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PurposeThis multicenter, open-label, phase Ib/II study aimed to assess the efficacy and safety of cadonilimab, a humanized, tetravalent, bispecific antibody plus lenvatinib in first-line treatment of advanced hepatocellular carcinoma (aHCC).MethodsPatients with histologically confirmed aHCC were included to receive either 6 mg/kg cadonilimab every 2 weeks plus lenvatinib (cohort A) or 15 mg/kg cadonilimab every 3 weeks plus lenvatinib (cohort B). The primary endpoint was objective response rate (ORR) by RECIST v1.1, while the secondary endpoints were safety, progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DoR), and time to response (TTR).ResultsA total of 59 patients were enrolled (31 in cohort A and 28 in cohort B). The median follow-up time was 27.4 months as of the data cutoff date (July 28, 2023). The ORR in cohort A was 35.5% (95% CI: 19.2, 54.6) and that in cohort B was 35.7% (95% CI: 18.6, 55.9), and the median DoR was 13.6 months (95% CI: 4.14, NE) and 13.67 months (95% CI: 3.52, NE), respectively. The median PFS was 8.6 months (95% CI: 5.2, 15.2) and 9.8 months (95% CI: 6.9, 15.2), respectively. The median OS was 27.1 months (95% C: 15.7, NE) for cohort A, while it was not reached for cohort B. Grade ≥ 3 treatment-related adverse events (TRAEs) were reported in 66.1% of patients, with serious TRAEs occurring in 39.0% of cases. Decreased platelet count (47.5%), proteinuria (45.8%), hypertension (44.1%), and white blood cell count (44.1%) were the most common TRAEs.ConclusionThis novel combination therapy showed promising efficacy and manageable toxicity that could provide an option in first-line setting of aHCC.Clinical Trial Registration[www.ClinicalTrials.gov], NCT04444167.

Long noncoding RNAs (lncRNAs) have recently been verified to have significant regulatory functions in many types of human cancers. The lncRNA ANRIL is transcribed from the INK4b‐ARF‐INK4a gene cluster in the opposite direction. Whether ANRIL can act as an oncogenic molecule in cholangiocarcinoma (CCA) remains unknown. Our data show that ANRIL knockdown greatly inhibited CCA cell proliferation and migration in vitro and in vivo. According to the results of RNA sequencing analysis, ANRIL knockdown dramatically altered target genes associated with the cell cycle, cell proliferation, and apoptosis. By binding to a component of the epigenetic modification complex enhancer of zeste homolog 2 (EZH2), ANRIL could maintain lysine residue 27 of histone 3 (H3K27me3) levels in the promoter of ERBB receptor feedback inhibitor 1 (ERRFI1), which is a tumor suppressor gene in CCA. In this way, ERRFI1 expression was suppressed in CCA cells. These data verified the key role of the epigenetic regulation of ANRIL in CCA oncogenesis and indicate its potential as a target for CCA intervention. ANRIL can adjust the proliferation and migration of cholangiocarcinoma (CCA) cells in vitro. Mechanistic investigations indicated that ANRIL could inhibit the expression of ERRFI1 by directly binding to EZH2, which mediated H3K27me3 in the promoter region of ERRFI1, thus accelerating CCA tumorigenesis.

