A Pooled Analysis of Trastuzumab Deruxtecan in Patients With HER2-Positive Metastatic Breast Cancer With Brain Metastases.

BACKGROUND: This exploratory pooled analysis investigated the efficacy and safety of trastuzumab deruxtecan (T-DXd) versus comparator treatment in patients with HER2-positive metastatic breast cancer (mBC) with brain metastases (BMs) at baseline, categorized according to previous local treatment. PATIENTS AND METHODS: T-DXd data were pooled from DESTINY-Breast01/-02/-03. Comparator data, from patients receiving physician's choice therapy and trastuzumab emtansine, were pooled from DESTINY-Breast02 and -03, respectively. Baseline BM status was assessed according to US Food and Drug Administration criteria. Endpoints included intracranial objective response rate (ORR; complete or partial response in brain) per blinded independent central review (BICR) by RECIST v1.1, time to intracranial response, intracranial duration of response (DoR), central nervous system progression-free survival (CNS-PFS) by BICR, overall survival (OS), and safety. RESULTS: 148 patients who received T-DXd and 83 patients who received comparator treatment had BMs at baseline. In those who were treated with T-DXd, the intracranial ORR of patients with treated/stable and untreated/active BMs was 45.2% and 45.5%, respectively. The median (range) time to intracranial response was 2.8 months (1.1-13.9 months) and 1.5 months (1.2-13.7 months) in patients with treated/stable and untreated/active BMs, respectively. For those with treated/stable BMs, the median (95% CI) intracranial DoR was 12.3 months (9.1-17.9 months), and for those with untreated/active BMs it was 17.5 months (13.6-31.6 months). The median (95% CI) CNS-PFS and OS was 12.3 months (11.1-13.8 months) and not reached (22.1 months-not estimable [NE]) in those with treated/stable BMs, and 18.5 months (13.6-23.3 months) and 30.2 months (21.3 months-NE) in those with untreated/active BMs, respectively. Drug-related TEAEs grade ≥3 were experienced by 43.2% of patients with BMs and 46.4% without BMs with T-DXd. CONCLUSIONS: T-DXd demonstrated meaningful intracranial efficacy and clinical benefit in OS, with an acceptable and manageable safety profile in patients with HER2-positive mBC with treated/stable and untreated/active BMs.

Examining the combined effect of antenatal care visits and iron-folic acid supplementation on low birth weight: a pooled analysis of two national data sets from Nepal.

BACKGROUND: The prevalence of low birth weight (LBW) has stagnated at approximately 12% for the past 15 years in Nepal, significantly impacting newborn survival. While antenatal care (ANC) visits and iron-folic acid supplementation are recognised as important interventions to reduce LBW, there is a lack of evidence regarding their combined effect. This study aimed to explore the potential synergistic impact of ANC and iron-folic acid supplementation on LBW in Nepal by analyzing data from two national surveys. METHODS: The nationally representative Nepal Demographic and Health Surveys of 2016 and 2022 were used, and the pooled dataset was analysed. Birth weight and the prevalence of LBW (i.e. birthweight < 2500 g) were reported using descriptive statistics. The associations among LBW, ANC visits, and iron-folic acid supplementation were examined using logistic regression analyses. RESULTS: The mean birth weight was 3011 g, with an LBW prevalence of 11.2%. Not attending ANC (Adjusted Odds Ratio (AOR): 1.49; 95% Confidence Interval (CI): 1.14, 1.95) and not consuming iron-folic acid supplements (AOR: 1.43; 95% CI: 1.11, 1.84) were independently associated with a higher likelihood of having LBW. Furthermore, when considering both factors together, mothers who attended less than four ANC visits and consumed iron-folic acid for ≤ 90 days had the higher likelihood of having LBW (AOR: 1.99; 95% CI: 1.35, 2.60) compared to those who did not. CONCLUSIONS: This study highlights that the individual and joint influence of ANC visits and iron-folic acid supplementation on having LBW. These findings underscore the significance of ANC attendance and iron-folic acid supplementation in preventing LBW. Traditionally, these two interventions were primarily considered as maternal survival strategies. However, our findings indicate that these existing interventions could be utilised further for both maternal and newborn survival. Given that these services are offered free of cost and are available near people's homes through the National Safe Motherhood Programme in Nepal, efforts to increase the uptake of these services should be strengthened while emphasising their role in preventing LBW.

Real-Life Effectiveness of iGlarLixi (Insulin Glargine 100 U/ml and Lixisenatide) in People with Type 2 Diabetes (T2D) According to Baseline HbA1c and BMI.

