Randomized Study Research Articles

Endovascular Recanalization in Patients With Vertebral Artery Stump Syndrome: A Single-Center Experience.

To evaluate the feasibility, success rate, and safety of endovascular revascularization of patients with vertebral artery stump syndrome (VASS). This single-center retrospective study analyzed clinical and imaging data from consecutive patients with VASS who underwent endovascular recanalization from January 2020 until June 2023. Our study enrolled 30 patients [mean age 69 (range 51-84) years; 26 men]. The rate of successful technical revascularization was 96.7% (n = 29), and the rate of complications was 3.3% (n = 1). At the 6-month follow-up, the patients with successful endovascular revascularization of VASS did not have any neurological symptoms, and computed tomography angiography showed 3/29 (10.3%) re-occlusions and 4/29 (13.8%) restenosis of the stent, which was confirmed by digital subtraction angiography. Endovascular recanalization in patients with VASS is feasible in selected patients and has a high procedural success rate and low rate of complications. A large, multicenter, randomized study is warranted to confirm these findings.

Efficacy and safety of endoscopic retrograde cholangiopancreatography (ERCP) vs percutaneous transhepatic biliary drainage (PTBD) for cholangiocarcinoma biliary obstruction: An updated systematic review and meta analysis.

557 Background: Perioperative and/or palliative biliary drainage for the management of cholangiocarcinoma biliary obstruction has been part of the backbone of the multidisciplinary approach that this condition requires. For both intrahepatic and perihilar cholangiocarcinoma, ERCP and PTBD are the two main techniques available. There has yet to be consensus favoring one approach over the other. Methods: Following the PRISMA guidelines, a systematic review and meta-analysis were performed to determine if there was a difference in efficacy and safety of ERCP compared to PTBD for Cholangiocarcinoma Biliary Obstruction. Primary outcomes were successful biliary drainage, mean number of needed procedures, length of stay and overall adverse events rate. Data were analyzed using R version 4.2.2. The risk of bias was assessed by the Robins-I and RoB 2 tool. The quality of evidence was graded using the GRADE scale and Newcastle-Ottawa guidelines. Results: Three randomized clinical trials and two observational studies described the successful biliary drainage rate of ERCP vs PTBD for cholangiocarcinoma associated biliary obstruction, totaling 340 patients. Meta-analysis test for overall effect, showed no statistical difference between groups (RR = 0.88; 95% CI = [0.69; 1.13]; p = 0.23; Fig. 1). Similarly, in terms of the mean number of needed procedures per patient, a total of three randomized clinical trials and two observational studies, totaling 340 patients were included, no statistically significant difference was found (SMD = 0.64; 95% CI = [- 9.36; 10.63]; p = 0.57; Fig. 2). Likewise, one randomized clinical trial and two observational studies showed no statistically significant difference on the length of stay (days) mean between groups (SMD = 0.06; 95% CI = [- 1.57; 1.68]; p = 0.73; Fig. 3). Although, the three clinical trials and three observational studies showed a mild decreased adverse event and death (within 3 months) rate in the ERCP group, after undergoing statistical analysis, meta-analysis test for overall effect, showed no statistical difference (RR = 0.99; 95% CI = [0.55; 1.77]; p = 0.97; Fig. 4 and RR = 0.61; 95% CI = [0.10; 3.87]; p = 0.22; Fig. 5, respectively). The risk of bias was low with moderate-to-high quality of evidence amongst the included studies. Conclusions: Our updated systematic review and meta-analysis demonstrated no statistically significant difference in the successful biliary drainage rate, mean number of needed procedures, length of stay, death within 3 months and adverse event rate between ERCP vs PTBD for management of cholangiocarcinoma biliary obstruction. Further randomized studies are needed to confirm these findings.

NRG-GI007: Secondary endpoints of safety assessment and clinical complete response (cCR) of chemoradiation with endoscopically injected oncolytic virus OBP-301 in medically inoperable esophageal cancer.