Immunotherapy combinations have revolutionised the therapeutic landscape of advanced hepatocellular carcinoma (HCC), but not all yield a significant overall survival benefit, underscoring the need for novel effective agents. Anlotinib plus penpulimab has demonstrated encouraging activity and safety in a phase 2 study. In this phase 3 trial, we aimed to assess whether the combination of anlotinib plus penpulimab improved survival versus sorafenib in patients with unresectable HCC. APOLLO was a multicentre, open-label, parallel-controlled, randomised, phase 3 trial conducted at 79 centres in China. Patients aged 18–75 years with unresectable HCC, no previous systemic therapy, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were randomly assigned (2:1) to anlotinib (10 mg orally once daily on days 1–14) plus penpulimab (200 mg intravenously on day 1), or sorafenib (400 mg orally twice daily) every 3 weeks. Randomisation was done centrally using block randomisation with a fixed block size of 3 and stratified by the presence of macrovascular invasion or extrahepatic metastasis, α-fetoprotein concentration, and ECOG performance status. Sex (male or female) and ethnicity (Chinese or other) were self-reported. The co-primary endpoints were progression-free survival assessed by masked independent review committee and overall survival in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of the study drug and had at least one recorded safety assessment. Final progression-free survival and second interim overall survival analyses are presented. This trial is registered at ClinicalTrials.gov, NCT04344158, and follow-up is ongoing. From Aug 11, 2020, to June 20, 2023, 940 patients were screened for inclusion in the trial, 291 were excluded, and 649 were randomly assigned to an intervention (433 were assigned to the anlotinib plus penpulimab group and 216 were assigned to the sorafenib group. 551 (85%) of the 649 patients were male and 98 (15%) were female. All patients were Chinese with a median age of 57 years (IQR 50–65). For the final analysis of progression-free survival (June 5, 2023), 636 patients (424 patients in the anlotinib plus penpulimab group vs 212 patients in the sorafenib group) comprised the intention-to-treat population. For the second interim analysis of overall survival (Jan 29, 2024), 649 patients (433 vs 216) comprised the intention-to-treat population. Median follow-up was 6·2 months (IQR 5·5–7·5) for the anlotinib plus penpulimab group and 4·2 months (2·9–7·1) for the sorafenib group for final progression-free survival analysis, and 15·3 months (14·3–17·3) for the anlotinib plus penpulimab group and 14·5 months (11·5–17·0) for the sorafenib group for the second interim overall survival analysis. Median progression-free survival was significantly extended with anlotinib plus penpulimab versus sorafenib (6·9 months [95% CI 5·8–8·0] vs 2·8 months [2·7–4·1]; hazard ratio [HR] 0·52 [95% CI 0·41–0·66]; p<0·0001). Median overall survival was significantly prolonged with anlotinib plus penpulimab compared with sorafenib (16·5 months [95% CI 14·7–19·0] vs 13·2 months [9·7–16·9]; HR 0·69 [95% CI 0·55–0·87]; p=0·0014). The most common grade 3 or worse treatment-related adverse events were hypertension (75 [17%] patients in the anlotinib plus penpulimab group vs 22 [10%] in the sorafenib group) and decrease in platelet count (39 [9%] vs 13 [6%]). Treatment-related serious adverse events occurred in 90 (21%) and 19 (9%) patients in the respective groups; treatment-related deaths occurred in one (<1%) patient in the anlotinib plus penpulimab group (upper gastrointestinal haemorrhage) and two (1%) patients in the sorafenib group (hepatic failure and death of unknown cause). Anlotinib plus penpulimab significantly improved progression-free survival and overall survival versus sorafenib in unresectable HCC and might be a new first-line option. These findings require verification in other regions of the world. Chia Tai Tianqing Pharmaceutical Group.

Background and aims Donafenib, a deuterium-modified sorafenib derivative, has improved survival outcomes in patients with advanced hepatocellular carcinoma (HCC). This study aimed to investigate the treatment-related adverse events and their associations with overall survival (OS) and time to progression (TTP) in patients with advanced HCC treated with donafenib. Methods In this retrospective analysis, data from 334 patients with unresectable or metastatic HCC who had a Child–Pugh liver function score ≤ 7 and had not received prior systemic treatment were collected from the ZGDH3 study. Donafenib (0.2 g) was administered orally twice daily until either intolerable toxicity or disease progression occurred. The associations between adverse events (AEs) and OS/TTP were analyzed using the Kaplan–Meier method, and statistical significance was tested using the log-rank test. A stratified Cox proportional hazards model was used to estimate hazard ratios (HR) and 95% confidence intervals (CIs). Results Univariate analysis revealed that the median OS (mOS) was significantly longer in patients who experienced Grade 3 hand-foot skin reaction (HFSR), diarrhea, Grade ≥ 3 thrombocytopenia, hypertension, alopecia, rash, and proteinuria compared to those without these AEs ( P  < 0.05). Conversely, patients with fatigue and Grade ≥ 3 increased blood bilirubin had significantly shorter mOS than those without these AEs ( P  < 0.05). HFSR was associated with improved survival outcomes, with the mOS of patients with HFSR being 17.6 months, compared to 7.9 months in those without (HR = 0.498, 95% CI 0.384–0.648, P  < 0.0001). The mOS was 14.2 months in patients with Grade ≥ 3 AEs, compared to 10.5 months in those without (HR = 0.687, 95% CI 0.442–0.802, P  = 0.0061). There was no significant difference in the overall incidence of AEs between patients aged ≥ 65 and those < 65. Conclusions The occurrence of HFSR, diarrhea, thrombocytopenia, hypertension, alopecia, rash, proteinuria, fatigue, and Grade ≥ 3 increased blood bilirubin may be associated with the efficacy of donafenib in the treatment of advanced HCC, though these are exploratory associations and not established predictive markers. The AEs associated with donafenib are generally well tolerated, though further validation is needed. Trial Registry : NCT02645981.

