Background & Aims
Atezolizumab plus bevacizumab (Ate/Bev) has demonstrated efficacy and safety in patients with advanced hepatocellular carcinoma (HCC) in the phase III trial. Further evaluation is ...necessary to investigate the safety and efficacy of Ate/Bev in real settings.
Methods
This was a multicentre retrospective analysis. Between May 2020 and February 2021, 138 patients received Ate/Bev as first‐line treatment for advanced HCC from 11 institutions. We excluded patients with Child‐Pugh B or C and BCLC D stage, and the remaining 121 patients were included in this analysis.
Results
According to RECIST 1.1, the objective response and disease control rates were 24.0% and 76.0%. The median follow‐up duration was 5.9 months (95% confidence interval CI, 5.4‐6.4), the median progression‐free survival (PFS) was 6.5 months (95% CI, 4.1‐9.0), and median overall survival (OS) was not reached (95% CI, not available). The most frequent grade 3‐4 adverse event was aspartate aminotransferase elevation (10.7%). In the multivariate analyses, AFP increase (P = .037), baseline neutrophil‐to‐lymphocyte ratio (NLR) ≥ 5 (P = .023), and best response to stable disease or progressive disease (P = .019) were significantly associated with worse PFS. Macrovascular invasion (P = .048) and baseline NLR ≥5 (P < .001) were significantly associated with worse OS.
Conclusions
Ate/Bev showed real‐life efficacy and safety in Korean patients with advanced HCC, in line with results from phase III trial. Considering unfavourable survival outcomes of Ate/Bev in patients with elevated NLR, careful assessment of treatment response needs to be performed in this group.
Introduction
Regorafenib is an approved agent in patients with advanced hepatocellular carcinoma (HCC) who progressed on sorafenib, but little is known about its clinical outcomes in Child‐Pugh B ...patients. We aimed to investigate the safety and effectiveness of regorafenib in Child‐Pugh B HCC patients.
Methods
This multicentre retrospective study included 59 patients with Child‐Pugh B HCC who received regorafenib. Comparative analyses were performed with an independent cohort of Child‐Pugh class A patients from the same registry (n = 440).
Results
The median age was 58 years (range, 19‐83). All patients had progression on prior sorafenib. Regorafenib was given as 2nd line, and 3rd‐4th line systemic therapy in 37 (62.7%) and 22 (37.3%) patients respectively. Compared to Child‐Pugh A cohort, grade 3‐4 AEs were more common in the Child‐Pugh B cohort (27.1% vs 14.1%, P = .017). The median progression‐free survival (PFS) and overall survival (OS) were 1.8 and 4.6 months, respectively, and these were significantly poorer than the Child‐Pugh A cohort (P = .008 and P < .001 respectively). Child‐Pugh B patients with albumin‐bilirubin (ALBI) grade 3 had a significantly higher frequency of increased bilirubin (P = .01 for any grade and P = .01 for grade 3‐4) and showed significantly poorer OS (P = .021), compared to those with ALBI grade 1 or 2.
Conclusion
Regorafenib's poor clinical outcomes and increased frequency of severe adverse events lead us to discourage its use in the Child‐Pugh B population. In particular, regorafenib should not be used in Child‐Pugh B patients with ALBI grade 3.
Immunotherapy has emerged as a promising anti-cancer treatment, however, little is known about the genetic characteristics that dictate response to immunotherapy. We develop a transcriptional ...predictor of immunotherapy response and assess its prediction in genomic data from ~10,000 human tissues across 30 different cancer types to estimate the potential response to immunotherapy. The integrative analysis reveals two distinct tumor types: the mutator type is positively associated with potential response to immunotherapy, whereas the chromosome-instable type is negatively associated with it. We identify somatic mutations and copy number alterations significantly associated with potential response to immunotherapy, in particular treatment with anti-CTLA-4 antibody. Our findings suggest that tumors may evolve through two different paths that would lead to marked differences in immunotherapy response as well as different strategies for evading immune surveillance. Our analysis provides resources to facilitate the discovery of predictive biomarkers for immunotherapy that could be tested in clinical trials.
