Efficacy and safety of fentanyl inhalant for the treatment of breakthrough cancer pain: a multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Breakthrough cancer pain (BTcP) has a negative impact on patients' quality of life, general activities, and is related to worse clinical outcomes. Fentanyl inhalant is a hand-held combination drug-device delivery system providing rapid, multi-dose (25µg/dose) administration of fentanyl via inhalation of a thermally generated aerosol. This multicenter, randomized, placebo-controlled, multiple-crossover, double-blind study evaluated the efficacy, safety, and tolerability of fentanyl inhalant in treating BTcP in opioid-tolerant patients. METHODS: The trial was conducted in opioid-tolerant cancer patients with 1 ~ 4 BTcP outbursts per day. Each patient was treated and observed for 6 episodes of BTcP (4 with fentanyl inhalant, 2 with placebo). During each episode of targeted BTcP, patients were allowed up to six inhalations, with an interval of at least 4 min between doses. Primary outcome was the time-weighted sum of PID (pain intensity difference) scores at 30 min (SPID30). RESULTS: A total of 335 BTcP episodes in 59 patients were treated. The mean SPID30 was -97.4 ± 48.43 for fentanyl inhalant-treated episodes, and -64.6 ± 40.25 for placebo-treated episodes (p < 0.001). Significant differences in PID for episodes treated with fentanyl inhalant versus placebo was seen as early as 4 min and maintained for up to 60 min. The percentage of episodes reported PI (pain intensity) scores ≤ 3, a ≥ 33% or ≥ 50% reduction in PI scores at 30 min, PR30 (pain relief scores at 30 min) and SPID60 favored fentanyl inhalant over placebo. Only 4.4% of BTcP episodes required rescue medication in fentanyl inhalant group. Most AEs were of mild or moderate severity and typical of opioid drugs. CONCLUSION: Treatment with fentanyl inhalant was shown to be a promising therapeutic option for BTcP, with significant pain relief starting very soon after dosing. Confirmation of effectiveness requires a larger phase III trial. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05531422 registered on 6 September 2022 after major amendment, NCT04713189 registered on 14 January 2021.

Efficacy and safety of standard BEACOPP regimen versus ABVD regimen for treatment of advanced Hodgkin's lymphoma.

INTRODUCTION: The current treatment regimens for Hodgkin's lymphoma (HL) are associated with high incidences of adverse events. PURPOSE: This study aimed to compare the efficacy and safety of doxorubicin + bleomycin + vincristine + dacarbazine (ABVD) and standard bleomycin + etoposide + doxorubicin + cyclophosphamide + vincristine + procarbazine + prednisone (BEACOPP) chemotherapy in the treatment of advanced stage HL. METHODS: This multicenter, randomized, parallel, open, positive control noninferiority trial was conducted from 2016 to 2019 and comprised 93 subjects who were randomized in a 1:1 ratio between the treatment (BEACOPP; n = 44) and control (ABVD; n = 49) groups. RESULTS: The primary efficacy endpoint of this trial was the objective response rate (ORR) after eight cycles of chemotherapy, which was 100.00% (36/36) in the treatment group and 95.74% (45/49) in the control group. The incidence of adverse reactions was 100% in both groups. Significant differences (P < 0.05) in the incidences of grade 3 (39/44 [88.64%] vs. 23/49 [46.94%]) and grade 4 (27/44 [61.36%] vs. 8/49 [16.94%]) adverse events were observed between the treatment and control groups, respectively. However, most of these reactions were manageable, with no serious consequences, and were reversible after discontinuation of the treatment. CONCLUSION: Both regimens had a similar ORR and were associated with a high number of adverse events. The ABVD regimen was better tolerated and safer than the standard BEACOPP regimen. This study indicates that the standard BEACOPP regimen may be considered as a treatment option for patients with advanced HL.

Isolation and characterization of ZK002, a novel dual function snake venom protein from Deinagkistrodon acutus with anti-angiogenic and anti-inflammatory properties.