435 Background: Definitive chemoradiation (CRT) is a standard-of-care for patients (Pts) with medically inoperable esophageal cancer (EC). The NRG/RTOG 0436 study of cisplatin/paclitaxel and RT (+/- cetuximab) as definitive therapy showed that 58% of control arm Pts have locally persistent disease. OBP-301 is a conditionally-restricted, replication-competent adenovirus derived from human adenovirus type 5 that adds a human Telomerase Reverse Transcriptase gene promoter, replicating only in tumor cells to cause lysis.It may cause immunogenic cell death, enhance RT increasing radiosensitization by blocking DNA repair and improve local control. Methods: In NRG-GI007, a phase 1 study (NCT04391049), OBP-301 was added to weekly carboplatin/paclitaxel and RT (50.4 Gy/28 fxs) for medically inoperable EC Pts with pathologically proven adenocarcinoma or squamous cell carcinoma (SCC) of the esophagus or Siewert Type I/II gastroesophageal junction. Pts receive 1-2mL of intratumoral OBP-301 1×10 12 virus particles/ml via endoscopy 3 days prior to and then at days 12 and 26 of CRT. The primary endpoint was protocol-defined dose-limiting toxicity, already reported. Secondary endpoints reported here are treatment-related (definitely or probably related to any protocol treatment) AEs - all and grade 4+ non-hematologic, and cCR in the primary tumor, defined as negative EGD/biopsy 6-8 weeks post-CRT. Per the protocol design, no statistical testing is done for these endpoints. Results: Initially, 6 evaluable (eligible and started protocol treatment) Pts were enrolled from June 2020 to April 2023. As initial dose level was deemed safe, an additional 9 Pts were enrolled from August 2023 to July 2024, totaling 15 evaluable Pts for secondary endpoints. Median age was 74 years, 9 Pts (60%) with ECOG PS 1. 11 Pts (73%) had adenocarcinoma and 4 had SCC; 11 Pts had N+ disease. 14 Pts (93%) received all planned OBP-301 injections and received 50.4 Gy RT. The most common treatment-related grade 3/4 AEs were decreased neutrophil (6 Pts; 40%) and lymphocyte counts (5 Pts; 33%), expected with CRT. No grade ≥3 OBP-301-related non-hematologic AEs were reported. 2 Pts died prior to restaging neitherdefinitely or probably related to OBP-301: 1 Pt developed grade 5 respiratory failure 6 weeks after CRT (suspected RT pneumonitis), while a 2 nd Pt had an unrecognized tumor invasion of the bronchus at baseline, which worsened during week 3 of CRT, resulting in a grade 5 tracheo-esophageal fistula. 2 Pts have not yet reached time for restaging. All 11 Pts who have been restaged had a cCR, for a preliminary cCR rate of 100% (95% CI: 74.1%, 100%). Conclusions: OBP-301 + CRT is safe and the preliminary cCR rate compares favorably to the historical control from NRG/RTOG 0436. Updated safety and cCR data will be presented. A randomized study is being planned. Clinical trial information: NCT04391049 .

Causal association of inflammation with ischemic stroke and its subtypes: a bidirectional Mendelian randomization study.

Emerging evidence underscores a bidirectional relationship between ischemic stroke (IS) and inflammation, yet the causality of this association remains uncertain. We conducted a two-sample bidirectional Mendelian randomization (MR) study aimed at investigating the causal links between inflammation and IS. Single nucleotide polymorphism from genome-wide association studies of 112 inflammatory cytokines and IS were chosen as instrumental variables. We evaluated the causal effects of inflammatory factors on IS outcomes and examined the mediating effects of risk factors for IS. Additionally, reverse MR analysis was conducted to determine whether the occurrence of IS influenced levels of inflammatory cytokines. Causal associations were assessed using inverse variance weighting, complemented by sensitivity analyses incorporating weighted median and MR-Egger methods. We found associations between genetically predicted plasma levels of 25 inflammatory factors and IS along with its subtypes. MR supports smoking, body mass index, atrial fibrillation, coronary artery disease, heart failure, systolic blood pressure, diastolic blood pressure and type 2 diabetes as risk factors for IS. Notably, coronary artery disease and heart failure seemed to mediate the RANTES, HGF, IL-5 associations with IS. In addition, reverse MR analysis suggested a causal relationship between IS and its subtypes and 19 inflammatory factors. In summary, inflammation was suggestively causally associated with the risk of IS, and inflammatory cytokines had downstream effect on IS. Future studies should explore whether inflammatory factors found to have significant associations with IS risk could be manipulated to reduce IS risk, and the neuroinflammatory mechanisms after IS.

Implementing Mental Practice in Postgraduate Surgical Training for Minimally Invasive Surgery: A Systematic Review and Thematic Analysis.

Unprecedented pressure on the National Health Service (NHS) has meant that there are increasing obstacles to surgical training. Simulation training is an option to improve surgical performance but is limited due to availability, accessibility and financial constraints. Mental practice (MP) has been proposed as a potential solution to supplement the traditional method of apprenticeship-style learning. Despite increasing evidence that MP may be a useful tool to improve surgical performance and reduce surgeon anxiety, it is not widely adopted. This systematic review and thematic analysis aims to identify key themes that would allow for the successful implementation of MP in postgraduate surgical training. Medline, Embase and PsycINFO databases were systematically searched to identify articles that investigate the role of MP in improving surgical performance amongst surgical trainees. Retrieved papers were studied to inform thematic analysis of their content and studies were assessed for bias. A total of 321 studies were retrieved, of which 11 met the inclusion criteria. Overall risk of bias was assessed to be between critical and moderate for seven nonrandomized studies and between fair and good for four randomized studies. Key themes were identified and discussed using a thematic analysis approach. This study has identified that attaining high quality mental imagery is fundamental to success in mental practice and this can be augmented by the use of relaxation therapy and/or motivational imagery. Future research should focus on the application of MP in real-world surgical practice and breaking down complex procedures into fewer operative steps.

