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Inspired by tug-of-war, a game-changing bone-tendon fixation paradigm was developed. Specifically, injectable citrate-based bioactive self-expansive and planar-fixing screw (iCSP-Scr) consisting of reactive isocyanate (NCO) terminalized citrate-based polyurethane, proanthocyanidin modified hydroxyapatite (HAp) and water (with/without porogen) was developed and administrated in the bone-tendon gap. Instead of the "point to point" tendon fixation by traditional interface screws, along with the moisture-induced crosslinking and expansion of iCSP-Scr within the confined space of the irregularly shaped bone-tendon gap, the tendon graft was evenly squeezed into the bone tunnel in a "surface to surface" manner to realize strong and stable bone-tendon fixation via physical expansion, mechanical interlocking and chemical bonding (between -NCO and the -NH2, -SH groups on bone matrix). The optimized iCSP-Scr exhibited rapid crosslinking, moderate expansion rate, high porosity after crosslinking, as well as tunable elasticity and toughness. The iCSP-Scr possessed favorable biodegradability, biocompatibility, and osteoinductivity derived from citrate, PC and HAp, it was able to promote osteogenesis and new bone growth inward of bone tunnel thus further enhanced the bone/iCSP-Scr mechanical interlock, ultimately leading to stronger tendon fixation (pull-out force 106.15 ± 23.15 N) comparing to titanium screws (93.76 ± 17.89 N) after 14 weeks' ACL reconstruction in a rabbit model. The iCSP-Scr not only can be used as a self-expansive screw facilitating bone-tendon healing, but also can be expanded into other osteogenic application scenarios.
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BACKGROUND: The combination of anti-programmed death 1 (PD-1) inhibitors and tyrosine kinase inhibitors is an effective treatment strategy in endometrial cancer. We aimed to explore the efficacy and safety of camrelizumab plus apatinib as an alternative therapeutic option in patients with previously treated endometrial cancer. METHODS: This single-arm Simon's two-stage phase II trial was conducted at the Fudan University Shanghai Cancer Center. Patients with advanced or recurrent endometrial cancer who had failed at least one prior systemic therapy were screened for potential participation. Eligible patients were treated with intravenous camrelizumab (200 mg d1 q2w) and oral apatinib (250 mg qd) every 4 weeks. The primary end point was the objective response rate (ORR) per RECIST v1.1 in the intention-to-treat principle. RESULTS: Between January 20, 2020, and October 14, 2022, 36 patients (29 with microsatellite stability/mismatch repair proficient [MSS/pMMR] tumors; two with microsatellite instability-high/mismatch repair deficient [MSI-H/dMMR] tumors) were enrolled and treated. The confirmed ORR was 44.4% (95% CI: 27.9, 61.9) and the disease control rate was 91.7% (95% CI: 77.5, 98.2). The median duration of response was 9.3 (95% CI: 4.3, not reached) months, the median progression-free survival was 6.2 (95% CI: 5.3, 11.1) months, and the median overall survival was 21.0 (95% CI: 13.4, not reached) months during a median follow-up of 14.2 (interquartile range: 10.3, 27.6) months. Treatment-related adverse events of grade 3 or 4 occurred in 20 (55.6%) patients, with the most common being increased γ-glutamyl transferase (27.8%), alanine aminotransferase (16.7%) and aspartate aminotransferase (13.9%), and hypertension (11.1%). No treatment-related death occurred. CONCLUSIONS: Camrelizumab plus apatinib showed promising antitumor activity with manageable toxicity in patients with advanced or recurrent endometrial cancer who had failed at least one prior systemic therapy. The findings of this study support further investigation of camrelizumab plus apatinib as an alternative therapeutic option, especially for patients with MSS/pMMR tumors. TRIAL REGISTRATION: This trial was retrospectively registered with ChiCTR.org.cn, number ChiCTR2000031932.
