Clinical Trial Research Articles

Treatment of prehypertension among adults with HIV: a randomized clinical trial

Objective: Elevated blood pressure (BP), even at prehypertensive levels, increases cardiovascular disease risk among people with HIV (PWH); yet international guidelines in low-income countries recommend treatment initiation at BP at least 140/90 mmHg. We determined the efficacy, feasibility, and acceptability of treating prehypertension in PWH in Haiti. Design: An unblinded randomized clinical trial (enrolled April 2021–March 2022) with 12-month follow-up. Setting: GHESKIO Centres, Port-au-Prince, Haiti. Participants: Two hundred fifty adults with HIV with prehypertension (SBP 120–138 or DBP 80–89) not on medication, aged 18–65 years, virally suppressed, and without pregnancy, diabetes, or kidney disease. Intervention: Participants were randomized to treatment (amlodipine 5 mg) or control (no amlodipine unless two BP ≥140/90 mmHg). Main outcome measure: Primary outcome was mean change in SBP between intervention versus control groups from enrollment to 12 months. Results: Among 250 adults, median age was 49 years, 40.8% were women. Baseline median BP was 129/78 mmHg intervention versus 128/77 mmHg control. After 12 months, the difference in mean change between study groups for SBP was -5.9 mmHg [95% confidence interval (95% CI) -8.8 to -3.0] and for DBP was -5.5 mmHg (95% CI -7.9 to -3.2). At 12 months, 5.6% intervention and 23.0% control participants developed incident hypertension (hazard ratio 0.18; 95% CI 0.07–0.47). There were no differences in viral load suppression at 12 months or drug-related serious adverse events. Intervention acceptability was high among providers and participants in qualitative interviews. Conclusion: In PWH in a resource-poor setting, prehypertension treatment was feasible, acceptable, and effective in reducing mean SBP and incident hypertension. Registration: Clinicaltrials.gov NCT04692467

Abstract PR004: Second generation RNA Polymerase I inhibitor PMR-116 targets ribsomal RNA synthesis to potently treat a broad spectrum of malignancies

Abstract Purpose and rational for the study: The purpose of the study was to develop novel 2nd generation ribosomal RNA synthesis inhibitors for cancer treatment. Ribosome biogenesis (RiBi) is essential for cell growth and proliferation. Transcription of ribosomal RNA genes by Pol I is a critical step in RiBi and is tightly regulated by tumor suppressors and oncoproteins. Indeed, the ability of the potent oncoprotein, MYC, to drive RiBi is necessary for its oncogenic activity (Bywater et al., Cancer Cell, 2011). These data suggested that targeting RiBi, might be a promising strategy to treat malignancies, especially those driven by MYC. To test this, we developed the 1st small molecule inhibitor of Pol I transcription, CX-5461 (Drgyin et al., Cancer Research 2011). While CX-5461 has shown promising activity in pre-clinical studies (Bywater et al., Cancer Cell, 2011; Rebello et al., Clin Cancer Res., 2016; Hein et al., Blood, 2017) and in early Phase trials (Khot et al., Cancer Discovery, 2019; Hilton et al., Nat Commun. 2022) its mechanism of action remains controversial with evidence of off-target activity inducing DNA damage through inhibition of TOPO2a (Cameron et al., Biomedicines, 2024; Koh et al., Nature Genetics, 2024). Thus, to determine if selective inhibition of Pol I transcription in the absence of DNA damage can be used to therapeutical treat cancer in vivo, we developed a series of more selective 2nd generation Pol I inhibitors with our lead compound being PMR-116. Methods and summary of data: We demonstrate that PMR-116 is selective for inhibition of Pol I over Poll II transcription and functions by stalling the Pol I complex at the rDNA promoter. PMR-116, exhibits improved drug-like properties and pharmacokinetics compared to 1st generation CX-5461. As a single agent PMR-116 efficiently treats a range of pre-clinical models of hematologic and solid tumors including lymphoma, AML, hepatocellular carcinoma and prostate cancer. MYC expression positively correlates with sensitivity to PMR-116 in human cancer cell lines and high MYC tumors in vivo are exceptionally sensitive to PMR-116. In contrast to CX-5461, the therapeutic response to PMR-116 occurs in the absence of DNA damage suggesting that DNA damage is not an obligatory response to Pol I transcription inhibition but rather an off-target effect of the 1st generation drug. Small molecule drug combination screens in AML cells demonstrate that PMR-116 works synergistically to reduce cell viability with a range of drugs including carfilzomib and quisinostat used for treatment of hematologic malignancies. Conclusions: Our data establishes inhibition of RNA polymerase I as a bone fide therapeutic target for cancer therapy and demonstrated that PMR-116 is a promising new broad- spectrum anti-cancer drug particularly for those tumors driven by MYC, which are highly refractory to standard therapies. Based on these data we have launched a Phase I clinical trial of PMR-116 in patients with advanced solid tumors (CTRN12620001146987). Citation Format: Rita Ferreira, Katherine M. Hannan, Konstantin Panov, Thejanni Udumanne, Amee J George, Zaka Yuen, Perlita Poh, Eric Kusnadi, Alisee Huglo, Mitchell Lawrence, Mustapha Haddach, Denis Drygin, Luc Furic, Ross D Hannan, Nadine Hein. Second generation RNA Polymerase I inhibitor PMR-116 targets ribsomal RNA synthesis to potently treat a broad spectrum of malignancies [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr PR004.