Individual FiO2 guided by SPO2 prevents hyperoxia and reduces postoperative atelectasis in colorectal surgery: A randomized controlled trial.

To determine whether individualized fraction of inspired oxygen (iFiO2) improves pulmonary atelectasis after elective laparoscopic colorectal surgery relative to 60% FiO2. This was a single-center, prospective, randomized study. This study was conducted in a single tertiary care hospital in China. A total of 84 eligible inpatients who underwent elective laparoscopic colorectal surgery between August 2021 and May 2022 were included in the study. The patients were randomly assigned to receive either a fixed fraction of inspiration oxygen (fFiO2 group) or individualized FiO2 based on physiological SpO2 (iFiO2 group). The primary outcome was the lung ultrasound score (LUS) at 30min after extubation. Secondary outcomes included the length of hospital stay, admission to the intensive care unit, the length of post-anesthetic care unit stay, the ratio of lung capacity on the third day after surgery compared with before surgery, the incidence of nausea and vomiting, and surgical site infections after surgery. Additionally, the airway plate pressure, airway peak pressure, pulmonary dynamic compliance, PaO2, oxygenation index, alveolar-arterial oxygen tension gradient (A-aDO2), and pulmonary shunt fraction (Qs/Qt) were considered. The LUS was significantly lowered in the iFiO2 group (5 [4, 7]) compared with the fFiO2 group (8 [4, 10]) (P=0.03). Based on the criterion for determining atelectasis, 25 patients (62.5%) in the fFiO2 group experienced significant atelectasis compared with 15 patients (37.5%) in the iFiO2 group (P=0.025). At the end of surgery, PaO2, A-aDO2, and Qs/Qt were significantly reduced in patients in the iFiO2 group compared with those in the fFiO2 group. The use of iFiO2 during operation significantly reduces the LUS and pulmonary atelectasis in patients undergoing laparoscopic colorectal surgery under general anesthesia. ChiCTRT2100049615.

Linking psoriasis to atrial fibrillation: Insights from "Association between psoriasis and atrial fibrillation: A systematic review and meta-analysis".

Patients with psoriasis indeed face an elevated risk of developing atrial fibrillation (AF), underscoring the need for vigilant monitoring to facilitate early detection and intervention. Given the current body of evidence linking psoriasis and AF is derived from observational studies, there is a clear need for more robust, multicenter, large-scale randomized studies. Such research would help to validate and reinforce the findings from observational data. Large-scale, randomized studies are necessary to confirm the association between psoriasis and AF, addressing potential biases and confounding factors present in observational research. Future studies should consider a broader range of factors that may influence the incidence of AF in psoriasis patients. This includes assessing the impact of AF "burden," which could refer to the frequency, duration, or overall impact of AF episodes on patients' health. Research should delve into the role of genetic predispositions that may contribute to the development of AF in patients with psoriasis. The influence of smoking and lipid levels, among other lifestyle and environmental factors, should be examined for their potential effects on the incidence of AF in psoriasis patients. An interdisciplinary team, including dermatologists, cardiologists, and other healthcare professionals, should collaborate to provide comprehensive care for patients with psoriasis.

The effect of tonsillectomy on clinical manifestations in Familial Mediterranean fever.

Familial Mediterranean fever (FMF) is the most prevalent genetic autoinflammatory disease worldwide. There are several novel advancements in pathophysiology, genetic testing, diagnosis, comorbidities, disease-related damage, and treatment strategies. This study aimed to assess the effect of tonsillectomy on FMF disease severity and activity. This prospective randomized cohort study was conducted on 43 patients diagnosed with FMF and chronic tonsillitis, who were divided randomly into two groups: Group I, a case group including 23 patients subjected to tonsillectomy and medical treatment using colchicine; Group II, a control group consisting of 20 cases receiving only colchicine. The monthly frequency of the attacks and average duration of the three symptoms, such as fever, abdominal/chest pain, and musculoskeletal pain in days, were evaluated and recorded. A highly significant reduction in the monthly frequency of attacks, duration of fever, abdominal/chest pain, and musculoskeletal pain was observed three months after management in both study groups (p<0.00001 for all). Evaluation of the values of both groups revealed a significant increase in the degree of change for the duration of fever, abdominal/chest pain in Group I relative to Group II (p=0.0003 and 0.006 respectively) and a significant increase in the degree of change for musculoskeletal pain in Group II relative to Group I (p=0.007). Survival analysis showed a nonsignificant difference between the two groups regarding the resolution of fever, abdominal/chest pain, and musculoskeletal pain at 12, 18, and 24 months (p=0.26, 0.08, and 0.42, respectively) CONCLUSION: Tonsillectomy operation combined with colchicine resulted in a greater but nonsignificant decrease in the monthly frequency of the FMF attacks and a significant greater decrease in the duration of fever and abdominal/chest pain compared with the use of colchicine alone. Further research is recommended to confirm these results on a larger scale.