INTRODUCTION: This study aimed to evaluate the effect of baseline body mass index (BMI) and glycated hemoglobin (HbA1c) on the effectiveness and safety of initiating iGlarLixi (insulin glargine 100 U/ml and lixisenatide) in people with type 2 diabetes (T2D) in routine clinical practice. METHODS: We pooled patient-level data from 1406 people with inadequately controlled T2D, initiating a 24-week iGlarLixi treatment. Analysis sets were based on baseline BMI and HbA1c. In the BMI set, 894 (64%) people had a BMI ≥ 30 kg/m2 and 510 (36%) a BMI < 30 kg/m2; in the HbA1c set, 615 (44%) people had an HbA1c >9%, 491 (35%) between 8 and 9%, and 298 (21%) < 8%. RESULTS: After initiating iGlarLixi, HbA1c decreased in all participants, with the greatest least-squares mean reduction at 2.15% from baseline to week 24 in those with baseline HbA1c > 9% (using a mixed model for repeated measures). Overall, mean ± standard deviation body weight decreased by 1.9 ± 4.8 kg, with the most prominent loss of 2.6 ± 4.9 kg recorded in people presenting with obesity. Reported hypoglycemia rates were low across all groups. CONCLUSIONS: Initiation of iGlarLixi in people with uncontrolled T2D is effective and safe in clinical practice, across different baseline HbA1c and BMI categories.

Chemoradiotherapy plus induction or consolidation chemotherapy as total neoadjuvant therapy for locally advanced rectal cancer: Pooled analysis of the CAO/ARO/AIO-12 and the OPRA randomized phase 2 trials.

BACKGROUND: Total neoadjuvant therapy (TNT) has been used for patients with locally advanced rectal cancer. The optimal sequence of chemoradiotherapy (CRT) and chemotherapy (CT) is a matter of debate. METHODS: We performed a pooled analysis of the CAO/ARO/AIO-12 and OPRA multicenter, randomized phase 2 trials to identify patient subsets that could benefit from one TNT sequence over the other regarding disease-free survival (DFS). Patients with stage II/III rectal cancer were randomized to CRT (50.4-54 Gy) with either induction (INCT-CRT) or consolidation CT (CRT-CNCT) with fluorouracil, leucovorin, oxaliplatin (CAO/ARO/AIO-12 and OPRA) or capecitabine and oxaliplatin (OPRA) followed by mandatory total mesorectal excision (TME) (CAO/ARO/AIO-12) or selective watch-and-wait surveillance (OPRA). 311 and 324 patients were recruited from June 15, 2015 to January 31, 2018; and from April 12, 2014 to March 30, 2020 in the two trials, respectively. Pretreatment clinical and tumor characteristics included were age, sex, ECOG, cT-category, cN-category, clinical UICC stage, location from anal verge, and tumor grade. FINDINGS: In total, 628 eligible patients were included in the pooled analysis (CAO/ARO/AIO-12, n = 304; OPRA, n = 324). Of those, 313 were randomly assigned to the INCT-CRT group, and 315 to the CRT-CNCT group. Median follow-up was 43 months (IQR, 35-49) months in the CAO/ARO/AIO-12 trial and 61,2 months (IQR, 42-68,4) in the OPRA trial. Pooled analysis of baseline clinical and tumor characteristics did not identify any subgroups of patients that would benefit by the one TNT sequence over the other with regard to DFS. INTERPRETATION: To our knowledge, this is the first pooled analysis of two randomized trials after direct head-to-head comparison of both TNT sequences. Both trials reported higher rates of complete response with CRT-CNCT, and this should be considered the preferred TNT sequence if organ preservation is a priority.

Strategies to Address Statin Medication Intolerance Among Patients at Risk of Cardiovascular Disease Identified Through Electronic Health Records: A Literature Review and Pooled Analysis.

Statins are a group of medications that lower lipid and are used for primary and secondary prevention of cardiovascular diseases (CVD). Patients can either be partially (15%) or completely (5%) intolerant to statins. Symptoms of statin intolerance can include muscle aches (myalgia), weakness, cramps, myopathy, diabetes mellitus, and elevated creatine kinase levels. Decreasing statin intolerance also improves statin adherence, which in turn results in lower number of CVD events among patients. Studies on statin intolerance is often embedded within studies of statin adherence. However, relevant data can be obtained from digital health systems. This preliminary literature review looks at studies from the past 10 years to identify and determine the effectiveness of strategies to address statin intolerance. The NLA definition for statin intolerance was used in this review. The initial search results on EMBASE, PubMed, SCOPUS, and CINAHL showed 91 articles and applying the inclusion and exclusion criteria, four articles were used in this review and pooled analysis. The study patients were identified through electronic health records. The pooled analysis was done using the Metafor package in R, applying a random-effect model to estimate pooled effect size. The findings suggest that using fixed dose combination therapy and switching from a lipophilic statin to a hydrophilic statin, while correcting metabolic abnormalities, or initiating evolocumab alongside statin can address statin intolerance. The overall relative risk (RR) was 0.40 (95% CI, 0.09 to 1.70) with I2 90%, and the overall odds ratio (OR) was 0.11 (95% CI, 0.01 to 1.59) with I2 94%, suggesting that the interventions work well in addressing statin intolerance. Since statin intolerance is has a vast range of effects, further research works may be done on exploring the possibility of using digital health systems to identify and provide targeted interventions to patients.