Introduction: Pathological angiogenesis, the abnormal or excessive generation of blood vessels, plays an important role in many diseases including cancer, diabetic retinopathy, psoriasis, and arthritis. Additionally, increasing evidence supports the close linkage between angiogenesis and inflammation. Snake venoms are a rich natural source of biologically active molecules and carry rich potential for the discovery of anti-angiogenic and anti-inflammatory modulators. Methods: Here, we isolated and purified a novel protein, ZK002, from the venom of the snake Deinagkistrodon acutus, and investigated its anti-angiogenic and anti-inflammatory activities and mechanisms. Results: ZK002 was identified as a 30 kDa heterodimeric protein of α and ß chains, which exhibited anti-angiogenic activity in various in vitro assays. Mechanistically, ZK002 inhibited activation of VEGF signaling and related mediators including eNOS, p38, LIMK, and HSP27. ZK002 also upregulated the metalloproteinase inhibitor TIMP3 and inhibited components of the VEGF-induced signaling cascade, PPP3R2 and SH2D2A. The anti-angiogenic activity of ZK002 was confirmed in multiple in vivo models. ZK002 could also inhibit the in vitro expression of pro-inflammatory cytokines, as well as in vivo inflammation in the carrageenin-induced edema rat model. Conclusion: Our findings highlight the potential for further development of ZK002 as a dual function therapeutic against diseases with involvement of pathogenic angiogenesis and chronic inflammation.

Revealing the Adsorption Mechanisms of Methanol on Lithium-Doped Porous Carbon through Experimental and Theoretical Calculations.

Previous reports have shown that it is difficult to improve the methanol adsorption performance of nitrogen and oxygen groups due to their low polarity. Here, we first prepared porous carbon with a high specific surface area and large pore volume using benzimidazole as a carbon precursor and KOH as an activating agent. Then, we improved the surface polarity of the porous carbon by doping with Lithium (Li) to enhance the methanol adsorption performance. The results showed that the methanol adsorption capacity of Li-doped porous carbon reached 35.4 mmol g-1, which increased by 57% compared to undoped porous carbon. Molecular simulation results showed that Li doping not only improved the methanol adsorption performance at low pressure, but also at relatively high pressure. This is mainly because Li-modified porous carbon has higher surface polarity than nitrogen and oxygen-modified surfaces, which can generate stronger electrostatic interactions. Furthermore, through density functional theory (DFT) calculations, we determined the adsorption energy, adsorption distance, and charge transfer between Li atom and methanol. Our results demonstrate that Li doping enhances the adsorption energy, reduces the adsorption distance, and increases the charge transfer in porous carbon. The mechanism of methanol adsorption by Li groups was revealed through experimental and theoretical calculations, providing a theoretical basis for the design and preparation of methanol adsorbents.

Efficacy and Safety of Anti-Programmed Death-Ligand 1 Monoclonal Antibody Socazolimab With Carboplatin and Etoposide for Extensive-Stage SCLC: Results From the Phase 1b Clinical Trial.

Introduction: The study (ClinicalTrials.gov, NCT04346914) is an open label, single-arm, phase 1b clinical trial investigating the safety, tolerability, and efficacy of the recombinant human anti-programmed death-ligand 1 monoclonal antibody socazolimab in combination with carboplatin and etoposide in the first-line treatment of extensive-stage SCLC. Good safety and efficacy were found in previous phase 1 clinical trials of other cancers, such as cervix cancer. Methods: Patients received socazolimab (5 mg/kg) every three weeks until disease progression or physician decision. Carboplatin (area under the curve: 5) was also administered every three weeks and etoposide (100 mg/m2) on days 1, 2, and 3 of the treatment cycle. The primary purpose of the study was safety measured by the Common Terminology Criteria for Adverse Events. Secondary purposes included objective response rate, progression-free survival, duration of response, and overall survival. Results: From April 15, 2020 (enrollment date), to December 30, 2021 (data cutoff), 20 patients with extensive-stage SCLC were administered with socazolimab, carboplatin, and etoposide. Objective response rate was 70.0% (95% confidence interval [CI]: 45.72%-88.11%). Median progression-free survival was 5.65 months (95% CI: 4.14-6.54), and the median duration of response was 4.29 months (95% CI: 2.76-5.85). Median overall survival was 14.88 months (95% CI: 10.09-not evaluated). The highest incidence of treatment-related adverse events included anemia (100%), decreased neutrophil count (95%), decreased platelet count (95%), and decreased white blood cell count (95%), which occurred during combination therapy. The most common grade 3 or 4 treatment-related adverse events were neutropenia (90%), decreased white blood cell count (65%), decreased platelet count (50%), and anemia (30%), which were also common adverse reactions of chemotherapy. No adverse events leading to death had occurred. Conclusions: Results revealed that the combination therapy of socazolimab, carboplatin, and etoposide had preliminarily confirmed the safety of socazolimab in the first-line treatment of SCLC combined with EC chemotherapy. Currently, a phase 3, randomized, placebo-controlled trial (ClinicalTrials.gov, NCT04878016) is being conducted with 498 patients.

