Background and Aims
Programmed death 1 (PD‐1) inhibitors have improved survival outcomes and produced durable responses in advanced hepatocellular carcinoma (HCC) for some patients. Here, we ...evaluated the relationship between the baseline and kinetics of the neutrophil‐lymphocyte ratio (NLR) and clinical outcomes in nivolumab‐treated HCC patients.
Methods
All consecutive HCC patients treated with nivolumab between July 2017 and June 2020 were screened for the eligibility. The NLRs were calculated before and at 2, 4 and 6 weeks after treatment. Survival outcomes were compared based on the baseline and kinetics of NLR. We additionally analysed the association of the baseline and dynamic changes in the NLR with hyperprogression (HPD).
Results
Among the 194 included cases, most patients were male (82.0%) and had a Child–Pugh Class A disease (70.6%). Patients with a baseline NLR ≥ 3 (hazard ratio HR 2.46; 95% CI 1.63‐3.71) had a poorer overall survival than patients with baseline NLR < 3. During the treatment, the NLR increased rapidly in patients developing HPD, and only a ΔNLR at 4 weeks was predictive of HPD. The risk of HPD increased by 20% for every 20% increase in the ΔNLR at 4 weeks. Accordingly, an NLR increase at 4 weeks (HR 1.79; 95% CI 1.19‐2.68) was associated with an increased risk of death, especially among patients with a baseline NLR ≥ 3.
Conclusions
The baseline and on‐treatment kinetics for the NLR are effective prognostic indicators in nivolumab‐treated patients with HCC. This may help to guide patient selection and on‐treatment strategies for immunotherapies in advanced HCC.
Introduction: Atezolizumab-bevacizumab is the new standard of care for first-line treatment of advanced hepatocellular carcinoma (HCC). However, the optimal sequence of therapy after disease ...progression on atezolizumab-bevacizumab is unclear. Methods: This multinational, multicenter, and retrospective study assessed clinical outcomes of patients with advanced HCC who received subsequent systemic therapy after progression on atezolizumab-bevacizumab between July 2016 and April 2019. Results: Among 71 patients treated with atezolizumab-bevacizumab, a total of 49 patients who received subsequent systemic therapy were included in this analysis; the median age was 60 years (range, 37–80) and 73.5% were male. All patients were classified as Child-Pugh A and Barcelona-Clinic Liver Cancer stage C. Multikinase inhibitors (MKIs), including sorafenib (n = 29), lenvatinib (n = 19), and cabozantinib (n = 1), were used as second-line therapy for all patients. The objective response rate and disease control rate were 6.1 and 63.3%, respectively, in all patients. With a median follow-up duration of 11.0 months, median progression-free survival (PFS) and overall survival (OS) were 3.4 months (95% confidence interval CI 1.8–4.9) and 14.7 months (95% CI 8.1–21.2) in all patients. Median PFS with lenvatinib was significantly longer than that with sorafenib (6.1 vs. 2.5 months; p = 0.004), although there was no significant difference in median OS (16.6 vs. 11.2 months; p = 0.347). Treatment-related adverse events (TRAEs) of any grade and grade 3 occurred in 42 (85.7) and 8 (16.3%) of patients. Common TRAEs included hand-foot syndrome (n = 26, 53.1%), fatigue (n = 14, 28.6%), hypertension (n = 14, 28.6%), and diarrhea (n = 12, 24.5%). Conclusion: Second-line treatment with MKIs, mostly sorafenib and lenvatinib, showed comparable efficacy and manageable toxicities in patients with advanced HCC after disease progression on atezolizumab-bevacizumab.
