Anticancer research最新文献

Background/aim: Recent advances in systemic therapies, including immune checkpoint inhibitors (ICIs), have improved outcomes for patients with advanced hepatocellular carcinoma (HCC). Radiotherapy and ICI therapy have been reported to have synergistic effects. This study aimed to identify factors associated with the response to treatment with tremelimumab-durvalumab in patients with advanced HCC, including the impact of prior radiotherapy.

Patients and methods: Forty-six patients with advanced HCC who received tremelimumab-durvalumab were retrospectively investigated. Intratumoral CD8⁺ infiltration was evaluated in 23 patients who underwent liver tumor biopsy before starting tremelimumab-durvalumab.

Results: Sixteen of the 45 patients had received radiotherapy before starting chemotherapy (the RT group) and 29 had not (the non-RT group). The objective response rate was significantly higher in the RT group (56.3% vs. 17.2%, p=0.007), as was the disease control rate (75.0% vs. 34.4%, p=0.008). Median progression-free survival (PFS) was significantly longer in the RT group (14.6 months vs. 2.7 months, p=0.008). The adverse event rate was not significantly increased in the RT group. Intratumoral CD8⁺ infiltration was significantly greater in the RT group [87.5% (7/8) vs. 40.0% (6/15), p=0.029]. Multivariate analysis identified prior radiotherapy to be a significant predictor of improved PFS (hazard ratio=0.290, 95% confidence interval=0.106-0.794, p=0.016).

Conclusion: Prior radiotherapy improves PFS in patients treated with tremelimumab-durvalumab for advanced HCC. The abscopal effect and up-regulation of immune mechanisms may contribute to improved outcomes.

Background/aim: Cytoreductive surgery (CRS) and intraperitoneal chemotherapy are standard treatments for the peritoneal spreading from appendiceal tumours. We aimed to assess and compare outcomes after CRS, with or without intraperitoneal chemotherapy, in patients with peritoneal spreading from appendiceal neoplasms and malignancies.

Patients and methods: In this retrospective study, we analysed prospectively collected data from patients with appendiceal tumours and peritoneal metastases who were treated with CRS and intraperitoneal chemotherapy. Survival analysis was performed to evaluate overall survival, completeness of cytoreduction (CCR) 0-1, subgroup outcomes, and survival-influencing factors.

Results: We analysed data on 47 patients, including 10 (21.3%) with appendiceal neoplasms and 37 (78.7%) with appendiceal cancer. By the last follow-up visit, 23 patients had survived. The 5-year survival rate was significantly higher in the appendiceal neoplasm group (50%) than in the appendiceal cancer group (21.6%). Patients with CCR grades 2-3 had a 6.7-fold higher risk of mortality than those with CCR grades 1-2. Additionally, appendiceal cancer was associated with an 8-fold higher risk of mortality than low-grade appendiceal neoplasms. Postoperative chemotherapy was associated with 74.6% risk reduction, highlighting its potential benefits.

Conclusion: Peritoneal metastases from appendiceal tumours, particularly pseudomyxoma peritonei arising from low-grade appendiceal mucinous neoplasms, show acceptable oncologic outcomes with aggressive treatment approaches, such as CRS combined with intraperitoneal chemotherapy. Therefore, CRS should be performed in cases where complete cytoreduction is achievable.

Background/aim: Homochlorcyclizine dihydrochloride, a clinically approved antihistamine for allergic conditions, has not been previously explored for hepatocellular carcinoma (HCC) therapy. This study aimed to investigate homochlorcyclizine dihydrochloride's anti-HCC activity and underlying mechanisms, focusing on its effects on proliferation, migration, cancer stem cell (CSC) characteristics, and key cell cycle regulators.

Materials and methods: The antiproliferative and anti-migratory effects of homochlorcyclizine dihydrochloride were evaluated using in vitro assays, including CCK-8 and wound healing assays, and in vivo xenograft mouse models. CSC properties were examined through sphere formation and limiting dilution xenograft assays. RNA-seq analysis was performed to identify differentially expressed genes (DEGs), followed by KEGG pathway enrichment. Cell cycle progression was analyzed by flow cytometry, and CDC20/CDK1 expression was quantified via qRT-PCR and western blot. Clinical relevance was evaluated using TCGA-LIHC data.

