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World Journal of Surgical Oncology Jan 2024Head and neck cancer (HNC) is one of the most frequent malignancies in Asian males with a poor prognosis. Apart from well-known prognostic indicators, markers of tumor... (Review)
Review
BACKGROUND
Head and neck cancer (HNC) is one of the most frequent malignancies in Asian males with a poor prognosis. Apart from well-known prognostic indicators, markers of tumor hypoxia can help us predict response to treatment and survival.
METHODS
A review of the literature on the present evidence and potential clinical importance of tumor hypoxia in head and neck cancer was carried out. The data obtained from the literature search is presented as a narrative review.
RESULTS
The literature shows possible associations between prognosis and low tumor oxygenation. Intermediate hypoxia biomarkers like HIF-1, GLUT-1, miRNA, and lactate, can help in predicting the response to therapy and survival as their altered expression is related to prognosis.
CONCLUSIONS
Hypoxia is common in HNC and can be detected by use of biomarkers. The tumors that show expression of hypoxia biomarkers have poor prognosis except for patients with human papilloma virus-associated or VHL-associated cancers. Therapeutic targeting of hypoxia is emerging; however, it is still in its nascent stage, with increasing clinical trials hypoxia is set to emerge as an attractive therapeutic target in HNC.
Topics: Male; Humans; Tumor Hypoxia; Mouth Neoplasms; Hypoxia; Lactic Acid; Biomarkers
PubMed: 38200568
DOI: 10.1186/s12957-023-03284-3 -
Cancer Cell International Jan 2024Patients with recurrent or metastatic cervical cancer are in urgent need of novel prognosis assessment or treatment approaches. In this study, a novel prognostic gene...
Patients with recurrent or metastatic cervical cancer are in urgent need of novel prognosis assessment or treatment approaches. In this study, a novel prognostic gene signature was discovered by utilizing cuproptosis-related angiogenesis (CuRA) gene scores obtained through weighted gene co-expression network analysis (WGCNA) of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. To enhance its reliability, the gene signature was refined by integrating supplementary clinical variables and subjected to cross-validation. Meanwhile, the activation of the VEGF pathway was inferred from an analysis of cell-to-cell communication, based on the expression of ligands and receptors in cell transcriptomic datasets. High-CuRA patients had less infiltration of CD8 + T cells and reduced expression of most of immune checkpoint genes, which indicated greater difficulty in immunotherapy. Lower IC50 values of imatinib, pazopanib, and sorafenib in the high-CuRA group revealed the potential value of these drugs. Finally, we verified an independent prognostic gene SFT2D1 was highly expressed in cervical cancer and positively correlated with the microvascular density. Knockdown of SFT2D1 significantly inhibited ability of the proliferation, migration, and invasive in cervical cancer cells. CuRA gene signature provided valuable insights into the prediction of prognosis and immune microenvironment of cervical cancer, which could help develop new strategies for individualized precision therapy for cervical cancer patients.
PubMed: 38200479
DOI: 10.1186/s12935-023-03189-x -
Translational Cancer Research Dec 2023Gastric cancer (GC) is one of the most prevalent cancer types that reduce human life expectancy. The current tumor-node-metastasis (TNM) staging system is inadequate in...
BACKGROUND
Gastric cancer (GC) is one of the most prevalent cancer types that reduce human life expectancy. The current tumor-node-metastasis (TNM) staging system is inadequate in identifying higher or lower risk of GC patients because of tumor heterogeneity. Research shows that complement plays a dual role in the tumor development and progression of GC.
METHODS
We downloaded GC data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). A complement-related risk signature was constructed through bioinformatics analysis. Subsequently, the predictive ability of this signature was validated with GSE84437 dataset, and a nomogram integrating risk score and common clinical factors was established. Besides, we evaluated the association of risk score with the immune and stromal cell infiltration in TCGA. Furthermore, immunotherapy response prediction and drug susceptibility analysis were conducted to access the ability of the risk signature in predicting the therapeutic effect.
RESULTS
A complement-related gene (CRG) signature, based on six genes (, , , , , and ), was established. In both the training and validation sets, the overall survival of GC patients in the high-risk group was lower than that of the low-risk group, and the nomogram to predict the 1-, 2-, and 3-year survival rates of GC patients was developed. In addition, CIBERSORT algorithm showed the high-risk patients had higher levels of immune cell infiltration than low-risk patients, and the ESTIMATE results implied that the high-risk group had more stromal component in tumor microenvironment. Besides, compared to the low-risk group, there were higher expressions of most immune checkpoint genes and HLA genes in the high-risk group, and the high-risk patients showed higher sensitivity to the chemotherapy and targeted drugs (axitinib, dasatinib, pazopanib, saracatinib, sunitinib and temsirolimus).
