 participants provided data suitable for analysis. We compared six interventions: manual acupuncture, electroacupuncture, acupoint catgut embedding, moxibustion, acupoint application, and warm acupuncture. The results of the network meta-analysis revealed that, when compared to conventional Western medication (CWM), multiple acupuncture therapies had a greater impact on the overall clinical effectiveness rate. Electroacupuncture combined with CWM demonstrated superior clinical effectiveness and lumbar spine BMD improvement. Moxibustion with CWM ranked highest for femoral neck BMD, while warm acupuncture showed optimal effects on Ward’s triangle and trochanter BMD. Acupoint catgut embedding provided the greatest pain reduction. The most prevalent minor adverse effects included hematoma, discomfort, and scorching.ConclusionThe results suggest that several acupuncture-related therapies, either alone or in conjunction with CWM, outperform CWM alone and may be regarded as an alternative or supplementary therapy to PMOP, though higher-quality trials are needed.

Computational Modeling of Effects of PKP2 Gene Therapy on Ventricular Conduction Properties in Arrhythmogenic Cardiomyopathy.

Patients with arrhythmogenic cardiomyopathy due to pathogenic variants in PKP2, the gene for the desmosomal protein plakophilin-2, are being enrolled in gene therapy trials designed to replace the defective allele via adeno-associated viral transduction of cardiac myocytes. Evidence from experimental systems and patients indicates that ventricular myocytes in PKP2 arrhythmogenic cardiomyopathy have greatly reduced electrical coupling at gap junctions and reduced Na+ current density. In previous adeno-associated viral gene therapy trials, <50% of ventricular myocytes have generally been transduced. We used established computational models of ventricular cell electrophysiology to define the effects of varying levels of successful gene therapy on conduction in patients with PKP2 arrhythmogenic cardiomyopathy. Conduction velocity and development of conduction block were analyzed in tissue constructs composed of cells with levels of electrical coupling and Na+ current density observed in experimental studies. We observed a nonlinear relationship between conduction velocity and the proportion of transduced cells. Conduction velocity increased only modestly when up to 40% of myocytes were transduced. Conduction block did not occur in tissue constructs with moderate levels of uncoupling (0.10 or 0.15 of normal) as this degree of coupling was sufficient to allow electrotonic current to pass through diseased cells. Thus, low levels of transduction, likely to occur in phase 1 clinical trials, do not seem to pose a major safety concern. However, our models did not incorporate the potential effects of fibrosis and inflammation, both of which are presumably present in PKP2 arrhythmogenic cardiomyopathy patients undergoing gene therapy and could impact arrhythmogenesis. The extent of successful ventricular myocyte transduction anticipated to be achieved in PKP2 adeno-associated viral gene therapy trials will likely not restore conduction velocity to levels sufficient to decrease the risk of reentrant arrhythmias. Transduction efficiency of 60% to 80% would be required to restore conduction velocity to 50% of normal.

First-in-Human Trial of NRTX-1001 GABAergic Interneuron Cell Therapy for Focal Epilepsy - Updated Clinical Trial Results (P8-9.003)

First-in-Human Trial of NRTX-1001 GABAergic Interneuron Cell Therapy for Focal Epilepsy - Updated Clinical Trial Results (P8-9.003)

Intracranial neuromodulation for pediatric drug-resistant epilepsy: early institutional experience

