OncoTargets and therapy最新文献

Background: Exact detection of lymphovascular infiltration (LVI) status can guide accurate surgical operation scope in cervical cancer, but LVI reduces the overall survival (OS) of patients and is not easily detected by hematoxylin-eosin (H&E) staining. The role of tumor-associated macrophages (TAMs) in this process is not well defined.

Methods: Early-stage cervical cancer patients received carbon nanoparticles for sentinel lymph-node mapping, laparotomy pelvic lymph-node dissection, and radical hysterectomy. The excised specimens were analyzed using ultrastaging, double immunohistochemical (IHC) staining, flow cytometry, and Western blot analysis. Single-cell data from the Gene Expression Omnibus for cervical cancer were obtained and analyzed.

Results: The integration of carbon nanoparticle mapping, ultrastaging, and double IHC staining enhanced the detection of tumor LVI over H&E staining (41.8% [41/98] vs. 20.4% [20/98], P=0.046). When the number of vascular invasion foci was greater than two, there was a negative correlation with OS (P<0.05). More M2 TAMs emerged surrounding the tumor vasculature labeled by double IHC staining, accompanied by a higher M2:M1 ratio detected with flow cytometry (P<0.05). M2 TAM numbers were positively correlation with the degree of tumor LVI (P=0.0024), combined with higher protein expression of MMP2, SPARC, and GNLY in the tumor LVI-positive group on Western blot analysis, and the OS of the patients decreased accordingly. Single-cell data showed that the M1:M2 ratio decreased significantly, accompanied by higher M2 TAM-related gene expression. Immunosurveillance and anti-immunoescape scores for M1 were obviously higher than for M2 TAMs. GO and KEGG analysis showed M2 TAM activity increased from precancerous lesions to cervical cancer.

Conclusion: Combining different methods may accurately determine tumor LVI status, guide exact surgical operation scope, and improve cervical cancer patient outcomes. M2 TAM activity increased in cervical cancer, forming an immunosuppressive environment, TAM-related genes could be good markers in determining cervical cancer LVI and serve as potential targets for immunotherapy.

Lung cancer is a malignant tumor with the highest morbidity and mortality rate worldwide, with nearly 2.5 million new cases and more than 1.8 million deaths reported globally in 2022. Lung cancer is broadly categorized into two main types: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), with NSCLC accounting for about 85% of all cases. Early-stage lung cancers often present without obvious symptoms, resulting in most patients being diagnosed at an advanced stage where traditional chemotherapy has limited efficacy. Recent advances in molecular biology have elucidated the pivotal role of gene mutations in tumor development, paving the way for targeted therapies that have markedly benefited patients. Beyond the well-known epidermal growth factor receptor (EGFR) mutation, an increasing number of new molecular targets have been identified, including ROS1 rearrangement, BRAF mutation, NTRK fusion, RET fusion, MET mutation, KRAS G12C mutation, HER2 mutation, ALK rearrangement, and NRG1 fusion. Some of these targeted therapies have already been approved by the Food and Drug Administration (FDA), and many others are currently undergoing clinical trials. This review summarizes recent advances in NSCLC treatment with molecular targets, highlighting progress, challenges, and their impact on patient prognosis.

Background: Cuproptosis, a metal-ion-dependent form of regulated cell death induced by copper overload, is emerging as a potential mechanism in high-grade glioma (HGG). Despite its significance, the role of cuproptosis in predicting the prognostic and therapeutic response in HGG remains poorly understood.

Methods: We performed unsupervised clustering to stratify patients with HGG in the Chinese Glioma Genome Atlas (CGGA) according to the expression of 14 cuproptosis-related genes (CRGs) and validated in The Cancer Genome Atlas (TCGA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were applied to explore the biological processes and pathways involved within distinct groups. We constructed the CupScore model to predict the responsiveness to immune checkpoint inhibitors (ICIs) therapy and chemotherapy in patients with HGG. Additionally, in vivo and in vitro experiments were performed to investigate the potential biological function of CDKN2A in HGG.

Results: We identified two cuproptosis-related molecular subgroups with significantly different survival probabilities. Patients with HGG in cluster 1 were characterized as immune-desert phenotype with higher CupScore and lower expression of MHC complex, interferons, chemokines, interleukins, and immune checkpoints. In contrast, cluster 2 showed an immune-inflamed signature. We screened PI-103 as the most promising candidate for patients with higher CupScore and confirmed its experimental evidence and clinical trial status. Patients with lower CupScore showed higher response rates to anti-PD-L1 and anti-PD1 combined with anti-CTLA4 ICI therapy. Furthermore, in vivo and in vitro experiments revealed that CDKN2A enhanced the malignant phenotype of HGG.

Conclusion: Cuproptosis has the ability to reprogram the tumor microenvironment (TME) in HGG, leading to the stratification of patients into two distinct molecular subgroups. The CupScore model emerged as a robust metric for predicting the prognostic and therapeutic benefits, as well as may therefore facilitate personalized treatment strategies for patients with HGG.

