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  • 1
    In: The Lancet Oncology, Elsevier BV, Vol. 24, No. 11 ( 2023-11), p. 1181-1195
    Type of Medium: Online Resource
    ISSN: 1470-2045
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 2049730-1
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  • 2
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 42, No. 16_suppl ( 2024-06-01), p. e24058-e24058
    Abstract: e24058 Background: Breakthrough cancer pain (BTcP) can significantly impact the life quality of the cancer patient. Wide-used rapid-onset opioids (ROOs) for BTcP are transmucosal fentanyl-based preparations. Inhaled fentanyl demonstrated similar pharmacokinetic properties as intravenous administration in healthy volunteers. Fentanyl aerosol can be generated via hand-held drug-device delivery system, providing rapid, consistent multi-dose administration. Fentanyl inhalant was explored as alternative treatment of BTcP in cancer patients in this study to evaluate its efficacy, safety, and tolerability in BTcP patients with well-controlled background cancer pain. Methods: Adults ≥18 years with cancer are eligible if they were experiencing persistent cancer- or treatment-related pain with above mild severity and 1-4 episode occurrences daily. Each patient was treated and observed for 6 BTcP episodes (4 with fentanyl inhalant, 2 with placebo). During each episode, patients were allowed to inhale up to six shots within 1 hour. Pain intensity was recorded using 11-point Numerical Rating Scale (NRS) at predefined time points. The primary endpoint was the time-weighted Sum of Pain Intensity Difference scores at 30 minutes (SPID30) after the first inhalation. Results: 335 BTcP episodes in 59 patients were treated. SPID30 was analyzed using mixed model of repeated measures with treatment (fentanyl inhalant or placebo), BTcP episode, baseline pain intensity score as fixed factors, and subject as random factor. Mean SPID30 ± SD was -97.4 ± 48.43 for fentanyl-treated episodes, and -64.6 ± 40.25 for placebo-treated episodes. Based on treatment adjustment in the mixed covariance model, significant difference (p 〈 0.001) was reported with mean treatment difference of -27.7 (LS-mean ± SD, -94.2 ± 4.49 for fentanyl and -66.5 ± 4.86 for placebo). It enlarged at 60 minutes (SPID60) with a mean treatment difference of -57.9 (LS-mean ± SD, -231.4 ±105.14 for fentanyl and -162.2 ± 91.21 for placebo, p 〈 0.001). Significant differences in PID for episodes treated with fentanyl versus placebo were seen 4 minutes after the first dosing and maintained up to 60 minutes. Other endpoints showed statistical significance favoring fentanyl treatment, including the proportion of NRS ≤ 3, NRS pain scores decreased ≥ 33% or ≥ 50% from baseline after completion of BTcP treatment within 30 minutes of first dose, and Pain Relief Score Within 30 Minutes of the First Dose (PR30). Only 4.4% of BTcP episodes required rescue medication in fentanyl group. Major adverse events were mild or moderate in severity and were typical for opioid drugs. Conclusions: Fentanyl inhalant is safe, effective, and well-tolerated for managing BTcP. It provides a non-invasive route for systemic drug delivery and can be self-administered or given by family caregivers as personalized and regular pain management. Clinical trial information: NCT05531422 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2024
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    detail.hit.zdb_id: 604914-X
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  • 3
    In: JAMA, American Medical Association (AMA), Vol. 326, No. 10 ( 2021-09-14), p. 916-
    Type of Medium: Online Resource
    ISSN: 0098-7484
    RVK:
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2021
    detail.hit.zdb_id: 2958-0
    SSG: 5,21
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  • 4
    In: JAMA Network Open, American Medical Association (AMA), Vol. 6, No. 5 ( 2023-05-01), p. e2310909-