The beneficial effect of probiotics in the prevention of irinotecan-induced diarrhea in colorectal cancer patients with colostomy: a pooled analysis of two probiotic trials (Probio-SK-003 and Probio-SK-005) led by Slovak Cooperative Oncology Group.

Background: Probiotics could decrease irinotecan-induced diarrhea due to the reduction of intestinal beta-d-glucuronidase activity. This study included a combined analysis of two clinical trials aimed to determine the effectiveness of the probiotics in the prophylaxis of irinotecan-induced diarrhea in metastatic colorectal cancer (CRC) patients. Methods: This combined analysis included 46 patients with CRC enrolled in the Probio-SK-003 (NCT01410955) and 233 patients from Probio-SK-005 (NCT02819960) starting a new line of irinotecan-based therapy with identical eligibility criteria. Patients were randomized in a ratio 1:1 to probiotic formulas vs. placebo administered for 12 and 6 weeks, respectively. Due to the different durations of study treatments, only the first 6 weeks of therapy were used for analysis. Results: In total, 279 patients were randomized, including 142 patients in the placebo and 137 participants in the probiotic arm. Administration of probiotics did not significantly reduce the incidence of grade 3/4 diarrhea compared to placebo (placebo 12.7% vs. probiotics 6.6%, p = 0.11). Neither the overall incidence of diarrhea (placebo 48.6% vs. probiotics 41.6%, p = 0.28) nor the incidence of enterocolitis (placebo 4.2% vs. probiotics 0.7%, p = 0.12) was different in the placebo vs. probiotic arm. However, subgroup analysis revealed that patients with a colostomy who received a placebo had a significantly higher incidence of any diarrhea (placebo 51.2% vs. probiotics 25.7%, p = 0.028) and grade 3/4 diarrhea (placebo 14.6% vs. probiotics 0.0%, p = 0.03) compared to the probiotic arm. Conclusions: This combined analysis suggests that probiotics could be beneficial in the prevention of irinotecan-induced diarrhea in colorectal cancer patients with colostomy.

Factors influencing the efficacy and safety of esaxerenone in hypertensive patients: a pooled analysis of five clinical studies on different comorbidities.

This study aimed to identify factors associated with a strong home blood pressure (BP)-lowering effect of esaxerenone and the incidence of elevated serum potassium levels in hypertensive patients treated with esaxerenone. A pooled analysis of five multicenter, prospective, open-label single-arm studies was conducted, including 479 patients in the full analysis set (FAS) and 492 patients in the safety analysis set. Multivariate linear regression analysis of morning home systolic BP (SBP) and diastolic BP (DBP) changes from baseline to Week 12 in the FAS (primary endpoint) showed that male sex (estimated change 4.37 mmHg), office pulse rate ≥100 beats/min (25.10 mmHg), and calcium channel blocker (CCB) use as a basal antihypertensive agent (4.53 mmHg) were significantly associated with a positive estimated change (weaker BP-lowering effect) in morning home SBP. CCB use (3.70 mmHg) was associated with a positive estimated change in morning home DBP. Urine albumin-to-creatinine ratio 30 to <300 mg/gCr (-4.13 mmHg) was significantly associated with a negative estimated change (stronger BP-lowering effect) in morning home SBP. Based on multivariate logistic regression analysis, elevated baseline serum potassium level (≥4.5 vs < 4.5 mEq/L, odds ratio 13.502) was significantly associated with a high incidence of serum potassium level ≥5.5 mEq/L after esaxerenone treatment. In conclusion, factors associated with a strong BP-lowering effect of esaxerenone were female sex and use of renin-angiotensin system inhibitors as a basal antihypertensive drug. Patients with baseline serum potassium levels ≥4.5 mEq/L had an increased risk of developing elevated serum potassium levels (≥5.5 mEq/L) after esaxerenone treatment.

A pooled analysis of clinical outcome in driver-gene negative non-small cell lung cancer patients with MET overexpression treated with gumarontinib.