Background: Recent studies have shown that inflammatory indicators are closely related to the prognosis of patients with hepatocellular carcinoma, and they can serve as powerful indices for predicting recurrence and survival time after treatment. However, the predictive ability of inflammatory indicators has not been systematically studied in patients receiving transarterial chemoembolization (TACE). Therefore, the objective of this research was to determine the predictive value of preoperative inflammatory indicators for unresectable hepatocellular carcinoma treated with TACE. Methods: Our retrospective research involved 381 treatment-naïve patients in 3 institutions, including the First Affiliated Hospital of Soochow University, Nantong First People’s Hospital, and Nantong Tumor Hospital, from January 2007 to December 2020 that received TACE as initial treatment. Relevant data of patients were collected from the electronic medical record database, and the recurrence and survival time of patients after treatment were followed up. Least absolute shrinkage and selection operator (LASSO) algorithm was used to compress and screen the variables. We utilized Cox regression to determine the independent factors associated with patient outcomes and constructed a nomogram based on multivariate results. Finally, the nomogram was verified from discriminability, calibration ability, and practical applicability. Results: Multivariate analysis revealed that the levels of aspartate aminotransferase-to-platelet ratio index (APRI) and lymphocyte count were independent influential indicators for overall survival (OS), whereas the levels of platelet-to-lymphocyte ratio (PLR) was an independent influential index for progression. Nomograms exhibited an excellent concordance index (C-index), in the nomogram of OS, the C-index was 0.753 and 0.755 in training and validation cohort, respectively; and in the nomogram of progression, the C-index was 0.781 and 0.700, respectively. The time-dependent C-index, time-dependent receiver operating characteristic (ROC), and time-dependent area under the curve (AUC) of the nomogram all exhibited ideal discrimination ability. Calibration curves significantly coincided with the standard lines, which indicated that the nomogram had high stability and low degree of over-fitting. Decision curve analysis revealed a wider range of threshold probabilities and could augment net benefits. The Kaplan-Meier curves for risk stratification indicated that the prognosis of patients varied significantly between risk categories (P < .0001). Conclusions: The developed prognostic nomograms based on preoperative inflammatory indicators revealed high predictive accuracy for survival and recurrence. It can be a valuable clinical instrument for guiding individualized treatment and predicting prognosis.

Abstract Introduction: KEYNOTE-394 showed pembrolizumab significantly improved overall survival, progression-free survival, and objective response rate with manageable safety versus placebo for patients from Asia with previously treated advanced hepatocellular carcinoma. We present results on health-related quality of life (HRQoL). Methods: HRQoL was evaluated using the EORTC Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and EuroQol-5D-3L (EQ-5D-3L) questionnaires. Key HRQoL endpoints were least squares mean (LSM) score changes from baseline to week 12 and time to deterioration (TTD) for EORTC QLQ-C30 global health status (GHS)/QoL. p values were one-sided and nominal without adjustment for multiplicity. Results: The HRQoL population included patients randomly assigned to pembrolizumab (n = 298) and placebo (n = 152). From baseline to week 12, a greater decline in EORTC QLQ-C30 GHS/QoL score was observed with placebo (LSM, −8.4; 95% CI: −11.7 to −5.1) versus pembrolizumab (−4.0; 95% CI: −6.4 to −1.6; difference vs. placebo: 4.4; 95% CI: 0.5–8.4; nominal p = 0.0142). Similarly, a greater decline in the EQ-5D-3L visual analog scale score was observed with placebo (−6.9; 95% CI: −9.4 to −4.5) versus pembrolizumab (−2.7; 95% CI: −4.5 to −1.0; difference vs. placebo: 4.2; 95% CI: 1.2–7.2; nominal p = 0.0030). TTD in EORTC QLQ-C30 GHS/QoL score was similar between arms (hazard ratio, 0.85; 95% CI: 0.58–1.25; nominal p = 0.1993). Conclusion: Patients receiving placebo showed a greater decline in HRQoL than those receiving pembrolizumab. Combined with efficacy and safety data from KEYNOTE-394 and the global KEYNOTE-240 and KEYNOTE-224 trials, our data support the clinically meaningful benefit and manageable tolerability of pembrolizumab as second-line therapy for patients with advanced hepatocellular carcinoma.