Development and Validation of a Flow-Dependent Endothelialized 3D Model of Intracranial Atherosclerotic Disease

Abstract Intracranial atherosclerotic disease (ICAD) is a major cause of stroke globally, with mechanisms presumed to be shared with atherosclerosis in other vascular regions. Due to the scarcity of relevant animal models, testing biological hypotheses specific to ICAD is challenging. We developed a workflow to create patient-specific models of the middle cerebral artery (MCA) from neuroimaging studies, such as CT angiography. These models, which can be endothelialized with human endothelial cells and subjected to flow forces, provide a reproducible ICAD model. Using imaging from the SAMMPRIS clinical trial, we validated this novel model. Computational fluid dynamics flow velocities correlated strongly with particle-derived flow, regardless of stenosis degree. Post-stenotic flow disruption varied with stenosis severity. Single-cell RNA-seq identified flow-dependent endothelial gene expression and specific endothelial subclusters in diseased MCA segments, including upregulated genes linked to atherosclerosis. Confocal microscopy revealed flow-dependent changes in endothelial cell proliferation and morphology in vessel segments related to stenosis. This platform, rooted in the specific anatomy of cerebral circulation, enables detailed modeling of ICAD lesions and pathways. Given the high stroke risk associated with ICAD and the lack of effective treatments, these experimental models are crucial for developing new ICAD-related stroke therapies.

Transversus abdominis plane block in minimally invasive colon surgery: a multicenter three-arm randomized controlled superiority and non-inferiority clinical trial

Background and objectivesThe transversus abdominis plane (TAP) block is the most widely used abdominal field block in colorectal surgery with a postoperative enhanced recovery pathway. We aimed to determine whether the laparoscopic-assisted and ultrasound-guided TAP (US-TAP) blocks provide superior pain relief compared with placebo. We separately investigated whether the laparoscopic-assisted technique was non-inferior to the ultrasound-guided technique in providing pain relief, with a non-inferiority margin of 10 mg morphine dose equivalents.Methods340 patients undergoing elective minimally invasive colon surgery were randomly allocated to one of three groups: (1) US-TAP block, (2) laparoscopic-assisted TAP (L-TAP) block, or (3) placebo. Superiority and non-inferiority were tested for the primary outcome: 24-hour postoperative morphine equivalent consumption. Secondary outcomes, including patient-reported quality of recovery, were included in the superiority analysis.Results127 patients were included in each block group and 86 in the placebo group. The US-TAP block was no different from placebo at −1.4 mg morphine (97.5% CI −6.8 to 4.0 mg; p=0.55). The L-TAP block was superior to placebo at −5.9 mg morphine (97.5% CI −11.3 to −0.5 mg; p=0.01) and non-inferior to the US-TAP block at −4.5 mg morphine (98.75% CI −10.0 to 1.1 mg).ConclusionThe L-TAP block was superior to placebo and non-inferior to the US-TAP block. However, neither met our predetermined estimate of the minimal clinically important difference of 10 mg morphine.Trial registration numberNCT04311099.

Abstract B005: A robust NSCLC biomarker: miR-7-5p: in-silico validation and potential SPR- based probe for detection

Abstract The abundance of micro RNAs as a specific biomarker for accurately detecting cancer metastasis has arisen recently. The expression levels of miRNA are analyzed to get insights into cancer tissue detection and subtypes. Similar to other cancer types, the miRNA shows high levels of target mRNA dysregulation in association with non-small cell lung carcinoma (NSCLC). Among many promising cancer biomarkers for NSCLC, miR-7-5p has shown significant downregulation in the NSCLC tissues and targets proto-oncogenes like PAK2 and NOVA2. The expression levels of different proto-oncogenes targeting the miR-7-5p in NSCLC show that the EGFR- mutated NSCLC has an experimental validation. And, the target validation of the miR-7-5p could be analyzed using SPR (Surface plasmon resonance) based sensors at a single nanoparticle level such as Au nanocube due to its high specificity and accountability. Despite being an accountable tool for cancer diagnosis, miRNA-based biomarkers sometimes cause poor diagnostic specificity and reproducibility due to their heterogenicity and immunogenicity in cancer detection. To overcome these shortcomings, the biomarkers need to be validated according to recent clinical studies. Citation Format: Chandrajeet Dhara, Anindita Dhara, Saumyatika Gantayat. A robust NSCLC biomarker: miR-7-5p: in-silico validation and potential SPR- based probe for detection [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr B005.