    Abstract: Baseline findings from the China Dialysis Calcification Study (CDCS) revealed a high prevalence of vascular calcification (VC) among patients with end-stage kidney disease; however, data on VC progression were limited. Objectives To understand the progression of VC at different anatomical sites, identify risk factors for VC progression, and assess the association of VC progression with the risk of cardiovascular events and death among patients receiving maintenance dialysis. Design, Setting, and Participants This cohort study was a 4-year follow-up assessment of participants in the CDCS, a nationwide multicenter prospective cohort study involving patients aged 18 to 74 years who were undergoing hemodialysis or peritoneal dialysis. Participants were recruited from 24 centers across China between May 1, 2014, and April 30, 2015, and followed up for 4 years. A total of 1489 patients receiving maintenance dialysis were included in the current analysis. Data were analyzed from September 1 to December 31, 2021. Exposures Patient demographic characteristics and medical history; high-sensitivity C-reactive protein laboratory values; serum calcium, phosphorus, and intact parathyroid hormone (iPTH) values; and previous or concomitant use of medications. Main Outcomes and Measures The primary outcome was progression of VC at 3 different anatomical sites (coronary artery, abdominal aorta, and cardiac valves) and identification of risk factors for VC progression. Participants received assessments of coronary artery calcification (CAC), abdominal aortic calcification (AAC), and cardiac valve calcification (CVC) at baseline, 24 months, 36 months, and 48 months. Secondary outcomes included (1) the association between VC progression and the risk of all-cause death, cardiovascular (CV)–related death, and a composite of all-cause death and nonfatal CV events and (2) the association between achievement of serum calcium, phosphorus, and iPTH target levels and the risk of VC progression. Results Among 1489 patients, the median (IQR) age was 51.0 (41.0-60.0) years; 59.5% of patients were male. By the end of 4-year follow-up, progression of total VC was observed in 86.5% of patients; 69.6% of patients had CAC progression, 72.4% had AAC progression, and 33.4% had CVC progression. Common risk factors for VC progression at the 3 different anatomical sites were older age and higher fibroblast growth factor 23 levels. Progression of CAC was associated with a higher risk of all-cause death (model 1 [adjusted for age, sex, and body mass index]: hazard ratio [HR] , 1.97 [95% CI, 1.16-3.33]; model 2 [adjusted for all factors in model 1 plus smoking status, history of diabetes, and mean arterial pressure] : HR, 1.89 [95% CI, 1.11-3.21]; model 3 [adjusted for all factors in model 2 plus calcium, phosphorus, intact parathyroid hormone, and fibroblast growth factor 23 levels and calcium-based phosphate binder use] : HR, 1.92 [95% CI, 1.11-3.31]) and the composite of all-cause death and nonfatal CV events (model 1: HR, 1.98 [95% CI, 1.19-3.31] ; model 2: HR, 1.91 [95% CI, 1.14-3.21]; model 3: HR, 1.95 [95% CI, 1.14-3.33] ) after adjusting for all confounding factors except the presence of baseline calcification. Among the 3 targets of calcium, phosphorus, and iPTH, patients who achieved no target levels (model 1: odds ratio [OR], 4.75 [95% CI, 2.65-8.52] ; model 2: OR, 4.81 [95% CI, 2.67-8.66]; model 3 [for this analysis, adjusted for all factors in model 2 plus fibroblast growth facto r 23 level and calcium-based phosphate binder use]: OR, 2.76 [95% CI, 1.48-5.16] ), 1 target level (model 1: OR, 3.71 [95% CI, 2.35-5.88]; model 2: OR, 3.62 [95% CI, 2.26-5.78] ; model 3: OR, 2.19 [95% CI, 1.33-3.61]), or 2 target levels (model 1: OR, 2.73 [95% CI, 1.74-4.26] ; model 2: OR, 2.69 [95% CI, 1.71-4.25]; model 3: OR, 1.72 [95% CI, 1.06-2.79] ) had higher odds of CAC progression compared with patients who achieved all 3 target levels. Conclusions and Relevance In this study, VC progressed rapidly in patients undergoing dialysis, with different VC types associated with different rates of prevalence and progression. Consistent achievement of serum calcium, phosphorus, and iPTH target levels was associated with a lower risk of CAC progression. These results may be useful for increasing patient awareness and developing appropriate strategies to improve the management of chronic kidney disease–mineral and bone disorder among patients undergoing dialysis.