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Anticuerpos Monoclonales Humanizados , Neoplasias Endometriales , Piridinas , Humanos , Femenino , Persona de Mediana Edad , Piridinas/uso terapéutico , Piridinas/administración & dosificación , Neoplasias Endometriales/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anciano , Adulto , Recurrencia Local de Neoplasia/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificaciónRESUMEN
Recent single-arm studies involving neoadjuvant camrelizumab, a PD-1 inhibitor, plus chemotherapy for resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC) have shown promising results. This multicenter, randomized, open-label phase 3 trial aimed to further assess the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy followed by adjuvant camrelizumab, compared to neoadjuvant chemotherapy alone. A total of 391 patients with resectable thoracic LA-ESCC (T1b-3N1-3M0 or T3N0M0) were stratified by clinical stage (I/II, III or IVA) and randomized in a 1:1:1 ratio to undergo two cycles of neoadjuvant therapy. Treatments included camrelizumab, albumin-bound paclitaxel and cisplatin (Cam+nab-TP group; n = 132); camrelizumab, paclitaxel and cisplatin (Cam+TP group; n = 130); and paclitaxel with cisplatin (TP group; n = 129), followed by surgical resection. Both the Cam+nab-TP and Cam+TP groups also received adjuvant camrelizumab. The dual primary endpoints were the rate of pathological complete response (pCR), as evaluated by a blind independent review committee, and event-free survival (EFS), as assessed by investigators. This study reports the final analysis of pCR rates. In the intention-to-treat population, the Cam+nab-TP and Cam+TP groups exhibited significantly higher pCR rates of 28.0% and 15.4%, respectively, compared to 4.7% in the TP group (Cam+nab-TP versus TP: difference 23.5%, 95% confidence interval (CI) 15.1-32.0, P < 0.0001; Cam+TP versus TP: difference 10.9%, 95% CI 3.7-18.1, P = 0.0034). The study met its primary endpoint of pCR; however, EFS is not yet mature. The incidence of grade ≥3 treatment-related adverse events during neoadjuvant treatment was 34.1% for the Cam+nab-TP group, 29.2% for the Cam+TP group and 28.8% for the TP group; the postoperative complication rates were 34.2%, 38.8% and 32.0%, respectively. Neoadjuvant camrelizumab plus chemotherapy demonstrated superior pCR rates compared to chemotherapy alone for LA-ESCC, with a tolerable safety profile. Chinese Clinical Trial Registry identifier: ChiCTR2000040034 .
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MnO2 is commonly used as the cathode material for aqueous zinc-ion batteries (AZIBs). The strong Coulombic interaction between Zn ions and the MnO2 lattice causes significant lattice distortion and, combined with the Jahn-Teller effect, results in Mn2+ dissolution and structural collapse. While proton intercalation can reduce lattice distortion, it changes the electrolyte pH, producing chemically inert byproducts. These issues greatly affect the reversibility of Zn2+ intercalation/extraction, leading to significant capacity degradation of MnO2. Herein, we propose a novel method to enhance the cycling stability of δ-MnO2 through selenium doping (Se-MnO2). Our work indicates that varying the selenium doping content can regulate the intercalation ratio of H+ in MnO2, thereby suppressing the formation of ZnMn2O4 by-products. Se doping mitigates the lattice strain of MnO2 during Zn2+ intercalation/deintercalation by reducing Mn-O octahedral distortion, modifying Mn-O bond length upon Zn2+ insertion, and alleviating Mn dissolution caused by the Jahn-Teller effect. The optimized Se-MnO2 (Se concentration of 0.8 at.%) deposited on carbon nanotube demonstrates a notable capacity of 386 mAh g-1 at 0.1 A g-1, with exceptional long-term cycle stability, retaining 102 mAh g-1 capacity after 5000 cycles at 3.0 A g-1.
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Vanadium oxide has been extensively studied as a host of zinc ion intercalation but still suffers from low conductivity, dissolution, and byproduct accumulation during cycling. Here, we hydrothermally synthesize the VO2@MXene Ti3C2 (MV) composite and find that in the MV//3 M Zn(CF3SO3)2//Zn system, the double hydroxide Zn12(CF3SO3)9(OH)15·nH2O (ZCOH) uniformly covers VO2 during the charging process and dissolves reversibly during the discharge process. In situ X-ray diffraction of the MV combined with in situ pH measurements reveals that ZCOH acts as a pH buffer during cycling, which is beneficial to the cycling stability of batteries. And the theoretical calculation indicates that the decomposition energy required by ZCOH on the MV surface is lower than that on pure VO2, which is more conducive to ZCOH dissolution. The coin battery exhibits high-rate performance of 65.1% capacity retention at a current density of 15 A g-1 (compared to 0.6 A g-1) and a long cycling life of 20,000 cycles with a capacity retention of 80.7%. For a 22.4 mA h soft-packaged battery, its capacity remains at 72.1% after 2000 cycles. This work demonstrates the active role of ZCOH in the electrochemical process of VO2 and provides a new perspective for exploiting this mechanism to develop high-performance aqueous zinc-ion battery vanadium oxide cathode materials.
