scholarly journals A Ferroptosis-Related Prognostic Risk Score Model to Predict Clinical Significance and Immunogenic Characteristics in Glioblastoma Multiforme

2021 ◽  
Vol 2021 ◽  
pp. 1-30
Author(s):  
Dongdong Xiao ◽  
Yujie Zhou ◽  
Xuan Wang ◽  
Hongyang Zhao ◽  
Chuansheng Nie ◽  
...  
Keyword(s):  
Overall Survival ◽  
Drug Resistance ◽  
Immune Escape ◽  
Progression Free Survival ◽  
Cancer Drug ◽  
Sequencing Data ◽  
Hub Genes ◽  
Glioma Invasion ◽  
Free Survival ◽  
Cell Death Pathway

Background. Ferroptosis is a recently identified cell death pathway, and the susceptibility to ferroptosis inducers varies among cancer cell types. There have been recent attempts to clarify the mechanisms implicated in ferroptosis, glioma invasion, and the immune microenvironment but little is known about ferroptosis regulation in GBM. Methods. Screening ferroptosis-related genes from published reports and existing databases, we constructed an integrated model based on the RNA-sequencing data in GBM. The association of FRGPRS and overall survival is identified and validated across several different datasets. Genomic and clinical characteristics, immune infiltration, enriched pathways, pan-cancer, drug resistance, and immune checkpoint inhibitor therapy are compared among various FRGPRS subgroups. Results. We identified and confirmed the influences of five ferroptosis key hub genes in the FRGPRS model. The FRGPRS model could serve to predict overall survival and progression-free survival in GBM patients, and high FRGPRS was associated with comparatively stronger immunity, higher proportions of tumour tissue, and good cytolytic immune and chemotherapeutics response in GBM patients. Conclusions. The five ferroptosis key hub genes constituting the FRGPRS model could serve to predict overall survival and progression-free survival in patients with GBM and help guide timely and efficacious therapeutic strategies customised and optimised for each individual patient. This discovery may lay the foundation for the development and optimisation of other iterations of this model for the improved forecasting, detection, and treatment of other malignancies notorious for their drug resistance and immune escape.

scholarly journals Identification and Analysis of Genes Associated with Epithelial Ovarian Cancer by Integrated Bioinformatics Methods

2020 ◽  
Author(s):  
Ting Gui ◽  
Chenhe Yao ◽  
Binghan Jia ◽  
Keng Shen
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Epithelial Ovarian Cancer ◽  
Protein Interactions ◽  
Therapeutic Targets ◽  
Progression Free Survival ◽  
The Cancer Genome Atlas ◽  
Ppi Network ◽  
Hub Genes ◽  
Free Survival

Abstract Background: Though considerable efforts have been made to improve the treatment of epithelial ovarian cancer (EOC), the prognosis of patients has remained poor. Identifying differentially expressed genes (DEGs) involved in EOC progression and exploiting them as novel biomarkers or therapeutic targets for EOC is highly valuable. Methods: Overlapping DEGs were screened out from three independent gene expression omnibus (GEO) datasets and subjected to Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses. The protein-protein interactions (PPI) network of DEGs was constructed in the STRING database. The top 20 hub genes were selected using cytoHubba. The expression of hub genes was detected in GEPIA, Oncomine, and human protein atlas (HPA) databases. The relationship of hub genes with the pathological stage and the overall survival and progression-free survival in EOC patients was investigated using the cancer genome atlas data. Results: A total of 306 DEGs were identified, including 265 up-regulated and 41 down-regulated. Through the PPI network analysis, the top 20 genes were screened out, among which 4 hub genes were selected after literature retrieval, including CDC45, CDCA5, KIF4A, ESPL1. The four genes were up-regulated in EOC tissues and the expression of these four genes decreased gradually with the continuous progression of EOC. Survival curves illustrated that patients with a lower level of CDCA5 and ESPL1 had better overall survival and progression-free survival. Conclusions: Two hub genes, CDCA5 and ESPL1, identified as playing tumor-promotive roles, could be utilized as potential novel therapeutic targets for EOC treatment.

scholarly journals Identification and analysis of genes associated with epithelial ovarian cancer by integrated bioinformatics methods

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0253136
Author(s):  
Ting Gui ◽  
Chenhe Yao ◽  
Binghan Jia ◽  
Keng Shen
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Epithelial Ovarian Cancer ◽  
Protein Interactions ◽  
Therapeutic Targets ◽  
Progression Free Survival ◽  
The Cancer Genome Atlas ◽  
Ppi Network ◽  
Hub Genes ◽  
Free Survival

