Liming Wang

Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide, and liver metastases stands as a leading contributor to its high mortality rate in advanced stages. Regorafenib plus anti-PD-1 is a new therapeutic option for patients with colorectal cancer liver metastases (CRCLM). However, a considerable number of patients have not benefited from it. In this study, KRAS mutation was identified associated with resistance to regorafenib plus anti-PD-1 in CRCLM. Dihydroartemisinin (DHA), a clinically approved anti-malaria agent, was verified to selectively downregulate KRAS ^G12D mutant with no discernible influences on wild-type KRAS, which is consistent with the higher sensitivity of KRAS -mutant CRC cells and organoids to DHA treatment. In preclinical KRAS ^G12D CRCLM models, DHA substantially potentiated the therapeutic efficacy of regorafenib plus anti-PD-1 by remodeling the tumor immune microenvironment, including enhancing the cytotoxicity of CD8 ⁺ effector T cells and promoting pro-inflammatory macrophage polarization. Mechanically, DHA could restore interferon response that was impaired by oncogenic KRAS mutations, and inhibit ERBB signaling activation induced by regorafenib. Collectively, these findings support DHA as a potential adjunct to regorafenib plus anti-PD-1 for KRAS ^G12D CRCLM and suggest a therapeutic strategy with translational potential for KRAS -driven malignancies.

Purpose: This study aimed to assess the efficacy and safety of intensity‐modulated radiotherapy (IMRT) combined with regorafenib with or without immune checkpoint inhibitors (ICIs) as a second‐ or later‐line treatment for advanced hepatocellular carcinoma (HCC). Materials and Methods: Patients diagnosed with advanced HCC who had received RT combined with concurrent or sequential regorafenib treatment or regorafenib plus ICIs after failures of at least one line of systemic treatment in a single center from April 2018 to August 2022 were retrospectively reviewed. Progression‐free survival (PFS) was the primary endpoint, while overall survival (OS), objective response rate (ORR), disease control rate (DCR), and toxicity were the secondary endpoints. Results: Fifty patients were included, with 44 (88.0%) in BCLC stage C, 37 (74.0%) having portal vein tumor thrombosis (PVTT), and 12 (24.0%) with extrahepatic metastasis. Thirty‐eight patients received conventional fractionated RT (56.4Gy/22–28f), while 12 received hyperfractionated RT (50Gy/5–10f). Twenty‐six were treated concurrently with regorafenib and 24 sequentially. ICIs were applied in 34 patients. For the entire cohort, when measured from the start of RT initiation, the median PFS and OS were 10.9 months and not reached. The corresponding 2‐year PFS and OS rates were 25.3% and 53.5%, respectively. When assessed from regorafenib initiation, the median PFS and OS were 5.9 months and not reached, with 2‐year PFS and OS rates of 22.8% and 54.9%, respectively. For tumors in the RT field, the ORR was 74.0% (RECIST) and 92.0% (mRECIST). The most common grade 3 toxicities were hand‐foot syndrome (16.0%), thrombocytopenia (8.0%), dermatitis (8.0%), and transaminase elevation (6.0%). Conclusion: IMRT concurrently or sequentially combined with regorafenib with or without ICIs is an effective, well‐tolerated, and promising regimen as second‐line or further‐line treatment in patients with advanced HCC.

Intrahepatic cholangiocarcinoma (ICC) is a rare, highly malignant, and heterogeneous group of primary hepatic adenocarcinomas that differs distinctly from conventional hepatocellular carcinoma. A specific cell population plays a crucial role in ICC named cancer-associated fibroblasts (CAFs). CAFs are involved in the connective tissue proliferative response in ICC, and this response manifests as a dense, fibrocollagen-rich tumor stroma. Thus, although chemotherapy and radiotherapy are the primary approaches to improve survival rates in patients with ICC, the presence of CAFs still render many patients refractory to these therapies. In this article, we explored the complex disease process of ICC in depth, reviewed the origin, heterogeneity, and function of CAFs, and focused on how CAFs subpopulations could be used as biomarkers and contribute to ICC treatment resistance. We also described current breakthroughs in targeting CAFs to overcome cancer treatment resistance and discussed emerging targeted therapies for CAFs. This article aims to provide a comprehensive overview of the latest advances and breakthrough directions in ICC treatment, hoping to offer new insights for future research and clinical practice.