NEW TECHNOLOGIES AVAILABLE FOR MICRONEUROSURGICAL REMOVAL OF ACOUSTIC NEUROMAS

Introduction The aim of this study was to analyze the results of microsurgery removal of acoustic neuromas (AN) using new technologies: flexible hand-held laser fiber, Sonopet Ultrasound Aspirator, Facial Nerve “detector” monopolar stimulation (for localize position and course of facial nerve), BAER’s with level specific (LS) CE-Chirp stimulus for hearing preservation, endoscope for IAC final check, and injectable bone substitute for closure. We report a retrospective nonrandomized clinical study on 300 cases consecutively operated on. Material and Methods From July, 2010 to December, 2023, 350 consecutive patients suffering from AN have been operated on with microneurosurgical technique by key-hole retrosigmoid approach. In majority of cases tumor resection was performed with the aid of a handheld flexible laser fiber. In the same period, Sonopet Ultrasound aspirator was used for tumor debulking and/or opening of the internal auditory meatus and canal. From May 2015, hearing preservation by means LS CE-Chirp BAER was attempted in patients with preoperative socially useful hearing (AAO-HNS class A and B). In addition, we check the removal of tumor inside the internal auditory canal (IAC) by using the flexible and/or rigid endoscope, for completing tumor removal near the fundus. Results Overall time from incision to skin suture changed in relation to size of tumor (from 165 to 575 minutes) and was not affected by the use of hand-held laser. Facial nerve function was clinically assessed with the House-Brackmann (HB) scale preoperatively, in the early postoperative period (after 1 week), and at 6-month follow-up. In 3 cases a preoperative facial nerve palsy was observed (HB III and HB IV, respectively). In the remaining cases, 6 months after surgery facial nerve preservation rate (HB I) was 92%, Hearing preservation rate (AAO-HNS A and B, pre- and postoperatively) was 52% in eligible cases. Total and “nearly total” removal of tumor was possible in about 80% of cases. Dura closure was performed with underlaying autologous pericranium. Injectable bone substitute in the gaps after bone flap repositioning minimized postoperative CSF leakage and improved the aesthetic result. Conclusions The use of new technologies (handheld flexible laser fibers, Sonopet Ultrasound Aspirator, fluoreceine, Nimbus facial nerve continuous monitoring, LS CE-Chirp BAER, endoscope for IAC final check) in AN microsurgery seems to be safe and efficacious and facilitates tumor resection, especially in ‘‘difficult’’ conditions (e.g., large size, highly vascularized, or hard tumors). The good functional outcome following conventional microsurgery seems to be further improved and the extent of tumor removal could be increased with the proper use of the new technologies available in the neurosurgical armamentarium.

Housing conditions and COVID-19 in Barcelona: do they change by gender?

Abstract Background Evidence has linked poor housing conditions to negative health outcomes. However, in urban contexts characterized by social vulnerability and population-level inequalities, the gender perspective is often overlooked, despite evidence showing that housing conditions impact men and women differently in terms of health. This study aimed to describe the association between housing conditions and the prevalence of COVID-19 among men and women in Barcelona, Spain. Methods An observational cross-sectional study was conducted using the 2021 Barcelona Health Survey. The study population consisted of non-institutionalized residents over 14 years of age in Barcelona. The survey was administered to a sample of 3,545 participants during the COVID-19 pandemic, between February 2021 and February 2022. Crude and adjusted prevalence ratios of COVID-19 (aPR), along with 95% confidence intervals (95% CI), were estimated using multivariate Poisson regression models with robust variance. The analysis was stratified by gender. Results A significant gradient was observed across age groups for both men and women, with higher COVID-19 prevalence in younger categories. The prevalence was notably higher among individuals born in low-income countries, particularly for women (aPR 1.62). We also identified a significant association between housing conditions, vulnerability factors, and COVID-19 prevalence in both men and women. Living with four or more cohabitants was associated with higher prevalence (aPR 1.96 for women and 1.89 for men), as was the presence of dampness in the home (aPR 1.34 for women and 1.27 for men). Additionally, energy poverty was significantly associated with higher COVID-19 prevalence in women (aPR 1.36), but not in men. Conclusion This study highlights the association between housing conditions and COVID-19 in Barcelona, with a pronounced impact on young people, women from low-income countries, and women experiencing energy poverty.

Assessment of building information modeling adoption in building material scheduling in Tanzania’s construction industry

The building construction industry continues to face challenges that affect project delivery, one of which is the traditional practices used for building material scheduling (BMS). Studies indicate that these practices are often inefficient and prone to errors, leading to delays, cost overruns, and low-quality work, affecting the project objectives. Building Information Modeling (BIM) presents a promising solution for addressing these challenges, proven through existing integrations. However, its adoption in BMS practices in construction is still relatively low. Therefore, this study aimed to assess BIM use in BMS in Tanzania’s building construction industry. The study adopted a quantitative research approach, and the study population of 153 registered quantity surveying firms was purposively selected. The study data was collected using online questionnaires and analyzed with the Statistical Package for Social Sciences (SPSS). The study findings indicate that traditional practices are still favored over BIM when scheduling building materials in Tanzania, with the most predominant practices being spreadsheets and paper-based methods. Additionally, findings suggest that BIM is not a new concept in Tanzania. However, its adoption in the current practices is relatively low, mainly due to insufficient expertise, training resources, and limited access to BIM software/tools. Moreover, findings indicate a significant belief that BIM can improve BMS practices. These insights can inform policymakers, industry stakeholders, and educational institutions on the necessary steps to promote BIM integration. Therefore, it is recommended that BIM adoption be prioritized by addressing these barriers to enhance project outcomes. Shifting from traditional methods to BIM will lead to more efficient and effective construction processes, making BIM's broader adoption essential for the industry's future success.

