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Neuro-oncology Jul 2024Encorafenib plus binimetinib (EB) is a standard of care treatment for advanced BRAFV600-mutant melanoma. We assessed efficacy and safety of encorafenib plus binimetinib...
BACKGROUND
Encorafenib plus binimetinib (EB) is a standard of care treatment for advanced BRAFV600-mutant melanoma. We assessed efficacy and safety of encorafenib plus binimetinib in patients with BRAFV600-mutant melanoma and brain metastasis (BM) and explored if radiotherapy improves the duration of response.
METHODS
E-BRAIN/GEM1802 was a prospective, multicenter, single arm, phase II trial that enrolled patients with melanoma BRAFV600-mutant and BM. Patients received encorafenib 450 mg once daily plus binimetinib 45 mg BID, and those who achieved partial response or stable disease at first tumor assessment were offered radiotherapy. Treatment continued until progression.Primary endpoint was intracranial response rate (icRR) after 2 months of EB, establishing a futility threshold of 60%.
RESULTS
The study included 25 patients with no BM symptoms and 23 patients with BM symptoms regardless of using corticosteroids. Among them, 31 patients (64.6%) received sequential radiotherapy. After two months, icRR was 70.8% (95% CI: 55.9-83.1); 10.4% complete response. Median intracranial PFS and OS were 8.5 (95% CI: 6.4-11.8) and 15.9 (95% CI: 10.7-21.4) months, respectively (8.3 months for icPFS and 13.9 months OS for patients receiving RDT). Most common grade 3-4 treatment-related adverse event was alanine aminotransferase (ALT) increased (10.4%).
CONCLUSION
Encorafenib plus binimetinib showed promising clinical benefit in terms of icRR, and tolerable safety profile with low frequency of high grade TRAEs, in patients with BRAFV600-mutant melanoma and BM, including those with symptoms and need for steroids. Sequential radiotherapy is feasible but it does not seem to prolong response.
PubMed: 38946469
DOI: 10.1093/neuonc/noae116 -
Journal of the American Geriatrics... Jun 2024Clinical trials in older adults are increasingly focused on functional outcomes, and the composite outcome of dementia, disability, and death is gaining pivotal...
BACKGROUND
Clinical trials in older adults are increasingly focused on functional outcomes, and the composite outcome of dementia, disability, and death is gaining pivotal importance. Genetic variation, particularly the APOE epsilon(ε) variants, may modify responses to new treatments. Although APOE ε4 is known to influence these outcomes separately, the magnitude of its effect on this composite outcome remains unknown. We tested the hypothesis that APOE ε4 increases, whereas APOE ε2 decreases, the risk of a composite outcome of dementia, disability, and death.
METHODS
We evaluated clinical and genomic data from the Health and Retirement Study collected from 1992 to 2020. We used variants rs429358 and rs7412 to determine APOE genotypes, modeled dominantly (carriers/noncarriers). We conducted survival analysis, using multivariable Cox proportional hazards models with a composite endpoint of dementia, disability, and death. Our primary analysis evaluated participants with genetic data and no previous dementia or disability. In secondary analyses, we focused on persons aged > = 75 years without heart disease or stroke, a subpopulation increasingly important in clinical trials of older adults.
RESULTS
We included 14,527 participants in the primary analysis. Over a median of 18 (Interquartile Range [IQR] 12-24) years, 6711 (46%) participants developed the composite outcome. In Cox analyses, APOE ε4 associated with higher risk (HR:1.15, 95%CI:1.09-1.22) of the composite outcome, whereas APOE ε2 associated with lower risk (HR:0.92, 95%CI:0.86-0.99). In the secondary analysis, we included 3174 participants. Over a median of 7 (IQR 4-11) years, 1326 participants (42%) developed the composite outcome. In Cox analyses, APOE ε4 associated with higher risk (HR:1.25, 95%CI:1.10-1.41) of the composite outcome, whereas APOE ε2 associated with lower risk (HR:0.84, 95%CI:0.71-0.98).
CONCLUSIONS
APOE ε variants are linked to the risk of dementia, disability, and death in older adults. By examining these variants in clinical trials, we can better elucidate how they might alter the effectiveness of tested interventions. Importantly, this genetic information could help identify participants who may have greater absolute benefit from such interventions.
PubMed: 38946154
DOI: 10.1111/jgs.19043 -
Pacing and Clinical Electrophysiology :... Jun 2024Postoperative atrial fibrillation (POAF) is one of the most common types of acute AF and can complicate the treatment course of approximately one third of patients...
