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.

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.

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.

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.

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