Background Though considerable efforts have been made to improve the treatment of epithelial ovarian cancer (EOC), the prognosis of patients has remained poor. Identifying differentially expressed genes (DEGs) involved in EOC progression and exploiting them as novel biomarkers or therapeutic targets is of great value. Methods Overlapping DEGs were screened out from three independent gene expression omnibus (GEO) datasets and were subjected to Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses. The protein-protein interactions (PPI) network of DEGs was constructed based on the STRING database. The expression of hub genes was validated in GEPIA and GEO. The relationship of hub genes expression with tumor stage and overall survival and progression-free survival of EOC patients was investigated using the cancer genome atlas data. Results A total of 306 DEGs were identified, including 265 up-regulated and 41 down-regulated. Through PPI network analysis, the top 20 genes were screened out, among which 4 hub genes, which were not researched in depth so far, were selected after literature retrieval, including CDC45, CDCA5, KIF4A, ESPL1. The four genes were up-regulated in EOC tissues compared with normal tissues, but their expression decreased gradually with the continuous progression of EOC. Survival curves illustrated that patients with a lower level of CDCA5 and ESPL1 had better overall survival and progression-free survival statistically. Conclusion Two hub genes, CDCA5 and ESPL1, identified as probably playing tumor-promotive roles, have great potential to be utilized as novel therapeutic targets for EOC treatment.

scholarly journals Mutational processes impact the evolution of anti-EGFR antibody resistance in colorectal cancer

2020 ◽  
Author(s):  
Andrew Woolston ◽  
Louise J Barber ◽  
Beatrice Griffiths ◽  
Nik Matthews ◽  
Sheela Rao ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Acquired Resistance ◽  
Genetic Resistance ◽  
Progression Free Survival ◽  
Driver Mutations ◽  
Cancer Drug ◽  
Sequencing Data ◽  
Mutational Signatures ◽  
Resistance Evolution ◽  
Mutational Signature

SUMMARYAnti-EGFR antibodies such as cetuximab are active against KRAS/NRAS wild-type colorectal cancers (CRC) but acquired resistance invariably evolves. Which mutational mechanisms enable resistance evolution and whether adaptive mutagenesis, a transient cetuximab-induced increase in mutagenesis, contributes in patients is unknown. We investigated this in exome sequencing data of 42 baseline and progression biopsies from cetuximab treated CRCs. Mutation loads did not increase from baseline to progression. Evidence for a contribution of cetuximab-induced mutagenesis was limited. However, the mutational Signature 17 was a key contributer of specific KRAS/NRAS and EGFR driver mutations that are common at acquired resistance. Signature 17 activity before treatment predicted shorter progression free survival. This demonstrates the utility of mutational signatures to predict cancer drug resistance evolution.SIGNIFICANCEDrug resistance evolution occurs ubiquitously in solid tumours during treatment with targeted drugs. Biomarkers that can be assessed prior to treatment to predict the time to resistance evolution and the genetic resistance mechanisms that will evolve have not been described. We identified the mutational Signature 17 as the first candidate biomarker that predicts shorter time to progression and several specific KRAS/NRAS and EGFR mutations that will likely evolve in CRCs during cetuximab treatment. Understanding the mutational mechanism underlying Signature 17 may open opportunities to delay resistance acquisition. The potential of mutational signatures to predict resistance to a broader range of drugs in other tumor types should be assessed.

LINAC-based stereotactic radiosurgery/radiotherapy for brain metastases in patients with breast cancer

2021 ◽  
pp. 1-9
Author(s):  
Ankita Gupta ◽  
Budhi Singh Yadav ◽  
Nagarjun Ballari ◽  
Namrata Das ◽  
Ngangom Robert
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Brain Metastases ◽  
Stereotactic Radiosurgery ◽  
Progression Free Survival ◽  
Rank Test ◽  
Karnofsky Performance Score ◽  
Breast Cancer Patients ◽  
Free Survival ◽  
Prior Surgery