BACKGROUND
Postoperative atrial fibrillation (POAF) is one of the most common types of acute AF and can complicate the treatment course of approximately one third of patients undergoing cardiac surgery. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are among the newest antidiabetic drugs which can be therapeutic options for preventing POAF by different mechanisms.
METHODS
Empagliflozin to Prevent POAF (EMPOAF) is an interventional, investigator-initiated, double-blind, placebo-controlled, multicenter, randomized controlled trial which will be conducted in two referral teaching cardiology hospitals in Tehran. Four-hundred ninety-two adult patients who are scheduled for elective isolated coronary artery bypass graft (CABG) surgery will be randomly assigned to one of the groups of intervention (empagliflozin 10 mg daily) or placebo starting at least 3 days before surgery until discharge. Key exclusion criteria are a history of diabetes mellitus, AF, ketoacidosis, or recurrent urinary tract infections along with severe renal or hepatic impairment, unstable hemodynamics, and patients receiving SGLT2 inhibitors for another indication. The primary outcome will be the incidence of POAF. Key secondary endpoints will be the composite rate of life-threatening arrhythmias, postoperative acute kidney injury, hospitalization length, in-hospital mortality, stroke, and systemic embolization. Key safety endpoints will be the rate of life-threatening and/or genitourinary tract infections, hypoglycemia, and ketoacidosis.
CONCLUSIONS
EMPOAF will prospectively evaluate whether empagliflozin 10 mg daily can reduce the rate of POAF in patients undergoing elective CABG. Enrolment into this study has started by November 2023 and is expected to be ended before the end of 2025.
PubMed: 38946138
DOI: 10.1111/pace.15038 -
European Journal of Endocrinology Jul 2024There is increasing evidence that multisystem morbidity in patients with Cushing's disease (CD) is only partially reversible following treatment. We investigated...
OBJECTIVE
There is increasing evidence that multisystem morbidity in patients with Cushing's disease (CD) is only partially reversible following treatment. We investigated complications from multiple organs in hospitalized patients with CD compared to patients with non-functioning pituitary adenoma (NFPA) after pituitary surgery.
DESIGN
Population-based retrospective cohort study using data from the Swiss Federal Statistical Office between January 2012 and December 2021.
METHODS
Through 1:5 propensity score matching, we compared hospitalized patients undergoing pituitary surgery for CD or NFPA, addressing demographic differences. The primary composite endpoint included all-cause mortality, major adverse cardiac events (i.e., myocardial infarction, unstable angina, heart failure, cardiac arrest, ischemic stroke), hospitalization for psychiatric disorders, sepsis, severe thromboembolic events, and fractures in need of hospitalization. Secondary endpoints comprised individual components of the primary endpoint and surgical reintervention due to disease persistence or recurrence.
RESULTS
After matching, 116 patients with CD (mean age 45.4 years [SD, 14.4], 75.0% female) and 396 with NFPA (47.3 years [14.3], 69.7% female) were included and followed for a median time of 50.0 months (IQR 23.5, 82.0) after pituitary surgery. CD presence was associated with a higher incidence rate of the primary endpoint (40.6 vs. 15.7 events per 1,000 person-years, HR 2.75; 95% CI, 1.54 to 4.90). CD patients also showed increased hospitalization rates for psychiatric disorders (HR 3.27; 95% CI, 1.59 to 6.71) and a trend for sepsis (HR 3.15; 95% CI, 0.95 to 10.40).
CONCLUSIONS
Even after pituitary surgery, CD patients faced a higher hazard of complications, especially psychiatric hospitalizations and sepsis.
PubMed: 38946089
DOI: 10.1093/ejendo/lvae069 -
Chemical & Pharmaceutical Bulletin 2024Amyloid-β (Aβ) plaques and neurofibrillary tangles containing phosphorylated tau protein are major hallmarks of Alzheimer's disease (AD). Drug discovery efforts to... (Review)
Review
Amyloid-β (Aβ) plaques and neurofibrillary tangles containing phosphorylated tau protein are major hallmarks of Alzheimer's disease (AD). Drug discovery efforts to target Aβ and tau have been the primary focus for several decades. Recently, substantial breakthroughs have been achieved in the clinical development of Aβ antibodies; aducanumab was approved under conditional accelerated pathway by Food and Drug Administration (FDA) in the U.S. as the first disease-modifying agent for treating AD, and lecanemab has been granted traditional full approved in the U.S. and Japan. In addition, donanemab met the primary endpoint in a phase 3 study. On the other hand, tau-targeting therapies have failed to show clinical benefit although that increased tau levels show a strong correlation with cognitive impairment relative to Aβ depositions. Currently, tau immunotherapies, such as anti-tau antibodies and tau vaccines, have shown functional benefits in clinical trials. Also, clinical trials for combination therapy of Aβ and tau antibodies to see their potential are being investigated. In this review, we provide updates on the results of clinical trials of anti-Aβ antibodies and anti-tau therapeutics and suggest future directions for these therapeutics.