    Type of Medium: Online Resource
    ISSN: 2574-3805
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2023
    detail.hit.zdb_id: 2931249-8
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  • 5
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 42, No. 16_suppl ( 2024-06-01), p. 5551-5551
    Abstract: 5551 Background: RC88 is a first-in-class, antibody-drug conjugate (ADC) targeting mesothelin (MSLN) with the payload of Monomethyl auristatin E. MSLN, a glycosylphosphatidylinositol-anchored protein, is overexpressed in several solid tumors with limited expression in normal tissues. RC88-C001 is a single-arm, open-label, multi-center phase 1/2 study evaluating RC88 in patients (pts) with MSLN-expressing advanced solid tumor (NCT04175847). This abstract mainly reports the efficacy results from the dose expansion part (phase 2) of the study. Methods: Pts with MSLN-expressing advanced malignant solid tumors that have failed after standard therapies were enrolled in this study. MSLN was tested by IHC. For phase 2 study, the primary endpoint was ORR by investigator per RECIST v1.1 with secondary endpoints including DCR, PFS, and safety. Results: As of 19 December, 2023, 164 pts with advanced solid tumor were enrolled. Dose escalation phase was completed, and 2.0 mg/kg and 2.5 mg/kg Q3W were expanded in phase 2. In ovarian cancer cohort, 60 pts were enrolled and all with 2+ or 3+ MSLN expression. Forty-two (70%) were FIGO stage IV. Thirty-three (55%) had prior bevacizumab, and 29 (48.3%) had prior PARPi. The number of previous lines of systemic therapy were 2-7. Fifty-four (90%) pts were platinum-resistant. Among the 43 pts with at least one post-baseline tumor assessment, the ORR was 37.2% (16/43). In pts with prior 2-4 lines of therapies, the ORR was 45.5% (10/22) in 2.0 mg/kg and 33.3% (2/6) in 2.5mg/kg. In non-squamous-non-small-cell lung-carcinoma, 26 pts progressed on previous systemic therapy were enrolled and 23 (88.4%) had received ≥ 2 lines of prior therapies. Twenty-three pts had one post-baseline tumor assessment; the ORR was 21.7% (5/23). Among the 15 pts without driver gene mutations, 11 (73%) had received prior platinum-doublet chemotherapy and PD-(L)1 inhibitor. The ORR was 33.3% (5/15) with 1 CR. In cervical cancer, 18 pts progressed on previous systemic therapy were enrolled. In 17 pts with one post-baseline tumor assessment, 11 (64.7%) had received ≥ 2 lines of prior therapies; 12 (70.5%) had prior platinum-doublet chemotherapy and PD-(L)1 inhibitor. The ORR was 35.3% (6/17). TEAEs were reported in 161 pts (98.2%), with 40.2% ≥grade 3 TEAEs. Twenty-three pts (14%) had SAE related to RC88. The most frequent TRAEs were white blood cell count decreased (46.3%), neutrophil count decreased (42.1%), anemia (34.1%), nausea (32.3%), and aspartate aminotransferase increased (31.1%). The overall safety profile was better in 2.0mg/kg than 2.5mg/kg, therefore 2.0mg/kg was chosen as RP2D in further studies in China. Conclusions: RC88 demonstrated tolerable safety and encouraging preliminary efficacy in MSLN-expressing solid tumors, warranting further investigations. Clinical trial information: NCT04175847 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2024
    detail.hit.zdb_id: 2005181-5
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  • 6
    In: BMC Medicine, Springer Science and Business Media LLC, Vol. 20, No. 1 ( 2022-10-25)
    Abstract: Dual inhibition of PD-1/PD-L1 and TGF-β pathways is a rational therapeutic strategy for malignancies. SHR-1701 is a new bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused with the extracellular domain of TGF-β receptor II. This first-in-human trial aimed to assess SHR-1701 in pretreated advanced solid tumors and find the population who could benefit from SHR-1701. Methods This was a dose-escalation, dose-expansion, and clinical-expansion phase 1 study. Dose escalation was initiated by accelerated titration (1 mg/kg q3w; intravenous infusion) and then switched to a 3+3 scheme (3, 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w), followed by dose expansion at 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w. The primary endpoints of the dose-escalation and dose-expansion parts were the maximum tolerated