FISIOTERAPIA NO ZUMBIDO SOMATOSENSSORIAL: REVISÃO SISTEMÁTICA

Somatosensory tinnitus is a type of tinnitus that can be influenced by musculoskeletal and somatic factors, such as cervical or temporomandibular disorders. Physiotherapy has emerged as a noninvasive treatment option with the aim of addressing these musculoskeletal abnormalities to reduce tinnitus intensity and improve patients' quality of life. This review aims to evaluate the effectiveness of physiotherapeutic approaches in the management of somatosensory tinnitus, exploring different treatment modalities and the results obtained in clinical studies. The article was analyzed through clinical trials and observational studies were conducted, focusing on the impact of physiotherapy on somatosensory tinnitus, using outcome measures such as the Visual Analog Scale (VAS) for tinnitus intensity and the Tinnitus Handicap Inventory (THI) for quality of life. Most studies reported significant improvements in tinnitus severity and functional well-being of patients after physiotherapy interventions. Techniques such as manual therapy and myofascial release have been particularly effective in reducing symptoms in patients with cervical or temporomandibular disorders. However, a major limitation identified was the lack of standardized treatment protocols, which makes it difficult to generalize the results. Physiotherapy appears to be a promising therapeutic option for somatosensory tinnitus, particularly for patients with associated cervical and temporomandibular disorders. Future research should aim to standardize treatment protocols and include larger randomized controlled trials to further validate these findings and establish evidence-based clinical guidelines.

Abstract A001: Analytical validation of a novel multiomic metastatic breast cancer liquid biopsy test that combines ctDNA analysis with CTC HER2-ultralow and ER co-expression, as well as single-cell chromosomal instability

Abstract Background: Metastatic breast cancer (MBC) subtype characterization is critical for effective treatment. The DefineMBC™ multiomic blood biopsy clinical diagnostic combines ctDNA and circulating tumor cell (CTC) analyses to characterize MBC patients when a tissue biopsy is not feasible. Innovation in the DefineMBC 2.0 5-channel immunofluorescent (IF) CTC characterization assay now measures ultralow (UL) levels of HER2 protein expression, ER protein expression, and chromosomal instability (CI) as well as ERBB2 amplification via single- cell sequencing. Cell-level HER2/ER co-detection enables monitoring of receptor conversion during a patient’s MBC treatment journey. As trastuzumab-deruxtecan (T-DxD) has become standard of care for HER2-low disease, distinguishing HER2-UL from HER2[-] by DefineMBC’s liquid biopsy approach may identify additional patients who can benefit from such therapy. This addresses an unmet need given the known shortcomings of tissue biopsy IHC in the metastatic setting as recently noted by communications from NCCN, ASCO, and the College of American Pathologists. Methods: Assay development including analytical validation studies utilized biologically relevant cell lines of epithelial origin and known expression levels of HER2 and ER (MDA-MB-453: HER2[+] & ER[-]; MCF-7: HER2-low & ER[+]; and MCF-7/ERBB2 knockout: HER2[-]) that were spiked into healthy donor blood. Additionally, patients with various forms of MBC were characterized with the new assay. As with all samples, following red blood cell lysis, nucleated cells were deposited on glass slides at high density (∼3E6 WBC/slide). Slides underwent IF staining for cytokeratins (CK), CD31, CD45, HER2, ER, and Hoechst to localize nuclear DNA, followed by scanning and machine learning-based rare cell detection. CK[+], CD31[-]/CD45[-] cells were classified as CTC candidates and assessed for HER2/ER expression. Pathologist-selected CTCs were isolated for single-cell whole genome sequencing and analyzed using a proprietary CTC DNA copy number pipeline to detect CI and amplification at the ERBB2 locus. Results: Analytical validation studies demonstrated the limit of detection at 1 CTC per 12E6 WBC (∼1.6 mL of blood) with a linear range of 1- 300 CTCs per slide. Sensitivity, specificity, accuracy, and precision metrics of the HER2 and ER IF assays were 96%, 96%, 96%, 2% CV; 91%, 95%, 93%, 3% CV; respectively. CTC enumeration precision was validated at greater than 80% for enumeration bins of 0, 1-10, 11-50, and>50 CTCs per sample. During patient testing 7 patients previously called HER2[-] are now designated as consistent with HER2-low by the pathologist, suggesting improved test performance in future clinical validation studies is likely. Conclusions: Advancement of our comprehensive cancer profiling platform now includes ER/HER2-UL/CI co-detection on enumerated CTCs in MBC patients. Clinical studies currently in progress will reveal whether HER2-UL/HER2[+] detection on CTCs will identify patients better suited for T-DxD or trastuzumab, respectively. Citation Format: Raj Srikrishnan, Jordan Ritchie, Alessandra Cunsolo, Andrew Kunihiro, Brandon Guillory, Sara Tin, Zhuo Meng, Ernest T Lam, Bharat Annaldas, Evan Schwab, Nilesh Dharajiya, Timothy Pluard, Martin Blankfard, David Bourdon. Analytical validation of a novel multiomic metastatic breast cancer liquid biopsy test that combines ctDNA analysis with CTC HER2-ultralow and ER co-expression, as well as single-cell chromosomal instability [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 A001.

