Objective: The purpose of this study was to investigate the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of ursolic acid liposomes (UAL), as a new drug, in healthy adult volunteers and patients with advanced solid tumors. Methods: All subjects received a single-dose of UAL (11, 22, 37, 56, 74, 98, and 130 mg/m²) administered as a 4-h intravenous infusion. Toxicity was assessed and plasma samples were analyzed using validated ultra-performance liquid chromatograph/tandem mass spectroscopy method. Results: A total of 63 subjects including 4 patients and 35 healthy adult volunteers for toxicity study and 24 healthy adult volunteers for pharmacokinetic study were enrolled in this trial. The DLT was encountered at 74, 98, and 130 mg/m², and consisted of hepatotoxicity and diarrhea. Other adverse events included grade 1 nausea, grade 2 abdominal distention, grade 1 microscopic hematuria, grade 2 elevated serum sodium, grade 1 vascular stimulation, and grade 1 skin rash. The MTD was 98 mg/m². The single-dose pharmacokinetic parameters revealed a linear relationship between C_max, AUC_{0→24 h}, or AUC_0→∞ and escalated doses. Conclusions: The clinical data reported for the first time that UAL had manageable toxicities with MTD of 98 mg/m². The DLT were hepatotoxicity and diarrhea. Meanwhile, UAL had a linear pharmacokinetic profile. The registration number of this trial is ChiCTR-ONC-12002385.

Ursolic acid liposome (UAL), a new antitumor drug, has potential therapeutic value. However, limited clinical data exists regarding multiple-dose safety, antitumor activity, and the recommended dose (RD) of UAL for subjects with advanced solid tumors. All subjects were intravenously administered UAL for 14 consecutive days of a 21-day treatment cycle. Twenty-one subjects were enrolled in 1 of 3 sequential cohorts (56, 74, and 98 mg/m²) to evaluate multiple-dose tolerability and efficacy. Eight additional subjects were treated with UAL (74 mg/m²) to evaluate multiple-dose pharmacokinetics. No ≥grade 3 adverse events (NCI-CTC) were observed. Sixty percent subjects achieved stable disease after 2 treatment cycles. Multiple-dose pharmacokinetic analysis suggested UAL does not accumulate in the body. This trial demonstrates that UAL was tolerable, had manageable toxicity, and could potentially improve patient remission rates. A large phase II study is recommended to confirm these results (i.e., RD of 98 mg/m²).

Relatively little information is available on quantitative risks of therapy-induced second malignant neoplasm (SMN) in patients with non-Hodgkin lymphoma (NHL). A nested case–control study was conducted in a cohort of 3412 patients treated for NHL between 1990 and 2006, including 118 patients with SMN and 472 controls. Risks of leukemia/lung/breast/colorectal and bladder cancer were higher in NHL compared with the general population. A higher risk of leukemia was restricted to patients given a cumulative dose of cyclophosphamide more than 11 250 mg/m². However, no significant association was found between SMN risk with rituximab, fludarabine, anthracyclines, epipodophyllotoxins and platinum, respectively. In combined modality treatment, involved-field radiation therapy (IFRT) had a higher risk for second solid cancers as compared to involved-nodal radiation therapy (INRT). For patients receiving radiation doses exceeding 40 Gy, the risk of lung cancer and breast cancer was increased. In conclusion, we found that cyclophosphamide-based therapy increased the risk of SMN in NHL. Leukemia risk was linked with high-dose cyclophosphamide. A received larger radiation field or higher radiation dose also could be an important risk factor for the development of SMN.

Objectives: This study aims to assess the prognostic implications of gene signature of the tertiary lymphoid structures (TLSs) in head and neck squamous cell carcinoma (HNSCC) and scrutinize the influence of TLS on immune infiltration. Methods: Patients with HNSCC from the Cancer Genome Atlas were categorized into high/low TLS signature groups based on the predetermined TLS signature threshold. The association of the TLS signature with the immune microenvironment, driver gene mutation status, and tumor mutational load was systematically analyzed. Validation was conducted using independent datasets (GSE41613 and GSE102349). Results: Patients with a high TLS signature score exhibited better prognosis compared to those with a low TLS signature score. The group with a high TLS signature score had significantly higher immune cell subpopulations compared to the group with a low TLS signature score. Moreover, the major immune cell subpopulations and immune circulation characteristics in the tumor immune microenvironment were positively correlated with the TLS signature. Mutational differences in driver genes were observed between the TLS signature high/low groups, primarily in the cell cycle and NRF2 signaling pathways. Patients with TP53 mutations and high TLS signature scores demonstrated a better prognosis compared to those with TP53 wild-type. In the independent cohort, the relationship between TLS signatures and patient prognosis and immune infiltration was also confirmed. Additionally, immune-related biological processes and signaling pathways were activated with elevated TLS signature. Conclusion: High TLS signature is a promising independent prognostic factor for HNSCC patients. Immunological analysis indicated a correlation between TLS and immune cell infiltration in HNSCC. These findings provide a theoretical basis for future applications of TLS signature in HNSCC prognosis and immunotherapy.

MDSCs, which are defined as a kind of negatively regulatory cells, could suppress T cell immune response in many tumor-bearing animal models and cancer patients. We supposed that MDSCs also contributed to the impaired antitumor immunity in MDS. Here we demonstrated that STAT3-ARG1 pathway could be a critical signal transduction pathway that regulated MDSCs-mediated immunosuppression. Increased MDSCs was revealed in MDS patients when compared to healthy controls. Especially, MDSCs performed higher activated STAT3 and CCR2 expression in high-risk MDS patients. The CCL2 and IL-6 levels in MDS patients were also higher than in healthy controls, which could drive recruitment and activation of MDSCs. Meanwhile, lower expression levels of CD3ζ chain, perforin and granzyme B were demonstrated in MDS patients, which were associated with downregulated activation of CD8+ T lymphocytes. The results were supported by the decreased perforin, granzyme B and IFN-γ levels in the mixed-culture system of MDSCs and CD8+ T lymphocytes in vitro. Notably, targeting STAT3 pathway by selective inhibitor could decrease ARG1 expression in MDSCs and partially reverse the lower expression levels of effector molecules on CD8+ T lymphocytes. Therefore, this study revealed the potential STAT3-ARG1 mechanism behind MDSCs and provided a promising STAT3 targeting strategy in MDS.

Traditional Chinese medicine has been used in China for thousands of years. In 2022, the 14th Five-Year Plan for the Development of Traditional Chinese Medicine was released, aiming to enhance traditional Chinese medicine health services and improve policies and systems for high-quality traditional Chinese medicinal development by 2025. ERIANIN, the main component of the traditional Chinese medicine Dendrobium, plays an important role in anti-inflammatory, antiviral, antitumor, antiangiogenic, and other pharmacological effects. ERIANIN has broad-spectrum antitumor effects, and its tumor-suppressive effects have been confirmed in the study of various diseases, such as precancerous lesions of the stomach, gastric cancer, liver cancer, lung cancer, prostate cancer, bladder cancer, breast cancer, cervical cancer, osteosarcoma, colorectal cancer, leukaemia, nasopharyngeal cancer and melanoma through the multiple signaling pathways. Thus, the aim of this review was to systematically summarise the research on ERIANIN with the aim of serving as a reference for future research on this compound and briefly discuss some future perspectives development of ERIANIN in combined immunotherapy.