Background Right hemicolectomy (RHC) and ileocecal resection (ICR) are two widely used surgical approaches for right-sided colon cancer. However, controversies persist regarding their differences in lymph node (LN) dissection completeness, LN metastasis patterns, and long-term oncologic outcomes in patients with stage III disease. This study aimed to compare LN distribution, surgical outcomes, and survival profiles between RHC and ICR in patients with stage III right-sided colon cancer. Methods A retrospective analysis was conducted on patients with primary right-sided colon cancer who underwent RHC or ICR at a large oncology center in Japan. Propensity score matching (PSM) was applied to balance baseline characteristics between the two groups at a 1:1 ratio. Comparisons were made regarding LN metastasis rates at different stations (pericolic, intermediate, and apical LNs), surgical outcomes, 5-year overall survival (OS), cancer-specific survival (CSS), relapse-free survival (RFS), and recurrence patterns. Results A total of 216 patients in the RHC group and 223 patients in the ICR group were enrolled. After PSM, 185 patients were included in each group. The mean number of excised lymph nodes was significantly higher in the RHC group than in the ICR group both before (36.0 ± 15.0 vs. 26.4 ± 10.6, p < 0.001) and after PSM (36.0 ± 13.8 vs. 26.0 ± 10.7, p < 0.001). The D1 nodal metastasis rate was significantly lower in the RHC group both before (13.9% vs. 4.0%, p < 0.001) and after PSM (13.0% vs. 4.3%, p = 0.005). No significant differences were observed in 5-year OS (70.8% vs. 62.7%, p = 0.137), CSS (77.4% vs. 69.4%, p = 0.190), or RFS (72.2% vs. 71.4%, p = 0.526) between the two groups after PSM. Multivariate logistic regression analysis revealed that histology type (poorly differentiated, signet ring, or mucinous carcinoma), venous invasion, and pN stage were independent prognostic factors for OS, while pN stage was an independent prognostic factor for RFS. A high carcinoembryonic antigen (CEA) level was identified as a common independent high-risk factor for OS, CSS, and RFS. Recurrence patterns (involving the liver, lung, lymph nodes, peritoneum, etc.) were similar between the two groups (all non-significant [N.S]). Conclusion For stage III right-sided colon cancer, RHC achieves a higher number of excised lymph nodes compared with ICR. However, the number of metastatic lymph nodes does not differ significantly between the two groups, and there are no significant differences in long-term oncologic outcomes. The selection of surgical procedure should be individualized based on tumor location, size, and patient-specific factors.

The prognosis of patients with intrahepatic cholangiocarcinoma (ICC) remains poor owing to the lack of effective targeted therapeutic strategies. Thus, the exploration of the molecular pathogenesis of ICC is urgently required. The cytoskeleton protein, anillin (ANLN), has been reported to contribute to various tumor growth by participating in cytokinesis via RhoA signaling. However, the exact physiological role and potential regulatory mechanism of ANLN in ICC are still not well understood. Based on spindle-related genes, integrated bioinformatic analyses identified ANLN as a potential candidate target for ICC. ANLN was elevated in ICC and predicted worse survival. Mechanistically, VIRMA-mediated m6A modification and IGF2BP3-dependent interaction collectively accounted for the upregulation of ANLN by maintaining its mRNA stability. Furthermore, the combination of ANLN and VIRMA or IGF2BP3 offered a greater predictive value than each marker alone in a large ICC cohort. Functional studies indicated that ANLN was involved in cancer cell proliferation and cell cycle. ANLN knockdown induced cytokinesis failure, DNA damage, and apoptosis in ICC cells. In addition to discovering the crucial role of ANLN in cytokinesis via RhoA activation, we also illustrated that ANLN restrained the Hippo pathway by enhancing the activity of RhoA signaling, which together contributed to ANLN-mediated tumor-promoting effects on ICC. Furthermore, YAP1-TEAD1 transcriptionally activated ANLN, subsequently establishing a self-reinforcing loop between ANLN and Hippo pathway, which was mediated by RhoA signaling as an intermediate regulatory node. Importantly, two clinical drugs, the RhoA inhibitor simvastatin and the YAP1/TEAD inhibitor verteporfin were determined to be the disruptors of this feed-forward signaling axis, inhibiting ICC tumor growth. These findings reveal the vital function of ANLN in ICC growth and provide promising treatment strategies for ICC.

Background: The prognosis of metastatic or recurrent hepatocellular carcinoma (HCC) remains poor, and new treatment strategies are warranted. Despite promising preclinical results demonstrating that radiation primes the immune system and produces a synergistic antitumor response for long-term disease control, limited clinical data are available. Therefore, in this study, we investigated the efficacy and safety of combining radiotherapy with immune checkpoint inhibitors (ICIs) for patients with metastatic and recurrent HCC in a real-world setting.Materials and methods: Patients with stage IV or recurrent HCC who received sequential or concurrent radiotherapy and ICIs in our institution were enrolled in this study. Data regarding clinicopathological characteristics, treatment protocols, response rates, toxicities, and survival were collected.Results: From January 2018 to December 2021, 108 patients were included. Extra-hepatic metastasis and portal vein tumor thrombosis were recorded in 58 (53.7%) and 69 patients (63.9%), respectively. A median radiation dose of 55 Gy was administered, and ICIs were administered for 3 weeks until disease progression or limiting toxicities occurred. After treatment, the overall response rate was 75.0%, and the median follow-up duration was 18.8 months. Median overall survival and progression-free survival were 17.0 and 12.6 months, respectively. Only one patient experienced in-field recurrence. Grade ≥3 adverse events were observed in 30.6% of patients. Dermatitis was the most common toxicity-related event and thrombocytopenia was the most common grade ≥3 adverse event, occurring overall in 17.6% of patients.Conclusion: The ICI and radiotherapy combination was effective and well-tolerated in real-world patients, achieving more favorable results compared with historical ones and providing a new multimodality therapy for patients with recurrent and metastatic HCC.