Primary dedifferentiated liposarcoma of the gallbladder: a case report and literature review

BackgroundLiposarcoma (LPS) is a kind of malignancy of soft tissue usually found in the retroperitoneal, limb, or neck region, and some may be detected with delayed symptoms (pain or palpable mass), and less frequently occurs in organs of the digestive system. In contrast, Dedifferentiated liposarcoma (DDLPS) is a common histological subtype of LPS. The present study reported a case of dedifferentiated liposarcoma originating in the gallbladder. Differentiated liposarcoma originating from the gallbladder is rarely reported.Case descriptionA 64-year-old female patient presented to our hospital with a painless abdominal mass. Abdominal computed tomography (CT) showed that the gallbladder had lost its normal shape, and a 9.1 cm × 7.1 cm × 12.1 cm mass was seen in the area of the gallbladder fossa and the right upper abdomen below it, which had an irregular morphology, inhomogeneous density, and nodular calcification, with marked inhomogeneous enhancement on enhancement scan. Preoperative tumor markers and liver function indicators were not abnormal. With suspicion of a giant malignant tumor of the gallbladder, she underwent a cholecystectomy combined with abdominal mass resection. After surgery, the tumor and gallbladder, were completely resected, and postoperative pathological results confirmed the diagnosis of dedifferentiated liposarcoma deriving from gallbladder. After surgery, the patient and his family refused to continue treatment. After 15 months follow-up, the patient remains asymptomatic and does not show any signs of recurrence. And she is now under continued follow - up.ConclusionsTreatment of dedifferentiated liposarcoma is still at exploratory stage, and a lack of clinical evidence for this condition might hinder access to clinical trials and studies. Currently, the treatment of choice for dedifferentiated liposarcoma remains radical resection. In the available clinical studies, there are no robust data to support clinical use of neoadjuvant and adjuvant radiochemotherapy. As with other diseases, the use of radiotherapy and chemotherapy before and after surgery may be a potential future treatment.

Modulation of neural networks and symptom correlated in fibromyalgia: A randomized double-blind multi-group explanatory clinical trial of home-based transcranial direct current stimulation

Background Transcranial direct current stimulation (tDCS) might modulate neural activity and promote neural plasticity in patients with fibromyalgia (FM). This multi-group randomized clinical trial compared home-based active tDCS (HB-a-tDCS) on the left dorsolateral prefrontal cortex (l-DLPFC) or home-based sham tDCS (HB-s-tDCS), and HB-a-tDCS or HB-s-tDCS on the primary motor cortex (M1) in the connectivity analyses in eight regions of interest (ROIs) across eight resting-state electroencephalography (EEG) frequencies. Methods We included 48 women with FM, aged 30 to 65, randomly assigned to 2:1:2:1 to receive 20 sessions during 20 minutes of HB-a-tDCS 2mA or HB-s-tDCS, over l-DLPFC or M1, respectively. EEG recordings were obtained before and after treatment with eyes open (EO) and eyes closed (EC). Results In the EC condition, comparing pre to post-treatment, the HB-a-tDCS on l-DLPFC decreased the lagged coherence connectivity in the delta frequency band between the right insula and left anterior cingulate cortex (ACC) (t = -3.542, p = .048). The l-DLPFC HB-a-tDCS compared to HB-s-tDCS decreased the lagged coherence connectivity in the delta frequency band between the right insula and left ACC (t = -4.000, p = .017). In the EO condition, the l-DLPFC HB-a-tDCS compared to M1 HB-s-tDCS increased the lagged coherence connectivity between the l-DLPFC and left ACC in the theta band (t = -4.059, p = .048). Regression analysis demonstrated that the HB-a-tDCS effect on the l-DLPFC was positively correlated with sleep quality. On the other hand, the HB-a-tDCS on l-DLPFC and HB-s-tDCS on M1 were positively correlated with pain catastrophizing. Conclusions These results show that HB-a-tDCS affects the neural connectivity between parts of the brain that control pain’s emotional and attentional aspects, which are most noticeable at lower EEG frequencies in a rest state. This effect on neural oscillations could serve as a neural marker associated with its efficacy in alleviating fibromyalgia symptoms. Clinical trial registration identifier [NCT03843203].

Abstract B032: Genome-wide 5-hydroxymethylation mapping in cell-free DNA to characterize the epigenetic differences in minimal residual disease of multiple myeloma