We investigated the role of connexin 43 (Cx43) in maintaining the integrity of mitochondria in brown adipose tissue (BAT). The functional effects of Cx43 were evaluated using inducible, ...adipocyte-specific Cx43 knockout in mice (Gja1
KO) and by overexpression and knockdown of Cx43 in cultured adipocytes. Mitochondrial morphology was evaluated by electron microscopy and mitochondrial function and autophagy were assessed by immunoblotting, immunohistochemistry, and qPCR. The metabolic effects of adipocyte-specific knockout of Cx43 were assessed during cold stress and following high fat diet feeding. Cx43 expression was higher in BAT compared to white adipose tissue. Treatment with the β3-adrenergic receptor agonist CL316,243 increased Cx43 expression and mitochondrial localization. Gja1
KO mice reduced mitochondrial density and increased the presence of damaged mitochondria in BAT. Moreover, metabolic activation with CL316,243 further reduced mitochondrial integrity and upregulated autophagy in the BAT of Gja1
KO mice. Inhibition of Cx43 in cultured adipocytes increased the generation of reactive oxygen species and induction of autophagy during β-adrenergic stimulation. Gja1
KO mice were cold intolerant, expended less energy in response to β3-adrenergic receptor activation, and were more insulin resistant after a high-fat diet challenge. Collectively, our data demonstrate that Cx43 is required for maintaining the mitochondrial integrity and metabolic activity of BAT.
Chromatin remodelers regulate the nucleosome barrier during transcription, DNA replication, and DNA repair. The chromatin remodeler RSF1 is enriched at mitotic centromeres, but the functional ...consequences of this enrichment are not completely understood. Shugoshin (Sgo1) protects centromeric cohesion during mitosis and requires BuB1-dependent histone H2A phosphorylation (H2A-pT120) for localization. Loss of Sgo1 at centromeres causes chromosome missegregation. Here, we show that RSF1 regulates Sgo1 localization to centromeres through coordinating a crosstalk between histone acetylation and phosphorylation. RSF1 interacts with and recruits HDAC1 to centromeres, where it counteracts TIP60-mediated acetylation of H2A at K118. This deacetylation is required for the accumulation of H2A-pT120 and Sgo1 deposition, as H2A-K118 acetylation suppresses H2A-T120 phosphorylation by Bub1. Centromeric tethering of HDAC1 prevents premature chromatid separation in RSF1 knockout cells. Our results indicate that RSF1 regulates the dynamics of H2A histone modifications at mitotic centromeres and contributes to the maintenance of chromosome stability.
Portosystemic shunt embolization (PSSE) is a promising treatment for hepatic encephalopathy (HEP) and gastric varix (GV) in cirrhotic patients with a spontaneous portosystemic shunt. However, PSSE ...may worsen portal hypertension causing hepatorenal syndrome, liver failure, and mortality. This study aimed to develop and validate a prognostic model that helps identify patients with a risk of poor short-term survival after PSSE.
We included 188 patients who underwent PSSE for recurrent HEP or GV at a tertiary center in Korea. To develop a prediction model for 6-month survival after PSSE, Cox proportional-hazard model was used. The developed model was validated in a separate cohort of 184 patients from two other tertiary centers.
In multivariable analysis, the 1-year overall survival after PSSE was significantly associated with baseline levels of serum albumin, total bilirubin, and international normalized ratio (INR). We therefore developed the albumin-bilirubin-INR (ABI) score by assigning 1 point each for albumin < 3.0 g/dL, total bilirubin ≥ 1.5 mg/dL, and INR ≥ 1.5. Time-dependent areas under the curve of the ABI score for predicting 3-month and 6-month survival were 0.85 and 0.85 in the development cohort and 0.83 and 0.78 in the validation cohort, indicating good discrimination performance. The ABI score showed a better discrimination and calibration performance than the model for end-stage liver disease and the Child-Pugh scores, especially in high-risk patients.
The ABI score is a simple prognostic model that helps decide whether to proceed with PSSE for the prevention of HEP or GV bleeding in patients with spontaneous portosystemic shunt.
