Summary Background There are no systemic treatments for patients with hepatocellular carcinoma (HCC) whose disease progresses during sorafenib treatment. We aimed to assess the efficacy and safety of ...regorafenib in patients with HCC who have progressed during sorafenib treatment. Methods In this randomised, double-blind, parallel-group, phase 3 trial done at 152 sites in 21 countries, adults with HCC who tolerated sorafenib (≥400 mg/day for ≥20 of last 28 days of treatment), progressed on sorafenib, and had Child-Pugh A liver function were enrolled. Participants were randomly assigned (2:1) by a computer-generated randomisation list and interactive voice response system and stratified by geographical region, Eastern Cooperative Oncology Group performance status, macrovascular invasion, extrahepatic disease, and α-fetoprotein level to best supportive care plus oral regorafenib 160 mg or placebo once daily during weeks 1–3 of each 4-week cycle. Investigators, patients, and the funder were masked to treatment assignment. The primary endpoint was overall survival (defined as time from randomisation to death due to any cause) and analysed by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT01774344. Findings Between May 14, 2013, and Dec 31, 2015, 843 patients were screened, of whom 573 were enrolled and randomised (379 to regorafenib and 194 to placebo; population for efficacy analyses), and 567 initiated treatment (374 received regorafenib and 193 received placebo; population for safety analyses). Regorafenib improved overall survival with a hazard ratio of 0·63 (95% CI 0·50–0·79; one-sided p<0·0001); median survival was 10·6 months (95% CI 9·1–12·1) for regorafenib versus 7·8 months (6·3–8·8) for placebo. Adverse events were reported in all regorafenib recipients (374 100% of 374) and 179 (93%) of 193 placebo recipients. The most common clinically relevant grade 3 or 4 treatment-emergent events were hypertension (57 patients 15% in the regorafenib group vs nine patients 5% in the placebo group), hand–foot skin reaction (47 patients 13% vs one 1%), fatigue (34 patients 9% vs nine patients 5%), and diarrhoea (12 patients 3% vs no patients). Of the 88 deaths (grade 5 adverse events) reported during the study (50 patients 13% assigned to regorafenib and 38 20% assigned to placebo), seven (2%) were considered by the investigator to be related to study drug in the regorafenib group and two (1%) in the placebo group, including two patients (1%) with hepatic failure in the placebo group. Interpretation Regorafenib is the only systemic treatment shown to provide survival benefit in HCC patients progressing on sorafenib treatment. Future trials should explore combinations of regorafenib with other systemic agents and third-line treatments for patients who fail or who do not tolerate the sequence of sorafenib and regorafenib. Funding Bayer.
Background and Aims
Atezolizumab plus bevacizumab (AtezoBev) is the standard of care for first‐line treatment of unresectable HCC. No evidence exists as to its use in routine clinical practice in ...patients with impaired liver function.
Approach and Results
In 216 patients with HCC who were consecutively treated with AtezoBev across 11 tertiary centers, we retrospectively evaluated treatment‐related adverse events (trAEs) graded (G) according to Common Terminology Criteria for Adverse Events v5.0, including in the analysis all patients treated according to label (n = 202, 94%). We also assessed overall survival (OS), progression‐free survival (PFS), overall response (ORR), and disease control rates (DCR) defined by Response Evaluation Criteria in Solid Tumors v1.1. Disease was mostly secondary to viral hepatitis, namely hepatitis C (n = 72; 36%) and hepatitis B infection (n = 35, 17%). Liver function was graded as Child‐Pugh (CP)‐A in 154 patients (76%) and CP‐B in 48 (24%). Any grade trAEs were reported by 143 patients (71%), of which 53 (26%) were G3 and 3 (2%) G4. Compared with CP‐A, patients with CP‐B showed comparable rates of trAEs. Presence and grade of varices at pretreatment esophagogastroduodenoscopy did not correlate with bleeding events. After a median follow‐up of 9.0 months (95% CI, 7.8–10.1), median OS was 14.9 months (95% CI, 13.6–16.3), whereas median PFS was 6.8 months (95% CI, 5.2–8.5). ORR and DCR were respectively 25% and 73%, with no difference across CP classes.
