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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 -
Indian Journal of Nuclear Medicine :... 2023Our case highlights the 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scan findings in a rare case of biopsy-proven...
Our case highlights the 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scan findings in a rare case of biopsy-proven epithelioid hemangioendothelioma (EHE) in a 66-year-old woman with multi-organ involvement (lung, liver, and bone) who was subsequently treated with palliative radiation therapy and oral pazopanib. Furthermore, follow-up 18F-FDG PET/CT findings are detailed. EHE is a rare malignant vascular neoplasm (<1% of all vascular tumors) with an epithelioid and histiocytoid appearance arising from the vascular endothelial and preendothelial cells.
PubMed: 38046956
DOI: 10.4103/ijnm.ijnm_171_22 -
JAMA Network Open Nov 2023The association of tyrosine kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFR-TKIs) with aneurysm and artery dissection (AAD) has been...
IMPORTANCE
The association of tyrosine kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFR-TKIs) with aneurysm and artery dissection (AAD) has been frequently reported in spontaneous reporting databases.
OBJECTIVE
To investigate the risk and incidence of AAD occurrence in patients with cancer treated with oral VEGFR-TKIs, with capecitabine as an active comparator.
DESIGN, SETTING, AND PARTICIPANTS
This national, historical cohort study was conducted using national claims data from the National Health Insurance Service in Korea from 2007 to 2020, with a 1-year follow-up. Patients with cancer aged 40 years or older prescribed oral VEGFR-TKIs or capecitabine were enrolled. Data were analyzed from September 2022 through April 2023.
EXPOSURE
Oral VEGFR-TKIs (sorafenib, regorafenib, vandetanib, sunitinib, lenvatinib, axitinib, and pazopanib) or capecitabine as a comparator.
MAIN OUTCOMES AND MEASURES
Hazard ratios (HRs) were used to investigate the association between VEGFR-TKI use and AAD after propensity score matching. The primary outcome was AAD, and secondary outcomes were aortic aneurysm and dissection and AAD with rupture. Outcomes were defined using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnosis codes.
RESULTS
Among 127 710 patients with cancer eligible for the study (80 386 males [62.9%]; mean [SD] age, 62.6 [10.9] years), 37 308 patients received VEGFR-TKIs and 90 402 patients received capecitabine. Among 27 535 matched patients receiving VEGFR-TKIs, the incidence of AAD within 1 year of treatment initiation was 6.0 per 1000 person-years. The median (IQR) time to AAD onset in the matched AAD group was 114 (67-257) days after treatment initiation, with the highest incidence observed during the first 3 months (45 incidents vs 31, 17, and 16 incidents during 3- to 6-month, 6- to 9-month, and 9- to 12-month periods, respectively). Cox regression modeling showed that the risk of AAD occurrence was significantly higher among patients prescribed VEGFR-TKIs than those receiving capecitabine (HR, 1.48; 95% CI, 1.08-2.02); similar results were obtained among females (HR, 2.08; 95% CI, 1.26-3.42), older adults (aged ≥65 years; HR, 1.42; 95% CI, 1.01-1.99), and patients with dyslipidemia (HR, 1.58; 95% CI, 1.11-2.24).
CONCLUSIONS AND RELEVANCE
In this study, the use of oral VEGFR-TKIs was associated with an increased risk of AAD occurrence. These findings elucidate vascular toxic effects and may provide a substantial reference for reducing the socioeconomic burden of adverse events associated with VEGFR-TKI use.
Topics: Aged; Female; Humans; Male; Middle Aged; Aneurysm; Aortic Dissection; Arteries; Capecitabine; Cohort Studies; Neoplasms; Vascular Endothelial Growth Factor A; Tyrosine Kinase Inhibitors
PubMed: 38019511
DOI: 10.1001/jamanetworkopen.2023.45977 -
Journal of Radiation Research Jan 2024Combined modality therapy, including radiotherapy (RT), is a common treatment for scalp or face angiosarcoma. Although intensity-modulated radiotherapy (IMRT) can...
Combined modality therapy, including radiotherapy (RT), is a common treatment for scalp or face angiosarcoma. Although intensity-modulated radiotherapy (IMRT) can deliver homogeneous doses to the scalp or face, clinical data are limited. This multicenter study aimed to evaluate scalp or face angiosarcoma treated with definitive or post-operative IMRT. We retrospectively analyzed data from patients who received IMRT for scalp or face angiosarcoma at three institutions between January 2015 and March 2020. Local control (LC) rate, overall survival (OS), progression-free survival (PFS), recurrence patterns and toxicity were evaluated. Fifteen patients underwent IMRT during the study period. Definitive RT was performed on 10 patients and post-operative RT was performed on 5 patients. The 1-year LC rate was 85.7% (95% confidence interval [CI], 53.9-96.2%). The 1-year OS and PFS rates were 66.7% (95% CI, 37.5-84.6%) and 53.3% (95% CI, 26.3%-74.4%), respectively. Univariate analysis revealed that a clinical target volume over 500 cm3 was associated with poor LC. Distant metastasis was the most common recurrence pattern. All patients experienced Grade 2 or 3 radiation dermatitis, and five patients experienced grade ≥ 3 skin ulceration. One patient who underwent maintenance therapy with pazopanib developed Grade 5 skin ulceration. Fisher's exact test showed that post-operative RT was significantly associated with an increased risk of skin ulceration of grade ≥ 3. These results demonstrate that IMRT is a feasible and effective treatment for scalp or face angiosarcoma, although skin ulceration of grade ≥ 3 is a common adverse event in patients who receive post-operative RT.
Topics: Humans; Hemangiosarcoma; Radiotherapy, Intensity-Modulated; Scalp; Retrospective Studies; Treatment Outcome; Radiotherapy Dosage
PubMed: 37996084
DOI: 10.1093/jrr/rrad089