MARCH5, a mitochondrial E3 ubiquitin ligase, controls mitochondrial dynamics proteins and misfolded proteins, and has been proposed to play a role in mitochondria quality control. However, it remains ...unclear how mutant MARCH5 found in cancer tissues is removed from cells. Here, we show that mutation in the MARCH5 ligase domain increased its half‐life fourfold, resulting in a drastic increase in its protein level. Abnormal accumulation of the E3 ligase‐defective MARCH5 mutants MARCH5ᴴ⁴³ᵂ and MARCH5C⁶⁵/⁶⁸S was diminished by overexpression of active MARCH5ᵂᵀ; the mutant proteins were degraded through the ubiquitin–proteasome pathway. Coimmunoprecipitation revealed that MARCH5 forms homodimers, and that substitution of Gly to Leu at the first putative GxxxG dimerization motif, but not the second, resulted in a loss of dimeric interaction. Moreover, overexpression of the dimerization‐defective mutant MARCH5⁴ᴳᴸ could not decrease the level of accumulated MARCH5ᴴ⁴³ᵂ, suggesting that dimerization of MARCH5 is necessary for self‐clearance. Abnormal accumulation of MARCH5ᴴ⁴³ᵂ and mitochondrial hyperfusion led to NF‐ĸB activation, which was suppressed by overexpression of MARCH5ᵂᵀ. Together, the data reveal a self‐protective mechanism involving MARCH5, which can target its own dysfunctional mutant for degradation in order to maintain mitochondrial homeostasis.
Hepatitis B virus (HBV) reactivation is a well-known complication in patients with chronic hepatitis B treated with cytotoxic chemotherapy. However, the risk of HBV reactivation through use of immune ...checkpoint inhibitors (ICIs) is not well understood. Therefore, we aimed to evaluate the risk of HBV reactivation and hepatic adverse events in patients with cancer receiving ICIs according to cancer type and virologic serology.
This historical cohort study included 3465 patients with cancer treated with ICIs between January 2015 and September 2020. The primary outcome was the occurrence of HBV reactivation, and the secondary outcome was presence of hepatic adverse events during ICI treatment.
The mean patient age was 62.2 years, and 68.8% of patients were men. Of the 3465 eligible patients, 511 (14.7%) showed hepatitis B surface antigen (HBsAg) positivity. The incidence rates of HBV reactivation of the total patients, HBsAg-positive patients, and HBsAg-negative patients were 0.14% (5/3465), 1.0% (5/511), and 0.0% (0/2954), respectively. Among HBsAg-positive patients, HBV reactivation occurred at a rate of 0.5% (2/409) and 2.9% (3/102) in patients with and without hepatocellular carcinoma, respectively. The HBV reactivation rates were 0.4% (2/464) and 6.4% (3/47) in patients with and without antiviral prophylaxis, respectively. Grade 3-4 hepatitis occurred in 23 (4.5%) HBsAg-positive, and 218 (7.4%) HBsAg-negative patients. No HBV-related fatality occurred. Only 2 patients (0.4%) experienced HBsAg seroclearance after ICI treatment among HBsAg-positive patients.
In general, HBV reactivation was rarely observed in patients with antiviral prophylaxis while undergoing ICI treatment. However, HBV reactivation may occur in HBsAg-positive patients without antiviral prophylaxis or noncompliant with antiviral prophylaxis.
Background & Aims
The optimal systemic chemotherapy for combined hepatocellular‐cholangiocarcinoma (cHCC‐CCA) has not yet been defined. The definition and classification of cHCC‐CCA has changed ...recently in the 5th edition of WHO classification. We reviewed the pathological findings with the new classification and analysed the efficacy of systemic chemotherapy in patients with unresectable/metastatic cHCC‐CCA.
Methods
Among 254 patients with histologically confirmed cHCC‐CCA from 1999 to 2015 in Asan Medical Center, Seoul, Korea, 99 patients who received systemic chemotherapy for unresectable/metastatic disease were included. Overall response rate (ORR), progression‐free survival (PFS) and overall survival (OS) were retrospectively evaluated.