Results: Homochlorcyclizine dihydrochloride significantly inhibited HCC cell proliferation and migration in vitro, and suppressed HCC tumor growth in xenograft mouse models. Homochlorcyclizine dihydrochloride also reduced sphere-forming efficiency and tumor-initiating potential, indicating inhibition of CSC characteristics. RNA-seq revealed 915 DEGs in homochlorcyclizine dihydrochloride-treated Huh7 cells, with significant down-regulation of cell cycle pathway genes, including CDC20 and CDK1. HCD down-regulated CDC20 and CDK1 protein expression, impairing cell cycle progression. In the TCGA-LIHC cohort, elevated CDC20 and CDK1 expression in HCC correlated with reduced survival and advanced clinical stage, underscoring their prognostic relevance.

Conclusion: Homochlorcyclizine dihydrochloride exerts potent anti-HCC activity by suppressing proliferation, migration, and CSC characteristics, likely mediated by down-regulation of CDC20 and CDK1. Its established safety profile positions homochlorcyclizine dihydrochloride as a compelling candidate for repurposing as a novel HCC therapy, warranting further clinical exploration.

Background/aim: Optimal treatment strategies following disease progression on cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) for patients with hormone receptor-positive (HR⁺) and human epidermal growth factor receptor 2-negative (HER2^-) metastatic breast cancer (MBC) remain undefined. Oral 5-fluorouracil (5-FU) derivatives, such as tegafur/gimeracil/oteracil (S-1) and capecitabine, are widely used and offer convenience of administration. This study aimed to evaluate the efficacy and safety of oral 5-FU derivatives in such a treatment setting in patients with HR⁺/HER2^- MBC.

Patients and methods: We retrospectively analyzed 40 patients with HR⁺/HER2^- MBC who received oral 5-FU derivatives following progression on CDK4/6i plus ET. Clinical outcomes including time to treatment failure and adverse events were assessed.

Results: Of the 40 patients, 97.5% received abemaciclib, and 95.0% were treated with S-1. The median time to treatment failure was 12.3 (range=1.2-29.2) months. Grade 3 adverse events noted were reduced neutrophil count, anemia, alanine aminotransferase increase, and generalized edema, which led to dose reduction but did not result in treatment discontinuation.

Conclusion: These findings highlight the potential of oral 5-FU derivatives as effective and safe treatment options to use after progression on CDK4/6i plus ET for patients with HR⁺/HER2^- MBC.

Background/aim: Bone metastasis of prostate cancer is a recalcitrant disease treated by androgen-deprivation therapy (ADT), chemotherapy, and radiation. We have previously shown that methionine restriction with oral recombinant methioninase (o-rMETase) alone or in combination with chemotherapeutic agents was apparently effective for prostate-cancer patients, including a patient with extensive bone metastases. In the present study, we described a patient with spinal metastases of prostate cancer treated with ADT, chemotherapy with docetaxel, and methionine restriction with o-rMETase and a low-methionine diet.

Case report: The present report is on a 62-year-old male prostate-cancer patient with a history of prostatectomy who was subsequently diagnosed by prostate specific membrane antigen (PSMA)-PET imaging to have extensive spinal metastases. The patient then received combination therapy with ADT (relugolix and darolutamide), docetaxel chemotherapy, o-rMETase (twice a day 250 units, 5 mg), and a low-methionine diet. Six months later, a second PSMA-PET demonstrated marked regression of metastases, with only residual uptake in the cervical spine. At nine months, [¹¹C]methionine-PET confirmed complete disappearance of the residual lesion, and no distant metastases were detected. The present findings suggest remission of spinal metastases from prostate cancer.

Conclusion: The patient achieved an apparent complete response of prostate-cancer spinal metastases after treatment with ADT, chemotherapy, and methionine restriction. Further studies, including controlled clinical trials are necessary to validate this new paradigm of treatment for prostate-cancer bone metastases.