China has a high burden of hepatocellular carcinoma, and hepatitis B virus (HBV) infection is the main causative factor. Patients with hepatocellular carcinoma have a poor prognosis and a substantial unmet clinical need. The phase 2–3 ORIENT-32 study aimed to assess sintilimab (a PD-1 inhibitor) plus IBI305, a bevacizumab biosimilar, versus sorafenib as a first-line treatment for unresectable HBV-associated hepatocellular carcinoma. This randomised, open-label, phase 2–3 study was done at 50 clinical sites in China. Patients aged 18 years or older with histologically or cytologically diagnosed or clinically confirmed unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment, and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible for inclusion. In the phase 2 part of the study, patients received intravenous sintilimab (200 mg every 3 weeks) plus intravenous IBI305 (15 mg/kg every 3 weeks). In the phase 3 part, patients were randomly assigned (2:1) to receive either sintilimab plus IBI305 (sintilimab–bevacizumab biosimilar group) or sorafenib (400 mg orally twice daily; sorafenib group), until disease progression or unacceptable toxicity. Randomisation was done using permuted block randomisation, with a block size of six, via an interactive web response system, and stratified by macrovascular invasion or extrahepatic metastasis, baseline α-fetoprotein, and ECOG performance status. The primary endpoint of the phase 2 part of the study was safety, assessed in all patients who received at least one dose of study drug. The co-primary endpoints of the phase 3 part of the study were overall survival and independent radiological review committee (IRRC)-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03794440. The study is closed to new participants and follow-up is ongoing for long-term outcomes. Between Feb 11, 2019 and Jan 15, 2020, we enrolled 595 patients: 24 were enrolled directly into the phase 2 safety run-in and 571 were randomly assigned to sintilimab–bevacizumab biosimilar (n=380) or sorafenib (n=191). In the phase 2 part of the trial, 24 patients received at least one dose of the study drug, with an objective response rate of 25·0% (95% CI 9·8–46·7). Based on the preliminary safety and activity data of the phase 2 part, in which grade 3 or worse treatment-related adverse events occurred in seven (29%) of 24 patients, the randomised phase 3 part was started. At data cutoff (Aug 15, 2020), the median follow-up was 10·0 months (IQR 8·5–11·7) in the sintilimab–bevacizumab biosimilar group and 10·0 months (8·4–11·7) in the sorafenib group. Patients in the sintilimab–bevacizumab biosimilar group had a significantly longer IRRC-assessed median progression-free survival (4·6 months [95% CI 4·1–5·7]) than did patients in the sorafenib group (2·8 months [2·7–3·2]; stratified hazard ratio [HR] 0·56, 95% CI 0·46–0·70; p<0·0001). In the first interim analysis of overall survival, sintilimab–bevacizumab biosimilar showed a significantly longer overall survival than did sorafenib (median not reached [95% CI not reached–not reached] vs 10·4 months [8·5–not reached]; HR 0·57, 95% CI 0·43–0·75; p<0·0001). The most common grade 3–4 treatment-emergent adverse events were hypertension (55 [14%] of 380 patients in the sintilimab–bevacizumab biosimilar group vs 11 [6%] of 185 patients in the sorafenib group) and palmar-plantar erythrodysaesthesia syndrome (none vs 22 [12%]). 123 (32%) patients in the sintilimab–bevacizumab biosimilar group and 36 (19%) patients in the sorafenib group had serious adverse events. Treatment-related adverse events that led to death occurred in six (2%) patients in the sintilimab–bevacizumab biosimilar group (one patient with abnormal liver function, one patient with both hepatic failure and gastrointestinal haemorrhage, one patient with interstitial lung disease, one patient with both hepatic faliure and hyperkalemia, one patient with upper gastrointestinal haemorrhage, and one patient with intestinal volvulus) and two (1%) patients in the sorafenib group (one patient with gastrointestinal haemorrhage and one patient with death of unknown cause). Sintilimab plus IBI305 showed a significant overall survival and progression-free survival benefit versus sorafenib in the first-line setting for Chinese patients with unresectable, HBV-associated hepatocellular carcinoma, with an acceptable safety profile. This combination regimen could provide a novel treatment option for such patients. Innovent Biologics. For the Chinese translation of the abstract see Supplementary Materials section.