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BACKGROUND: The current standard of care for locally advanced gastric cancer (GC) involves neoadjuvant chemotherapy followed by radical surgery. Recently, neoadjuvant treatment for this condition has involved the exploration of immunotherapy plus chemotherapy as a potential approach. However, the efficacy remains uncertain. METHODS: A single-arm, phase 2 study was conducted to evaluate the efficacy and tolerability of neoadjuvant camrelizumab combined with mFOLFOX6 and identify potential biomarkers of response through multi-omics analysis in patients with resectable locally advanced GC. The primary endpoint was the pathological complete response (pCR) rate. Secondary endpoints included the R0 rate, near pCR rate, progression-free survival (PFS), disease-free survival (DFS), and overall survival (OS). Multi-omics analysis was assessed by whole-exome sequencing, transcriptome sequencing, and multiplex immunofluorescence (mIF) using biopsies pre- and post-neoadjuvant therapy. RESULTS: This study involved 60 patients, of which 55 underwent gastrectomy. Among these, five (9.1%) attained a pathological complete response (pCR), and 11 (20.0%) reached near pCR. No unexpected treatment-emergent adverse events or perioperative mortality were observed, and the regimen presented a manageable safety profile. Molecular changes identified through multi-omics analysis correlated with treatment response, highlighting associations between HER2-positive and CTNNB1 mutations with treatment sensitivity and a favourable prognosis. This finding was further supported by immune cell infiltration analysis and mIF. Expression data uncovered a risk model with four genes (RALYL, SCGN, CCKBR, NTS) linked to poor response. Additionally, post-treatment infiltration of CD8+ T lymphocytes positively correlates with pathological response. CONCLUSION: The findings suggest the combination of PD-1-inhibitor and mFOLFOX6 showed efficacy and acceptable toxicity for locally advanced GC. Extended follow-up is required to determine the duration of the response. This study lays essential groundwork for developing precise neoadjuvant regimens.
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Terapia Neoadyuvante , Neoplasias Gástricas , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Fluorouracilo/uso terapéutico , Leucovorina/uso terapéutico , Multiómica , Terapia Neoadyuvante/métodos , Compuestos Organoplatinos/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Resultado del TratamientoRESUMEN
Patients with advanced gastric cancer typically face a grim prognosis. This phase 1a (dose escalation) and phase 1b (dose expansion) study investigated safety and efficacy of first-line camrelizumab plus apatinib and chemotherapy for advanced gastric or gastroesophageal junction adenocarcinoma. The primary endpoints included maximum tolerated dose (MTD) in phase 1a and objective response rate (ORR) across phase 1a and 1b. Phase 1a tested three dose regimens of camrelizumab, apatinib, oxaliplatin, and S-1. Dose regimen 1: camrelizumab 200 mg on day 1, apatinib 250 mg every other day, oxaliplatin 100 mg/m² on day 1, and S-1 40 mg twice a day on days 1-14. Dose regimen 2: same as dose regimen 1, but oxaliplatin 130 mg/m². Dose regimen 3: same as dose regimen 2, but apatinib 250 mg daily. Thirty-four patients were included (9 in phase 1a, 25 in phase 1b). No dose-limiting toxicities occurred so no MTD was identified. Dose 3 was set for the recommended phase 2 doses and administered in phase 1b. The confirmed ORR was 76.5% (95% CI 58.8-89.3). The median progression-free survival was 8.4 months (95% CI 5.9-not evaluable [NE]), and the median overall survival (OS) was not mature (11.6-NE). Ten patients underwent surgery after treatment and the multidisciplinary team evaluation. Among 24 patients without surgery, the median OS was 19.6 months (7.8-NE). Eighteen patients (52.9%) developed grade ≥ 3 treatment-emergent adverse events. Camrelizumab plus apatinib and chemotherapy showed favorable clinical outcomes and manageable safety for untreated advanced gastric cancer (ChiCTR2000034109).
