The efficacy and safety of intravesical gemcitabine vs Bacille Calmette-Guerin for adjuvant treatment of non-muscle invasive bladder cancer: a meta-analysis Ziqi Ye,1,* Jie Chen,2,* Yun Hong,1 Wenxiu Xin,3 Si Yang,1 Yuefeng Rao1 1Department of Pharmacy, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 2The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 3Laboratory of Clinical Pharmacy, Zhejiang Cancer Hospital, Hangzhou, People’s Republic of China *These authors contributed equally to this work Objective: Several studies have compared the safety and efficacy of intravesical gemcitabine (Gem) with Bacille Calmette-Guérin (BCG) for non-muscle invasive bladder cancer. However, the results are not consistent. We carried out a meta-analysis to provide a more comprehensive analysis of the efficacy and safety of these 2 drugs. Methods: We searched PubMed, EMBASE, Cochrane Library, Clinical Trials.gov, and reference lists. Randomized controlled trials and retrospective controlled trials comparing intravesical Gem and BCG in adjuvant therapy for non-muscle invasive bladder cancer published in English were included in this study. The strength of association was weighed by pooled risk ratio (RR) with 95% CIs. Sensitivity analysis was performed to examine whether the findings of the meta-analysis were robust. Results: We analyzed 386 subjects from 5 pooled trials. Compared with BCG, intravesical Gem had lower incidence of dysuria (overall RR =0.31, 95% CI: 0.16, 0.61, I2=0%, p=0.001) and hematuria (overall RR =0.27, 95% CI: 0.11, 0.71, I2=0%, p=0.008). There were no statistical differences in risk of recurrence, progression, incidence of fever, and any adverse events between intravesical Gem and BCG therapy (p>0.05). No publication bias was found. Conclusion: This meta-analysis suggests that intravesical Gem may have similar efficacy and lower incidence of dysuria and hematuria compared with BCG. Nevertheless, we recommend additional high-quality randomized controlled trials to confirm these results. Keywords: intravesical therapy, non-muscle invasive bladder cancer, NMIBC, gemcitabine, Bacille Calmette-Guérin, meta-analysis

A novel baccharane-type triterpenoid glycoside named fatsioside A (1), together with ten oleanane glycosides, were isolated from the fruits of Fatsia japonica. The structure of fatsioside A was assigned as 3β,15α,18α-trihydroxy-18,19-secolupane-12,19-dione 3-O-β-D-glucopyranosyl-(1 → 2)-β-D-glucopyranoside by extensive NMR and HRESIMS analyses. F. japonica is the third baccharane glycoside-containing species reported to date in the plant kingdom, while fatsioside A represents the first baccharane glycoside found in the Araliaceae family. Fatsioside A inhibited the growth of rat glioma C6 cells and human glioma U251 cells with IC₅₀ values of 33.48 ± 2.01 µM and 77.58 ± 6.19 µM, respectively. Further investigation indicated that fatsioside A induced apoptosis and necrosis in glioma cells, and arrested the cell cycle at the G0/G1 phase.

Background Pembrolizumab was recently demonstrated to have survival benefit in patients with recurrent or metastatic head and neck squamous cell carcinoma (r/mHNSCC). However, the cost-effectiveness of pembrolizumab versus chemotherapy in China remains uncertain. Objective This analysis aimed to describe the cost-effectiveness of pembrolizumab versus standard-of-care (SOC) therapy in r/mHNSCC in China. Design A Markov model consisting of three health states (stable, progressive and dead) was developed to compare the cost and effectiveness of pembrolizumab with SOC in platinum-resistant r/mHNSCC. Model inputs for transition probabilities and toxicity were collected from the KEYNOTE-040 trial, while health utilities were estimated from a literature review. Cost data were acquired for the payer’s perspective in China. Costs and outcomes were discounted at an annual rate of 3.0%. Sensitivity analyses were conducted to test the uncertainties surrounding model parameters. Outcome measures The primary outcome was incremental cost-effectiveness ratios (ICERs), which were calculated as the cost per quality-adjusted life years (QALYs). Results The total mean cost of pembrolizumab and SOC was US$45 861 and US$41 950, respectively. As for effectiveness, pembrolizumab yielded 0.31 QALYs compared with 0.25 QALYs for SOC therapy. The ICER for pembrolizumab versus SOC was US$65 186/QALY, which was higher than the willingness-to-pay threshold (WTP) of US$28 130/QALY in China. The univariate sensitivity analysis indicated that utility values for progressive state, probability from stable to progressive in the SOC group, as well as cost of pembrolizumab were the three most influential variables on ICER. The probabilistic sensitivity analysis demonstrated that standard therapy was more likely to be cost-effective compared with pembrolizumab at a WTP value of US$28 130/QALY. Results were robust across both univariate analysis and probabilistic sensitivity analysis. Conclusions Pembrolizumab is not likely to be a cost-effective strategy compared with SOC therapy in patients with platinum-resistant r/mHNSCC in China. Trial registration number NCT02252042; Post-results.