dose and recommended phase 2 dose. In the clinical-expansion part, selected tumors were enrolled to receive SHR-1701 at the recommended dose, with a primary endpoint of confirmed objective response rate (ORR). Results In total, 171 patients were enrolled (dose-escalation: n =17; dose-expansion, n =33; clinical-expansion, n =121). In the dose-escalation part, no dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. SHR-1701 showed a linear dose-exposure relationship and the highest ORR at 30 mg/kg every 3 weeks, without obviously aggravated toxicities across doses in the dose-escalation and dose-expansion parts. Combined, 30 mg/kg every 3 weeks was determined as the recommended phase 2 dose. In the clinical-expansion part, SHR-1701 showed the most favorable efficacy in the gastric cancer cohort, with an ORR of 20.0% (7/35; 95% CI, 8.4–36.9) and a 12-month overall survival rate of 54.5% (95% CI, 29.5–73.9). Grade ≥3 treatment-related adverse events occurred in 37 of 171 patients (22%), mainly including increased gamma-glutamyltransferase (4%), increased aspartate aminotransferase (3%), anemia (3%), hyponatremia (3%), and rash (2%). Generally, patients with PD-L1 CPS ≥1 or pSMAD2 histochemical score ≥235 had numerically higher ORR. Conclusions SHR-1701 showed an acceptable safety profile and encouraging antitumor activity in pretreated advanced solid tumors, especially in gastric cancer, establishing the foundation for further exploration. Trial registration ClinicalTrials.gov , NCT03710265
    Type of Medium: Online Resource
    ISSN: 1741-7015
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 7
    In: JAMA, American Medical Association (AMA), Vol. 330, No. 21 ( 2023-12-05), p. 2064-
    Abstract: Gastric and gastroesophageal junction cancers are diagnosed in more than 1 million people worldwide annually, and few effective treatments are available. Sintilimab, a recombinant human IgG4 monoclonal antibody that binds to programmed cell death 1 (PD-1), in combination with chemotherapy, has demonstrated promising efficacy. Objective To compare overall survival of patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction cancers who were treated with sintilimab with chemotherapy vs placebo with chemotherapy. Also compared were a subset of patients with a PD ligand 1 (PD-L1) combined positive score (CPS) of 5 or more (range, 1-100). Design, Setting, and Participants Randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 62 hospitals in China that enrolled 650 patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma between January 3, 2019, and August 5, 2020. Final follow-up occurred on June 20, 2021. Interventions Patients were randomized 1:1 to either sintilimab (n = 327) or placebo (n = 323) combined with capecitabine and oxaliplatin (the XELOX regimen) every 3 weeks for a maximum of 6 cycles. Maintenance therapy with sintilimab or placebo plus capecitabine continued for up to 2 years. Main Outcomes and Measures The primary end point was overall survival time from randomization. Results Of the 650 patients (mean age, 59 years; 483 [74.3%] men), 327 were randomized to sintilimab plus chemotherapy and 323 to placebo plus chemotherapy. Among the randomized patients, 397 (61.1%) had tumors with a PD-L1 CPS of 5 or more; 563 (86.6%) discontinued study treatment and 388 (59.7%) died; 1 patient ( & amp;lt;0.1%) was lost to follow-up. Among all randomized patients, sintilimab improved overall survival compared with placebo (median, 15.2 vs 12.3 months; stratified hazard ratio [HR], 0.77 [95% CI, 0.63-0.94] ; P  = .009). Among patients with a CPS of 5 or more, sintilimab improved overall survival compared with placebo (median, 18.4 vs 12.9 months; HR, 0.66 [95% CI, 0.50-0.86]; P  = .002). The most common grade 3 or higher treatment-related adverse events were decreased platelet count (sintilimab, 24.7% vs placebo, 21.3%), decreased neutrophil count (sintilimab, 20.1% vs placebo, 18.8%), and anemia (sintilimab, 12.5% vs placebo, 8.8%). Conclusions and Relevance Among patients with unresectable locally advanced or metastatic gastric and gastroesophageal junction adenocarcinoma treated with first-line chemotherapy, sintilimab significantly improved overall survival for all patients and for patients with a CPS of 5 or more compared with placebo. Trial Registration ClinicalTrials.gov Identifier: NCT03745170