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Anticuerpos Monoclonales Humanizados , Piridinas , Neoplasias Gástricas , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Oxaliplatino , Piridinas/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Quimioterapia Combinada/métodosRESUMEN
The separator located between the positive and negative electrodes not only provides a lithium-ion transmission channel but also prevents short circuits for direct contact of electrodes. The inferior dimension thermostability of commercial polyolefin separators intensifies the thermal runaway of batteries under abuse such as short circuits, overcharge, and so on. a polyvinylidene fluoride/polyether imide (PVDF/PEI) separator with high thermal stability in which the high thermostable PEI microspheres are evenly dispersed in the PVDF film matrix and also located in the micro holes of the PVDF film is developed. They not only function as strong skeleton that enables the rare shrink of the separator at 200 °C avoiding short circuit but also act as ball valve that blocks the lithium ion transmission channel at 150 °C interrupting the further heat aggregation. Thus, the LiNi0.6 Co0.2 Mn0.2 O2 /Li batteries exhibit high cycle stability of 96.5% capacity retention after 100 cycles at 0.2C and 80°C. Further, the LiNi0.6 Co0.2 Mn0.2 O2 /graphite pouch cells are constructed and deliver good safety performance without smoke release and catching fire after the nail penetration test.
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Background: Currently preferred single-agent nonplatinum chemotherapy or its combination with bevacizumab results in a low response rate and modest survival benefit for platinum-resistant recurrent ovarian cancer, and thus more effective regimens are needed. In our previous phase 2 trial, apatinib plus etoposide showed promising efficacy and an acceptable safety profile in platinum-resistant recurrent ovarian cancer patients. Due to the single-arm design, the role of apatinib still needs to be determined. Methods: In this phase 2 trial, 54 adult patients with platinum-resistant current ovarian cancer will be recruited at 17 sites in China. Patients with prior administration of small-molecule tyrosine kinase inhibitors or etoposide will be excluded. Patients will be randomized (1:1) to receive apatinib (375 mg, orally, once daily) alone or in combination with etoposide (50 mg, orally on days 1-14 of each 21-day cycle) until disease progression or intolerable toxicity. Randomization will be performed using a computerized central randomization system, stratified by platinum resistance for the first time (yes or no). Imaging examinations will be conducted every 6 weeks. The primary endpoint is the objective response rate (ORR) according to the Response Evaluation Criteria In Solid Tumors (version 1.1), which will be compared between groups using the Cochran-Mantel-Haenszel test. Discussion: This study will provide prospective data of 2 experimental regimens using a randomized design. It will help determine whether apatinib monotherapy can provide favorable clinical benefits or needs to be combined with chemotherapy to be effective. Trial Registration: ClinicalTrials.gov Identifier: NCT04383977. It was registered on May 12, 2020.
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PURPOSE: Apatinib combined with gefitinib was proven to benefit advanced EGFR-mutant NSCLC patients in first-line treatment. This study aimed to evaluate the drug-drug interaction of gefitinib and apatinib when coadministered in EGFR-mutated NSCLC patients. METHODS: In this phase 1b, multi-center, open-label, fixed-sequence study, the drug-drug interaction of gefitinib and apatinib was evaluated when coadministered in EGFR-mutated NSCLC patients. Patients received single-agent apatinib 500 mg QD on days 1-4. Gefitinib 250 mg QD was given on days 5-15 and combined with apatinib 500 mg QD on days 12-15. Serial blood samples were drawn on days 4 and 15. The plasma concentrations and other pharmacokinetics parameters were measured for apatinib with and without gefitinib. RESULTS: The study enrolled 22 patients and 20 were analyzed for pharmacokinetics. There were no distinct differences in apatinib Cmax and AUC0-τ with versus without gefitinib (geometric LSM ratio, 0.96 [90% CI 0.84-1.10] for Cmax and 1.12 [90% CI 0.96-1.30] for AUC0-τ). Similar PFS and grade of treatment-emergent adverse events (TEAEs) were found between different Cmax and AUC0-τ of apatinib and gefitinib at 500 mg apatinib and 250 mg gefitinib dose levels. CONCLUSIONS: Apatinib pharmacokinetics parameters were not significantly changed when coadministered with gefitinib. All TEAEs were manageable, and there was no need to change the dose level when combining apatinib and gefitinib (ClinicalTrials.gov identifier: NCT04390984, May 18, 2020).
