Recent advances in immune checkpoint inhibitor-induced type 1 diabetes mellitus.

As a new group of anticancer drugs, immune checkpoint inhibitors (ICIs) have exhibited favorable antitumor efficacy in numerous malignant tumors. Anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4), anti-programmed cell death-1 (PD-1) and anti-programmed cell death ligand-1 (PD-L1) are three kinds of ICIs widely used in clinical practice. However, ICI therapy (monotherapy or combination therapy) is always accompanied by a unique toxicity profile known as immune-related adverse events (irAEs) affecting multiple organs. The endocrine glands are common targets of irAEs induced by ICIs, which cause type 1 diabetes mellitus (T1DM) when the pancreas is affected. Although the incidence rate of ICI-induced T1DM is rare, it will always lead to an irreversible impairment of ß-cells and be potentially life-threatening. Hence, it is vital for endocrinologists and oncologists to obtain a comprehensive understanding of ICI-induced T1DM and its management. In our present manuscript, we have reviewed the epidemiology, pathology and mechanism, diagnosis, management, and treatments of ICI-induced T1DM.

Changes of tumor microenvironment in non-small cell lung cancer after TKI treatments.

Non-small cell lung cancer (NSCLC) is the most common lung cancer diagnosis, among which epidermal growth factor receptor (EGFR), Kirsten rat sarcoma (KRAS), and anaplastic lymphoma kinase (ALK) mutations are the common genetic drivers. Their relative tyrosine kinase inhibitors (TKIs) have shown a better response for oncogene-driven NSCLC than chemotherapy. However, the development of resistance is inevitable following the treatments, which need a new strategy urgently. Although immunotherapy, a hot topic for cancer therapy, has shown an excellent response for other cancers, few responses for oncogene-driven NSCLC have been presented from the existing evidence, including clinical studies. Recently, the tumor microenvironment (TME) is increasingly thought to be a key parameter for the efficacy of cancer treatment such as targeted therapy or immunotherapy, while evidence has also shown that the TME could be affected by multi-factors, such as TKIs. Here, we discuss changes in the TME in NSCLC after TKI treatments, especially for EGFR-TKIs, to offer information for a new therapy of oncogene-driven NSCLC.

Recent Advances in the Management of Adverse Events Associated with Lorlatinib.

As a novel third-generation ALK tyrosine kinase inhibitor (TKI), lorlatinib has shown excellent systemic and intracranial activity in non-small cell lung cancer (NSCLC) patients who carry sensitizing ALK-activating mutations and progress on first- and second-generation TKIs. In comparison with other ALK-TKIs, lorlatinib has a unique safety profile for hyperlipidemia and central nervous system adverse events. Lorlatinib-induced adverse events are well tolerated, permanent discontinuations are rarely reported, and dose modifications and/or standard medical therapy are useful for the management of adverse events. Our present study reviews the safety profile of lorlatinib as well as the relevant management strategies. Our present study aims to provide a practical guide for the scientific management and application of lorlatinib.

Advances in pharmacokinetics and pharmacodynamics of PD-1/PD-L1 inhibitors.

Immune checkpoint inhibitors (ICIs) are a group of drugs designed to improve the therapeutic effects on various types of malignant tumors. Irrespective of monotherapy or combinational therapies as first-line and later-line therapy, ICIs have achieved benefits for various tumors. Programmed cell death protein-1 (PD-1) / ligand 1 (PD-L1) is an immune checkpoint that suppresses antitumor immunity, especially in the tumor microenvironment (TME). PD-1/PD-L1 immune checkpoint inhibitors block tumor-related downregulation of the immune system, thereby enhancing antitumor immunity. In comparison with traditional small-molecule drugs, ICIs exhibit pharmacokinetic characteristics owing to their high molecular weight. Furthermore, different types of ICIs exhibit different pharmacodynamic characteristics. Hence, ICIs have been approved for different indications by the Food and Drug Administration (FDA) and National Medical Products Administration (NMPA). This review summarizes pharmacokinetic and pharmacodynamic studies of PD-1/ PD-L1 inhibitors to provide a reference for rational clinical application.

Recent Advancements of Monotherapy, Combination, and Sequential Treatment of EGFR/ALK-TKIs and ICIs in Non-Small Cell Lung Cancer.