BeiDou regional navigation satellite system （BDS） also called BeiDou-2 has been in full operation since December 27, 2012. It consists of 14 satellites, including 5 satellites in Geostationary Orbit （GEO）, 5 satellites in Inclined Geosynchronous Orbit （IGSO）, and 4 satellites in Medium Earth Orbit （MEO）. In this paper, its basic navigation and positioning performance are evaluated preliminarily by the real data collected in Beijing, including satellite visibility, Position Dilution of Precision （PDOP） value, the precision of code and carrier phase measurements, the accuracy of single point positioning and differential position- ing and ambiguity resolution （AR） performance, which are also compared with those of GPS. It is shown that the precision of BDS code and carrier phase measurements are about 33 cm and 2 mm, respectively, which are comparable to those of GPS, and the accuracy of BDS single point positioning has satisfied the design requirement. The real-time kinematic positioning is also feasible by BDS alolae in the opening condition, since its fixed rate and reliability of single-epoch dual-frequency AR is comparable to those of GPS. The accuracy of BDS carrier phase differential positioning is better than 1 cm for a very short baseline of 4.2 m and 3 cm for a short baseline of 8.2 km, which is on the same level with that of GPS. For the combined BDS and GPS, the fixed rate and reliability of single-epoch AR and the positioning accuracy are improved significantly. The accu- racy of BDS/GPS carrier phase differential positioning is about 35 and 20 % better than that of GPS for two short baseline tests in this study. The accuracy of BDS code differential positioning is better than 2.5 m. However it is worse than that of GPS, which may result from large code multipath errors of BDS GEO satellite measurements.

Background. A number of researches focused on the study of tumors have concluded that the expression level of lncRNA NKILA was decreased in different tumors. This is an indication that NKILA might influence the start and growth of a cancer. In addition, studies have fatalities and worsening health of cancer patients is associated with a reduced level of NKILA. Results. The results are the collective screening of nine total studies which included 937 cancer patients. The prognosis of the meta-analysis indicated that cancer patients with a higher expression of NKILA had an overall longer survival (OS) (HR=0.808, 95% CI: 0.736, 0.887); with regard to the clinical prognosis, the results indicated that reduced NKILA was associated with advanced clinical stage (OR=0.313, 95% CI: 0.225, 0.434), poor histological grades (OR=0.833, 95% CI: 0.508, 1.367), positive lymph node metastasis (OR=0.253, 95% CI: 0.144, 0.444), and additional tumor invasion depth (OR=0.326, 95% CI: 0.234, 0.454). Materials and Methods. Related research conducted was accessed by searching in PubMed and Web of Science with the keywords. The accessed material was till the 25th of February, 2020. The present quantitative meta-analysis was done using Stata SE12.0. The aim of the meta-analysis was to investigate the relationship between NKILA expression level and clinical prognosis. Conclusions. In the result of this meta-analysis, decreased NKILA expression is typical of different kinds of cancer. Moreover, it can perform as a predictive element of prognosis in varied kinds of cancer. Nonetheless, till now, it is deemed essential to carry out larger-size as well as better designed research works for the confirmation of our findings.