2024年 · 第02卷第03期

Dostarlimab, a programmed death receptor-1 (PD-1)-blocking IgG4 humanized monoclonal antibody, gained accelerated approval from the US Food and Drug Administration (FDA) in April 2021, and received a full approval in February 2023. Dostarlimab was approved for treating adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer (EC) that progressed during or after prior treatment who have no other suitable treatment options. Herein, we review the structure-based mechanism of action of dostarlimab and the results of a clinical study (GARNET; NCT02715284) to comprehensively clarify the efficacy and toxicity of the drug. The efficacy and safety of dostarlimab as monotherapy was assessed in a non-randomized, multicenter, open-label, multi-cohort trial that included 209 patients with dMMR recurrent or advanced solid tumors after receiving systemic therapy. Patients received 500 mg of dostarlimab intravenously every three weeks until they were given four doses. Then, patients received 1000 mg dostarlimab intravenously every six weeks until disease progression or unacceptable toxicity. The overall response rate, as determined by shrinkage in tumor size, was 41.6% (95% confidence interval [CI]; 34.9, 48.6), with 34.7 months as the median response duration. In conclusion, dostarlimab is an immunotherapy-based drug that has shown promising results in adult patients with recurrent or advanced dMMR EC. However, its efficacy in other cancer subtypes, the development of resistance to monotherapy, and efficacy and safety in combination with other immunotherapeutic drugs have not yet been studied.

Micro ribonucleic acids (miRNAs) are a highly conserved class of single-stranded non-coding RNAs. Within the miR-545/374a cluster, miR-545 resides in the intron of the long non-coding RNA (lncRNA) FTX on Xq13.2. The precursor form, pre-miR-545, is cleaved to generate two mature miRNAs, miR-545-3p and miR-545-5p. Remarkably, these two miRNAs exhibit distinct aberrant expression patterns in different cancers; however, their expression in colorectal cancer remains controversial. Notably, miR-545-3p is affected by 15 circular RNAs (circRNAs) and 10 long non-coding RNAs (lncRNAs), and it targets 27 protein-coding genes (PCGs) that participate in the regulation of four signaling pathways. In contrast, miR-545-5p is regulated by one circRNA and five lncRNAs, it targets six PCGs and contributes to the regulation of one signaling pathway. Both miR-545-3p and miR-545-5p affect crucial cellular behaviors, including cell cycle, proliferation, apoptosis, epithelial-mesenchymal transition, invasion, and migration. Although low miR-545-3p expression is associated with poor prognosis in three cancer types, studies on miR-545-5p are yet to be reported. miR-545-3p operates within a diverse range of regulatory networks, thereby augmenting the efficacy of cancer chemotherapy, radiotherapy, and immunotherapy. Conversely, miR-545-5p enhances immunotherapy efficacy by inhibiting T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) expression. In summary, miR-545 holds immense potential as a cancer biomarker and therapeutic target. The aberrant expression and regulatory mechanisms of miR-545 in cancer warrant further investigation.

Background: Lung cancer is the leading cause of cancer-related death, and non-small-cell lung cancer (NSCLC) is the predominant subtype. Programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors are widely used to treat stage IV NSCLC. This study systematically reviewed the literature to clarify the impact of PD-1/PD-L1 inhibitor treatment on the survival of patients with stage III NSCLC. Methods: Randomized phase III clinical trials of PD-1/PD-L1 inhibitors administered to patients with stage III NSCLC that were written in English and published between November 2012 and November 2022 were eligible for review. The sources of information were the MEDLINE database (last consulted on December 26, 2022), ScienceDirect website (last consulted on December 26, 2022), and CENTRAL register (last consulted on December 27, 2022). The outcomes of interest were overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), and event-free survival (EFS). Risk of bias assessments were performed according to the Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0. The findings have been assessed for certainty according to the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) guidelines. Results: Fourteen eligible studies and 2788 participants were included in the review. The key characteristics used to group the participants were disease histology, percentage of PD-L1 expression in cancer cells, and timeline of therapy. OS and PFS were improved (risk ratio [RR]: 0.85; 95% confidence interval [CI]: 0.75–0.96 and RR: 0.75; 95% CI: 0.70–0.86, respectively) based on the use of PD-L1 inhibitors after chemoradiation and OS was improved using first-line PD-1 inhibitors plus chemotherapy in non-squamous NSCLC (RR: 0.40; 95% CI: 0.17–0.95), with the GRADE results indicating moderate quality of evidence. Conclusion: This review highlights the OS and PFS benefits of PD-L1 inhibitors in stage III NSCLC when used after chemoradiation and OS benefits of first-line PD-1 inhibitors added to chemotherapy in non-squamous stage III disease.