Comparing a PD-L1 inhibitor plus chemotherapy to chemotherapy alone in neoadjuvant therapy for locally advanced ESCC: a randomized Phase II clinical trial : A randomized clinical trial of neoadjuvant therapy for ESCC.

BACKGROUND: A Phase II study was undertaken to evaluate the safety and efficacy of the neoadjuvant socazolimab, a novel PD-L1 inhibitor, in combination with nab-paclitaxel and cisplatin for locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Sixty-four patients were randomly divided between the Socazolimab + nab-paclitaxel + cisplatin (TP) arm (n = 32) and the control arm (n = 32), receiving either socazolimab (5 mg/kg intravenously (IV), day 1) or a placebo with nab-paclitaxel (125 mg/m2 IV, day 1/8) and cisplatin (75 mg/m2 IV, day 1) repeated every 21 days for four cycles before surgery. The primary endpoint was major pathological response (MPR), and the secondary endpoints were pathological complete response (pCR), R0 resection rate, event-free survival (EFS), overall survival (OS), and safety. RESULTS: A total of 29 (90.6%) patients in each arm underwent surgery, and 29 (100%) and 28 (98.6%) patients underwent R0 resection in the Socazolimab + TP and Placebo + TP arms, respectively. The MPR rates were 69.0 and 62.1% (95% Confidence Interval (CI): 49.1-84.0% vs. 42.4-78.7%, P = 0.509), and the pCR rates were 41.4 and 27.6% (95% CI: 24.1-60.9% vs. 13.5-47.5%, P = 0.311) in the Socazolimab + TP and Placebo + TP arms, respectively. Significantly higher incidence rates of ypT0 (37.9% vs. 3.5%; P = 0.001) and T downstaging were observed in the Socazolimab + TP arm than in the Placebo + TP arm. The EFS and OS outcomes were not mature. CONCLUSIONS: The neoadjuvant socazolimab combined with chemotherapy demonstrated promising MPR and pCR rates and significant T downstaging in locally advanced ESCC without increasing surgical complication rates. TRIAL REGISTRATION: Registration name (on clinicaltrials.gov): A Study of Anti-PD-L1 Antibody in Neoadjuvant Chemotherapy of Esophageal Squamous Cell Carcinoma. REGISTRATION NUMBER: NCT04460066.

Organic-inorganic composite modifiers enhance restoration potential of Nerium oleander L. to lead-zinc tailing: application of phytoremediation.

Lead-zinc tailings are complex heavy metal solid wastes produced in the mining process. In this study, two kinds of organic-inorganic mixed improvers mushroom residue + calcium carbonate (M + C) and peat soil + calcium carbonate (N + C) were selected. Then, the effect of two improvers and a woody plant, Nerium oleander L., on the combined remediation of lead-zinc tailings was compared, respectively. The results showed that two combined improvers can slightly improve the pH of tailing, significantly increase the activity of phosphatase and catalase, effectively reduce the contents of DTPA-extractable Pb and Zn, and significantly improve the structure of tailing. However, the improvement effect of M + C was better than that of N + C on tailings' physical and chemical properties. Two improvers can reduce the enrichment and the stress degree of Pb and Zn on the N. oleander and increase the accumulation of Pb and Zn while promoting the growth of the N. oleander. The content of Pb and Zn showed the trend of root > stem > leaf under the two improvers, and the content of Zn was basically higher than that of Pb. To sum up, the combination of two modifiers and N. oleander has a good effect on the remediation of lead-zinc tailings, and the remediation effect of M + C was better than N + C.

Safety and Tolerability of Tecarfarin (ATI-5923) in Healthy Chinese Volunteers: Multiple Oral Dose-Escalation Phase I Trial.