Abstract Background: Multiple myeloma (MM), a B-cell neoplasm characterized by the infiltration of malignant plasma cells into the bone marrow, is the second most common blood malignancy in the United States. The molecular pathogenesis of MM involves both genetic and epigenetic alterations. While 60-75% of newly diagnosed patients achieve a complete response or better with current modern combination therapies, almost all patients eventually progress largely due to the persistence or re-emergence of minimal residual disease (MRD). Monitoring for MRD has become essential for evaluating treatment efficacy and predicting long-term outcomes in MM patients. We aimed to investigate whether epigenetic changes, particularly 5- hydroxymethylcytosines (5hmC), at diagnosis are associated with MRD status following treatment. Methods: Utilizing 5hmC-Seal, a highly sensitive chemical labeling technique, we profiled genome-wide 5hmC in circulating cell-free DNA (cfDNA) and bone marrow genomic DNA (gDNA) at baseline and after 8 cycles of treatment (C8) from newly diagnosed MM patients (n=25) enrolled in a clinical trial (NCT01816971). MRD testing was performed on bone marrow samples using the clonoSEQ next generation sequencing assay (limit of detection 10-6). Results: The 5hmC modification levels were summarized across various genomic features, revealing enrichment in gene bodies and enhancer regions, consistent with the known regulatory role of 5hmC. We ranked 5hmC-modified genes at baseline by their variability, and found that the number of overlapping genes between cfDNA and gDNA was significantly higher than expected by permutation analysis. Subsequently, we identified the top 100 most variable 5hmC- modified genes in gDNA, which exhibited a higher Pearson correlation with cfDNA within individuals (mean r=0.90) compared to between individuals (mean r=0.82; p<0.05), suggesting that cfDNA has the potential to reflect gDNA in capturing some MM-related variations. Among the 11 patients with MRD+ at C8, a genome-wide scan of 5hmC in cfDNA comparing baseline and C8 identified 1,614 differentially modified genes (p<0.05) after adjusting for age and sex. [BC1] Furthermore, we identified 459 differentially modified genes comparing baseline 5hmC levels between patients who were MRD+ (n=11) and MRD- (n= 14) at C8 (p<0.05), after adjusting for age and sex. These results highlight the differential epigenetic landscape associated with MRD status. Conclusions: Genome-wide 5hmC profiling of cfDNA from blood revealed a similar epigenetic landscape to gDNA from bone marrow in patients with MM, suggesting that cfDNA may offer a less invasive alternative for assessing epigenetic modifications. Moreover, this profiling identified distinct epigenetic changes associated with the achievement of MRD- negativity. These findings provide a foundation for further investigation into the molecular alterations linked to MM disease biology that could potentially lead to MRD negativity. Future directions will focus on identifying biomarkers that could inform personalized treatment strategies. Citation Format: Zhou Zhang, Bei Wang, Krissana Kowitwanich, John Cursio, Daniel Appelbaum, Chuan He, Wei Zhang, Benjamin Derman, Brian Chiu, Andrzej Jakubowiak. Genome-wide 5-hydroxymethylation mapping in cell-free DNA to characterize the epigenetic differences in minimal residual disease of multiple myeloma [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 B032.

Effects of dietary cellulose on clinical and gut microbiota recovery in dogs with uncomplicated acute diarrhea: a randomized prospective clinical trial

Abstract OBJECTIVE To assess the impact of dietary fiber supplementation with cellulose on clinical course, fecal consistency, and intestinal microbiota composition in dogs with uncomplicated acute diarrhea (AD). METHODS From September 2022 to November 2023, a total of 19 dogs presenting with uncomplicated AD were included in this prospective, randomized, and double-blinded clinical trial. The time to resolution of diarrhea was evaluated via owner surveys and a fecal scoring chart. The client-owned dogs were randomly assigned to a cellulose group (CG) or control group. The intestinal microbiota was analyzed via quantitative PCR. RESULTS A marginally significant, faster improvement in stool consistency on day 1 was observed in the CG (P = .09). All dogs improved clinically, with a median recovery time of 3.0 days in the CG and 3.2 days in the control group (range, 1 to 6 days in both groups). There was no significant difference regarding the Canine Acute Diarrhea Severity index or composition of the intestinal microbiota during the study. CONCLUSIONS All dogs with uncomplicated AD exhibited rapid clinical improvement and recovery of the core intestinal microbiota within the first few days. Cellulose improved the fecal consistency in a subset of dogs, and intestinal dysbiosis was mild and self-limiting. CLINICAL RELEVANCE The administration of dietary cellulose has the potential to accelerate improvements of stool consistency. Mild changes in pathobionts, such as an increased amount of Clostridium perfringens, are self-limiting; thus, antibiotic intervention is not warranted.

The effect of sevelamer on serum calcification propensity in patients with chronic kidney disease: the results of a multicentre, double-blind, placebo-controlled, randomized clinical trial

Abstract Background The serum calcification propensity test (or T50 test) might become a standard tool for the assessment of vascular calcification risk, and T50 might be a valuable biomarker in clinical trials of treatments intended to slow the progression of vascular calcification. Literature data suggest that non-calcium-containing phosphate binders can influence T50 in chronic dialyzed patients. However, it is not clear whether similar interventions are effective in patients at earlier stages of chronic kidney disease (CKD). Methods The “FGF23 Reduction efficacy of a new Phosphate Binder in CKD” (FRENCH) trial was a multi-centre, double-blind, placebo-controlled, randomized trial of sevelamer carbonate in participants with stage 3b/4 CKD. In this subanalysis of the FRENCH data, T50 and other laboratory variables (including fetuin A, and ionized and total magnesium) were measured centrally at baseline and after 12 weeks of treatment. Results A total of 96 patients were screened; 78 (55 men and 23 women) met the inclusion criteria and were randomized to receive placebo (n=39) or sevelamer carbonate (n=39). The median [interquartile range] patient age was 66 [56-72], the median eGFR was 25 [21-30] mL/min/1.73m², and the mean T50 was 335 (82) minutes. In a linear regression model, T50 was independently associated with serum ionized magnesium, fetuin-A and bicarbonate levels; and inversely associated with phosphate concentration. The within-group changes in the mean [95% confidence interval] T50 between week 0 and week 12 were not significant in the sevelamer group or the placebo group (4.6 [-13.6; 22.8] minutes (p=0.61) and 7.8 [-16.4; 32.1] minutes (p=0.51), respectively). Furthermore, we did not observe significant changes in fetuin-A and magnesium levels. Conclusion A 12-week course of the non-calcium-containing phosphate binder sevelamer carbonate was not associated with a significant change in T50 in patients with stage 3b/4 CKD. Phosphate binders might not be an effective strategy for modifying serum calcification propensity in non-dialysis-dependent patients with CKD.