Fibroblast growth factor receptor 4 (FGFR4) is known to induce cancer cell proliferation, invasion, and antiapoptosis through activation of RAS/RAF/ERK and PI3K/AKT pathways, which are also known as ...major molecular bases of colon cancer carcinogenesis related with epidermal growth factor receptor (EGFR) signaling. However, the interaction between FGFR4 and EGFR signaling in regard to colon cancer progression is unclear. Here, we investigated a potential cross‐talk between FGFR4 and EGFR, and the effect of anti‐EGFR therapy in colon cancer treatment. To explore the biological roles of FGFR4 in cancer progression, RNA sequencing was carried out using FGFR4 transfected colon cell lines. Gene ontology data showed the upregulation of genes related to EGFR signaling, and we identified that FGFR4 overexpression secretes EGFR ligands such as amphiregulin (AREG) with consequent activation of EGFR and ErbB3. This result was also shown in in vivo study and the cooperative interaction between EGFR and FGFR4 promoted tumor growth. In addition, FGFR4 overexpression reduced cetuximab‐induced cytotoxicity and the combination of FGFR4 inhibitor (BLU9931) and cetuximab showed profound antitumor effect compared to cetuximab alone. Clinically, we found the positive correlation between FGFR4 and AREG expression in tumor tissue, but not in normal tissue, from colon cancer patients and these expressions were significantly correlated with poor overall survival in patients treated with cetuximab. Therefore, our results provide the novel mechanism of FGFR4 in connection with EGFR activation and the combination of FGFR4 inhibitor and cetuximab could be a promising therapeutic option to achieve the optimal response to anti‐EGFR therapy in colon cancer.
Our study has characterized the cross‐talk between fibroblast growth factor receptor 4 (FGFR4) and epidermal growth factor receptor (EGFR)/ErbB3 signaling by the contribution of EGFR ligands secreted from FGFR4. These findings provide experimental evidence for combined treatment with FGFR4 inhibitor and anti‐EGFR therapy in colon cancer.
BACKGROUNDImmunotherapy has revolutionized the clinical outcomes of intractable cancer patients. Little is known about the intestinal nonpathogenic bacterial composition of hepatocellular carcinoma ...(HCC) patients treated by immunotherapy. AIMTo determine whether there is a correlation between gut bacterial composition and prognosis in HCC patients. METHODSFrom September 2019 to March 2020, we prospectively collected fecal samples and examined the gut microbiome of 8 advanced HCC patients treated with nivolumab as a second- or third-line systemic treatment. Fecal samples were collected before the start of immunotherapy. Fecal samples of patients with progression during treatment were collected at the time of progression, and fecal samples of patients who showed good response to nivolumab were collected after 5-7 mo as follow-up. Metagenomic data from 16S ribosomal RNA sequencing were analyzed using CLC Genomics Workbench. Microbiome data were analyzed according to therapeutic response. RESULTSAll 8 patients were male, of which 6 had underlying chronic hepatitis B. A higher Shannon index was found in the responders than in the non-responders after nivolumab therapy (P = 0.036). The unweighted beta diversity analysis also showed that the overall bacterial community structure and phylogenetic diversity were clearly distinguished according to therapeutic response. There was no significant difference in the diversity or composition of the patient gut microbiome according to the immunotherapy used. Several taxa specific to therapeutic response were designated as follows: Dialister pneumosintes, Escherichia coli, Lactobacillus reteri, Streptococcus mutans, Enterococcus faecium, Streptococcus gordonii, Veillonella atypica, Granulicatella sp., and Trchuris trichiura for the non-responders; Citrobacter freundii, Azospirillum sp. and Enterococcus durans for the responders. Of note, a skewed Firmicutes/Bacteroidetes ratio and a low Prevotella/Bacteroides ratio can serve as predictive markers of non-response, whereas the presence of Akkermansia species predicts a good response. CONCLUSIONThe current presumptive study suggests a potential role for the gut microbiome as a prognostic marker for the response to nivolumab in treatment of HCC patients.
Background & Aims
Regorafenib demonstrated a clinical benefit for patients with unresectable hepatocellular carcinoma (uHCC) in the phase III RESORCE trial. Considering the heterogeneity of uHCC and ...discrepancies in its characteristics between prospective trials and daily practice, real‐life evidence is necessary.
Methods
This multicentre, retrospective analysis was performed by the Korean Cancer Study Group. In total, 440 patients who received regorafenib between January 2017 and November 2019 were identified in nine tertiary referral hospitals in Korea.
Results
All patients received prior sorafenib, and the median time‐to‐progression (TTP) on sorafenib was 3.9 months (range, 0.2‐71.6). Regorafenib was used as the second, third and fourth to seventh lines of therapy in 305 (69.3%), 115 (26.1%) and 20 (4.5%) patients respectively. According to the RECIST v1.1, the overall response rate was 7.7% (n = 34), and the median progression‐free survival (PFS) and overall survival (OS) were 3.2 (95% CI, 2.8‐3.5) and 12.1 (95% CI, 9.7‐14.5) months respectively. Immune checkpoint inhibitors (ICIs) were given in 115 patients (26.1%) prior to regorafenib. There were no differences in PFS and OS with regorafenib according to the prior use of ICIs (PFS, P = .61; OS, P = .63). The occurrence of hand‐foot skin reaction (HFSR) was associated with a better OS (P < .001).