Topics: Alzheimer Disease; Humans; tau Proteins; Amyloid beta-Peptides; Immunotherapy; Animals
PubMed: 38945936
DOI: 10.1248/cpb.c24-00069 -
Clinical Lung Cancer Jun 2024Third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have significant antitumor activity to advanced non-small-cell lung cancer...
The Design for a Phase II, Randomized, Multicenter Study of CtDNA-Guided Treatment With Furmonertinib Combined Therapy or Furmonertinib Alone for Untreated Advanced EGFR Mutant Non-small-cell Lung Cancer Patients: The FOCUS-C Study.
BACKGROUND
Third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have significant antitumor activity to advanced non-small-cell lung cancer (NSCLC) patients with classic EGFR mutations. However, EGFR-TKI monotherapy shows poor efficacy in patients whose circulating tumor cell DNA (ctDNA) of EGFR mutations cannot be rapidly cleared.
MATERIALS AND METHODS
As a third-generation TKI, furmonertinib has shown superior antitumor activity and minor toxicity. The FOCUS-C study is a prospective, multicenter, randomized controlled trial (NCT05334277) to explore the efficacy and safety of furmonertinib plus pemetrexed-platinum doublet chemotherapy with or without bevacizumab versus furmonertinib monotherapy in untreated advanced EGFR mutant NSCLC patients without EGFR clearance after the induction therapy of furmonertinib. Patients with EGFR clearance will still receive furmonertinib as Arm A. Patients without ctDNA clearance will be randomized in a 2:2:1 ratio as Arm B1 (furmonertinib), Arm B2 (furmonertinib combined with carboplatin and pemetrexed for 4 cycles, and then furmonertinib and pemetrexed as maintenance therapy) and Arm B3 (Arm B2 regimen plus bevacizumab). The primary endpoint is progression-free survival (PFS) in Arm B2/B1. Secondary endpoints include PFS in Arm B3/B1, PFS in Arm A/B1, PFS in Arm B3/B2, objective response and disease control rate, overall survival and safety in all Arms. Exploratory endpoints are focused on the efficacy based on plasma NGS at different timepoints.
CONCLUSION
This study will evaluate the efficacy and tolerability of furmonertinib plus carboplatin and pemetrexed with or without bevacizumab verses furmonertinib alone in untreated patients with advanced EGFR mutant NSCLC without EGFR clearance.
PubMed: 38945800
DOI: 10.1016/j.cllc.2024.06.002 -
Journal of Vascular Surgery. Venous and... Jun 2024We evaluated the impact of completion intraoperative venography on clinical outcomes for axillosubclavian vein (AxSCV) thrombosis due to venous thoracic outlet syndrome...
INTRODUCTION
We evaluated the impact of completion intraoperative venography on clinical outcomes for axillosubclavian vein (AxSCV) thrombosis due to venous thoracic outlet syndrome (vTOS).
METHODS
We performed a retrospective, single-center review of all patients with vTOS treated with First Rib Resection and intraoperative venography from 2011 - 2023. We reviewed intraoperative venographic films to classify findings, collected demographics, clinical and perioperative variables, and clinical outcomes. Primary endpoints were symptomatic relief and primary patency at 3 months and 1 year. Secondary endpoints were time free from symptoms, reintervention rate, perioperative complications, and mortality.
RESULTS
Fifty-one AxSCVs (49 patients, mean age of 31.3 ± 12.6, 52.9% female) were treated for vTOS with first rib resection and external venolysis followed by completion intraoperative venography with a mean follow up of 15.5 ± 13.5 months. Prior to FRR, 32 underwent catheter-directed thrombolysis (62.7%). Completion intraoperative venography identified 16 patients with No Stenosis (Group 1, 31.3%), 17 with No Stenosis after Angioplasty (Group 2, 33.3%), 10 with Residual Stenosis after Angioplasty (Group 3, 19.7%), and 8 with Complete Occlusion (Group 4, 15.7%). The overall symptomatic relief was 44 of 51 (86.3%) and did not differ between venographic classifications (Group 1: 14 of 16, Group 2: 13 of 17, Group 3: 10 of 10, and Group 4: 7 of 8; Log-Rank Test, p = 0.5). The overall 3-month and 1-year primary patency was 42 of 43 (97.7%) and 32 of 33 (97.0%), respectively (Group 1: 16 of 16 and 9 of 9; Group 2: 16 of 17 and 12 of 13; Group 3: 10 of 10, 5 of 5; Group 4: primary patency not obtained). There was one asymptomatic re-thrombosis that resolved with anticoagulation, and three patients underwent reintervention with venous angioplasty for significant symptom recurrence an average 2.89 ± 1.7 months after FRR.