Background: Myxoid liposarcoma, a rare type of tumor, accounts for approximately 30% of all liposarcomas. Myxoid liposarcomas harboring the FUS/CHOP fusion gene have shown promising results with trabectedin in basic research and some clinical experiments. However, the efficacy and safety of trabectedin in chemotherapy-naive soft tissue sarcomas or FUS/CHOP fusion gene-positive myxoid liposarcomas have not yet been established. Therefore, we evaluated the effectiveness and safety of trabectedin monotherapy in four cases of myxoid liposarcoma harboring the FUS/CHOP fusion gene at our hospital.

Patients and methods: We analyzed four patients with metastatic myxoid liposarcoma who underwent surgery at Okayama University and received chemotherapy at Kawasaki Medical School. These patients had positive test results for the FUS/CHOP fusion gene as an aid to pathological diagnosis by RT-PCR. RNA was extracted from tumor tissue sliced from frozen tumor specimens. Following reverse transcription, PCR was performed using TLS/FUS-CHOP primers. The resulting products were electrophoresed, and then the nucleotide sequences were confirmed.

Case presentation: Case 1: A 44-year-old male started trabectedin as second-line therapy after initial chemotherapy, which included doxorubicin. To date, he has completed 9 cycles, showing a response for 6 months. Case 2: A 71-year-old male, deemed intolerant to doxorubicin, started trabectedin as his first-line treatment. He has undergone 50 cycles to date, maintaining a response for 56 months. Case 3: A 59-year-old female began trabectedin as second-line therapy after initial chemotherapy, including doxorubicin. She responded for 6 months before experiencing disease progression. Case 4: A 79-year-old male developed new lesions after one course of initial chemotherapy, including doxorubicin. He then began trabectedin and has maintained a response for 10 months to date.

Conclusion: Compared to other chemotherapies, trabectedin demonstrated potentially higher efficacy and a favorable safety profile for patients with myxoid liposarcoma harboring the FUS/CHOP fusion gene.

In non-small cell lung cancer (NSCLC), Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are found in up to 30% of all cases, with the most prevalent mutations occurring in codons 12 and 13. The development of KRAS-targeted drugs like sotorasib and adagrasib has generated significant excitement in the clinical arena, offering new therapeutic options. Their potential for combination with other treatments broadens the scope for clinical exploration. Acquired resistance to KRAS exon 2 p.G12C inhibitors is a significant challenge, with several reported mechanisms. In this scenario, combination therapy strategies that include targeting Src Homology Region 2 Domain-Containing Phosphatase-2 (SHP2), Son of Sevenless Homolog 1 (SOS1), or downstream effectors of KRAS exon 2 p.G12C are showing promise in overcoming such resistance. However, the efficacy of immune checkpoint inhibitors in this context still requires comprehensive evaluation. The response to anti-Programmed Cell Death Protein 1/Programmed Cell Death Protein 1 Ligand (anti-PD-1/PD-L1) drugs in NSCLC may be significantly influenced by co-occurring mutations, underscoring the need for a personalized approach to treatment based on the specific genetic profile of each tumor.

Background: Thyroid gland metastasis from distant primary tumors is uncommon, with liver cancer being a particularly rare source. This case report describes the clinical challenges and diagnostic journey of a thyroid mass in a patient with chronic hepatitis B, liver cirrhosis, and hepatocellular carcinoma, underscoring the rarity and complexity of such metastatic relationships.

Case presentation: A 63-year-old male with a long-standing history of hepatitis B-related liver cirrhosis and a recent diagnosis of hepatocellular carcinoma presented with a rapidly enlarging painful right-sided thyroid mass associated with swelling but no systemic symptoms such as fever or dysphonia. This prompted a thorough diagnostic workup. Enhanced neck scans indicated a mass potentially originating from the thyroid with tracheal compression, yet crucially, there was no evidence of lung involvement based on the chest CT. Despite the rarity of liver-to-thyroid metastasis, the patient's multifaceted medical history warranted a broad differential diagnosis.

Intervention and outcome: Surgical intervention included a right-sided thyroidectomy and partial left thyroidectomy under general anesthesia. Histopathological examination unexpectedly confirmed the presence of metastatic thyroid cancer originating from the primary liver tumor. This led to further extensive surgical management, including lymph node dissection in the central neck area. The postoperative regimen was adapted to include thyroid hormone replacement and ongoing treatment for hepatocellular carcinoma. The patient's postoperative recovery was closely monitored, reflecting stable disease with no immediate complications.

Conclusion: This case highlights the clinical rarity and diagnostic challenges of liver cancer metastasizing to the thyroid. It emphasizes the need for vigilance in patients with known primary malignancies, especially hepatocellular carcinoma, presenting with new thyroid abnormalities. This advocates for a comprehensive diagnostic approach in such atypical presentations.