CONCLUSIONS
The novel CRG signature may act as a reliable, efficient tool for prognostic prediction and treatment guidance in future clinical practice.
PubMed: 38192986
DOI: 10.21037/tcr-23-628 -
American Journal of Translational... 2023Gastric cancer (GC) has a high incidence and poor prognosis. Senescence genes are suggested to participate in immune cell infiltration, thus affecting the immunotherapy...
AIM
Gastric cancer (GC) has a high incidence and poor prognosis. Senescence genes are suggested to participate in immune cell infiltration, thus affecting the immunotherapy of GC. In this research, we established a senescence-related GC model to explore and verify the role of senescence genes in the prognosis, treatment, and tumor microenvironment (TME) of GC.
METHODS
The TCGA GC (TCGA-STAD) dataset was used to screen key senescence genes from differentially expressed genes (DEGs). A prognostic risk model was trained utilizing the TCGA-STAD dataset and validated using an external GEO dataset. The CIBERSORT algorithm was run to explore the relationship between senescence genes and TME. The chemotherapy drug sensitivities in GC patients were calculated utilizing R package pRRophetic.
RESULTS
A total of 37 senescence-related DEGs were obtained. Five key senescence-related genes were further screened to establish a senescence-related risk model based on Cox regression. The survival status of GC patients in the high-risk group was found to be worse than that in the low-risk group. According to the results of gene set enrichment analysis, the senescence-related risk was mainly associated with cytokine activity, immune mechanism, and related pathways. By analyzing the sensitivity of common chemotherapy drugs in GC patients, it was revealed that the sensitivities of high-risk patients to Dasatinib, Lapatinib, and Pazopanib were lower than those of low-risk patients. The CIBERSORT algorithm was executed to analyze the TME in the high-risk group, revealing elevated levels of CD8 T cells, Macrophages M2, and resting Mast cells. In addition, decreased levels of resting memory CD4 T cells , resting NK cells, activated Dendritic cells, and activated Mast cells were also observed.
CONCLUSION
Senescence genes were related to the prognosis, response to chemotherapy drugs, and TME of GC. Our senescence-related risk model could forecast the survival of patients, their response to chemotherapy drugs, and the TME to a certain extent.
PubMed: 38187003
DOI: No ID Found -
Cancer Science Feb 2024Of the drugs used in second-line chemotherapy for soft tissue sarcoma (STS), trabectedin is effective for liposarcoma and leiomyosarcoma (L-sarcoma), eribulin for...
Of the drugs used in second-line chemotherapy for soft tissue sarcoma (STS), trabectedin is effective for liposarcoma and leiomyosarcoma (L-sarcoma), eribulin for liposarcoma, and pazopanib for non-liposarcoma. The indications for these drugs in STS other than L-sarcoma have not been established. Here we explored the prognosis, mutation profiles, and drug-response factors in STS using real-world big data. Clinicogenomic data on 1761 patients with sarcoma who underwent FoundationOne CDx were obtained from a national database in Japan. Patients with TP53 and KDM2D mutations had a significantly shorter survival period of 253 (95% CI, 99-404) and 330 (95% CI, 20-552) days, respectively, than those without mutations. Non-supervised clustering based on mutation profiles generated 13 tumor clusters. The response rate (RR) to trabectedin was highest in an MDM2-amplification cluster (odds ratio [OR]: 2.2; p = 0.2). The RR was lowest for eribulin in an MDM2-amplification cluster (OR: 0.4; p = 0.03) and highest in a TERT-mutation cluster (OR: 3.0; p = 0.03). The RR was highest for pazopanib in a PIK3CA/PTEN-wild type cluster (OR: 2.1; p = 0.03). In particular, patients harboring mutations in genes regulating the PI3K/Akt/mTOR pathway had a lower RR than patients without mutations (OR: 0.3; p = 0.04). In STS, mutation profiles were more useful in predicting the drug response than histology. The present study demonstrated the potential of tailored therapy guided by mutation profiles established by comprehensive genomic profiling testing in optimizing second-line chemotherapy for STS. The findings of this study will hopefully contribute some valuable insights into enhancing STS treatment strategies and outcomes.