Background/aim: Previous studies have demonstrated low response rates and short progression-free survival (PFS) for platinum-based chemotherapy in patients with platinum-sensitive recurrent ovarian cancer during treatment with poly ADP-ribose polymerase (PARP) inhibitors. This retrospective study aimed to evaluate treatment outcomes in Japanese patients.

Patients and methods: The efficacy and safety of treatment were evaluated in 30 patients with ovarian, fallopian tube, or primary peritoneal cancers diagnosed with platinum-sensitive recurrence during PARP inhibitor treatment (administered between April 2019 and March 2025). Platinum-based chemotherapies included paclitaxel with carboplatin, paclitaxel with cisplatin, docetaxel with carboplatin, doxorubicin with carboplatin, or paclitaxel with nedaplatin. Chemotherapy was administered for six cycles, and PARP inhibitor rechallenge was performed when a treatment response was observed.

Results: The median number of platinum-based chemotherapy cycles was five (range=1-9). The objective response and disease control rates were 23.3% and 43.3%, respectively. The median PFS and overall survival were 4.5 months and 26 months, respectively. Grade 3 or higher hematological toxicities were observed, including leukopenia in 14 patients, neutropenia in 16, anemia in four, and thrombocytopenia in six. Non-hematological toxicities included nausea and constipation in one patient, hypertension in two, and carboplatin hypersensitivity in two. None of the patients discontinued chemotherapy owing to adverse events or treatment-related deaths.

Conclusion: Subsequent platinum-based chemotherapy in patients with platinum-sensitive recurrence during PARP inhibitor treatment demonstrated a low response rate and short PFS.

Background/aim: Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor with a high prevalence in Southeast Asia, Southern China, Singapore, and Taiwan. Despite advances in chemo-radiotherapy, approximately 30% of patients with NPC still have a poor prognosis due to distant metastasis, underscoring the urgent need for novel therapeutic agents. This study aimed to investigate the anticancer mechanism of a novel compound, bis-type triaziquone (BTZQ), in NPC cells.

Materials and methods: NPC/HK1 cells and immortalized nasopharyngeal epithelial NP69 cells were used. Cell viability, protein expression, cytokeratin 18 fragment release, and mitochondrial membrane potential (MMP) changes were assessed using the MTT assay, immunoblotting, ELISA, and JC-1 staining, respectively.

Results: BTZQ reduced NPC/HK1 cell viability (IC₅₀=0.38 μM) more effectively than that of NP69 cells (IC₅₀=1.53 μM), indicating selective cytotoxicity. BTZQ did not significantly increase apoptotic markers, including cleaved caspase-3, Bax, cleaved PARP1, and cytokeratin 18 fragment. Instead, BTZQ markedly elevated poly(ADP-ribose) levels, disrupted MMP, nuclear PARP1 levels, and promoted nuclear translocation of apoptosis-inducing factor, consistent with the induction of PARP1-mediated cell death (also referred to as parthanatos). Inhibition of PARP1 activity by 3-ABA or DPQ reversed BTZQ-induced loss of cell viability, confirming that PARP1 is involved in BTZQ-mediated cytotoxicity.

Conclusion: BTZQ selectively inhibits NPC cell viability by inducing PARP1-mediated cell death rather than apoptosis. These findings identify BTZQ as a promising candidate for NPC therapy and suggest that targeting PARP1-mediated cell death may represent a novel therapeutic strategy for this malignancy.

Background/aim: PD-L1 expression is a key biomarker for immune checkpoint inhibitor therapy in breast cancer treatment. However, many factors affect PD-L1 assessment. This study evaluated how specimen-related factors affect PD-L1 expression in breast cancer and provides a guide for optimal specimen selection.

Patients and methods: We retrospectively analyzed 30 consecutive breast cancer specimens submitted for PD-L1 testing at the Osaka University Hospital between November 2019 and November 2021. PD-L1 expression was evaluated using the VENTANA SP142 immunohistochemistry assay. Expression in tumor-infiltrating immune cells (IC) was quantified as the percentage of PD-L1-positive IC within the tumor area, and positivity was defined as IC ≥1%.

