The development of systemic therapy, including targeted drugs and immune checkpoint inhibitors, has significantly improved the prognosis of patients with advanced unresectable hepatocellular carcinoma (uHCC). Hepatic arterial infusion chemotherapy (HAIC) has been gradually applied to the treatment of advanced uHCC, showing good potential as conversion therapy. We aimed to investigate the efficacy and safety of HAIC combined with camrelizumab and apatinib as conversion therapy for uHCC. This study was a single-arm exploratory trial (NCT05099848) in patients with uHCC. Eligible patients received apatinib 250 mg once daily, camrelizumab 200 mg on day 3, and HAIC with FOLFOX regimen (oxaliplatin 85 mg/m2 at hours 0–2, leucovorin 400 mg/m2 at hours 2–3, and fluorouracil 400 mg/m2 at hour 3, followed by fluorouracil 2400 mg/m2 for 46 h) on days 4–5 of each 21-day cycle for up to 8 cycles. Primary endpoints were conversion rate and margin-free (R0) resection rate. Between March 2021 and July 2023, 19 patients were enrolled. Median follow-up was 14.9 months (interquartile range, 10.9–21.1). Disease became resectable in 14 (73.7%) of 19 patients; nine (47.4%) patients received R0 resection, while five (26.3%) refused surgery and opted for observation. Three (33.3%) of nine patients with surgery achieved major pathological response, including two (22.2%) with pathological complete response. Objective response and disease control rates were 47.4% (9/19) and 89.5% (17/19) per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 and both 89.5% (17/19) per modified RECIST. Survival data were immature. Fourteen (73.7%) of 19 patients had grade 3 or higher treatment-related adverse events, with the most common being increased alanine aminotransferase or aspartate aminotransferase (seven [36.8%]) and increased lymphocyte count (six [31.6%]). No treatment-related deaths occurred. The combination of HAIC, camrelizumab, and apatinib as conversion therapy shows promising clinical benefits and a manageable safety profile in patients with uHCC. Future randomized controlled trials are warranted. ClinicalTrials.gov NCT05099848. Registered on October 13, 2021.

Hepatocellular carcinoma (HCC) is regarded as a leading cause of cancer-related deaths, and its progression is associated with hypoxia and the induction of hypoxia-inducible factor (HIF). Meloxicam, a selective cyclooxygenase-2 (COX-2) inhibitor, induces cell death in various malignancies. However, the underlying mechanism remains to be elucidated in HCC, especially under hypoxic conditions. The alteration of COX-2 and HIF-1α oncogenicity was evaluated in HCC specimens by tissue microarray. Cell viability, angiogenesis assays, and xenografted nude mice were used to evaluate the effects of meloxicam, along with flow cytometry to detect the cell cycle, apoptosis, and mitochondrial membrane potential (ΔΨm) of HCC. qRT-PCR, Western blotting, immunofluorescence, immunohistochemistry, luciferase assay, and RNAi were carried out to determine the HIF-1α signaling affected by meloxicam. In this study, we showed that meloxicam exerts antiproliferative and antiangiogenesis efficacy in vitro and in vivo and causes disruption of mitochondrial membrane potential (ΔΨm), thus leading to caspase-dependent apoptosis under hypoxic environments. Exposure to meloxicam significantly reduced HIF-1α transcriptional activation and expression through sequestering it in the cytoplasm and accelerating degradation via increasing the von Hippel-Lindau tumor suppressor protein (pVHL) in HCC. These data demonstrated that inhibition of HIF-1α by meloxicam could suppress angiogenesis and enhance apoptosis of HCC cells. This discovery highlights that COX-2 specific inhibitors may be a promising therapy in the treatment of HCC.

The T7 peptide, an active fragment of full‑length tumstatin [the non‑collagenous 1 domain of the type IV collagen α3 chain, α3 (IV) NC1], has exhibited potential antitumor effects in several types of cancer cells. However, the mechanism underlying its action against human hepatocellular carcinoma (HCC) remains unclear. The present study aimed to investigate the role of autophagy in T7 peptide‑induced cytotoxicity in HCC cells in vitro and in vivo. The results revealed that the T7 peptide significantly reduced cell viability and induced cell cycle arrest in HCC cells. The T7 peptide induced apoptosis in HCC cells through upregulation of Bax, Fas, and Fas ligand, and through upregulation of the anti‑apoptotic protein Bcl‑2. In addition, treatment with the T7 peptide induced protective autophagy in HCC cells. Blocking autophagy by 3‑methyladenineor bafilomycin A1 enhanced T7 peptide‑induced apoptosis. Furthermore, co‑treatment with MK‑2206 (an Akt specific inhibitor) or rapamycin (an inhibitor of mTOR) enhanced T7 peptide‑induced autophagy, whereas co‑treatment with insulin (an activator of the Akt/mTOR signaling pathway) alleviated T7 peptide‑induced autophagy, which suggested that the T7 peptide may induce autophagy activation via inhibition of the Akt/mTOR signaling pathway. Taken together, the present results demonstrated that suppression of autophagy potentiated the cytotoxic effects of the T7 peptide, and suggested that the T7 peptide may serve as a potential alternative compound for HCC therapy.

Backgrounds: Programmed death receptor 1 (PD-1) monoclonal antibody has been approved for the first and second-line treatments of hepatocellular carcinoma (HCC). This study aimed to evaluate the efficacy and safety of tislelizumab + regorafenib as a second-line treatment option for advanced HCC. Methods: Treatment-related adverse events (TRAEs) were the primary endpoints in this clinical trial comprising 28 patients with advanced HCC. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Results: According to the mRECIST 1.1 evaluation criteria, the ORR was 28.6%. Complete and partial response were observed in 3 and 5 patients, respectively; stable disease was observed in 12 patients (DCR, 71.4%). The median PFS was 6.4 months. The incidence of grade 1–2 and 3–4 TRAEs was 57.1% and 39.3%, respectively. Conclusion: This study suggests that tislelizumab + regorafenib can be used as a second-line treatment for advanced HCC.

The purpose of this study was to interpret real-world clinical data to analyze the surgical safety and survival outcomes of patients with initial unresectable hepatocellular carcinoma (uHCC) after conversion therapy. A retrospective analysis was performed on 2984 hepatocellular carcinoma (HCC) patients hospitalized in Shandong Cancer Hospital Affiliated to Shandong First Medical University from June 1st, 2019 to June 1st, 2023. Clinicopathological features, response to systemic and/or loco-regional treatments, surgical resection rate after conversion therapy, surgical safety, and postoperative recurrence were analyzed. A total of 38 patients were successfully converted to obtain surgical resection. 35 patients underwent radical resection. A high objective response rate (ORR) (52.6% under RECIST v1.1 and 78.9% under mRECIST criteria) was observed in patients under conversion therapy, and the disease control rate (DCR) was 100%. Pathologic complete response (pCR) was 42.9%. Treatment-related adverse events (TRAEs) of any grade were observed in 37 patients (97.4%). Safety of conversion or direct surgery continues to improve. The median follow-up time was 19.3 months. The 1-year Disease-free survival (DFS) rate of patients with direct surgery and patients with conversion surgery were 91.4% and 86.8%, respectively. With conversion therapy, a small percentage (1.81%) of uHCC patients are likely to be converted to radical resection. Local combined systemic therapy is a relatively safe and effective conversion therapy, and the safety of surgery is gradually improved after successful conversion. Preliminary follow-up data showed satisfactory survival benefits for patients undergoing conversion surgery. This was a retrospective study and it did not interfere with treatment decisions.