Conclusions
This study confirms reproducible safety and efficacy of AtezoBev in routine practice. Patients with CP‐B reported similar tolerability compared with CP‐A, warranting prospective evaluation of AtezoBev in this treatment‐deprived population.
In this retrospective study on a real‐life cohort of 216 patients treated with Atezolizumab plus Bevacizumab, the combination did not show any unexpected safety signals. Treatment‐related adverse events were comparable across Child‐Pugh (CP) classes. CP‐B patients achieved similar response rates to CP‐A patients, despite inferior survival outcomes.
A thermally activated delayed fluorescent (TADF) emitter (DMAC-TRZ) was reported either as the emitting dopant in a host or as the non-doped (neat) emitting layer to achieve high EL EQEs of up to ...26.5% and 20% in OLEDs, respectively.
Background and Aim
The severity of liver dysfunction in hepatocellular carcinoma (HCC) is often estimated with Child–Turcotte–Pugh (CTP) classification or model for end‐stage liver disease (MELD) ...score. We aim to investigate the performance of albumin‐bilirubin (ALBI) and platelet‐albumin‐bilirubin (PALBI) grade, which are recently reported to be simple and objective measurements for liver reserve in HCC.
Methods
Between 2002 and 2014, consecutive 3182 HCC patients were enrolled to follow up their survival. The area under receiver‐operator‐characteristic curve (AUC) was calculated to test the discriminatory powers over 1‐year, 3‐year, and 5‐year survival.
Results
Significant survival differences were found across all ALBI and PALBI grades (both P < 0.001). The majority (73%) of patients were CTP class A. Within CTP class A, ALBI revealed two prognostic groups while PALBI segregated three prognostic groups. The PABLI grade also identified three different survival groups for patients undergoing resection, ablation, and chemoembolization. Both ALBI and PALBI grade were capable of discerning survival among different HCC stages. The PALBI grade had significantly higher AUC compared with CTP classification and ALBI grade at 1, 3, and 5 years. For CTP class A patients, the PALBI grade was also associated with significantly higher AUC compared with ALBI grade at 1‐year and 3‐year intervals. The MELD score has the lowest AUC compared with other systems.
Conclusions
Both ALBI and PALBI grade are adequate models to assess liver dysfunction in HCC. The PALBI grade is consistently better in all patients, in patients with minimally decreased liver function, and in patients receiving different aggressive therapies.
A 2.4-GHz full-duplex (FD) transceiver, which employs multiple self-interference (SI) cancellation techniques, is presented for future wideband wireless communication. The proposed FD radio features ...broadband SI suppression, cancellers calibrated for enhanced linearity, and the ability to cancel long-delay spread SI. A prototype chip is fabricated in a Taiwan Semiconductor Manufacturing Company's (TSMC) 40-nm CMOS process and works with a Xilinx RFSoC evaluation kit to complete the calibration loop for the radio analog front end (AFE). The FD AFE chip integrates an electrical-balanced duplexer (EBD) with a tuned impedance matching network (<inline-formula> <tex-math notation="LaTeX">{Z} </tex-math></inline-formula>Bal), two broadband five complex-tap continuous-time finite impulse response (FIR)-based RF cancellation filters, and a mixed-signal baseband cancellation path operating with a field-programmable gate array (FPGA) to complete a long-delay spread (<inline-formula> <tex-math notation="LaTeX">\tau =+174 </tex-math></inline-formula> ns) SI canceller. A fourth-order <inline-formula> <tex-math notation="LaTeX">{Z} </tex-math></inline-formula>Bal is employed to reduce SI group delay and improves the cancellation bandwidth (BW) when used with complex filters. This work reports a measured SI suppression of 62 dB across +120-MHz BW for delay spreads between 0 and 0.28 ns and SI cancellation of 23 dB across +120-MHz BW for delay spreads between 0.4 and 174 ns. The EBD achieves an enhanced common-mode rejection exceeding 55 dB through the use of a center-tap capacitor (<inline-formula> <tex-math notation="LaTeX">{C} </tex-math></inline-formula>CT) with minimal additional area. The RF canceller, calibrated by digitally controlled current digital-to-analog converters (DACs), demonstrates a maximum input-referred third order intercept point (IIP3) of +42 dBm. The receiver (RX) has a measured noise figure (NF) of 6.8 dB and an IIP3 of −21 dBm at the maximum gain setting of 40 dB. An integrated harmonic-rejection power amplifier (PA) achieves a measured maximum output power <inline-formula> <tex-math notation="LaTeX">{P} </tex-math></inline-formula>Sat and a PAE of 19.1 dBm and 27%, respectively. The overall FD transceiver, including an integrated phase-locked loop (PLL), occupies an area of 3.2 mm2 and consumes a total power of 373/78 mW including/excluding the PA.