Topics: Humans; Trabectedin; Phosphatidylinositol 3-Kinases; Sarcoma; Liposarcoma; Genomics; Pyrimidines; Polyether Polyketides; Ketones; Indazoles; Sulfonamides; Furans
PubMed: 38115234
DOI: 10.1111/cas.16050 -
Iranian Journal of Public Health Nov 2023The transmembrane protein (TMEM) family plays important roles in cancer. However, the expression pattern and biological roles of TMEM178, a member of TMEM family,...
BACKGROUND
The transmembrane protein (TMEM) family plays important roles in cancer. However, the expression pattern and biological roles of TMEM178, a member of TMEM family, remains unclear in breast cancer (BRCA).
METHODS
Methylation and RNA-seq data were obtained to explore methylation level. Expression of TMEM178, methylation inhibitor 5-Aza-CdR was used to verify the effect of methylation status on the expression of TMEM178. We comprehensively investigated the prognostic outcomes, biological functions and effects on immune cell infiltration of the TMEM178 in BRCA using multiple bioinformatics methods.
RESULTS
The expression of TMEM178 was downregulated and negatively correlated with the level of DNA methylation and DNA methyltransferase (DNMT1, DNMT3A, and DNMT3B) in BRCA. Consistently, TMEM178 mRNA were confirmed to be downregulated, while upregulated in response to treatment with methylation inhibitor 5-Aza-CdR by RT-qPCR. Patients with high expression of TMEM178 have better prognosis and are more sensitive to targeted drug Pazopanib. Immune infiltration analysis showed that the infiltration levels of CD4 T cell subsets were reduced in BRAC tissues with high TMEM178 expression, and immunosuppressive molecules of T-cell exhaustion were lower expression level.
CONCLUSION
Hypermethylation of the TMEM178 promoter region was a contributing factor to the downregulation of its expression, and TMEM178 may reflect a prognostic and immunosuppressive situation in BRCA.
PubMed: 38106832
DOI: 10.18502/ijph.v52i11.14042 -
Cancer Chemotherapy and Pharmacology Apr 2024Pazopanib is known to cause liver toxicity. A relationship between pazopanib exposure and alanine transaminase elevations has been described in clinical trials. This... (Observational Study)
Observational Study
PURPOSE
Pazopanib is known to cause liver toxicity. A relationship between pazopanib exposure and alanine transaminase elevations has been described in clinical trials. This study investigated the relation between pazopanib exposure and liver toxicity in real-world patients and evaluated the management of pazopanib-induced liver toxicity in routine care.
METHODS
A retrospective observational cohort study was performed in patients treated with pazopanib in whom pazopanib exposure was measured. The percentage of patients with and without liver toxicity during treatment with pazopanib was calculated as well as the average pazopanib exposure in both groups. Furthermore, the management of patients with liver toxicity was evaluated.
RESULTS
Liver toxicity was observed in 25 out of the 133 patients included (19%). Pazopanib exposure was comparable in patients with or without liver toxicity (27.7 mg/L versus 28.1 mg/L). Seven patients permanently discontinued pazopanib after the occurrence of liver toxicity. Of the remaining 18 patients, continuation or restart of pazopanib after liver toxicity was successful in 16 patients and half of these patients were able to safely continue pazopanib at the same dose as prior to liver toxicity for the remaining duration of treatment.
CONCLUSION
Our study did not demonstrate a clear relationship between pazopanib exposure and the occurrence of pazopanib-induced liver toxicity. Half of the patients were able to safely continue or restart pazopanib treatment after liver toxicity and received the same dose as prior to drug withdrawal. Successful interventions to address pazopanib-induced toxicity in the clinic led to an algorithm for the management of pazopanib-induced liver toxicity.
Topics: Humans; Carcinoma, Renal Cell; Retrospective Studies; Sarcoma; Kidney Neoplasms; Indazoles; Drug-Related Side Effects and Adverse Reactions; Liver; Pyrimidines; Sulfonamides
PubMed: 38104304
DOI: 10.1007/s00280-023-04615-7 -
Indian Journal of Cancer Sep 2023Data on occurrence of pneumothorax after the use of oral pazopanib in advanced soft tissue sarcoma (STS) with lung metastases are scarce in literature. We aimed to...
AIM
Data on occurrence of pneumothorax after the use of oral pazopanib in advanced soft tissue sarcoma (STS) with lung metastases are scarce in literature. We aimed to evaluate those in our patients.
METHODS
This was a single center retrospective study of incidence of pneumothorax in patients with lung metastases in advanced STS treated with oral pazopanib between July, 2016 and December, 2020. Patients were treated with pazopanib usually from 2nd line onwards with a dose ranging from 400 mg to 800 mg once daily.