Abstract Background: Brain metastases (BM) are common in patients with HER2-positive and triple-negative breast cancer. In this study we aim to report clinical outcomes with LINAC-based stereotactic radiosurgery/radiotherapy (SRS/SRT) for BM in patients of breast cancer. Methods: Clinical and dosimetric records of breast cancer patients treated for BM at our institute between May, 2015 and December, 2019 were retrospectively reviewed. Patients of previously treated or newly diagnosed breast cancer with at least a radiological diagnosis of BM; 1–4 in number, ≤3·5 cm in maximum dimension, with a Karnofsky Performance Score of ≥60 were taken up for treatment with SRS. SRT was generally considered if a tumour was >3·5 cm in diameter, near a critical or eloquent structure, or if the proximity of moderately sized tumours would lead to dose bridging in a single-fraction SRS plan. The median prescribed SRS dose was 15 Gy (range 7–24 Gy) and SRT dose was 27 Gy in 3 fractions. Clinical assessment and MR imaging was done at 6 weeks post-SRS and then every 3 months thereafter. Intracranial progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan–Meier method and subgroups were compared using log rank test. Results: Total, 40 tumours were treated in 31 patients. The median tumour diameter was 2·3 cm (range 1·0–4·6 cm). SRS and SRT were delivered in 27 and 4 patients, respectively. SRS/SRT was given as a boost to whole brain radiotherapy (WBRT) in four patients and as salvage for progression after WBRT in six patients. In general, nine patients underwent prior surgery. The median follow-up was 7·9 months (0·2–34 months). Twenty (64·5%) patients developed local recurrence, 10 (32·3%) patients developed distant intracranial relapse and 7 patients had both local and distant intracranial relapse. The estimated local control at 6 months and 1 year was 48 and 35%, respectively. Median intracranial progression free survival (PFS) was 3·73 months (range 0·2–25 months). Median intracranial PFS was 3·02 months in patients who received SRS alone or as boost after WBRT, while it was 4·27 months in those who received SRS as salvage after WBRT (p = 0·793). No difference in intracranial PFS was observed with or without prior surgery (p = 0·410). Median overall survival (OS) was 21·7 months (range 0·2–34 months) for the entire cohort. Patients who received prior WBRT had a poor OS (13·31 months) as compared to SRS alone (21·4 months; p = 0·699). Conclusion: In patients with BM after breast cancer SRS alone, WBRT + SRS and surgery + SRS had comparable PFS and OS.

scholarly journals IMMU-08. MODELING UPFRONT GLIOBLASTOMA SURGICAL RESECTION AND STEROID USE REVEALS IMMUNOSUPPRESSIVE CHANGES AND SUGGESTS THAT PERIPHERAL LYMPHOCYTE COUNTS ARE ASSOCIATED WITH TUMOR VOLUME AND PROGNOSIS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii106-ii106
Author(s):  
Balint Otvos ◽  
Tyler Alban ◽  
Matthew Grabowski ◽  
Defne Bayik ◽  
Robert Winkelman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Surgical Resection ◽  
Cd8 T Cells ◽  
Tumor Volume ◽  
Progression Free Survival ◽  
Peripheral Lymphocyte ◽  
Steroid Use ◽  
Free Survival ◽  
Steroid Administration

Abstract Glioblastoma (GBM) and its treatment produces systemic immunosuppression, which is being targeted by immunotherapies. However, it remains unclear how surgical resection and steroids specifically in GBM alter the immune system. To further explore this issue, immunocompetent C57Bl/6 mice were intracranially inoculated with syngeneic glioma cells (GL261 and CT-2A) and growth of tumors was evaluated by MRI. Host immune cell populations were analyzed during surgical resection and steroid administration. Mice with surgically resected tumors had a longer median survival compared to mice subjected to tumor biopsies, and had increased bone marrow sequestration of both CD4 and CD8 T cells with corresponding decreased blood lymphocytes. Furthermore, physiologic doses of dexamethasone administered perioperatively decreased tumor edema, but increased the number and proliferative capacity of both marrow and circulating MDSCs while generating no survival benefit. Independent of therapy or dexamethasone, intracranial tumor volume correlated linearly with decreased CD4 and CD8 T cells in peripheral blood, and increased T cell sequestration within the bone marrow. We validated these parameters in steroid-naïve newly diagnosed GBM patients and observed decreased lymphocytes correlated linearly with increased tumor volume. When initial lymphocyte counts in both steroid-naïve and steroid-administered patients were used in univariate and multivariate models predicting progression-free survival and overall survival, decreased initial lymphocyte counts were an independent predictor of decreased progression free survival and decreased overall survival, with steroid use and initial tumor size falling out of significance during stepwise selection. Taken together, tumor volume is linearly correlated with marrow sequestration of lymphoid cells, but both surgery and steroid administration further suppress active immune responses along lymphoid and myeloid lineages. Furthermore, decreasing peripheral lymphocyte counts at diagnosis of GBM indicate an immune system less able to mount responses to the tumor and portent a worse progression free and overall survival.