Comparison of Hyperbaric 0.5% Levobupivacaine and Hyperbaric 0.75% Ropivacaine for Intrathecal Use in Infraumbilical Surgeries: A Randomised Clinical Study

Introduction: Ropivacaine is a long-acting amide local anaesthetic agent and the pure S (-) enantiomer of propivacaine. It has been readily available as an isobaric solution for a long time. Recently, a hyperbaric solution has become available in the Indian market. Levobupivacaine is the pure S-enantiomer of bupivacaine, which is safer than racemic bupivacaine in regional anaesthesia. It has less affinity and strength of depressant effects on myocardial and Central Nervous System (CNS) vital centers in pharmacodynamic studies, along with a superior pharmacokinetic profile. Aim: To compare the sensory and motor blockade, time of twosegment regression, time for rescue analgesia, haemodynamic effects and sedative effects between hyperbaric 0.5% levobupivacaine and hyperbaric 0.75% ropivacaine. Materials and Methods: This prospective, double-blinded and randomised clinical study was conducted in the Department of Anaesthesiology, Shrimati Bhikhiben Kanjibhai Shah Medical Institute and Research Centre (a tertiary care institute), Sumandeep Vidyapeeth Deemed to be University, Piparia, Vadodara, Gujarat, India, from September 2023 to July 2024, with a sample size of 40 patients. Patients with American Society of Anaesthesiologists (ASA) I/II status were randomly allocated into two equal groups of 20 each. Group-R received 0.75% hyperbaric ropivacaine 3.5 mL+0.1 mL normal saline (total 3.6 mL) and Group-L received 0.5% hyperbaric levobupivacaine 3.5 mL+0.1 mL normal saline (total 3.6 mL). Data were recorded using MS Excel and analysed using Statistical Package for Social Sciences (SPSS version 22.0) software. The Student’s t-test was used for data comparison regarding the onset and duration of sensory and motor blockade, time of two-segment regression, time for rescue analgesia, haemodynamic stability and sedative effects between the study groups. Results: The mean age for Group-R was 45.00±7.1 years and Group-L 51.95±8.03 years. onset of sensory blockade at the T10 level and the onset of motor blockade in Group-R were slower than in Group-L (p-value &lt;0.05). The time to two-segment regression was significantly faster in Group-R than in Group-L (p-value &lt;0.05). The duration of sensory and motor blockade, as well as the time for rescue analgesia, was significantly prolonged in Group-L compared to Group-R (p-value &lt;0.05). The sedative effects, arterial oxygen saturation (SpO2 ) and respiratory rate were comparable in both groups. Intraoperatively, haemodynamics were more stable in Group-R compared to Group-L. Conclusion: The present study implies that in haemodynamically unstable patients, 0.75% hyperbaric ropivacaine can provide a less complicated neuraxial blockade. In contrast, levobupivacaine offers a superior effect in terms of the duration of blockade and analgesia. This makes levobupivacaine useful for longer-duration surgeries, while ropivacaine is more suitable for shorter-duration procedures.

Genetic association between inflammatory factors and abdominal aortic aneurysm: Insights from a genome-wide association study.

Abdominal aortic aneurysm (AAA) is a fatal vascular disorder. The current primary treatment for AAA remains restricted to surgical intervention during advanced stages of the disease, with no efficacious pharmaceutical options available for early-stage AAA patients. Inflammation is known to play a substantial role in the development of AAA, with various inflammatory factors implicated in its pathogenesis. However, conflicting findings have been reported in studies investigating the roles of these inflammatory factors in AAA, making it challenging to establish definitive causal relationships between inflammatory factors and AAA. The research conducted a bidirectional Mendelian randomization (MR) study using genetic variants. Inflammatory factors were obtained from a genome-wide association study (GWAS), while AAA were sourced from the FinnGen consortium. The primary method employed was inverse-variance weighted (IVW), with MR-Egger, weighted median, and MR-PRESSO approaches used as supplementary analyses. According to the IVW method, hepatocyte growth factor (HGF), matrix metalloproteinase-7 (MMP-7), MMP-12, and NF-kappa-B essential modulator (NEMO/ IKKγ) were associated with a potential increased risk of AAA, while platelet-derived growth factor BB (PDGFbb), interleukin-4 (IL-4), IL-12p70, IL-10, IL-6Rα, and myeloperoxidase (MPO) were associated with a potential decreased risk of AAA. In the reverse MR analysis, no causal relationship was observed between AAA and any of the inflammatory factors. This study provides evidence supporting a causal relationship between inflammatory factors and AAA. It suggests that targeting and modulating these specific inflammatory factors may serve as a potential approach for the prevention and noninvasive treatment of AAA.