Results: The overall PD-L1 positivity rate was 47%. PD-L1 expression was significantly higher in surgical specimens compared with biopsy samples (65% vs. 23%, p=0.032) and in primary tumors compared with metastatic/recurrent sites (58% vs. 0%, p=0.018). All specimens from patients with Stage IV or recurrent disease were PD-L1-negative, compared with 74% positivity at earlier stages (p<0.001). Although not statistically significant, specimens from patients who had received chemotherapy within 40 days showed lower PD-L1 positivity than chemotherapy-naïve specimens (14% vs. 57%, p=0.086). In advanced disease (Stage IV/recurrent), 82% of specimens were from biopsies and 55% from metastatic sites, potentially explaining the lower PD-L1 positivity.

Conclusion: For optimal PD-L1 assessment in breast cancer, surgical specimens from primary tumors without prior therapy are preferable due to larger evaluable tumor areas. For patients requiring neoadjuvant chemotherapy or with de novo Stage IV disease, multiple biopsies of primary tumors using thick needles before treatment, with attention being paid to sampling tumor margins to account for potential immune-excluded phenotypes, are recommended.

Background/aim: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer with aggressive behavior and poor prognosis. Dysregulation of DNA replication and repair, including alterations in replication protein A1 (RPA1), replication factor C subunit 1 (RFC1), and DNA polymerase epsilon (POLE), may influence tumor biology and immune interactions. This study investigated the expression of these proteins in ccRCC and their associations with systemic inflammation, tumor immune microenvironment (TME), and prognosis.

Materials and methods: Immunohistochemical expression of RPA1, RFC1, and POLE was evaluated in 52 ccRCC and adjacent normal tissues, with correlations to clinical data and preoperative blood parameters. Transcriptomic data from The Cancer Genome Atlas (TCGA) and immune deconvolution analyses (TIMER2.0, ConsensusTME) validated findings and explored associations with immune infiltration and survival.

Results: Tumor tissues showed increased RPA1 and decreased RFC1 expression, while POLE was unchanged. Elevated RPA1 correlated with reduced systemic inflammation, while low RFC1 correlated with larger tumor size. High POLE levels associated with lower preoperative platelet-to-lymphocyte ratio and an inverse trend with T stage. TCGA data confirmed these findings, showing that low RPA1 and RFC1 predicted poorer outcomes, while reduced POLE and RFC4 were linked to improved survival. TIMER2.0 analysis revealed that high RPA1 and RFC1 expression was linked to increased macrophage and neutrophil infiltration, whereas high POLE to CD4⁺ T-cell infiltration. Notably, RPA1, RFC1, and POLE expression correlated with immune-checkpoint molecules (including PD-L1, VISTA, and CTLA-4), suggesting implications for immunotherapy responsiveness. Immune TME composition, as estimated by ConsensusTME, influenced survival outcomes, with replication protein expression modulating prognostic relevance of immune subpopulations.

Conclusion: DNA replication proteins interact with systemic inflammation and the TME in ccRCC, supporting their role as biomarkers and potential therapeutic targets.

Platinum-based chemotherapeutic agents have been the cornerstone in cancer treatment for decades. However, their clinical utility is often limited by severe adverse effects and the development of drug resistance. Dicycloplatin (DCP), a novel platinum analog developed in China, has emerged as a promising alternative with potentially improved therapeutic profiles. This review examines the development, pharmacology, molecular mechanism, and clinical applications of DCP in various cancer types. Available evidence suggests that DCP maintains similar efficacy to conventional platinum compounds while demonstrating reduced toxicity. Both intravenous and oral formulations have shown promising results, particularly in bladder cancer, lung cancer, and hepatocellular carcinoma. The first American bladder cancer patient treated with DCP achieved complete remission twice. The first achievement for the bladder primary tumor was in 2016 by 8-weeks IV DCP chemotherapy. The second complete remission of tumor recurrence was in 2021 after 7-weeks oral DCP therapy. This case highlights DCP potential clinical value. This review also discusses ongoing research, regulatory status, and future directions for DCP in cancer chemotherapy. While more extensive clinical trials are needed, particularly in Western populations. Current data suggest that DCP may represent a significant advancement in platinum-based chemotherapy, potentially offering improved quality of life for cancer patients without compromising treatment efficacy.