Lung cancer is the leading cause of cancer-related deaths with high morbidity and mortality. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for 85% of all cases. Fortunately, the development of molecular oncology provides a promising and effective therapeutic strategy for lung cancers, including specific gene mutations/translocations and immune checkpoints, with epidermal growth factor receptor (EGFR) common mutations first and anaplastic lymphoma kinase (ALK) translocations later as the targeted therapy and immune checkpoint inhibitors (ICIs) as immunotherapy. This review summarized the recent therapy advancements of TKIs and ICIs in NSCLC and focused on the clinical effect of combination or sequential treatment so as to provide the effective advice for the treatment of NSCLC.

Two new triterpenoid glycosides from leaves of Cyclocarya paliurus.

Two dammarane glycosides (1-2) were isolated from the leaves of Cyclocarya paliurus. The structures of new compounds were established by application of spectroscopic methods, including one-dimensional and two-dimensional NMR, HRESIMS, and chemical hydrolysis. When evaluated against seven human cancer cell lines, the two compounds exhibited selective cytotoxicity to MCF-7 cells.[Formula: see text].

Single-Cell Profiling to Explore Immunological Heterogeneity of Tumor Microenvironment in Breast Cancer.

Immune infiltrates in the tumor microenvironment (TME) of breast cancer (BRCA) have been shown to play a critical role in tumorigenesis, progression, invasion, and therapy resistance, and thereby will affect the clinical outcomes of BRCA patients. However, a wide range of intratumoral heterogeneity shaped by the tumor cells and immune cells in the surrounding microenvironment is a major obstacle in understanding and treating BRCA. Recent progress in single-cell technologies such as single-cell RNA sequencing (scRNA-seq), mass cytometry, and digital spatial profiling has enabled the detailed characterization of intratumoral immune cells and vastly improved our understanding of less-defined cell subsets in the tumor immune environment. By measuring transcriptomes or proteomics at the single-cell level, it provides an unprecedented view of the cellular architecture consist of phenotypical and functional diversities of tumor-infiltrating immune cells. In this review, we focus on landmark studies of single-cell profiling of immunological heterogeneity in the TME, and discuss its clinical applications, translational outlook, and limitations in breast cancer studies.

Immunomodulatory Therapies for Renal Cell Carcinoma.

BACKGROUND: Renal Cell Carcinoma (RCC) is the most common tumor originating from the kidneys. In comparison to other solid tumors, RCC is poorly sensitive to conventional therapeutic modalities. As such, metastatic RCC (mRCC) continues to be associated with high rates of morbidity and mortality. Targeted agents have shown remarkable progress in RCC management with improved patients' outcomes, but rarely induce complete response and patients develop resistance to therapy eventually. However, it is well known that RCC represents one of the most immunogenic cancers and is able to evoke immune response naturally, thus prompted the emergence of several immunotherapeutic strategies in the management of RCC with variable degrees of success. Modulating the immune system with cytokines, vaccines, and T-cell modulating agents offer hope for the patients with RCC. CONCLUSION: This review critically summarizes the state of the art in RCC therapeutic regimen with immunomodulation agents. We will focus on the clinical data and ongoing clinical trials exploring the use of immunotherapy with different agents for RCC. In addition, different novel immunotherapeutic agents are being investigated for their combination therapy with other immune therapies or other modalities. Prospects (e.g., potential future immunological targets, combination regimens, appropriate sequencing) for immune therapies of RCC are also set forth in this work.

Therapeutic Drug Monitoring of Targeted Therapy in Metastatic Renal Cell Carcinoma.

BACKGROUND: Targeted therapy has been widely used in the treatment of patients with metastatic renal cell carcinoma. The current available therapies focus on the inhibition of angiogenesis through targeting the vascular endothelial growth factor receptor, and protein kinase such as the mammalian target of rapamycin. Compared with other traditional chemotherapies and radiotherapies, targeted therapies dramatically improved progression-free survival. However, microenvironment of patients' body, drug-drug interactions, as well as polymorphisms of metabolic enzymes and drug transporters ABC could influence pharmacokinetic characteristics. Therefore, targeted therapy has been shown to present a large interindividual variability. Therapeutic drug monitoring is the clinical practice aims at improving efficacy and reducing toxicity by measuring drug concentration in biological samples and adjusting drug dose for each individual. CONCLUSION: Therapeutic drug monitoring is widely employed under the situations such as lacking of therapeutic response, emerging of severe or unexpected toxicities, with narrow therapeutic windows or potential drug-drug interactions. The development of Therapeutic drug monitoring in targeted therapy have been proposed in recent years, more and more targeted therapies are benefit from therapeutic drug monitoring. It is showed significant benefit in the individual targeted treatment of metastatic renal cell carcinoma.