Sjögren's syndrome and psoriasis: a two-sample Mendelian randomization study.

Primary Sjögren's Syndrome (PSS) and psoriasis are frequently observed to co-occur in clinical settings. However, the causal associations and underlying mechanisms between PSS and psoriasis remain poorly defined. In this study, we conducted bidirectional MR analysis to explore the causal relationship between PSS and psoriasis using four MR methods: inversevariance weighted, MR-Egger regression, weighted median, and weighted mode. Sensitivity analyses were carried out, employing different models and testing methods for comparison to assess the influence of heterogeneity and pleiotropy on our findings and to confirm the robustness of these results. We primarily employed the Inverse Variance Weighting (IVW) method for our analysis. A p-value of less than 0.05 indicates a significant causal relationship, while a p-value greater than 0.05 suggests the absence of such a relationship. The IVW analysis confirmed a causal relationship between psoriasis and primary Sjögren's syndrome (PSS) (OR: 3.149E-10, 95% CI 1.114E-18-0.089, P = 0.028), with the weighted median yielding similar results. Conversely, there was no causal association found between PSS and the risk of developing psoriasis (OR: 1.000, 95% CI 0.999-1.000, P = 0.328). This study reveals a causal relationship between primary Sjögren's syndrome (PSS) and psoriasis, demonstrating that psoriasis increases the risk of developing PSS, while the reverse is not true. This potential causal link offers new insights into the etiology of both PSS and psoriasis.

Lipidomics-based investigation of its impact on the pathogenesis of coronary atherosclerosis: a Mendelian randomization study

BackgroundConsiderable attention has been devoted to investigating the association between lipid metabolites and cardiovascular diseases, particularly coronary atherosclerosis.MethodsA two-sample MR framework was used to investigate the relationship between lipid metabolites and the risk of coronary atherosclerosis. Two GWAS datasets were examined to take intersections of SNPs from 51,589 cases and 343,079 controls, and 14,334 cases and 346,860 controls to determine genetic susceptibility to coronary atherosclerosis. Random-effects inverse variance weighted (IVW) MR analyses were performed by a series of sensitivity assessments to measure the robustness of our findings and to detect any violations of MR assumptions.ResultsThrough IVW, MR-Egger and weighted median regression methods, we inferred that these six lipid metabolites: cholesterol levels, sterol ester (27:1/18:2) levels, triacylglycerol (52:4) levels, triacylglycerol (52:5) levels, diacylglycerol (18:1_18.2) levels, triacylglycerol (53:4), could directly impact the development of atherosclerosis.ConclusionIn conclusion, our study comprehensively illustrates a causal relationship between lipid metabolites and the risk of coronary atherosclerosis. Furthermore, cholesterol levels, sterol ester (27:1/18:2) levels, triacylglycerol (52:4) levels, triacylglycerol (52:5) levels, diacylglycerol (18:1_18.2) levels, and triacylglycerol (53:4) levels are positively correlated with the risk of coronary atherosclerosis. These six lipid metabolites have the potential as new predictors of the risk of atherosclerosis, providing new insights into the treatment and prevention of cardiovascular diseases.

Student pharmacist counseling performance after hands-on continuous glucose monitoring education: A multi-institutional pragmatic randomized study.

To assess the impact of wearing a continuous glucose monitoring (CGM) device on student pharmacist counseling ability (primary), knowledge, confidence, and empathy (secondary). Students from two institutions were randomized to wear a CGM device (intervention) vs not (control). All received CGM education via lecture and live demonstration. Intervention group students were provided a CGM device. After two weeks, all students completed a standardized patient (SP) encounter regarding CGM prescription counseling. Pre-post CGM-related knowledge, confidence, and empathy were assessed. Analysis of variance was used to compare between-group counseling score difference, and analysis of covariance was used to compare changes in pre-post knowledge, confidence, and empathy scores. Analyses were performed using Stata/BE17.0. Of 86 students enrolled, 63 consented and completed surveys (32 intervention, 31 control). The intervention group demonstrated higher average SP counseling score vs control (82.4% vs 77.7%, p=.046). The intervention group had greater change in confidence vs control from pre to post survey (+ 2.3 vs + 1.7, p=0.03, range 1-5). No between-group differences were observed in knowledge or empathy. The opportunity to wear a CGM device resulted in higher performance on CGM counseling and greater rise in CGM-related confidence. This study supports the use of resources to provide hands-on CGM training. Hands-on education about new diabetes technology can help students prepare to care for and counsel patients.