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Gefitinib/efectos adversos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Estudios de Factibilidad , Inhibidores de Proteínas Quinasas/efectos adversos , Receptores ErbB/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Mutación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
BACKGROUND: Apatinib, a highly selective VEGFR2 inhibitor, significantly improved efficacy versus placebo as a third- and later-line treatment for advanced gastric cancer in phase 2 and 3 trials. This prospective, single-arm, multicenter phase IV AHEAD study was conducted to verify the safety and efficacy of apatinib in patients with advanced or metastatic gastric or gastroesophageal adenocarcinoma after at least two lines of systematic therapy in clinical practice settings. METHODS: Patients with advanced gastric cancer who had previously failed at least two lines of chemotherapy received oral apatinib until disease progression, death or unacceptable toxicity. The primary endpoint was safety. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Adverse events were summarized by the incidence rate. Median OS and PFS were estimated using the Kaplan-Meier method. ORR, DCR, OS at 3 and 6 months, and PFS at 3 and 6 months were calculated, and their 95% CIs were estimated according to the Clopper-Pearson method. RESULTS: Between May 2015 and November 2019, a total of 2004 patients were enrolled, and 1999 patients who received at least one dose of apatinib were assessed for safety. In the safety population, 87.9% of patients experienced treatment-related adverse events (TRAEs), with the most common hypertension (45.2%), proteinuria (26.5%), and white blood cell count decreased (25.3%). Additionally, 51% of patients experienced grade ≥ 3 TRAEs. Fatal TRAEs occurred in 57 (2.9%) patients. No new safety concerns were reported. Among the 2004 patients included in the intention-to-treat population, the ORR was 4.4% (95% CI, 3.6-5.4%), and DCR was 35.8% (95% CI, 33.7-38.0%). The median PFS was 2.7 months (95% CI 2.2-2.8), and the median OS was 5.8 months (95% CI 5.4-6.1). CONCLUSIONS: The findings in the AHEAD study confirmed the acceptable and manageable safety profile and clinical benefit of apatinib in patients with advanced gastric cancer as a third- or later-line of treatment. TRIAL REGISTRATION: This study was registered with ClinicalTrials.gov NCT02426034. Registration date was April 24, 2015.
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Adenocarcinoma , Antineoplásicos , Neoplasias Gástricas , Humanos , Antineoplásicos/efectos adversos , Neoplasias Gástricas/tratamiento farmacológico , Estudios Prospectivos , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Unión Esofagogástrica/patologíaRESUMEN
Aqueous zinc metal batteries are limited in practical applications due to their short lifespans. Herein, a LaF3-coated Zn anode (LF@Zn) is investigated to induce the uniform Zn deposition and successfully build a separator-free quasi-solid-state zinc metal battery. The LF@Zn enables smooth and dendrite-free Zn deposition, owing to the homogeneous Zn2+ flux regulated by the LaF3-based quasi-solid-state electrolyte. It can also suppress the corrosion side reactions by modulating the [Zn(H2O)6]2+ solvation sheath. The polarization of plating and stripping is relatively modest due to the reduced diffuse energy of desolvated Zn2+ in the quasi-solid-state electrolyte. In a separator-free symmetric cell, the LF@Zn anode shows a significantly prolonged lifespan of over 1300 h at 2 mA cm-2 and a superior rate performance with only 156 mV at an ultrahigh current density of 50 mA cm-2. A LF@Zn//VO2 quasi-solid-state full cell exhibits outperforming rate capability and a long cyclic performance for up to 3000 cycles at 6.0 A g-1. A stable Zn anode is established in this work with a fluoride-based quasi-solid-state electrolyte, opening up a new avenue for protecting metal anodes.
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Current diabetic wound treatments remain unsatisfactory due to the lack of a comprehensive strategy that can integrate strong applicability (tissue adhesiveness, shape adaptability, fast self-healability, and facile dressing change) with the initiation and smooth connection of the cascade wound healing processes. Herein, benefiting from the multifaceted bonding ability of tannic acid to metal ions and various polymers, a family of tannin-europium coordination complex crosslinked citrate-based mussel-inspired bioadhesives (TE-CMBAs) are specially developed for diabetic wound healing. TE-CMBAs can gel instantly (< 60 s), possess favorable shape-adaptability, considerable mechanical strengths, high elasticity, considerable wet tissue adhesiveness (≈40 kPa), favorable photothermal antimicrobial activity, excellent anti-oxidant activity, biocompatibility, and angiogenetic property. The reversible hydrogen bond crosslinking and sensitive metal-phenolic coordination also confers TE-CMBAs with self-healability, pH-responsive europium ion and TA releasing properties and on-demand removability upon mixing with borax solution, enabling convenient painless dressing change and the smooth connection of inflammatory microenvironment modulation, angiogenesis promotion, and effective extracellular matrix production leveraging the acidic pH condition of diabetic wounds. This adhesive dressing provides a comprehensive regenerative strategy for diabetic wound management and can be extended to other complicated tissue healing scenarios.