Nephrology intervention to avoid acute kidney injury in patients awaiting cardiac surgery: randomized clinical trial

IntroductionCardiac surgery-associated acute kidney injury (CSA-AKI) is a well-known complication that increases morbidity and mortality rates. The objective of this study was to reduce CSA-AKI through nephrologist intervention in patients awaiting cardiac surgery.MethodsWe performed a single center, open-label, randomized clinical trial including 380 patients who underwent scheduled cardiac surgery at the Hospital de Bellvitge between July 2015 and October 2019. A total of 184 patients were evaluated by the same Nephrologist one month before the surgery to minimize the risk factors for AKI. In addition to assessments at the outpatient clinic, we also collected clinical data during hospitalization and during the first year.ResultsDespite the intervention, no differences were observed between the groups in the incidence of CSA-AKI (intervention group 26.37% vs. standard of care 25.13%, p=0.874), mortality (3.91% vs. 3.59%, p=0.999), length of Intensive Care Unit (ICU) stay (10 days [7.00;15.0] for both groups, p=0.347), or renal function after one year of follow-up (estimated glomerular filtration rate (eGFR) by CKD-EPI: 74.5 ml/min (standard deviation 20.6) vs 76.7 (20.8) ml/min, respectively, p=0.364). A reduction in the need for blood transfusion was observed in the intervention group, although the difference was not statistically significant (37.22% vs. 45.03%, p =0.155).ConclusionIn this clinical trial, nephrologist intervention in the entire population on the cardiac surgery waiting list did not show a nephroprotective benefit.Clinical trial registrationClinicalTrials.gov, identifier (NCT02643745).

Transcranial Direct Current Stimulation Combined With Repetitive Transcranial Magnetic Stimulation for Depression

ImportanceRepetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are both recognized as effective treatments for depression when applied individually. However, it is unknown whether rTMS combined with tDCS has better efficacy in the treatment of major depressive disorder (MDD).ObjectiveTo investigate the clinical effectiveness and safety of rTMS, tDCS, tDCS + rTMS, and sham tDCS + sham rTMS after 2 weeks of treatment in patients with MDD.Design, Setting, and ParticipantsThis double-blind, sham-controlled randomized clinical trial was conducted from November 2021 to April 2023 at 3 hospitals in China (Kangning Hospital affiliated with Ningbo University, Lishui Second People’s Hospital, and Taizhou Second People’s Hospital). Adult patients (aged 18-65 years) who were diagnosed with major depressive disorder were recruited. Participants were randomly assigned to 1 of 4 interventions: active tDCS + active rTMS, sham tDCS + active rTMS, active tDCS + sham rTMS, and sham tDCS + sham rTMS. Data analysis followed an intention-to-treat approach.InterventionPatients received a 2-week course of treatment. The tDCS was administered using a 2-mA direct current stimulator with electrodes placed on the left and right dorsolateral prefrontal cortex (DLPFC). Each tDCS session lasted 20 minutes and was conducted 30 to 60 minutes prior to the rTMS session for a total of 10 sessions. The rTMS was delivered at a frequency of 10 Hz using a figure-8 coil placed on the left DLPFC, with each session consisting of 1600 pulses. Treatments were administered 5 times per week for 2 weeks. Sham treatments were performed with a pseudostimulation coil and emitted only sound.Main Outcomes and MeasuresThe primary outcome was the change in total score from baseline to week 2 on the 24-item Hamilton Depression Rating Scale (HDRS-24; score range: 0-52, with the highest score indicating more severe symptoms).ResultsA total of 240 participants (139 females [57.9%]; mean [SD] age, 32.50 [15.18] years) were included. As a primary outcome, patients who received active tDCS + active rTMS showed a significantly greater reduction in mean (SD) HDRS-24 total scores compared with patients in the other 3 groups (active tDCS + active rTMS: 18.33 [5.39], sham tDCS + active rTMS: 14.86 [5.59], active tDCS + sham rTMS: 9.21 [4.61], and sham tDCS + sham rTMS: 10.77 [5.67]; F3,236 = 35.79; η2 = 0.31 [95% CI, 0.21-0.39]; P < .001).Conclusions and RelevanceThis trial found that tDCS + rTMS was a more effective and safe treatment option than either the tDCS or rTMS intervention alone for patients with MDD.Trial RegistrationChina Clinical Trial Registry Identifier ChiCTR2100052122.