Purpose: Approximately 20% of all breast cancer cases are classified as triple-negative breast cancer (TNBC), which represents the most challenging subtype due to its poor prognosis and high metastatic rate. Caffeic acid phenethyl ester (CAPE), the main component extracted from propolis, has been reported to exhibit anticancer activity across various tumor cell types. This study aimed to investigate the effects and mechanisms of CAPE on TNBC. Methods: MDA-MB-231 and MDA-MB-468 cells were treated with CAPE. CCK8 and colony formation assays were performed to analyze cell proliferation. Western blot, TUNEL and Annexin V-FITC/PI staining methods were employed to assess cell apoptosis. ROS, MDA, SOD, GSH, C11-bodipy staining, along with measurements of GPX4 and Ferritin levels, were utilized for ferroptosis detection. Western blot and immunofluorescence analysis were used to assess key regulatory molecules. The cells were subjected to treatments involving ferroptosis inhibition, AMPK inhibition, or Foxo3 inhibition, followed by CAPE administration to assess cell proliferation, apoptosis, and ferroptosis. Tumor xenografts were used to evaluate the antitumor efficacy of CAPE. Results: CAPE not only suppressed cell proliferation but also promoted apoptosis followed by ferroptosis. Co-incubation with Fer-1 (a ferroptosis inhibitor) diminished CAPE’s suppressive effects on proliferation and apoptosis induction. CAPE treatment enhanced the phosphorylation of AMPK and promoted the nuclear translocation of Foxo3. Inhibition of both AMPK and Foxo3 by siRNAs or inhibitors (Compc, TIC10) reversed the growth retardation induced by CAPE as well as its pro-apoptotic effects leading to ferroptosis. Specifically, AMPK inhibition abrogated the CAPE-induced nuclear translocation of Foxo3. CAPE significantly inhibited tumor growth in nude mice bearing TNBC xenografts. Conclusion: CAPE possesses a resistance effect on TNBC via activation of AMPK and Foxo3 signaling pathways.

This study aimed to estimate the toxicities of PARP inhibitors (PARPis), based on randomized controlled trials (RCTs) and the FDA Adverse Event Reporting System (FAERS) database. Four electronic databases were searched from inception to 16 April 2024, for RCTs of approved PARPis. The primary and secondary outcomes were grade 3-5 adverse events (AEs) and grade 3-5 hematological AE, respectively. We conducted network meta-analyses to calculate the relative risks (RRs) and 95% confidence intervals (CIs) of outcomes. A disproportionality analysis was conducted to estimate the signals of hematological AEs associated with PARPis from the FAERS database. Overall, 27 RCTs involving 11,067 patients with cancer were included. Olaparib had the best safety profile for any grade 3-5 AEs and hematological AEs among four approved PARPis. Olaparib did not increase the risk of thrombocytopenia (RR: 1.48; 95%CI: 0.64-3.39), but other PARPis did. Furthermore 14,780 hematological AE reports associated with PARPis were identified in the FAERS database, and all PARPis were associated with strong hematological AE signals. Hematological AEs mainly occurred within the first 3 months (80.84%) after PARPi initiation. Olaparib had the best safety profile among five PARPis. PARPi-associated hematological AEs mainly occurred within the first 3 months. PROSPERO (CRD42022385274).