RESULTS
Total of 34 patients with lung metastasis in a setting of advanced STS were treated with oral pazopanib during the study period. The setting of pazopanib use was 2nd line in four and 1st line in one of them. The starting dose was 600 mg once daily in three patients, 400 mg OD in one patient, and 800 mg OD in one patient. Five patients developed pneumothorax with duration on pazopanib of 6, 7, 24, 6, and 2.5 months, respectively. Three patients had symptoms and required chest tube drainage. None of them were smokers or had any other underlying lung disease. The disease response of those patients was stable disease in four and partial response in one during treatment with pazopanib. One patient had a rechallenge with further pazopanib course without any recurrence of pneumothorax.
CONCLUSIONS
Pneumothorax is a rare pulmonary complication after pazopanib use in patients with lung metastasis. Clinicians should be aware of this rare complication as literature is scarce. Rechallenge with pazopanib is feasible after pneumothorax.
PubMed: 38090966
DOI: 10.4103/ijc.IJC_95_21 -
World Journal of Clinical Cases Nov 2023Malignant schwannoma is a rare tumor in the peripheral nervous system, accounting for approximately 5% to 10% of systemic soft tissue sarcomas. Especially, malignant...
BACKGROUND
Malignant schwannoma is a rare tumor in the peripheral nervous system, accounting for approximately 5% to 10% of systemic soft tissue sarcomas. Especially, malignant schwannoma occurring in the broad ligament of the uterus with hemophilic syndrome and bone marrow fibrosis is extremely rare in clinical practice. Here, we report the first case of an patient diagnosed with malignant peripheral nerve sheath tumor (MPNST) of the broad ligament of the uterus with hemophilic syndrome and bone marrow fibrosis, and share our reference clinical diagnosis and treatment experience.
CASE SUMMARY
A patient was diagnosed with MPNST of the uterus harboring hemophilic syndrome and bone marrow fibrosis. She received combination, and repeated imaging revealed further encountered rare complications (hemophilia syndrome and bone marrow fibrosis) after two cycles of chemotherapy. Thereafter, combined treatment with pazopanib, gemcitabine, and dacarbazine was initiated. Unfortunately, the patient succumbed to death at hospital after two weeks.
CONCLUSION
This report firstly provided reference clinical practice for a patient with MPNST of the uterus harboring hemophilic syndrome and bone marrow fibrosis. Our case raises a reminder about the tolerance and safety of combination therapy, especially in young women.
PubMed: 38078124
DOI: 10.12998/wjcc.v11.i31.7673 -
European Journal of Medical Research Dec 2023Alzheimer's disease (AD) and Parkinson's disease (PD), two common irreversible neurodegenerative diseases, share similar early stage syndromes, such as olfaction...
BACKGROUND
Alzheimer's disease (AD) and Parkinson's disease (PD), two common irreversible neurodegenerative diseases, share similar early stage syndromes, such as olfaction dysfunction. Yet, the potential comorbidity mechanism of AD and PD was not fully elucidated.
METHODS
The gene expression profiles of GSE5281 and GSE8397 were downloaded from the Gene Expression Omnibus (GEO) database. We utilized a series of bioinformatics analyses to screen the overlapped differentially expressed genes (DEGs). The hub genes were further identified by the plugin CytoHubba of Cytoscape and validated in the hippocampus (HIP) samples of APP/PS-1 transgenic mice and the substantial nigra (SN) samples of A53T transgenic mice by real-time quantitative polymerase chain reaction (RT-qPCR). Meanwhile, the expression of the target genes in the olfactory epithelium/bulb was detected by RT-qPCR. Finally, molecular docking was used to screen potential compounds for the target gene.
RESULTS
One hundred seventy-four overlapped DEGs were identified in AD and PD. Five of the top ten enrichment pathways mainly focused on the synapse. Five hub genes were identified and further validated. As a common factor in AD and PD, the changes of synaptosomal-associated protein 25 (SNAP25) mRNA in olfactory epithelium/bulb were significantly decreased and had a strong association with those in the HIP and SN samples. Pazopanib was the optimal compound targeting SNAP25, with a binding energy of - 9.2 kcal/mol.
CONCLUSIONS
Our results provided a theoretical basis for understanding the comorbidity mechanism of AD and PD and highlighted that SNAP25 in the olfactory epithelium may serve as a potential target for early detection and intervention in both AD and PD.
Topics: Animals; Mice; Alzheimer Disease; Gene Expression Profiling; Mice, Transgenic; Molecular Docking Simulation; Parkinson Disease; Synaptosomal-Associated Protein 25
PubMed: 38053192
DOI: 10.1186/s40001-023-01360-8