scholarly journals Single arm, phase two study of low-dose metronomic eribulin in metastatic breast cancer

2021 ◽  
Author(s):  
Pavani Chalasani ◽  
Kiah Farr ◽  
Vicky Wu ◽  
Isaac Jenkins ◽  
Alex Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Metastatic Breast Cancer ◽  
Peripheral Neuropathy ◽  
Clinical Benefit ◽  
Low Dose ◽  
Response Rate ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Free Survival

Abstract Background Treatment options for metastatic breast cancer (MBC) refractory to anthracyclines and taxanes are limited. In a phase III trial, eribulin demonstrated a significant improvement in overall survival compared to treatment of physician’s choice, but had limited tolerability because of neutropenia and peripheral neuropathy. Based on prior studies of alternative treatment schedules with other therapies, we hypothesized that a low-dose metronomic schedule of eribulin would permit patients to remain on treatment more consistently without treatment delays, resulting in longer time to progression, and improved toxicity profile. Methods We conducted a multi-site single arm, phase II trial patients with MBC. All patients were treated with metronomic eribulin (0.9 mg/m2 administered intravenously on days 1, 8, and 15 of a 28-day cycle.) Treatment was continued until the patient developed disease progression, unacceptable toxicity, or chose to stop the study. Patients must have had prior taxane exposure. The primary endpoint was progression-free survival. Secondary end points were overall survival, response rate, and clinical benefit rate. Exploratory biomarkers were performed to analyze change in levels of circulating endothelial cells (CECs), circulating endothelial precursors, and carbonic anhydrase IX (CAIX) with response to therapy. Findings We consented 86 patients and 59 were evaluable for final analysis. Median age was 59 years; 78% had HER2 negative tumors. The median progression-free survival (PFS) was 3.5 months with overall survival (OS) of 14.3 months. Objective response rate was 15% with clinical benefit rate of 48%. Reported grade 3 neutropenia and peripheral neuropathy were 18% and 5%, respectively. Treatment discontinuation due to toxicity was seen in 3% of patients. Interpretation Metronomic weekly low-dose eribulin is an active and tolerable regimen with significantly less myelosuppression, alopecia, and peripheral neuropathy than is seen with the approved dose and schedule, allowing longer duration of use and disease control, with similar outcomes compared to the standard dose regimen.

scholarly journals Comparison of the survival outcomes of laparoscopy versus laparotomy in treatment of early-stage ovarian cancer: a systematic review and meta-analysis

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Qingduo Kong ◽  
Hongyi Wei ◽  
Jing Zhang ◽  
Yilin Li ◽  
Yongjun Wang
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Early Stage ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Cochrane Library ◽  
Survival Outcomes ◽  
Free Survival ◽  
Review Manager ◽  
Early Stage Ovarian Cancer

Abstract Background Laparoscopy has been widely used for patients with early-stage epithelial ovarian cancer (eEOC). However, there is limited evidence regarding whether survival outcomes of laparoscopy are equivalent to those of laparotomy among patients with eEOC. The result of survival outcomes of laparoscopy is still controversial. The aim of this meta-analysis is to analyze the survival outcomes of laparoscopy versus laparotomy in the treatment of eEOC. Methods According to the keywords, Pubmed, Embase, Cochrane Library and Clinicaltrials.gov were searched for studies from January 1994 to January 2021. Studies comparing the efficacy and safety of laparoscopy versus laparotomy for patients with eEOC were assessed for eligibility. Only studies including outcomes of overall survival (OS) were enrolled. The meta-analysis was performed using Stata software (Version 12.0) and Review Manager (Version 5.2). Results A total of 6 retrospective non-random studies were included in this meta-analysis. The pooled results indicated that there was no difference between two approaches for patients with eEOC in OS (HR = 0.6, P = 0.446), progression-free survival (PFS) (HR = 0.6, P = 0.137) and upstaging rate (OR = 1.18, P = 0.54). But the recurrence rate of laparoscopic surgery was lower than that of laparotomic surgery (OR = 0.48, P = 0.008). Conclusions Laparoscopy and laparotomy appear to provide comparable overall survival and progression-free survival outcomes for patients with eEOC. Further high-quality studies are needed to enhance this statement.

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