Background: MET overexpression represents the most MET aberration in advanced non-small-cell lung cancer (NSCLC). However, except MET exon 14 (METex14) skipping mutation was recognized as a clinical biomarker, the role of MET overexpression as a predictive factor to MET inhibitor is not clear. Objectives: The purpose of the pooled analysis is to explore the safety and efficiency of gumarontinib, a highly selective oral MET inhibitor, in drive-gene negative NSCLC patients with MET overexpression. Design and methods: NSCLC patients with MET overexpression [immunohistochemistry (IHC) ⩾3+ as determined by central laboratory] not carrying epidermal growth factor receptor mutation, METex14 skipping mutation or other known drive gene alternations who received Gumarontinib 300 mg QD from two single arm studies were selected and pooled for the analysis. The efficacy [objective response rate (ORR), disease control rate (DCR), duration of response, progression-free survival (PFS) and overall survival (OS)] and safety [treatment emergent adverse event (TEAE), treatment related AE (TRAE) and serious AE (SAE) were assessed. Results: A total of 32 patients with MET overexpression were included in the analysis, including 12 treatment naïve patients who refused or were unsuitable for chemotherapy, and 20 pre-treated patients who received ⩾1 lines of prior systemic anti-tumour therapies. Overall, the ORR was 37.5% [95% confidence interval (CI): 21.1-56.3%], the DCR was 81.3% (95% CI: 63.6-92.8%), median PFS (mPFS) and median OS (mOS) were 6.9 month (95% CI: 3.6-9.7) and 17.0 month (95% CI: 10.3-not evaluable), respectively. The most common AEs were oedema (59.4%), hypoalbuminaemia (40.6%), alanine aminotransferase increased (31.3%). Conclusion: Gumarontinib showed promising antitumour activity in driver-gene negative locally advanced or metastatic NSCLC patients with MET overexpression, which warranted a further clinical trial. Trial registration: ClinicalTrials.gov identifier: NCT03457532; NCT04270591.

Microvascular Obstruction in Patients With Anterior STEMI Treated With Supersaturated Oxygen.

Background: Supersaturated oxygen (SSO2) delivered into the left anterior descending coronary artery after percutaneous coronary intervention (PCI) for anterior ST-segment elevation myocardial infarction (STEMI) has been shown to reduce infarct size, but its effects on microvascular obstruction (MVO) are unknown. The aim of this study was to compare MVO in patients with anterior STEMI treated with SSO2 after successful primary PCI from 2 studies (the optimized SSO2 pilot and IC-HOT) with similar patients from 7 randomized trials who underwent primary PCI without SSO2 treatment. Methods: A total of 874 patients with anterior STEMI who underwent MVO assessment using cardiac magnetic resonance imaging within 10 days after primary PCI were included, of whom 90 patients (10.3%) were treated with SSO2. The primary end point was the extent of MVO as a continuous measure in a weighted multivariable model. The secondary end point was the presence of MVO. Results: SSO2 therapy was independently associated with a lower extent of MVO compared with no SSO2 therapy (coefficient, -1.35; 95% CI, -2.58 to -0.11; P = .03). SSO2 therapy was also associated with a borderline lower risk of any MVO (adjusted odds ratio, 0.56; 95% CI, 0.31-1.00; P = .051). Conclusions: In the present individual patient data pooled analysis from 9 studies, SSO2 therapy was associated with less MVO after successful primary PCI for anterior STEMI.

Efficacy of yoga for posttraumatic stress disorder: A systematic review and meta-analysis of randomized controlled trials.

Yoga is an increasingly popular complementary intervention to reduce posttraumatic stress disorder (PTSD) symptoms and related comorbidities, but its safety and treatment efficacy are not firmly established. We conducted a systematic review and meta-analysis of existing randomized control trials (RCTs) of yoga interventions for PTSD and related secondary outcomes (e.g., depression). Initial search results found over 668 potential papers. Twenty met inclusion criteria (e.g., RCTs on adult participants with PTSD that evaluated safety or efficacy outcomes). Meta-analysis indicated that, compared to control interventions, participation in yoga interventions significantly improved self-report PTSD (standardized mean difference [SMD]: -0.51; 95 % confidence interval [CI]: -0.68, -0.35) and immediate (SMD: -0.39; 95 % CI: -0.56, -0.22) and long-term (SMD: -0.44; 95 % CI: -0.74, -0.13) depression symptoms. However, using clinician-reported assessments, yoga interventions were not associated with improved PTSD symptoms. Type of yoga differentially predicted outcomes. Sensitivity analysis showed consistent effect sizes when omitting each study from main analyses. Six studies reported whether any serious adverse events occurred. None were indicated. No publication bias was found, although individual intervention studies tended to be high in bias. Results suggest yoga is likely a safe and effective complementary intervention for reducing PTSD and depressive symptoms in individuals with PTSD. More rigorous RCTs are warranted.

Combined immunogenicity evaluation for a new single-dose live-attenuated chikungunya vaccine.