Conclusions
The real‐life clinical outcomes of regorafenib for patients who progressed on prior systemic therapy including ICIs were consistent with the phase III trial results. HFSR was significantly associated with better OS with regorafenib.
The 29-item CareGiver Oncology Quality of Life (CarGOQoL) scale measures quality of life (QoL) based on the specific characteristics of informal caregivers of patients with cancer. The 29-item ...CarGOQoL has been translated to numerous other languages and validated, thus confirming its validation. This study aimed to evaluate the reliability and validity of the Korean version of the 29-item CarGOQoL. We recruited 316 informal caregivers of patients with cancer. Data were collected using structured questionnaires between January 23, 2019 and November 30, 2019, and analyzed using SPSS 27.0 and Amos 23.0. Internal consistency, construct validity, convergent and discriminant validity of the items, criterion validity, and known-group validity were tested. The 10-factor model was validated by a confirmatory factor analysis (χ2 = 687.633; P < .001; normed χ2 = 2.084; comparative fit index = .922; Tucker–Lewis index = .904; standardized root mean square residual = .050; root mean square error of approximation = .059). Criterion validity was demonstrated using the World Health Organization Quality of Life instrument-short version (r = .495-607), visual analog scale (VAS) for QoL (r = .509), and VAS for burden (r = −.457). The 29-item Korean version of the CarGOQoL had known-group validity according to the Eastern Cooperative Oncology Group performance status of the patients. Cronbach’s alpha coefficient for the total scale was .90. The 29-item Korean version of the CarGOQoL demonstrated acceptable validity and reliability for measuring QoL among Korean informal caregivers of patients with cancer. The 29-item Korean version of the CarGOQoL scale can be useful in Korean oncology clinical practice and research when assessing the quality of life of informal caregivers of patients with cancer.
Background The clinical features and therapeutic strategies for gastric cancer with positive peritoneal washing cytology but without visible gross peritoneal metastasis have not been defined. The aim ...of this study was to evaluate the effect and clinical prognostic value of postoperative chemotherapy in gastric cancer patients with positive peritoneal washing cytology without gross peritoneal metastasis who underwent radical D2 gastrectomy in terms of disease-free survival (DFS) and overall survival (OS). Materials and Methods Intraoperative peritoneal washing cytology was performed in 285 patients who underwent radical D2 gastrectomy between April 2004 and May 2016. Of them, 88 patients with positive cytology but without gross peritoneal metastasis were included in the study. In total, 64 patients received postoperative chemotherapy, whereas 24 patients underwent surgery only. Results Most gastric cancer patients with positive cytology without gross peritoneal metastasis demonstrated pT4 and/or pN3 disease. Postoperative chemotherapy improved DFS and OS compared to surgery only in gastric cancer patients with positive cytology without gross peritoneal metastasis (median DFS 11.63 vs. 6.98 months, p < 0.001; median OS 25.50 vs. 12.11 months, p < 0.001). In multivariate analyses of gastric cancer patients with positive cytology without gross peritoneal metastasis, no chemotherapy was the strongest clinical factor for poorer DFS (hazard ratio HR 3.76, p < 0.001) or OS (HR 4.37, p < 0.001). Conclusion Postoperative chemotherapy improves the survival outcome compared to surgery alone in gastric cancer patients with positive peritoneal washing cytology but without visible gross peritoneal metastasis who underwent radical D2 gastrectomy.
Galectin-3-binding protein (Gal-3BP) is a member of the family of scavenger receptor cysteine-rich (SRCR) domain-containing proteins, which are associated with the immune system. However, the ...functional roles and signaling mechanisms of Gal-3BP in host defense and the immune response remain largely unknown. Here, we identified cellular Gal-3BP as a negative regulator of NF-κB activation and proinflammatory cytokine production in lipopolysaccharide (LPS)-stimulated murine embryonic fibroblasts (MEFs). Furthermore, cellular Gal-3BP interacted with transforming growth factor β-activated kinase 1 (TAK1), a crucial mediator of NF-κB activation in response to cellular stress. Gal-3BP inhibited the phosphorylation of TAK1, leading to suppression of its kinase activity and reduced protein stability.
we found that
deficiency in mice enhanced LPS-induced proinflammatory cytokine release and rendered mice more sensitive to LPS-induced endotoxin shock. Overall, these results suggest that Gal-3BP is a novel suppressor of TAK1-dependent NF-κB activation that may have potential in the prevention and treatment of inflammatory diseases.
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