CONCLUSION
Our single-center retrospective study demonstrates that FRR with completion intraoperative venography has excellent symptomatic relief, short- and mid-term patency despite residual venous stenosis and complete occlusion. While completion intraoperative venographic classification did not correlate with adverse outcomes, this protocol yielded excellent results and provides important clinical data for postoperative management. Our results also support a conservative approach to AxSCV occlusion identified after FRR.
PubMed: 38945363
DOI: 10.1016/j.jvsv.2024.101936 -
Journal of Clinical Anesthesia Jun 2024This study aims to evaluate the effect of perioperative liberal drinking management, including preoperative carbohydrate loading (PCL) given 2 h before surgery and...
Perioperative liberal drinking management promotes postoperative gastrointestinal function recovery after gynecological laparoscopic surgery: A randomized controlled trial.
STUDY OBJECTIVE
This study aims to evaluate the effect of perioperative liberal drinking management, including preoperative carbohydrate loading (PCL) given 2 h before surgery and early oral feeding (EOF) at 6 h postoperatively, in enhancing postoperative gastrointestinal function and improving outcomes in gynecologic patients. The hypotheses are that the perioperative liberal drinking management accelerates the recovery of gastrointestinal function, enhances dietary tolerance throughout hospitalization, and ultimately reduces the length of hospitalization.
DESIGN
A prospective randomized controlled trial.
SETTING
Operating room and gynecological ward in Wuhan Union Hospital.
PATIENTS
We enrolled 210 patients undergoing elective gynecological laparoscopic surgery, and 157 patients were included in the final analysis.
INTERVENTIONS
Patients were randomly allocated in a 1:1:1 ratio into three groups, including the control, PCL, and PCL-EOF groups. The anesthetists and follow-up staff were blinded to group assignment.
MEASUREMENTS
The primary outcome was the postoperative Intake, Feeling nauseated, Emesis, Examination, and Duration of symptoms (I-FEED) score (range 0 to 14, higher scores worse). Secondary outcomes included the incidence of I-FEED scores >2, and other additional indicators to monitor postoperative gastrointestinal function, including time to first flatus, time to first defecation, time to feces Bristol grade 3-4, and time to tolerate diet. Additionally, we collected other ERAS recovery indicators, including the incidence of PONV, complications, postoperative pain score, satisfaction score, and the quality of postoperative functional recovery at discharge.
MAIN RESULTS
The PCL-EOF exhibited significantly enhanced gastrointestinal function recovery compared to control group and PCL group (p < 0.05), with the lower I-FEED score (PCL: 0[0,1] vs. PCL-EOF: 0[0,0] vs. control: 1[0,2]) and the reduced incidence of I-FEED >2 (PCL:8% vs. PCL-EOF: 2% vs. control:21%). Compared to the control, the intervention of PCL-EOF protected patients from the incidence of I-FEED score > 2 [HR:0.09, 95%CI (0.01-0.72), p = 0.023], and was beneficial in promoting the patient's postoperative first flatus [PCL-EOF: HR:3.33, 95%CI (2.14-5.19),p < 0.001], first defecation [PCL-EOF: HR:2.76, 95%CI (1.83-4.16), p < 0.001], Bristol feces grade 3-4 [PCL-EOF: HR:3.65, 95%CI (2.36-5.63), p < 0.001], first fluid diet[PCL-EOF: HR:2.76, 95%CI (1.83-4.16), p < 0.001], and first normal diet[PCL-EOF: HR:6.63, 95%CI (4.18-10.50), p < 0.001]. Also, the length of postoperative hospital stay (PCL-EOF: 5d vs. PCL: 6d and control: 6d, p < 0.001), the total cost (PCL-EOF: 25052 ± 3650y vs. PCL: 27914 ± 4684y and control: 26799 ± 4775y, p = 0.005), and postoperative VAS pain score values [POD0 (PCL-EOF: 2 vs. control: 4 vs. PCL: 4, p < 0.001), POD1 (PCL-EOF: 1 vs. control: 3 vs. PCL: 2, p < 0.001), POD2 (PCL-EOF: 1 vs. control:2 vs. PCL: 1, p < 0.001), POD3 (PCL-EOF: 0 vs. control: 1 vs. PCL: 1, p < 0.001)] were significantly reduced in PCL-EOF group.