Results
Sorafenib (n = 62) and cytotoxic chemotherapy (n = 37) were administered as first‐line chemotherapies; the ORR was 14.1%, and the median PFS and OS were 3.8 and 10.6 months, respectively, with a median follow‐up duration of 39.6 months. The efficacy outcomes were not significantly different between patients who received sorafenib and those who received cytotoxic chemotherapy (ORR, 9.7% vs 21.6%, P = .14; median PFS, 4.2 vs 2.9 months, P = .52; median OS, 10.7 vs 10.6 months, P = .34). In multivariate analysis, large intrahepatic tumour burden (≥30% of liver volume), elevated serum bilirubin and non‐platinum containing first‐line chemotherapy remained as significant prognostic factors for poorer OS.
Conclusions
The efficacy outcomes according to first‐line treatment were not significantly different between sorafenib and cytotoxic chemotherapy, and pathological findings were not found to help for determining appropriate therapeutic agent or assessing the prognosis. To overcome the poor treatment outcomes, further studies are needed to find proper treatment targets, biomarkers and the best treatment strategies.
Nivolumab has shown durable response and safety in patients with hepatocellular carcinoma (HCC) in previous trials. However, real-world data of nivolumab in HCC patients, especially those with ...Child–Pugh class B, are limited. To investigate the effectiveness and safety of nivolumab in a real-world cohort of patients with advanced HCC, we retrospectively evaluated 203 patients with HCC who were treated with nivolumab between July 2017 and February 2019. Of 203 patients, 132 patients were classified as Child–Pugh class A and 71 patients were Child–Pugh class B. Objective response rate was lower in patients with Child–Pugh class B than A (2.8% vs. 15.9%; p = 0.010). Child–Pugh class B was an independent negative predictor for objective response. Median overall survival was shorter in Child–Pugh B patients (11.3 vs. 42.9 weeks; adjusted hazard ratio AHR, 2.10; p < 0.001). In Child–Pugh B patients, overall survival of patients with Child–Pugh score of 8 or 9 was worse than patients with Child–Pugh score of 7 (7.4 vs. 15.3 weeks; AHR, 1.93; p < 0.020). In conclusion, considering the unsatisfactory response in Child–Pugh B patients, nivolumab may not be used in unselected Child–Pugh B patients. Further studies are needed in this patient population.
The mitochondrial antiviral signaling (MAVS) protein on the mitochondrial outer membrane acts as a central signaling molecule in the RIG-I-like receptor (RLR) signaling pathway by linking upstream ...viral RNA recognition to downstream signal activation. We previously reported that mitochondrial E3 ubiquitin ligase, MARCH5, degrades the MAVS protein aggregate and prevents persistent downstream signaling. Since the activated RIG-I oligomer interacts and nucleates the MAVS aggregate, MARCH5 might also target this oligomer. Here, we report that MARCH5 targets and degrades RIG-I, but not its inactive phosphomimetic form (RIG-IS8E). The MARCH5-mediated reduction of RIG-I is restored in the presence of MG132, a proteasome inhibitor. Upon poly(I:C) stimulation, RIG-I forms an oligomer and co-expression of MARCH5 reduces the expression of this oligomer. The RING domain of MARCH5 is necessary for binding to the CARD domain of RIG-I. In an in vivo ubiquitination assay, MARCH5 transfers the Lys 48-linked polyubiquitin to Lys 193 and 203 residues of RIG-I. Thus, dual targeting of active RIG-I and MAVS protein oligomers by MARCH5 is an efficient way to switch-off RLR signaling. We propose that modulation of MARCH5 activity might be beneficial for the treatment of chronic immune diseases.
•MARCH5 targets and degrades the RIG-I oligomer in addition to MAVS aggregates.•The RING domain of MARCH5 is necessary for binding to the CARD domain of RIG-I.•MARCH5 transfers the Lys 48-linked polyubiquitin to Lys 193 and 203 residue of RIG-I.
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