Immune checkpoint inhibitors (ICIs), a novel anti-tumor therapeutic modality, are monoclonal antibodies targeting certain immune checkpoints (ICs) that reactivate T cells to achieve anti-tumor immunity by targeting, binding, and blocking ICs. Targeted inhibitory antibodies against the ICs cytotoxic T-lymphocyte antigen and programmed death receptor-1 have demonstrated efficacy and durable anti-tumor activity in patients with cancer. ICs may prevent autoimmune reactions. However, ICIs may disrupt ICs properties and trigger autoimmune-related adverse reactions involving various organ systems including the cardiovascular, pulmonary, gastrointestinal, renal, musculoskeletal, dermal, and endocrine systems. Approximately 10% of patients with damage to target organs such as the thyroid, pituitary, pancreas, and adrenal glands develop endocrine system immune-related adverse events (irAEs) such as thyroid dysfunction, pituitary gland inflammation, diabetes mellitus, and primary adrenal insufficiency. However, the symptoms of immunotherapy-associated endocrine system irAEs may be nonspecific and similar to those of other treatment-related adverse reactions, and failure to recognize them early may lead to death. Timely detection and treatment of immunotherapy-associated endocrine irAEs is essential to improve the efficacy of immunotherapy, prognosis, and the quality of life of patients. This study aimed to review the mechanisms by which ICIs cause endocrine irAEs providing guidance for the development of appropriate management protocols. Here, we discuss (1) the biological mechanisms of ICs in tumorigenesis and progression, focusing on cytotoxic T-lymphocyte antigen and programmed cell death-1/programmed cell death-ligand 1; and (2) the epidemiology, clinical symptoms, diagnosis, and treatment of four immunotherapy-related endocrine complications.

Choroid plexus papilloma (CPP) is a rare, slow-growing, and typically benign brain tumor that predominantly affects children. CPP is characterized by well-defined circular or lobulated masses in the ventricles, leading to symptoms related to increased intracranial pressure and hydrocephalus. CPP diagnosis relies on a combination of clinical presentation, imaging findings, and histological examination. The World Health Organization (WHO) classification categorizes choroid plexus tumors into CPP (Grade I), atypical CPP (aCPP, Grade II), and choroid plexus carcinoma (CPC, Grade III). This article reviewed current diagnostics modalities and explored the emergence of new diagnostic methods for CPP. Research on molecular markers and genetic alterations associated with CPP is ongoing, and some potential markers have been identified. These results offered insights into potential therapeutic targets and personalized treatment approaches for CPP. Advancements in radiomics and liquid biopsy hold promise for improving diagnostic accuracy and monitoring treatment outcomes for choroid plexus tumors. Radiomics can provide quantitative data from imaging studies, whereas liquid biopsy can analyze tumor-derived genetic material and molecular markers from body fluids, such as cerebrospinal fluid (CSF) and blood. The rapidly evolving fields of molecular and genetic research and novel diagnostic methods require continuous updates and advancements before their application in clinical practice. We hope that these advancements will lead to earlier and more precise diagnoses, better treatment options, and improved outcomes in patients with CPP and other brain tumors.

Background: Concurrent chemoradiotherapy is the preferred treatment for stage IVB cervical cancer; however, some patients experience a poor prognosis. The prognostic significance of body composition indicators, including visceral obesity, has been extensively investigated in patients with cancer. This study aimed to assess the impact of body composition indicators, specifically pretreatment fat content, on the survival outcomes of patients with stage IVB cervical cancer. Methods: We retrospectively analyzed clinical information from patients diagnosed with stage IVB cervical cancer between 2010 and 2018. We measured visceral obesity (visceral-to-subcutaneous adipose tissue area ratio [VSR]) and skeletal muscle index (SMI) on pretreatment computed tomography (CT) images. We evaluated the impact of these body composition parameters on the prognosis of patients with cervical cancer. Results: Overall, 116 patients were included, 81 of whom had complete clinical and imaging information. Based on the cut-off values from X-tile analysis, we categorized patients into high and low VSR and SMI groups. The overall survival (OS) rate of patients with a high VSR was significantly higher than that of patients with a low VSR (P = 0.022). Multivariate Cox regression analysis showed that a low VSR was an independent risk factor for the prognosis of patients with stage IVB cervical cancer. Conclusion: Visceral obesity before radiotherapy and chemotherapy has a protective effect on the prognosis of patients with stage IVB cervical cancer, while low muscle index and VSR are associated with poor prognosis.