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Adhesivos , Diabetes Mellitus , Humanos , Adhesivos/química , Europio , Cicatrización de Heridas , Vendajes , Concentración de Iones de Hidrógeno , Hidrogeles/química , Antibacterianos/químicaRESUMEN
Capacitive deionization is an emerging desalination technology with mild operation conditions and high energy efficiency. However, its application is limited due to the low deionization capacity of traditional capacitive electrodes. Herein, we report a novel dual-ion capacitive deionization system with a lithium-ion battery cathode LiMn2O4/C and a sodium-ion battery anode NaTi2(PO4)3/C. Lithium ions could enhance the charge transfer during CDI desalination, while NaTi2(PO4)3/C provided direct intercalation sites for sodium ions. The electrochemical capacities of the battery electrodes fitted well, which was favorable for the optimization of the desalination capacity. The low potential of the redox couple Ti3+/Ti4+ (-0.8 V versus Ag/AgCl) and intercalation/deintercalation behaviors of sodium ions that suppressed hydrogen evolution could enlarge the voltage window of the CDI process to 1.8 V. The novel CDI cell achieved an ultrahigh desalination capacity of 140.03 mg·g-1 at 1.8 V with an initial salinity of 20 mM, revealing a new direction for the CDI performance enhancement.
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The synergistic effect of neoadjuvant immunotherapy and chemoradiotherapy in gastric adenocarcinoma is unclear. This phase II trial (NCT03631615) investigated this neoadjuvant combination in locally advanced adenocarcinoma of stomach or gastroesophageal junction. Thirty-six patients received capecitabine 850 mg/m2 twice daily and simultaneous radiotherapy for 5 weeks, sandwiched by a 21-day cycle of oxaliplatin 130 mg/m2 (day 1) plus capecitabine 1000 mg/m2 twice daily (days 1-14), respectively, followed by surgery. Camrelizumab 200 mg (day 1) was given for 5 cycles since initiating chemotherapy. Primary endpoint was pathological complete response (pCR, ypT0) rate. Secondary endpoints included total pCR (tpCR, ypT0N0) rate, major pathological response (MPR, < 10% residual tumor cells) rate, margin-free (R0) resection rate, downstaging, progression-free survival (PFS), overall survival (OS), and safety. The pCR rate was 33.3% (95% CI, 18.6-51.0), meeting pre-specified endpoint. TpCR, MPR, and R0 resection rates were 33.3%, 44.4%, and 91.7%, respectively. Twenty-eight (77.8%) patients reached ypN0. Two-year PFS and OS rates were 66.9% and 76.1%, respectively. The most common grade 3-4 adverse event was decreased lymphocyte count (27 [75.0%]). Neoadjuvant camrelizumab plus concurrent chemoradiotherapy exhibits promising pathological response in patients with locally advanced gastric adenocarcinoma, with an acceptable safety profile.
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Adenocarcinoma , Neoplasias del Recto , Neoplasias Gástricas , Humanos , Terapia Neoadyuvante/efectos adversos , Capecitabina/uso terapéutico , Planetas , Neoplasias del Recto/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quimioradioterapia/efectos adversos , Adenocarcinoma/tratamiento farmacológico , Unión Esofagogástrica/patología , Neoplasias Gástricas/tratamiento farmacológicoRESUMEN
The diffusion-limited aggregation (DLA) of metal ion (Mn+) during the repeated solid-to-liquid (StoL) plating and liquid-to-solid (LtoS) stripping processes intensifies fatal dendrite growth of the metallic anodes. Here, we report a new solid-to-solid (StoS) conversion electrochemistry to inhibit dendrites and improve the utilization ratio of metals. In this StoS strategy, reversible conversion reactions between sparingly soluble carbonates (Zn or Cu) and their corresponding metals have been identified at the electrode/electrolyte interface. Molecular dynamics simulations confirm the superiority of the StoS process with accelerated anion transport, which eliminates the DLA and dendrites in the conventional LtoS/StoL processes. As proof of concept, 2ZnCO3·3Zn(OH)2 exhibits a high zinc utilization of ca. 95.7% in the asymmetry cell and 91.3% in a 2ZnCO3·3Zn(OH)2 || Ni-based full cell with 80% capacity retention over 2000 cycles. Furthermore, the designed 1-Ah pouch cell device can operate stably with 500 cycles, delivering a satisfactory total energy density of 135 Wh kg-1.