BACKGROUND: Chikungunya is a serious and debilitating viral infection with a significant disease burden. VLA1553 (IXCHIQ®) is a live-attenuated vaccine licensed for active immunization for prevention of disease caused by chikungunya virus (CHIKV). METHODS: Immunogenicity following a single dose of VLA1553 was evaluated in healthy adults aged ≥18 years in two Phase 3 trials (N = 656 participants [per protocol analysis set]). Immunogenicity data to 180 days post-vaccination (geometric mean titers [GMTs], seroresponse rate, seroconversion rate) were pooled for the two trials. A comparison of subgroups based on age, sex, body mass index (BMI), race, and baseline seropositivity was included. All analyses were descriptive. RESULTS: Most participants were aged 18-64 years (N = 569/656 [86.7%]), there were slightly more females (N = 372/656 [56.7%]), most were not Hispanic/Latino (N = 579/656 [88.3%]), and most were White (N = 517/656 [78.8%]). In baseline seronegative participants, GMT peaked at Day 29 post-vaccination, and subsequently declined slightly but remained elevated until Day 180. At Days 29, 85, and 180, seroresponse rate was 98.3%, 97.7%, and 96.4% and seroconversion rate was 98.5%, 98.4%, and 98.2%. There were no differences in seroresponse rate in participants aged 18-64 years or ≥ 65 years at Day 29 (98.1% versus 100%), Day 85 (97.4% versus 100%), and Day 180 (96.3% versus 96.5%) nor based on sex, BMI, ethnicity, or race. An immune response was shown in a small heterogenous population of baseline seropositive participants, with GMTs showing the same trend as baseline seronegative participants. CONCLUSIONS: A single dose of VLA1553 elicited a very strong immune response by Day 29 that remained elevated at Day 180 in both baseline seronegative and seropositive participants in a combined evaluation of two Phase 3 trials. The vaccine was similarly immunogenic in participants aged ≥65 years and 18-64 years, and there were no differences based on subgroup analyses for sex, BMI, ethnicity, or race.

Efficacy of specific exercises in general population with non-specific low back pain: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: Localized exercises are employed to activate, train, or restore the function of particular muscles and they are usually considered as part of treating individuals suffering low back pain. So, this systematic review and meta-analysis aimed to assess the efficacy of specific exercises in general population with non-specific low back pain (LBP). METHODS: We conducted electronic searches in MEDLINE/PubMed, Scopus, Web of Science (WoS), and Google scholar from January 1990 to June 2021. Initially, 47,740 records were identified. Following the removal of duplicates, 32,138 records were left. After reviewing titles and abstracts, 262 papers were chosen for thorough assessment. Among these, 208 studies were excluded, resulting in 54 trials meeting the inclusion criteria for this study. Additionally, 46 of these trials were randomized controlled trials and were further evaluated for the meta-analysis. We included trials investigating the effectiveness of exercise therapy, including isometric activation of deep trunk muscles, strengthening exercises, stabilization exercises, stretching exercises, and proprioceptive neuromuscular facilitation exercises (PNF) in LBP patients. The primary outcome was pain intensity, measured using tools such as the visual analogue scale (VAS) and numeric pain rating scale (NPRS). The secondary outcome was disability, assessed through instruments such as the Roland Morris Disability Questionnaire (RMDQ) and Oswestry Disability Index (ODI). The quality of the eligible studies was assessed using the Verhagen tool, and the level of evidence was evaluated using the GRADE approach. RESULTS: Based on the Verhagen tool, 46 trials (85.2%) were categorized as having low methodological quality, while 8 studies (14.8%) were considered to have medium methodological quality. The meta-analysis indicated a small efficacy in favor of isometric activation of deep trunk muscles (-0.37, 95% CI: -0.88 to 0.13), a moderate efficacy in favor of stabilization exercises (-0.53, 95% CI: -1.13 to 0.08), and a large efficacy in favor of PNF exercises (-0.91, 95% CI: -1.62 to -0.2) for reducing pain intensity as assessed by VAS or NPRS tools. Moreover, the meta-analysis revealed a moderate efficacy for isometric activation of deep trunk muscles (-0.61, CI: -1.02 to -0.19), and a large efficacy for PNF exercises (-1.26, 95% CI: -1.81 to -0.72) in improving disability, assessed using RMDQ or ODI questionnaires. The level of certainty in the evidence, as determined by the GRADE approach, was very low to low. CONCLUSION: These findings emphasize the importance of incorporating localized therapeutic exercises as a fundamental aspect of managing non-specific LBP. Clinicians should consider utilizing localized therapeutic exercise tailored to individual patient needs. Furthermore, further research investigating optimal exercise therapy, optimal dose of the exercises, durations, and long-term adherence is warranted to enhance the precision and efficacy of exercise-based interventions for non-specific LBP.