Arterial pulse-wave velocity (PWV) is widely used in clinical applications to assess cardiovascular diseases. Ultrasound methods have been proposed for estimating regional PWV in human arteries. ...Furthermore, high-frequency ultrasound (HFUS) has been applied to perform preclinical small-animal PWV measurements; however, electrocardiogram (ECG)-gated retrospective imaging is required to achieve high-frame-rate imaging, which might be affected by arrhythmia-related problems. In this paper, HFUS PWV mapping based on 40-MHz ultrafast HFUS imaging is proposed to visualize PWV on mouse carotid artery to measure arterial stiffness without ECG gating. In contrast to most other studies that used cross-correlation methods to detect arterial motion, ultrafast Doppler imaging was applied in this study to measure arterial wall velocity for PWV estimations. The performance of the proposed HFUS PWV mapping method was verified using a polyvinyl alcohol (PVA) phantom with various freeze-thaw cycles. Small-animal studies were then performed in wild-type (WT) mice and in apolipoprotein E knockout (ApoE KO) mice that were fed a high-fat diet (for 16 and 24 weeks). The Young's modulus of the PVA phantom measured through HFUS PWV mapping was 15.3 ± 0.81, 20.8 ± 0.32, and 32.2 ± 1.11 kPa for three, four, and five freeze-thaw cycles, respectively, and the corresponding measurement biases (relative to theoretical values) were 1.59%, 6.41%, and 5.73%, respectively. In the mouse study, the average PWVs were 2.0 ± 0.26, 3.3 ± 0.45, and 4.1 ± 0.22 m/s for 16-week WT, 16-week ApoE KO, and 24-week ApoE KO mice, respectively. The PWVs of ApoE KO mice increased during the high-fat diet feeding period. HFUS PWV mapping was used to visualize the regional stiffness of mouse artery, and a histology confirmed that the plaque formation in the bifurcation region increased the regional PWV. All the results indicate that the proposed HFUS PWV mapping method is a convenient tool for investigating arterial properties in preclinical small-animal studies.
Influenza is one of the most common human respiratory diseases, and represents a serious public health concern. However, the high mutability of influenza viruses has hampered vaccine development, and ...resistant strains to existing anti-viral drugs have also emerged. Novel anti-influenza therapies are urgently needed, and in this study, we describe the anti-viral properties of a Spirulina (Arthrospira platensis) cold water extract. Anti-viral effects have previously been reported for extracts and specific substances derived from Spirulina, and here we show that this Spirulina cold water extract has low cellular toxicity, and is well-tolerated in animal models at one dose as high as 5,000 mg/kg, or 3,000 mg/kg/day for 14 successive days. Anti-flu efficacy studies revealed that the Spirulina extract inhibited viral plaque formation in a broad range of influenza viruses, including oseltamivir-resistant strains. Spirulina extract was found to act at an early stage of infection to reduce virus yields in cells and improve survival in influenza-infected mice, with inhibition of influenza hemagglutination identified as one of the mechanisms involved. Together, these results suggest that the cold water extract of Spirulina might serve as a safe and effective therapeutic agent to manage influenza outbreaks, and further clinical investigation may be warranted.