Safety and preliminary efficacy of ivaltinostat, an HDAC inhibitor, plus capecitabine in patients with pretreated metastatic pancreatic adenocarcinoma (mPDAC): Results of a phase Ib study.

742 Background: Front-line chemotherapy for patients (pts) with mPDAC typically consists of mFOLFIRINOX or gemcitabine/nab-paclitaxel given until disease progression or intolerable toxicity. For pts with durable disease control on front-line treatment, maintenance therapy that can effectively delay disease progression while preserving quality of life with minimal cumulative toxicity is highly desirable. Ivaltinostat (ival) is a pan-histone deacetylase inhibitor that increases histone acetylation, suppresses cell proliferation, and promotes apoptosis. Preclinical data demonstrated synergy with 5-FU/capecitabine (cape) in mouse models. We report here results of the Phase Ib portion of a Ib/2 trial evaluating the safety and recommended phase 2 dose (RP2D) of this combination to use in a randomized study of ival + cape vs cape as maintenance therapy. Methods: Key eligibility criteria for phase 1b included unresectable or metastatic PDAC; ≥18 years old; ≥1 prior therapy; ECOG PS 0-1; and no known germline BRCA1/2 mutation. Three cohorts were enrolled, receiving ivaltinostat at 60, 125, or 250mg/m 2 iv (weekly on days 1 and 8) in combination with cape (1000mg/m 2 po BID on days 1-14) of a 21-day cycle. 1o objectives: safety, tolerability and RP2D; 2o objectives: pharmacokinetics (PK) of ival + cape. Results: A total of 28 patients were enrolled at the 60 (n=6), 125 (n=10) and 250 (n=12) mg/m 2 ival dose levels. Median prior lines of therapy: 2 (range 1-7). Median age: 67 years (range 50-83). Only one DLT (G4 thrombocytopenia) was observed at 250mg/m 2 dose level. Treatment-emergent AE profile was similar across dose levels, with common TEAEs including fatigue (n=15, 53.6%), nausea (n=14, 50.0%), palmar-plantar erythrodysesthesia syndrome (n=12, 42.9%), diarrhea (n=10, 35.7%), and constipation (n=9, 32.1%). G3 AEs included neutropenia (n=6, 21.4%), anemia (n=4, 14.3%), abdominal pain (n=3, 10.7%) and diarrhea (n=3, 10.7%). G4 AEs included 1 (3.6%) event of neutropenia and 1 (3.6%) of thrombocytopenia. No SAEs related to study drugs occurred in any of the 3 dose cohorts. PK analyses indicated dose proportional increases in exposure with increasing doses of ival. Histone H3K27 acetylation for ival showed the similar trend in optical density evaluation. Across all dose levels and prior treatments, median OS and PFS were 9.6 and 3.3 months, respectively. Conclusions: The combination of ival and cape was generally well tolerated in this heavily pretreated patient population. Ival 250 mg/m 2 is the dose selected for the ongoing randomized study of ival + cape vs cape in the maintenance setting for mPDAC pts post-FOLFIRINOX, which is expected to finish accrual in 2025. Clinical trial information: NCT05249101 .

Phase 2 Randomised Study of Bulevirtide as Monotherapy or Combined With Peg-IFNα-2a as Treatment for Chronic Hepatitis Delta.

Bulevirtide (BLV) leads to beneficial virologic and biochemical responses when given alone to treat hepatitis delta virus (HDV) infection, which causes the most severe form of chronic viral hepatitis. We evaluated 48 weeks of BLV monotherapy, BLV + tenofovir disoproxil fumarate (TDF) and BLV + pegylated interferon alfa-2a (Peg-IFNα-2a), with 24-week follow-up. Ninety patients were enrolled into six arms of 15 each (A-F); 60 patients were included in the main randomisation (arms A-D), and 30 patients (arms E-F) were randomised to the extension phase: (A) Peg-IFNα-2a 180 μg once weekly (QW); (B) BLV 2 mg once daily (QD) + Peg-IFNα-2a 180 μg QW; (C) BLV 5 mg QD + Peg-IFNα-2a 180 μg QW; (D) BLV 2 mg QD; (E) BLV 10 mg QD + Peg-IFNα-2a 180 μg QW and (F) BLV 10 mg (5 mg twice daily) + TDF QD. The primary endpoint was undetectable HDV RNA at week (W)72. At W72, 53%, 27%, 7%, 7% and 33% of patients achieved undetectable HDV RNA in arms B, C, D, E and F, respectively, versus 0% in arm A. More arm B versus A patients had a > 1 log10 IU/mL decline in or loss of hepatitis B surface antigen (HBsAg) at W72 (p = 0.017), including four patients with loss of HBsAg. Bile acid elevations were dose-dependent and reversible following the completion of BLV treatment. BLV combined with Peg-IFNα-2a was well tolerated and resulted in high rates of HDV RNA undetectability off-treatment. NCT02888106.