Clinical evaluation of primary human papillomavirus (HPV) testing with extended HPV genotyping triage for cervical cancer screening: A pooled analysis of individual patient data from nine population-based cervical cancer screening studies from China.

OBJECTIVE: To assess the clinical values of extended human papillomavirus (HPV) genotyping in triage of high-risk HPV-positive women, focusing on the trade-off between cervical precancer detections and colposcopy referrals. METHODS: A bivariate random-effects model was used to estimate the diagnostic accuracy of primary HPV screening with following triage strategies to detect cervical precancers: (i) partial genotyping for HPV16/18 combined with cytological testing at atypical squamous cells of undetermined significance threshold (used as the comparator), (ii) genotyping for HPV16/18/58/52, (iii) genotyping for HPV16/18/58/52/33, (iv) genotyping for HPV16/18/58/33/31, (v) genotyping for HPV16/18/58/52/33/31, and (vi) genotyping for HPV16/18/58/52/33/31/39/51. Internal risk benchmarks for clinical management were used to evaluate the risk stratification of each triage strategy. RESULTS: A total of 16,982 women (mean age 46.1 years, range 17-69) were included in this analysis. For CIN3+ detection, triage with HPV16/18/58/33/31 genotyping achieved lower positivity (6.85% vs. 7.35%, p = 0.001), while maintaining similar sensitivity (91.35% vs. 96.42%, p = 0.32) and specificity (94.09% vs. 93.67%, p = 0.56) compared with the comparator strategy. Similar patterns were observed for CIN2+ detection. Women with a positive HPV16/18/58/33/31 genotyping test had high enough risk for CIN3+ for colposcopy referral, while the risk for women with a negative test was below the 1-year return decision threshold according to internal benchmarks. CONCLUSIONS: Our findings suggested extended HPV genotyping is of potential to be used as a triage technique integrated into HPV-based cervical cancer screening, leading to reduced need for colposcopy referral while maintaining similar disease detection and efficient risk stratification.

Safety of pembrolizumab as adjuvant therapy in a pooled analysis of phase 3 clinical trials of melanoma, non-small cell lung cancer, and renal cell carcinoma.

BACKGROUND: The safety profile of adjuvant pembrolizumab was evaluated in a pooled analysis of 4 phase 3 clinical trials. METHODS: Patients had completely resected stage IIIA, IIIB, or IIIC melanoma per American Joint Committee on Cancer, 7th edition, criteria (AJCC-7; KEYNOTE-054); stage IIB or IIC melanoma per AJCC-8 (KEYNOTE-716); stage IB, II, or IIIA non-small cell lung cancer per AJCC-7 (PEARLS/KEYNOTE-091); or postnephrectomy/metastasectomy clear cell renal cell carcinoma at increased risk of recurrence (KEYNOTE-564). Patients received adjuvant pembrolizumab 200 mg (2 mg/kg up to 200 mg for pediatric patients) or placebo every 3 weeks for approximately 1 year. Adverse events (AEs) were summarized for patients who received ≥ 1 dose of treatment. RESULTS: Data were pooled from 4125 patients treated with pembrolizumab (n = 2060) or placebo (n = 2065). Median (range) duration of treatment was 11.1 months (0.0-18.9) with pembrolizumab and 11.2 months (0.0-18.1) with placebo. Treatment-related AEs occurred in 78.6 % (1620/2060) of patients in the pembrolizumab group (grade 3-5, 16.3 % [336/2060]) and 58.7 % (1212/2065) in the placebo group (grade 3-5, 3.5 % [72/2065]). Immune-mediated AEs (e.g. adrenal insufficiency, hypophysitis, and thyroiditis) occurred in 36.2 % (746/2060) of patients in the pembrolizumab group (grade 3-5, 8.6 % [177/2060]) and 8.4 % (174/2065) in the placebo group (grade 3-5, 1.1 % [23/2065]). Of patients with ≥ 1 immune-mediated AE or infusion reaction, systemic corticosteroids were required for 35.2 % (268/761) and 20.2 % (39/193) of patients in the pembrolizumab and placebo groups, respectively. CONCLUSIONS: Adjuvant pembrolizumab demonstrated a manageable safety profile that was comparable to prior reports in advanced disease.

Long-Term Visit-to-Visit Blood Pressure Variability and Cognitive Decline Among Patients With Hypertension: A Pooled Analysis of 3 National Prospective Cohorts.