The Asia-Pacific Primary Liver Cancer Expert (APPLE) Consensus Statement on the treatment strategy for patients with intermediate-stage hepatocellular carcinoma (HCC) was established on August 31, ...2019, in Sapporo, Hokkaido during the 10th Annual APPLE Meeting. This manuscript summarizes the international consensus statements developed at APPLE 2019. Transarterial chemoembolization (TACE) is the only guideline-recommended global standard of care for intermediate-stage HCC. However, not all patients benefit from TACE because intermediate-stage HCC is a heterogeneous disease in terms of tumor burden and liver function. Ten important clinical questions regarding this stage of HCC were raised, and consensus statements were generated based on high-quality evidence. In intermediate-stage HCC, preservation of liver function is as important as achieving a high objective response (OR) because the treatment goal is to prolong overall survival. Superselective conventional TACE (cTACE) is recommended as the first choice of treatment in patients eligible for effective (curative) TACE, whereas in patients who are not eligible, systemic therapy is recommended as the first choice of treatment. TACE is not indicated as the first-line therapy in TACE-unsuitable patients. Another important statement is that TACE should not be continued in patients who develop TACE failure/refractoriness in order to preserve liver function. Targeted therapy is the recommended first-line treatment for TACE-unsuitable patients. Especially, the drug, which can have higher OR rate, is preferred. Immunotherapy, transarterial radioembolization, TACE + targeted therapy or other modalities may be considered alternative options in TACE-unsuitable patients who are not candidates for targeted therapy. Better liver function, such as albumin-bilirubin grade 1, is an important factor for maximizing the therapeutic effect of systemic therapy.
Vascular endothelial growth factor (VEGF) plays a role in the tumor microenvironment. Sorafenib, which inhibits the VEGF pathway, has an immune-modulation function but lacks substantial clinical ...data. This study aims to explore the efficacy of anti-PD-1 combined sorafenib in advanced hepatocellular carcinoma (HCC).
HCC patients who underwent anti-PD-1 treatment at Taipei Veterans General Hospital (Taipei, Taiwan) between January 2016 and February 2019 were reviewed. The efficacy was compared between groups after propensity-score matching.
There were 173 HCC patients receiving anti-PD-1. After excluding unsuitable cases, 140 patients were analyzed, of which 58 received combination therapy and 82 received anti-PD-1 alone. The combination therapy had a trend of higher CR rate (8.6% vs. 4.9%, ns.), ORR (22.4% vs. 19.5%, ns.) and significantly higher DCR (69.0% vs. 37.8%, p < 0.05) comparing to anti-PD-1 alone. After matching, combination group achieved longer progression-free survival (3.87 vs. 2.43 months, p < 0.05) and overall survival (not reached vs. 7.17 months, p < 0.05) than anti-PD-1 alone, without higher grade 3/4 AE (10.3% vs. 7.1%, p = 0.73). The tumor response varied among different metastatic sites, with high responses in adrenal glands, peritoneum and lungs. The more AFP declined (> 10, > 50 and > 66%), the higher the ORR (70, 80 and 92%) and CR rates (30, 35 and 58%) were achieved at day 28.
This is the first study to demonstrate the combination of anti-PD-1 and sorafenib had better efficacy and survival benefit. A prospective randomized study is needed to confirm this finding.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Nutritional administration in acute pancreatitis (AP) management has sparked widespread discussion, yet contradictory mortality results across meta‐analyses necessitate clarification. The ...optimal nutritional route in AP remains uncertain. Therefore, this study aimed to compare mortality among nutritional administration routes in patients with AP using consistency model.
Methods
This study searched four major databases for relevant randomized controlled trials (RCTs). Two authors independently extracted and checked data and quality. Network meta‐analysis was conducted for estimating risk ratios (RRs) with 95% confidence interval (CI) based on random‐effects model. Subgroup analyses accounted for AP severity and nutrition support initiation.
Results
A meticulous search yielded 1185 references, with 30 records meeting inclusion criteria from 27 RCTs (n = 1594). Pooled analyses showed the mortality risk reduction associated with nasogastric (NG) (RR = 0.34; 95%CI: 0.16–0.73) and nasojejunal (NJ) feeding (RR = 0.46; 95%CI: 0.25–0.84) in comparison to nil per os. Similarly, NG (RR = 0.45; 95%CI: 0.24–0.83) and NJ (RR = 0.60; 95%CI: 0.40–0.90) feeding also showed lower mortality risk than total parenteral nutrition. Subgroup analyses, stratified by severity, supported these findings. Notably, the timing of nutritional support initiation emerged as a significant factor, with NJ feeding demonstrating notable mortality reduction within 24 and 48 h, particularly in severe cases.
Conclusion
For severe AP, both NG and NJ feeding appear optimal, with variations in initiation timings. NG feeding does not appear to merit recommendation within the initial 24 h, whereas NJ feeding is advisable within the corresponding timeframe following admission. These findings offer valuable insights for optimizing nutritional interventions in AP.
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