Randomized phase II trial of olaparib + pembrolizumab vs olaparib alone as maintenance therapy in patients with metastatic pancreatic cancer with germline BRCA1 or BRCA2 mutations: SWOG S2001 NCT04548752.

TPS793 Background: Olaparib was approved in 2019 as maintenance therapy for gBRCA1/2+ metastatic pancreatic cancer (mPDA) patients (pts). The POLO trial showed an improvement in median progression-free survival (mPFS) with olaparib compared to placebo (7.4 vs 3.8 months) for platinum sensitive gBRCA1/2+ mPDA pts. Preclinical studies have demonstrated that PARP inhibitors modulate the immune microenvironment by increasing genomic instability, PD-L1 expression and activating the immune inflammatory stimulator of interferon genes (STING) pathway. Results of the phase 2 pembrolizumab and olaparib (POLAR) maintenance trial in patients with germline or somatic BRCA1/2 or PALB2 mutations responding to platinum-based chemotherapy for at least 4 months was presented at ESMO 2024. In 33 patients, a 35% overall response rate with 90% disease control rate at 6 months was observed. S2001 is an important randomized study to better define the impact of the combination. Methods: S2001 was developed in collaboration with the Alliance and was activated in SWOG in October 2020. Key eligibility criteria include: mPDA pts with gBRCA1/2 mutations identified with standard of care germline genetic testing and progression-free after receiving at least 4 months of platinum-based chemotherapy (FOLFIRINOX, FOLFOX or gemcitabine/cisplatin +/- nab-paclitaxel). One cycle of gemcitabine and nab-paclitaxel is allowed while waiting for germline testing. Zubrod performance status (PS) 0 or 1 pts are eligible. Pts are stratified according to first line chemotherapy, PS 0 vs 1, and disease status after 1st line treatment. The primary objective of this study is to evaluate the PFS of mPDA pts treated with olaparib + pembrolizumab compared to olaparib alone as maintenance therapy. Based upon the POLO trial, we expect a mPFS of 7 months in the control arm. Targeting a mPFS of 11.7 months in the experimental arm (hazard ratio 0.6) and assuming 15 months follow-up, 80% power and a 1-sided alpha = 0.10, this design requires 78 evaluable pts with a total sample size of 88 pts. Prospective serial blood samples will be collected to bank DNA and RNA for future correlative studies. Support: NIH/NCI grants U10CA180888 and U10CA180819, U10CA180821 and U10CA180868. Clinical trial information: NCT04548752 .

Association of organ iron levels with type 2 diabetes mellitus and glycemic traits: A bidirectional two-sample Mendelian randomization study.

Observational studies have found that higher iron levels are associated with an increased risk of diabetes mellitus. Given the limitations of causal inferences from observational studies and the expensive and time-consuming nature of randomized controlled trials, Mendelian randomization analysis presents a reasonable alternative to study causal relationships. Previous MR analyses studying iron levels and diabetes have used indirect markers of iron levels, such as serum ferritin, and found conflicting results. In this study, we performed bidirectional Mendelian Randomization analyses using organ iron (liver, spleen, and pancreas) levels, which are more direct markers of iron status, to study the causal association of iron levels with type 2 diabetes mellitus and glycaemic traits. Two sample MR analyses were employed bi-directionally to study the causal effect of liver, spleen, and pancreas iron levels on type 2 diabetes and glycaemic traits and the causal effect of type 2 diabetes on organ iron levels, using summary data from genome-wide association studies (UK-Biobank, DIAGRAM, and MAGIC consortia). SNPs associated with organ iron levels with a cut-off of P < 5 × 10-7 were used as instrumental variables for the MR analyses of the effect of organ iron levels on type 2 diabetes/glycaemic traits, and SNPs associated with diabetes mellitus with a cut-off of P < 5 × 10-8 were used as instrumental variables for the MR analyses of the causal effect of type 2 diabetes on organ iron levels. Serum ferritin (GWAS meta-analysis of deCODE, UK INTERVAL, and Denmark studies) and haemoglobin (Blood Cell consortium) were used as positive controls for the MR analysis with liver iron as the exposure. Primary analyses used the inverse variance weighted means of Wald's ratio. Sensitivity analyses included inverse variance weighted median, weighted mode, and MR-Egger methods. Our findings reveal no causal association between liver and pancreas iron levels with type 2 diabetes (Liver iron: OR = 1.02, P = 0.1, Pancreas iron: OR = 1.11, P = 0.5). This also holds for glycaemic traits, except for the negative causal effect of liver iron levels on HbA1c (OR = 0.93, P = 0.001). Spleen iron levels had a negative causal effect on type 2 diabetes (OR = 0.94, P = 0.049). However, these exceptions are likely due to possible pleiotropy, as these associations can be explained by the effect of the genetic variants on factors that falsely decrease HbA1c levels. No causal association was found for the effect of type 2 diabetes on organ iron levels. Organ iron levels, which are relatively more direct indicators of iron status, showed no causal association with type 2 diabetes in the European population.