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Although rechargeable zinc-ion batteries are promising candidates for next-generation energy storage devices, their inferior performance at subzero temperatures limits their practical application. Here, a strategy to destroy the H-bond network by adding synergistic chaotropic regents is reported, thus reducing the freezing point of the aqueous electrolyte below -90 °C. Owing to the synergistic chaotropic effect between urea and Zn(ClO4 )2 and the thermal release effect on the cathode interface during charging, Zn//VO2 batteries feature a specific capacity of 111.4 mAh g-1 and stability after ≈1000 cycles with 81.9% capacity retention at -40 °C. This work demonstrates that the synergistic chaotropic effect and the thermal effect on the interface can effectively widen the operation range of temperature of aqueous electrolytes and maintain fast kinetics, which provides a new design strategy for all-weather aqueous zinc batteries.
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Importance: There are substantial unmet therapeutic needs in patients with platinum-resistant recurrent ovarian cancer (PROC), and novel therapeutic strategies should be explored. Objective: To evaluate the efficacy and safety of treatment with apatinib (a vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor) plus pegylated liposomal doxorubicin (PLD) for PROC. Design, Setting, and Participants: The APPROVE trial was performed as an open-label, randomized clinical trial at 11 hospitals in China between March 22, 2018, and November 16, 2020. Patients with histologically confirmed ovarian cancer who had experienced disease progression during or within 6 months of discontinuing any prior line of treatment with platinum-based chemotherapy were eligible. This primary analysis was based on data that were current as of January 28, 2021. Interventions: Patients received PLD alone (40 mg/m2, intravenously, every 4 weeks, for up to 6 cycles) or PLD plus apatinib (250 mg, orally, daily). Main Outcomes and Measures: The primary end point was progression-free survival (PFS) by Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1, in the intent-to-treat population. Results: In total, 152 female patients were randomized, with 78 (51.3%) in the apatinib plus PLD group (median age, 54 years; range, 22-76 years) and 74 (48.7%) in the PLD group (median age, 56 years; range, 33-72 years). The median follow-up duration was 8.7 months (IQR, 4.7-14.1 months). The median PFS was 5.8 months (95% CI, 3.8-8.8) for treatment with apatinib plus PLD vs 3.3 months (95% CI, 2.1-3.8) for PLD (hazard ratio, 0.44; 95% CI, 0.28-0.71; P < .001). The median overall survival was 23.0 months (95% CI, 18.9 to not reached) with treatment with apatinib plus PLD vs 14.4 months (95% CI, 12.1-23.4) with PLD (hazard ratio, 0.66; 95% CI, 0.40-1.09). The most frequent grade 3 or higher treatment-emergent adverse events were decreased neutrophil counts (11 [14.9%] in the apatinib plus PLD group vs 6 [8.3%] in the PLD group), hypertension (6 [8.1%] vs none), and decreased white blood cell count (5 [6.8%] vs 3 [4.2%]). Two patients receiving treatment with apatinib plus PLD experienced grade 2 fistulas. Conclusions and Relevance: This randomized clinical trial found that treatment with apatinib plus PLD showed promising efficacy and manageable toxic effects in patients with PROC and may be a new alternative treatment option in this setting. Trial Registration: Clinicaltrials.gov Identifier: NCT04348032.