Background: Betel nut/areca nut/Areca catechu is one of the most commonly used psychoactive substance, and is also a major preventable cause of cancer. Unlike other psychoactive substances, such as nicotine, the mechanisms underlying addiction to areca nuts and related oncogenesis remain elusive. Recent reports suggest a possible overlap in the mechanisms of action of nicotine and areca nuts in the human body. Thus, this study aimed to investigate the interactome of human proteins associated with areca nut exposure and the intricate similarities and differences in the effects of the two psychoactive substances on humans. Methods: A list of proteins associated with areca nut use was obtained from the available literature using terms from Medical Subject Headings (MeSH). Protein-protein interaction (PPI) networks and functional enrichment were analyzed. The results obtained for both psychoactive substances were compared. Results: Given the limited number of common proteins (36/226, 16%) in the two sets, a substantial overlap (612/1176 nodes, 52%) was observed in the PPI networks, as well as in Gene Ontology. Areca nuts mainly affect signaling pathways through three hub proteins (alpha serine/threonine-protein kinase, tumor protein 53, and interleukin-6), which are common to both psychoactive substances, as well as two unique hub proteins (epidermal growth factor receptor and master regulator of cell cycle entry and proliferative metabolism). Areca nut-related proteins are associated with unique pathways, such as extracellular matrix organization, lipid storage, and metabolism, which are not found in nicotine-associated proteins. Conclusions: Areca nuts affect regulatory mechanisms, leading to systemic toxicity and oncogenesis. Areca nuts also affect unique pathways that can be studied as potential markers of exposure, as well as targets for anticancer therapeutic agents.

Background: Large cancer registries help analyze the prognosis of rare malignancies, such as advanced vulvar cancer. This study aimed to compare the overall survival (OS) rates of patients with metastatic vulvar cancer who had undergone chemoradiotherapy and radiotherapy alone and identify prognostic factors using data from the Surveillance, Epidemiology, and End Results (SEER) registry. Methods: In this retrospective cohort study, we used the SEER database to identify patients with metastatic vulvar cancer diagnosed between 2000 and 2019. Propensity score matching was performed to balance the covariates. Kaplan–Meier curves and Cox models were used to analyze OS. Results: A total of 685 patients were included and divided into chemoradiotherapy and radiotherapy groups, and 400 patients were included after propensity score matching. The chemoradiotherapy group had higher OS in the matched cohort (hazard ratio [HR] = 0.7367; 95% confidence interval [CI]: 0.5906–0.9190; P= 0.0049) than the radiotherapy group, which was similar to that in the pre-matched cohort (P < 0.0001). Patients who had undergone surgery + radiotherapy with or without chemotherapy showed higher OS rates than those who had received radiotherapy with or without chemotherapy for patients aged <75 years and local tumor excision/destruction or surgical removal of the primary site was the recommended surgical choice (P < 0.05). Chemoradiotherapy is sufficient for patients ≥75 years of age. Conclusions: Patients with metastatic vulvar cancer should undergo surgery if they can tolerate it. Adjuvant chemoradiotherapy should be encouraged because this treatment modality was associated with higher OS than radiotherapy alone.

Background: Multiple myeloma (MM) is a heterogeneous plasma-derived hematopoietic malignancy with complex genetic mutation contributing to the pathogenesis. Though gene sequencing has been applied in MM, genetic features from Chinese MM patients are reported less. We investigated the genetic mutation of newly diagnosed multiple myeloma (NDMM) patients and explore its correlation with cytogenetic abnormalities detected by fluorescence in situ hybridization (FISH). Methods: A total of 206 patients with NDMM were enrolled. After enriching plasma cells with CD138 magnetic beads, 92 MM-related target gene mutations were detected by the Illumina sequencing platform, and six common genetic abnormalities were detected by FISH. Results: 162 cases (78.6%) had at least one gene mutation detected by NDMM. The top 5 mutated genes were KRAS, NRAS, TRAF3, BRAF, and TP53. Cytogenetic abnormalities detected by FISH have a certain correlation with gene mutations, t(11;14) translocations are often accompanied by CCND1 and TP53 mutations, KLHL6 in t(4;14), SP140, CDKN1B and PRKD2 in t(14;16) and t(14;20) translocations. The mutation ratio was higher for EGR1, while lower of CCND1 in patients with gain 1q21. The TP53 mutation was more likely in patients with 17p deletion. The gene mutation affects the pathway of the RNA process is more frequently occurring in males and age less than 70 years patients. The International Staging System (ISS) Stage III correlated with gene mutations in the NK-κB pathway while Revised ISS (R-ISS) Stage III correlated with the DNA damage repair pathway. Conclusions: There are various gene mutations in NDMM patients, mainly RAS/MAPK and NF-κB pathway gene pathways.