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.
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.

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.

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.
RESULTS: 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.
CONCLUSIONS: 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.

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.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: This combined analysis suggests that probiotics could be beneficial in the prevention of irinotecan-induced diarrhea in colorectal cancer patients with colostomy.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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%).
UNASSIGNED: Gumarontinib showed promising antitumour activity in driver-gene negative locally advanced or metastatic NSCLC patients with MET overexpression, which warranted a further clinical trial.
UNASSIGNED: ClinicalTrials.gov identifier: NCT03457532; NCT04270591.

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.

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.

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.
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 β, -0.045 [95% CI, -0.065 to -0.029]) and diastolic BP (pooled β, -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.

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.
CONCLUSIONS: 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.