Purpose: Poor lung cancer patients' outcomes and survival rates demand the discovery of new biomarkers for the specific, significant, and less invasive detection of non-small cell lung cancer (NSCLC) progression. The present study aimed to investigate the potential of miRNA expression as biomarkers in NSCLC utilizing a preclinical cell culture setup based on screening of miRNAs in NSCLC cells grown in 3D cell culture.

Patients and methods: The study was performed using lung cancer cell lines, varying in different levels of aggressiveness: NCI-H1299, A549, Calu-1, and NCI-H23, as well as noncancerous bronchial epithelial cell line HBEC3, which were grown in 3D cell culture. Total RNA from all cell lines was extracted and small RNA libraries were prepared and sequenced using the Illumina NGS platform. The expression of 8 differentially expressed miRNAs was further validated in 89 paired tissue specimens and plasma samples obtained from NSCLC patients. Statistical analysis was performed to determine whether miRNA expression and clinicopathological characteristics of NSCLC patients could be considered as independent factors significantly influencing PFS or OS.

Results: Differentially expressed miRNAs, including let-7d-3p, miR-10a-3p, miR-28-3p, miR-28-5p, miR-100-3p, miR-182-5p, miR-190a-5p, and miR-340-5p, were identified through next-generation sequencing in NSCLC cell lines with varying levels of aggressiveness. Validation of patient samples, including tumor and plasma specimens, revealed that out of the 8 investigated miRNAs, only plasma miR-10a-3p showed a significant increase, which was associated with significantly extended progression-free survival (PFS) (p=0.009). Furthermore, miR-10a-3p in plasma emerged as a statistically significant prognostic variable for NSCLC patients' PFS (HR: 0.5, 95% CI: 0.3-0.9, p=0.029).

Conclusion: Our findings of screening miRNA expression patterns in NSCLC cells grown in 3D cell culture indicated that the expression level of circulating miR-10a-3p has the potential as a novel non-invasive biomarker to reflect the short-term prognosis of NSCLC patients.

In recent years, the incidence of prostate cancer has been increasing globally. Early stage of the disease can obtain a better clinical prognosis from surgery and endocrine therapy. The progression of advanced stage varies significantly between individuals, with some patients developing metastatic castration-resistant prostate cancer after standardized treatment. Therefore, staging of prostate cancer by accurate imaging is particularly important for the clinical management of patients. Simultaneously, the development of targeted therapy is also urgent for the treatment of advanced prostate cancer. Prostate specific membrane antigen as a prostate specific target has been widely used in the diagnosis and treatment of prostate cancer. This review summarizes the latest research progress of targeted prostate specific membrane antigen in the diagnosis and treatment of prostate cancer in detail, analyzes their value and challenges.

Tumors, as chronic malignant diseases that account for about 20% of all deaths worldwide, are the number one threat to human health. Until now there is no reliable treatment for most types of tumors. Tumorigenesis and cellular carcinogenesis remain difficult challenges due to their complex etiology and unknown mechanisms. As stress process regulating molecules and protein folding promoters, heat shock proteins (HSPs) play an important role in cancer development. Most studies have shown that HSPs are one of the major anticancer drug targets. HSPs are not only modulators of the cellular stress response, but are also closely associated with tumor initiation, progression, and drug resistance, so understanding the mechanism of the HSP family involved in cellular carcinogenesis is an important part of understanding tumorigenesis and enabling anticancer drug development. In this review, we discuss the functions and mechanisms of key members of the HSP family (HSP70, HSP90, and HSP110) in participating in the process of tumorigenesis and cell carcinogenesis, and look forward to the prospect of key members of the HSP family in targeted cancer therapy.

Background: Kaposi sarcoma (KS) is a cutaneous neoplasm of endothelial origin. The causative agent is the human herpes virus-8 (HHV-8) which, combined with an immune system impairment, causes cell proliferation. To date, high-quality evidence and treatment recommendations for the management of KS are confined to the acquired immune deficiency syndrome (AIDS)-related KS, while the clinical approach to the treatment of classic KS (CKS) is based on small retrospective case series and the experience of clinicians in selected referral centers.

Materials and methods: A search of the English literature was conducted through PubMed/MEDLINE databases for studies regarding CKS diagnosis, staging, and treatment, published between January 1990 and September 2023.

Results: Overall, 122 out of 565 articles were selected. Based on the results of this literature review, we proposed indications regarding the recommended flow chart for diagnosis, staging, and follow-up of patients with CKS. We assess available evidences regarding topic, locoregional, and systemic treatments of CKS. We also provide a focus on novel treatment strategies and therapeutic approaches currently under evaluation in clinical trials.

Conclusion: CKS is a rare disease and its management requires a multidisciplinary assessment. Treatment in referral centers and enrolment in clinical trials might impact on outcomes.