CONCLUSIONS
Our primary endpoint, I-FEED score demonstrated significant reduction with perioperative liberal drinking, serving as a protective intervention against I-FEED>2. Gastrointestinal recovery metrics, such as time to first flatus and defecation, also showed substantial improvements. Furthermore, the intervention enhanced postoperative dietary tolerance and expedited early recovery.
TRIAL REGISTRATION
ChiCTR2300071047(https://www.chictr.org.cn/).
PubMed: 38945059
DOI: 10.1016/j.jclinane.2024.111539 -
Inflammatory Bowel Diseases Jun 2024The patient perspective is essential for assessing disease severity, but it is not always adequately considered. We describe how a comprehensive clinical disease...
BACKGROUND
The patient perspective is essential for assessing disease severity, but it is not always adequately considered. We describe how a comprehensive clinical disease severity index (DSI) for inflammatory bowel disease (IBD) correlates with patient global self-assessment (PGSA).
METHODS
In an individually linked parallel online survey, physicians provided the DSI, and patients provided self-assessed severity using a global question and visual analog scale (0-100) (PGSA). Mean DSI values by PGSA were calculated with 95% confidence intervals. Pearson correlation (r) and the intraclass correlation coefficient were calculated for PGSA vs DSI. Positive predictive values for identifying severe disease with PGSA categories as a reference were based on a threshold >22 points.
RESULTS
The primary analysis included 89 pairs (46 Crohn's disease [CD], 43 ulcerative colitis [UC]) with strict criteria and 147 pairs when less stringent. Common reasons for exclusion were missing values for albumin or colonoscopy. Mean DSI values showed no clear trend with increasing PGSA in CD but good discrimination between moderate, severe, and very severe PGSA in UC. For PGSA on the visual analog scale, r was 0.54 for CD and 0.59 for UC (difference in means: CD 27.7, UC 13.8; intraclass correlation coefficient: CD 0.48, UC 0.58). A high DSI predicted severe disease in 76.2% of CD and 65.2% of UC.
CONCLUSIONS
The DSI showed good discrimination for patient-reported disease severity in UC but performed unsatisfactorily in CD. Correlations were moderate. Further refinement of the DSI is suggested to better reflect the patient perspective.
PubMed: 38944765
DOI: 10.1093/ibd/izae127 -
Journal of Veterinary Internal Medicine Jun 2024Grapiprant is a novel anti-inflammatory drug approved for the treatment of pain associated with osteoarthritis in dogs.
BACKGROUND
Grapiprant is a novel anti-inflammatory drug approved for the treatment of pain associated with osteoarthritis in dogs.
OBJECTIVE
Compare the efficacy of grapiprant vs meloxicam for the management of postoperative joint pain in dogs.
ANIMALS
Forty-eight dogs presented with cranial cruciate ligament disease and treated by tibial plateau leveling osteotomy (TPLO) between May 2020 and May 2022.
METHODS
In this randomized, double blinded, prospective clinical trial, client-owned dogs with naturally occurring unilateral cruciate ligament rupture were enrolled on the day of surgery. The day after surgery, all animals received a subcutaneous injection of 0.2 mg/kg of meloxicam and were randomly assigned to receive either oral grapiprant (2 mg/kg) or meloxicam (0.1 mg/kg), once a day for 14 days, in a blinded manner. The primary endpoint of the study was the pain severity (PSS) and interference (PIS) scores, assessed by the Canine Brief Pain Inventory (CBPI) at day 3, 7, 10 and 15 after the surgery.
RESULTS
Three days after surgery, grapiprant treated dogs had lower PSS compared to meloxicam treated dogs with a mean ± SD of 2.76 ± 0.18 vs 3.25 ± 0.23, respectively (difference of -0.49 [95% CI -0.94 to -0.04], P = .032). Pain Interference Score was also lower in grapiprant group at day 3 (4.11 ± 0.18 vs 4.69 ± 0.16 in meloxicam group [difference of -0.58 {95% CI -1.03 to -0.13}, P = .013]) and at day 10 (2.23 ± 0.13 vs 2.72 ± 0.28 [difference of -0.49 {95% CI -0.92 to -0.01}, P = .049]).
CONCLUSIONS AND CLINICAL IMPORTANCE
Our study supports the use of grapiprant as an alternative analgesic to meloxicam for management of postoperative joint pain in dogs.
PubMed: 38944675
DOI: 10.1111/jvim.17136