    Type of Medium: Online Resource
    ISSN: 0098-7484
    RVK:
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2023
    detail.hit.zdb_id: 2958-0
    SSG: 5,21
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  • 8
    In: European Journal of Immunology, Wiley, Vol. 46, No. 5 ( 2016-05), p. 1162-1167
    Abstract: It has been shown that while commensal bacteria promote Th1, Th17 and Treg cells in lamina propria (LP) in steady‐state conditions, they suppress mucosal Th2 cells. However, it is still unclear whether there are specific commensal organisms down‐regulating Th2 responses, and the mechanism involved. Here we demonstrate that commensal A4 bacteria, a member of the Lachnospiraceae family, which produce an immunodominant microbiota CBir1 antigen, inhibits LP Th2‐cell development. When transferred into the intestines of RAG −/− mice, CBir1‐specific T cells developed predominately towards Th1 cells and Th17 cells, but to a lesser extent into Th2 cells. The addition of A4 bacterial lysates to CD4 + T‐cell cultures inhibited production of IL‐4. A4 bacteria stimulated dendritic cell production of TGF‐β, and blockade of TGF‐β abrogated A4 bacteria inhibition of Th2‐cell development in vitro and in vivo. Collectively, our data show that A4 bacteria inhibit Th2‐cell differentiation by inducing dendritic cell production of TGF‐β.
    Type of Medium: Online Resource
    ISSN: 0014-2980 , 1521-4141
    URL: Issue
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2016
    detail.hit.zdb_id: 120108-6
    detail.hit.zdb_id: 1491907-2
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  • 9
    In: BioDrugs, Springer Science and Business Media LLC, Vol. 35, No. 4 ( 2021-07), p. 445-458
    Type of Medium: Online Resource
    ISSN: 1173-8804 , 1179-190X
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 1364202-9
    detail.hit.zdb_id: 2043743-2
    SSG: 15,3
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  • 10
    In: Remote Sensing, MDPI AG, Vol. 14, No. 3 ( 2022-01-31), p. 687-
    Abstract: A changing climate has been posing significant impacts on vegetation growth, especially in the Yellow River Basin (YRB) where agriculture and ecosystems are extremely vulnerable. In this study, the data for normalized difference vegetation index (NDVI) obtained from moderate-resolution imaging spectroradiometer (MODIS) sensors and climate data (precipitation and temperature) derived from the national meteorological stations were employed to examine the spatiotemporal differences in vegetation growth and its reaction to climate changes in the YRB from 2000–2019, using several sophisticated statistical methods. The results showed that both NDVI and climatic variables exhibited overall increasing trends during this period, and positive correlations at different significant levels were found between temperature/precipitation and NDVI. Furthermore, NDVI in spring had the strongest response to temperature/precipitation, and the correlation coefficient of NDVI with temperature and precipitation was 0.485 and 0.726, respectively. However, an opposite situation was detected in autumn (September to November) since NDVIs exhibited the weakest responses to temperatures/precipitation, and the NDVI’s correlation with both temperature and precipitation was 0.13. This indicated that, compared to other seasons, increasing the temperature and precipitation has the most significant effect on NDVI in spring (March to May). Except for a few places in the northern, southern, and southwestern regions of the YRB, NDVI was positively correlated with precipitation in most areas. There was an inverse relationship between NDVI and temperature in most parts of the central YRB, especially in summer (June to August) and growing season (May to September); however, there was a positive correlation in most areas of the YRB in spring. Finally, continuous attention must be given to the influence of other factors in the YRB.
    Type of Medium: Online Resource
    ISSN: 2072-4292
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2513863-7
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