BACKGROUND: A limited number of studies investigated the association between blood pressure variability (BPV) and cognitive impairment in patients with hypertension. This study aimed to identify the longitudinal association between BPV and cognitive decline and the role of blood pressure (BP) control in this association. METHODS AND RESULTS: Participants with hypertension from the HRS (Health and Retirement Study), the ELSA (English Longitudinal Study of Ageing), and the CHARLS (China Health and Retirement Longitudinal Study) were included. Variation independent of the mean (VIM) was adopted to measure BPV. Cognitive function was measured by standard questionnaires, and a standardized Z score was calculated. Linear mixed-model and restricted cubic splines were adopted to explore the association between BPV and cognitive decline. The study included 4853, 1616, and 1432 eligible patients with hypertension from the HRS, ELSA, and CHARLS, respectively. After adjusting for covariates, per-SD increment of VIM of BP was significantly associated with global cognitive function decline in Z scores in both systolic BP (pooled ß, -0.045 [95% CI, -0.065 to -0.029]) and diastolic BP (pooled ß, -0.022 [95% CI, -0.040 to -0.004]) among hypertensive patients. Similar inverse associations were observed in patients with hypertension taking antihypertensive drugs and in patients with hypertension with well-controlled BP. CONCLUSIONS: High BPV was independently associated with a faster cognitive decline among patients with hypertension, even those with antihypertensive medications or well-controlled BP. Further studies are needed to confirm our results and determine whether reducing BPV can prevent or delay cognitive decline.

A Comparative Analysis of Positive and Negative Stimuli for Takotsubo Cardiomyopathy: A Pooled Analysis of Two Studies and a Systematic Review.

Takotsubo cardiomyopathy (TTC) is characterized by transient myocardial dysfunction triggered by both negative and positive emotional experiences, known respectively as broken heart syndrome (BHS) and happy heart syndrome (HHS). Despite the scarcity of comparative analyses between HHS and BHS in the literature, our pooled analysis, incorporating two retrospective registry analyses of 1395 TTC patients (57 HHS and 1338 BHS), reveals that while BHS is more prevalent, both conditions exhibit similar clinical presentations and outcomes. Statistical analyses, utilizing binary random effects models, indicate that diabetes mellitus is less common in HHS patients and serves as a predictor for BHS. Furthermore, there are differences in cardiac imaging between the two groups; individuals with HHS have higher odds of experiencing midventricular ballooning, whereas those with BHS are more likely to have apical ballooning. These findings highlight the similarities in clinical features and outcomes between HHS and BHS, while also illustrating distinct imaging profiles. The study emphasizes the need for future prospective studies to delve deeper into the implications of these TTC subtypes, offering valuable insights into their comparative aspects and underlying mechanisms.

The Safety of Cold Versus Hot Snare Polypectomy in Polyps 10-20 mm: A Systematic Review and Meta-Analysis.

Colonoscopy remains the primary method for preventing colorectal cancer. Traditionally, hot snare polypectomy (HSP) was the method of choice for removing polyps larger than 5 mm. Yet, for polyps smaller than 10 mm, cold snare polypectomy (CSP) has become the favored approach. Lately, the use of CSP has expanded to include the removal of sessile polyps that are between 10 and 20 mm in size. Our systematic review and meta-analysis aimed to evaluate the safety of cold snare polypectomy (CSP) compared to hot snare polypectomy (HSP) for resecting polyps measuring 10-20 mm. We searched the Medical Literature Analysis and Retrieval System Online (MEDLINE), Embase, and Cochrane databases up to April 2020 to find studies that directly compared CSP to HSP for polyps larger than 10 mm. Our main focus was on assessing the risk of delayed bleeding after polypectomy; a secondary focus was the incidence of any adverse events that required medical intervention post procedure. Our search yielded three comparative studies, two observational studies, and one randomized controlled trial (RCT), together encompassing 1,193 polypectomy procedures. Of these, 485 were performed using CSP and 708 with HSP. The pooled odds ratio (OR) for post-polypectomy bleeding (PPB) was 0.36 (95% confidence interval {CI}: 0.02, 7.13), with a Cochran Q test P-value of 0.11 and an I2 of 53%. For the risk of any adverse events necessitating medical care, the pooled OR was 0.15 (95% CI: 0.01, 2.29), with a Cochran Q test P-value of 0.21 and an I2 of 35%. The quality of the two observational studies was deemed moderate, and the RCT was only available in abstract form, preventing quality assessment. Our analysis suggests that there is no significant difference in the incidence of delayed post-polypectomy bleeding or other adverse events requiring medical attention between CSP and HSP for polyps measuring 10-20 mm.

Dietary Fiber Intake and Risk of Advanced and Aggressive Forms of Prostate Cancer: A Pooled Analysis of 15 Prospective Cohort Studies.