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Neoplasias Ováricas , Factor A de Crecimiento Endotelial Vascular , Adulto , Anciano , Inhibidores de la Angiogénesis/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Doxorrubicina/efectos adversos , Doxorrubicina/análogos & derivados , Femenino , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Polietilenglicoles/efectos adversos , Piridinas , Adulto JovenRESUMEN
BACKGROUND: Camrelizumab, an anti-PD-1 antibody, has shown moderate efficacy in oesophageal squamous cell carcinoma. Apatinib, a selective inhibitor of VEGFR2, has a synergistic effect with immunotherapy. We aimed to assess the combination of camrelizumab and apatinib as second-line treatment for advanced oesophageal squamous cell carcinoma. METHODS: This single-arm, open-label, phase 2 study was conducted at eight centres in China. Eligible patients were aged 18-75 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, who had unresectable locally advanced, locally recurrent, or metastatic oesophageal squamous cell carcinoma, and had progressed after or were intolerant to first-line chemotherapy. Patients received intravenous camrelizumab 200 mg once every 2 weeks plus oral apatinib 250 mg once daily for a 28-day cycle until disease progression, unacceptable adverse events, or withdrawal of consent. The primary endpoint was investigator-assessed confirmed objective response rate. Efficacy was analysed in patients who had received at least one dose of study drug, and safety was analysed in patients who received the study drug and had at least one post-baseline safety assessment. The study of this cohort is complete and this trial is registered with ClinicalTrials.gov, number NCT03736863. FINDINGS: Between Dec 5, 2019, and Feb 10, 2021, 52 patients were enrolled and included in analyses. At data cutoff (June 20, 2021), median follow-up was 7·5 months (IQR 4·0-11·2). 18 (34·6%, [95% CI 22·0-49·1]) of 52 patients had a confirmed objective response. 23 (44%) of 52 patients had grade 3 or worse treatment-related adverse events. The most common grade 3 or worse treatment-related adverse events were increased aspartate aminotransferase (10 [19%]), increased gamma-glutamyltransferase (10 [19%]), and increased alanine aminotransferase (five [10%]). No treatment-related deaths occurred. INTERPRETATION: Camrelizumab combined with apatinib showed promising activity and manageable toxicity, and might be a potential second-line treatment option for patients with advanced oesophageal squamous cell carcinoma. Another cohort of this study, enrolling patients previously treated with first-line immunotherapy, is ongoing. FUNDING: Jiangsu Hengrui Pharmaceuticals.
Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Piridinas/administración & dosificación , Anciano , Alanina Transaminasa/sangre , Aspartato Aminotransferasas/sangre , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/mortalidad , Carcinoma de Células Escamosas de Esófago/patología , Femenino , Humanos , Masculino , Supervivencia sin Progresión , gamma-Glutamiltransferasa/sangreRESUMEN
IMPORTANCE: Patients with radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) have a poor prognosis and limited treatment options. OBJECTIVE: To assess the efficacy and safety of apatinib, a highly selective vascular endothelial growth factor (VEGFR-2) inhibitor, in patients with progressive locally advanced or metastatic RAIR-DTC. DESIGN, SETTING, AND PARTICIPANTS: This randomized, double-blind, placebo-controlled, phase 3 trial (Efficacy of Apatinib in Radioactive Iodine-refractory Differentiated Thyroid Cancer [REALITY]) was conducted in 92 patients with progressive locally advanced or metastatic RAIR-DTC between February 17, 2017, and March 2, 2020, at 21 sites within China, and the data cutoff date for this analysis was March 25, 2020. INTERVENTIONS: Patients were randomly assigned (1:1) to apatinib, 500 mg/d, or placebo. Patients who developed progression while receiving placebo were allowed to cross over to apatinib. MAIN OUTCOMES AND MEASURES: The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall survival, objective response rate (ORR), disease control rate (DCR), duration of response, time to objective response, and safety. Intention-to-treat analyses were performed to evaluate efficacy. RESULTS: Of the 92 patients included in the trial, 56 were women (60.9%); mean (SD) age at baseline was 55.7 (10.6) years. Patients were randomized to the apatinib (n = 46) or placebo (n = 46) group. The median follow-up duration was 18.1 (IQR, 12.7-22.2) months. The median PFS was 22.2 (95% CI, 10.91-not reached) months for apatinib vs 4.5 (95% CI, 1.94-9.17) months for placebo (hazard ratio, 0.26; 95% CI, 0.14-0.47; P < .001). The confirmed ORR was 54.3% (95% CI, 39.0%-69.1%) and the DCR was 95.7% (95% CI, 85.2%-99.5%) in the apatinib group vs an ORR of 2.2% (95% CI, 0.1%-11.5%) and DCR of 58.7% (95% CI, 43.2%-73.0%) in the placebo group. The median overall survival was not reached for apatinib (95% CI, 26.25-not reached) and was 29.9 months (95% CI, 18.96-not reached) for placebo (hazard ratio, 0.42; 95% CI, 0.18-0.97; P = .04). The most common grade 3 or higher-level treatment-related adverse events in the apatinib group were hypertension (16 [34.8%]), hand-foot syndrome (8 [17.4%]), proteinuria (7 [15.2%]), and diarrhea (7 [15.2%])-none of which occurred in the placebo group. CONCLUSIONS AND RELEVANCE: The REALITY trial met its primary end point of PFS at the prespecified interim analysis. Apatinib showed significant clinical benefits in both prolonged PFS and overall survival with a manageable safety profile in patients with progressive locally advanced or metastatic RAIR-DTC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03048877.