Exploring the causal relationship between inflammatory cytokines and myasthenia gravis: A two-way Mendelian randomization study

Exploring the causal relationship between inflammatory cytokines and myasthenia gravis: A two-way Mendelian randomization study

Modifiable lifestyle factors and risk of intracranial aneurysm: A univariate and multivariate Mendelian randomisation study.

The aim of this study was to assess the potential causal relationship between lifestyle factors and intracranial aneurysms (IAs) using a two-sample Mendelian randomization (MR) approach. The study used a pooled dataset from a genome-wide association study that covered information on 24 lifestyle factors, intracranial aneurysm cases, subarachnoid hemorrhage, and unruptured aneurysms. Five MR methods were applied for analysis by selecting single nucleotide polymorphisms as instrumental variables, with the inverse variance weighting method as the main method. To ensure the stability of the results, horizontal multiple validity tests, sensitivity analyses, and inverse MR were performed, and genetically determined exposure factors were adjusted by multivariate MR. Several lifestyle factors were found to have a significant genetic causal effect on the occurrence and development of intracranial aneurysms. For example, lamb intake, smoking initiation, number of cigarettes smoked per day, length of television viewing, and fatigue were identified as genetic risk factors and strongly associated with aneurysm rupture, whereas red wine intake showed some genetic protection against intracranial aneurysms and similarly affected aneurysm rupture. Sensitivity analyses and inverse MR verified the robustness of these results. After adjusting for exposure factors, multivariate MR confirmed daily smoking and smoking initiation as risk factors for intracranial aneurysms, unruptured aneurysms, and subarachnoid hemorrhage, whereas red wine intake was a genetically protective factor against intracranial aneurysms and subarachnoid hemorrhage. This MR analysis revealed a genetic causal link between specific lifestyle factors and intracranial aneurysms, emphasizing the need for further studies to confirm these findings and explore their mechanisms.

Combining low-dose regorafenib with pembrolizumab for patients with MSI-H colorectal cancer: REGPEM-CRC-01.

TPS313 Background: Currently, pembrolizumab is one of the front-line therapies for patients with MSI-H CRC. However, approximately 40% of patients who received pembrolizumab experienced disease progression early in the course of disease (KEYNOTE 177). Therefore, there is still an unmet need to enhance the efficacy of checkpoint inhibitors in MSI-H CRC. MSI-H CRC has a higher level of expression of VEGF in blood compared to patients compared to its MSS counterpart (Hansen et al. Colorectal Dis. 2011). Consistently, exploratory analysis of CALBG-80405 and PARADIGM trial showed that patients with MSI-H CRC were more likely to benefit from anti-VEGF therapy than anti-EGFR therapy regardless of the side of the tumor. NSABP C-08 also suggested that anti-VEGF therapy may have biological activity even in as adjuvant therapy for patients with MSI-H colon cancer. Regorafenib is a potent VEGF inhibitor, with preclinical evidence showing its immune modulatory effect in the tumor microenvironment. In this trial, we hypothesize that adding low-dose regorafenib to pembrolizumab may induce synergistic activity beyond their independent clinical efficacy and create deep and durable responses for patients with MSI-H CRC. Methods: In the lead arm of this prospective randomized study, 22 patients will be enrolled through Hoosier Cancer Research Network (HCRN-GI23-643). Patients with treatment naïve MSI-H CRC will be enrolled in this front-line trial. One cycle of pembrolizumab and up to 3 cycles of chemotherapy prior to determination of MMR-D/MSI-H is allowed. Patients will receive regorafenib 60 mg daily in combination with pembrolizumab 200mg IV in cycle 1, followed by regorafenib 90mg in subsequent cycles to improve treatment tolerance. The primary outcome that will be measured is ORR, defined as the percentage of partial or complete response to the treatment within 12 months. ORR will be measured using RECIST 1.1. criteria. A formal one-sided hypothesis test will be conducted for futility, assuming that we will reject the null hypothesis of a target ORR only if we have strong evidence. In this study, we assume a null hypothesis that ORR is 0.60, which would reflect significant clinical improvement over the current standard of ORR = 0.43 from KEYNOTE 177. The alternative hypothesis is that ORR is less than 0.60. For the lead-in phase of the study, the emphasis is on controlling Type I error to be small, approximately 0.05. The test statistic will be the number of ORRs in the 22 patients, which we assume to follow a binomial distribution. Clinical trial information: NCT06006923 .