BACKGROUND: Evidence of an association between dietary fiber intake and risk of advanced and aggressive forms of prostate cancer (PC) and PC mortality is limited. OBJECTIVE: The aim of this study was to examine associations between intakes of dietary fiber overall and by food source and risk of advanced and aggressive forms of PC. DESIGN: The study design was a pooled analysis of the primary data from 15 cohorts in 3 continents. Baseline dietary fiber intake was assessed using a validated food frequency questionnaire or diet history in each study. PARTICIPANTS/SETTING: There were 842 149 men followed for up to 9 to 22 years between 1985 and 2009 across studies. MAIN OUTCOME MEASURES: The primary outcome measures were advanced (stage T4, N1, or M1 or PC mortality), advanced restricted (excluded men with missing stage and those with localized PC who died of PC), and high-grade PC (Gleason score ≥8 or poorly differentiated/undifferentiated) and PC mortality. STATISTICAL ANALYSIS PERFORMED: Study-specific multivariable hazard ratios (MVHR) were calculated using Cox proportional hazards regression and pooled using random effects models. RESULTS: Intake of dietary fiber overall, from fruits, and from vegetables was not associated with risk of advanced (n = 4863), advanced restricted (n = 2978), or high-grade PC (n = 9673) or PC mortality (n = 3097). Dietary fiber intake from grains was inversely associated with advanced PC (comparing the highest vs lowest quintile, MVHR 0.84; 95% CI 0.76-0.93), advanced restricted PC (MVHR 0.85; 95% CI 0.74-0.97), and PC mortality (MVHR 0.78; 95% CI 0.68-0.89); statistically significant trends were noted for each of these associations (P ≤ .03), and a null association was observed for high-grade PC for the same comparison (MVHR 1.00; 95% CI 0.93-1.07). The comparable results were 1.06 (95% CI 1.01-1.10; P value, test for trend = .002) for localized PC (n = 35,199) and 1.05 (95% CI 0.99-1.11; P value, test for trend = .04) for low/intermediate grade PC (n = 34 366). CONCLUSIONS: Weak nonsignificant associations were observed between total dietary fiber intake and risk of advanced forms of PC, high-grade PC, and PC mortality. High dietary fiber intake from grains was associated with a modestly lower risk of advanced forms of PC and PC mortality.

Pembrolizumab Plus Chemotherapy for Metastatic NSCLC With Programmed Cell Death Ligand 1 Tumor Proportion Score Less Than 1%: Pooled Analysis of Outcomes After Five Years of Follow-Up.

BACKGROUND: We report long-term outcomes from a pooled analysis of patients with previously untreated metastatic NSCLC with programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS) less than 1% enrolled in phase III studies of pembrolizumab plus chemotherapy versus placebo plus chemotherapy. METHODS: This exploratory pooled analysis included individual patient data from the KEYNOTE-189 global (NCT02578680) and Japan extension (NCT03950674) studies of metastatic nonsquamous NSCLC without EGFR or ALK alterations and the KEYNOTE-407 global (NCT02775435) and People's Republic of China extension (NCT03875092) studies of metastatic squamous NSCLC. Patients received pembrolizumab or placebo plus pemetrexed and cisplatin or carboplatin in KEYNOTE-189 and pembrolizumab or placebo plus carboplatin and paclitaxel or nab-paclitaxel in KEYNOTE-407. PD-L1 TPS was centrally assessed using PD-L1 IHC 22C3 pharmDx (Agilent Technologies, Carpinteria, CA). RESULTS: Overall, 442 patients were included in this analysis (pembrolizumab plus chemotherapy, n = 255; chemotherapy, n = 187). The median follow-up was 60.7 (range, 49.9‒72.0) months. Pembrolizumab plus chemotherapy improved overall survival (hazard ratio, 0.64; 95% confidence interval [CI]: 0.51‒0.79) and progression-free survival (hazard ratio, 0.66; 95% CI: 0.54‒0.81) versus chemotherapy. The 5-year overall survival rates (95% CI) were 12.5% (8.6%‒17.3%) versus 9.3% (5.6%‒14.1%). Grades 3 to 5 treatment-related adverse events occurred in 59.1% of patients for pembrolizumab plus chemotherapy and 61.3% for chemotherapy. CONCLUSION: With approximately 5 years of follow-up, pembrolizumab plus chemotherapy provided clinically meaningful and durable improvements in survival outcomes versus chemotherapy alone in patients with previously untreated metastatic NSCLC with PD-L1 TPS less than 1%. These results continue to support pembrolizumab plus chemotherapy as a standard of care in this patient population. CLINICALTRIALS: gov, NCT02578680 (KEYNOTE-189 global), NCT03950674 (KEYNOTE-189 Japan extension), NCT02775435 (KEYNOTE-407 global), NCT03875092 (KEYNOTE-407 People's Republic of China extension).