Grief-Specific Cognitive Behavioral Therapy vs Present-Centered Therapy

ImportanceProlonged grief disorder (PGD) is included as a new diagnosis in international classification systems. Treatments following a cognitive behavioral model are most effective, but comparisons with active control treatments are scarce.ObjectiveTo examine whether integrative cognitive behavioral therapy for prolonged grief (PG-CBT) is superior to present-centered therapy (PCT).Design, Setting, and ParticipantsThis was a rater-blinded, multicenter, randomized clinical trial (stratified by center and relationship to the deceased) with enrollment from April 2017 to May 2022. The setting included 4 university outpatient clinics in Germany. Eligible participants were aged 18 to 75 years and had PGD based on the Prolonged Grief Disorder 13 (PG-13) interview. Participants were randomized 1:1 to PG-CBT and PCT.InterventionsPG-CBT focused on the exposure to the worst moment of the loss and cognitive restructuring of grief-related cognitions in combination with solution-focused and experiential methods (eg, walk to the grave exercise). PCT was adapted in session length and number to PG-CBT and focused on a supportive relationship and coping with daily problems that may have arisen from the loss or grief symptoms.Main Outcomes and MeasuresAll outcomes were assessed at baseline, after treatment, and 12 months after randomization at follow-up. The primary outcome was a blinded assessment of the PG-13 severity score at follow-up. Secondary outcomes were self-reported depressive, somatic, and overall psychopathological symptoms.ResultsOf 544 treatment-seeking individuals experiencing bereavement, 212 eligible participants (mean [SD] age, 51.8 [13.3] years; 173 female [82%]) with PGD based on the PG-13 interview were randomized to PG-CBT and PCT (n = 106 in each condition). In the intention-to-treat analysis, both treatments yielded high reductions in PGD severity at follow-up (PG-CBT: Cohen d = 1.64; 95% CI, 1.31-1.97; PCT: Cohen d = 1.38; 95% CI, 1.09-1.66). After treatment, participants receiving PG-CBT demonstrated significantly greater reductions in PGD severity than those receiving PCT (Cohen d = 0.31; 95% CI, 0.03-0.57). At follow-up, this effect was only visible on a trend level (Cohen d = 0.28; 95% CI, −0.02 to 0.57), whereas participants in the PG-CBT group had significantly less depressive and general psychopathological symptoms. Twenty-three participants (20%) discontinued PG-CBT treatment, and 17 participants (16%) discontinued PCT.Conclusion and RelevanceThis randomized clinical trial demonstrates that PG-CBT was superior to PCT after treatment and at follow-up with regard to comorbid symptoms. Both treatments were shown to be effective and acceptable, showing the potential for dissemination and increasing patient choice.Trial registrationGerman Clinical Trials Register (DRKS) identifier: DRKS00012317

Evaluating the Drug-Drug Interactions of SHR4640 on Repaglinide and midazolam in healthy subjects

ABSTRACT Background SHR4640, a highly selective URAT1 inhibitor, was evaluated to investigate its inhibitory effects on CYP2C8 and CYP3A4 in vivo clinical trial. This study assessed the pharmacokinetic (PK) impact of SHR4640 when co-administered with the CYP2C8 probe substrate repaglinide and the CYP3A4 probe substrate midazolam. Research design and methods In this single-center, randomized, double-blind, placebo-controlled study, participants were randomly allocated in a 1:1:1 ratio to SHR4640 Group A, SHR4640 Group B, and placebo group and received oral repaglinide, midazolam, SHR4640 or placebo at specific times. The primary endpoints included the main PK parameters of repaglinide and midazolam, both alone and in combination with SHR4640 (AUC0-inf, AUC0-t, and Cmax). Results The increase in the area under the concentration-time curve (AUC) for repaglinide, when co-administered with SHR4640, was less than 1.25-fold, while the AUC for midazolam exhibited a slight increase of 46%. Conclusions SHR4640 exerts a weak inhibitory effect on the AUC of CYP enzyme probe substrates and has minimal potential for drug-drug interactions and presents a favorable safety profile. Clinical trial registration www.clinicaltrials.gov identifier is NCT06196580 (Name: PK Effects of SHR4640 on Repaglinide and Midazolam, and the Impact of SHR4640 on QT Interval).

SOX combined with tislelizumab and low-dose radiation therapy for the neoadjuvant treatment of locally advanced gastric/gastroesophageal junction adenocarcinoma: study protocol for a prospective, multicenter, single-arm, phase Ib/II clinical trial

BackgroundRecently, the clinical benefits of neoadjuvant chemotherapy combined with immunotherapy have been observed in patients with locally advanced gastric or gastroesophageal junction (G/GEJ) cancer; however, the pathological complete response (pCR) and long-term survival rates are still unsatisfactory. The aim of this study is to investigate the efficacy and safety of chemotherapy combined with tislelizumab and low-dose radiation therapy (LDRT) for the neoadjuvant treatment of locally advanced G/GEJ cancer.MethodsThis is a prospective, multicenter, single-arm, phase Ib/II trial. In the phase Ib study, 5 patients will be enrolled in each treatment group with different radiation doses. In the phase II study, a total of 44 patients will be enrolled. Eligible patients will be registered and receive three cycles of SOX regimen chemotherapy (S-1: 40-60 mg Bid, d1-14, q3w; oxaliplatin: 130 mg/m2, iv drip, d1, q3w) plus tislelizumab (200 mg, iv drip, d1, q3w). Simultaneously, LDRT will be planned and administered after the first cycle of systemic therapy. Radical D2 gastrectomy will be performed 4-6 weeks after the last administration of chemotherapy plus tislelizumab. The primary endpoint of phase Ib study is to determine the optimal radiation dose for phase II study. The primary endpoint of phase II is the pCR rate. The secondary endpoints include R0 resection rate, major pathological response (MPR) rate, 2-year event-free survival (EFS) rate, 2-year overall survival (OS) rate and safety profile. Moreover, we will also explore potential molecular markers for predicting the benefit and safety of this neoadjuvant regimen. Written informed consent should be provided by all patients enrolled in the study. The study protocol was approved by the independent ethics committee at each institution.DiscussionThis is the first study to explore the efficacy and safety of neoadjuvant chemotherapy combined with tislelizumab and LDRT in G/GEJ cancer patients, the results of which may provide novel treatment strategy for patients with locally advanced G/GEJ adenocarcinoma.Clinical trial registrationClinicalTrials.Gov, identifier NCT06266871.