BACKGROUND: Tecarfarin (ATI-5923), a structural analog of warfarin, was designed to provide more uniform and stable anticoagulation. OBJECTIVE: We aimed to evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic profile of tecarfarin when administered in multiple ascending doses (MADs) to healthy Chinese volunteers. METHODS: Forty healthy Chinese volunteers were enrolled into four sequential cohorts (10, 20, 30, and 40 mg), with 10 subjects in each cohort. Participants in the MAD study for each sequential cohort were dose-titrated to achieve the target international normalized ratio (INR 1.7-2.0) for 14 days. Safety and tolerability were assessed throughout the study. RESULTS: The pharmacokinetic and pharmacodynamic profile of tecarfarin was investigated in a healthy Chinese population. Dose titration of tecarfarin was necessary to keep the INR in the target range in all subjects in the 20, 30 and 40 mg cohorts and a few subjects (n = 3) in the 10 mg cohort. Tecarfarin was well tolerated without serious adverse events. Only one treatment-related adverse event (hematochezia) resulted in early withdrawal from the MAD 40 mg cohort. CONCLUSION: Tecarfarin was well-tolerated by Chinese volunteers. Dose titration was needed for tecarfarin doses larger than 20 mg to keep the INR in the target range. REGISTRATION: ClinicalTrials.gov identifier: NCT04627116.

First-in-Maintenance Therapy for Localized High-Grade Osteosarcoma: An Open-Label Phase I/II Trial of the Anti-PD-L1 Antibody ZKAB001.

PURPOSE: We investigated the safety and preliminary efficacy of anti-PD-L1 antibody (ZKAB001) as maintenance therapy for localized patients with high-grade osteosarcoma to reduce the risk of recurrence and metastasis. PATIENTS AND METHODS: This open-label Phase I/II study was divided into dose-escalation Phase I and expansion Phase II. Phase I used a 3+3 design with ZKAB001 at three escalating doses ranging: 5, 10, 15 mg/kg every 2 weeks in 9 patients with localized high-grade osteosarcoma and Phase II tested 10 mg/kg in 12 patients for up to 24 cycles. Primary endpoints were safety and tolerability assessed using CTCAE4.0.3. RESULTS: Between October 2018 and 2019, 21 eligible patients were enrolled and accepted ZKAB001 treatment: 9 in the dose-escalation phase, and 12 in expansion phase. Six patients with disease progression withdrew from this study and follow-up is ongoing. The MTD was not defined in Phase I. All doses had a manageable safety profile. The recommended dose in Phase II was set at 10 mg/kg. Most frequent immune-related adverse events were thyroiditis (76.2%) and dermatitis (42.9%). Only 1 (4.8%) of 21 patients had a Grade 3 skin rash. The median 3-year event-free survival (EFS) and overall survival (OS) were not established; however, 24-month EFS was 71.4% (95% confidence interval, 47.2-86.0) and 2-year OS was 100%. Preliminary efficacy data showed EFS benefits in patients with PD-L1 positive or an MSI-H sub-population. CONCLUSIONS: Switching to maintenance using ZKAB001 showed an acceptable safety profile and provided preliminary evidence of clinical activity in localized patients with osteosarcoma.

Lead Responses and Tolerance Mechanisms of Koelreuteria paniculata: A Newly Potential Plant for Sustainable Phytoremediation of Pb-Contaminated Soil.

Phytoremediation could be an alternative strategy for lead (Pb) contamination. K. paniculata has been reported as a newly potential plant for sustainable phytoremediation of Pb-contaminated soil. Physiological indexes, enrichment accumulation characteristics, Pb subcellular distribution and microstructure of K. paniculata were carefully studied at different levels of Pb stress (0-1200 mg/L). The results showed that plant growth increased up to 123.8% and 112.7%, relative to the control group when Pb stress was 200 mg/L and 400 mg/L, respectively. However, the average height and biomass of K. paniculata decrease when the Pb stress continues to increase. In all treatment groups, the accumulation of Pb in plant organs showed a trend of root > stem > leaf, and Pb accumulation reached 81.31%~86.69% in the root. Chlorophyll content and chlorophyll a/b showed a rising trend and then fell with increasing Pb stress. Catalase (CAT) and peroxidase (POD) activity showed a positive trend followed by a negative decline, while superoxide dismutase (SOD) activity significantly increased with increasing levels of Pb exposure stress. Transmission electron microscopy (TEM) showed that Pb accumulates in the inactive metabolic regions (cell walls and vesicles) in roots and stems, which may be the main mechanism for plants to reduce Pb biotoxicity. Fourier transform infrared spectroscopy (FTIR) showed that Pb stress increased the content of intracellular -OH and -COOH functional groups. Through organic acids, polysaccharides, proteins and other compounds bound to Pb, the adaptation and tolerance of K. paniculata to Pb were enhanced. K. paniculata showed good phytoremediation potential and has broad application prospects for heavy metal-contaminated soil.