IntroductionPediatric drug-resistant epilepsy (DRE) is defined as epilepsy that is not controlled by two or more appropriately chosen and dosed anti-seizure medications (ASMs). When alternative therapies or surgical intervention is not viable or efficacious, advanced options like deep brain stimulation (DBS) or responsive neurostimulation (RNS) may be considered.ObjectiveDescribe the Stanford early institutional experience with DBS and RNS in pediatric DRE patients.MethodsRetrospective chart review of seizure characteristics, prior therapies, neurosurgical operative reports, and postoperative outcome data in pediatric DRE patients who underwent DBS or RNS placement.ResultsNine patients had DBS at 16.0 ± 0.9 years and 8 had RNS at 15.3 ± 1.7 years (mean ± SE). DBS targets included the centromedian nucleus of the thalamus (78% of DBS patients), anterior nucleus of the thalamus (11%), and pulvinar (11%). RNS placement was guided by stereo-EEG and/or intracranial monitoring in all RNS patients (100%). RNS targets included specific seizure onset zones (63% of RNS patients), bilateral hippocampi (25%) and bilateral temporal lobes (12%). Only DBS patients had prior trials of ketogenic diet (56%) and VNS therapy (67%). Four DBS patients (44%) had prior neurosurgical interventions, including callosotomy (22%) and focal resection (11%). One RNS patient (13%) and one DBS patient (11%) required revision surgery. Two DBS patients (22%) developed postoperative complications. Three RNS patients (38%) underwent additional resections; one RNS patient had electrocorticography recordings for seizure mapping before surgery. For patients with a follow-up of at ≥1 year (n = 7 for DBS and n = 5 for RNS), all patients had reduced seizure burden. Clinical seizure freedom was achieved in 80% of RNS patients and 20% had a &amp;gt;90% reduction in seizure burden. The majority (71%) of DBS patients had a ≥50% reduction in seizures. No patients experienced no change or worsening of seizure frequency.ConclusionIn the early Stanford experience, DBS was used as a palliatively for generalized or mixed DRE refractory to other resective or modulatory approaches. RNS was used for multifocal DRE with a clear seizure focus on stereo-EEG and no prior surgical interventions. Both modalities reduced seizure burden across all patients. RNS offers the additional benefit of providing data to guide future surgical planning.

Long COVID Brain Fog Treatment: Feasibility Metrics from An Early-phase Randomized Controlled Trial of Constraint-Induced Cognitive Therapy (S19.004)

Long COVID Brain Fog Treatment: Feasibility Metrics from An Early-phase Randomized Controlled Trial of Constraint-Induced Cognitive Therapy (S19.004)

Clinical features and implications of albuminuria trajectories in type 2 diabetes: The Fremantle Diabetes Study Phase II

Abstract Purpose The urinary albumin:creatinine ratio (uACR) can exhibit significant temporal changes but few studies have characterized transition patterns between uACR categories in type 2 diabetes. The study aim was to use group-based trajectory modelling (GBTM) to identify clusters of people with type 2 diabetes and distinct uACR trajectories. Participants and methods Of 1482 participants in the observational Fremantle Diabetes Study Phase II, 1145 (77.3%; mean age 65.4 years, 53.3% males) with ≥2 biennial uACR measurements over 6 years were included in GBTM. Independent baseline associates of uACR trajectory group membership were assessed using multinomial regression. Associations between group membership and changes in estimated glomerular filtration rate over four years were explored. Results The optimum GBTM model comprised six categories; normoalbuminuria (n=429, 37.5%), regression (n=82, 7.2%), progression (n=71, 6.2%), progression/regression (n=104, 9.1%), persistent microalbuminuria (n=401, 35.0%), persistent macroalbuminuria (n=58, 5.1%). The latter five groups had worse glycemic control than the normoalbuminuria group. The three groups starting from/returning to normoalbuminuria had heterogeneous baseline characteristics but a decline in renal function that was similar to the normoalbuminuric group. The persistent microalbuminuria group had adverse baseline cardiometabolic features and longitudinal renal outcomes relative to the normoalbuminuria/other microalbuminuria groups. The persistent macroalbuminuria group had, consistent with its baseline characteristics, the highest mortality (31.0% versus ≤18.5% in the other groups) and most rapid progression of renal dysfunction. Conclusions GBTM identified distinct uACR trajectory groups with clinical and prognostic implications, and could be used to stratify participants in clinical trials of new therapies for diabetic kidney disease.