Overall Survival Time Of Patients Research Articles

Correlation study of serum lipid levels and lipid metabolism-related genes in cervical cancer

ObjectiveLipid metabolism plays an important role in cancer. The aim of this study was to investigate the relationship between lipid metabolism and the development of cervical cancer, and to explore the prognostic significance of lipid metabolism-related genes in patients with cervical cancer.MethodsInitially, we retrospectively collected data from 1589 cervical cancer patients treated at the Affiliated Hospital of Qingdao University, with 1589 healthy individuals from the physical examination center serving as the control group. The correlation between their serum lipid levels and cervical cancer was analyzed. Subsequently, leveraging public databases, we conducted comprehensive studies on lipid metabolism-related genes. Additionally, we analyzed RNA expression profiling and clinical information sourced from TCGA and GTEx databases. Finally, we established a prognostic model integrating 9 genes associated with lipid metabolism and generated a nomogram model using R. GO and KEGG were performed to explore the functions and pathways of lipid metabolism-related genes.ResultsOur findings revealed that patients with cervical cancer exhibited dyslipidemia, characterized by elevated levels of TC, TG, and LDL-C, alongside reduced HDL-C levels compared to controls (P<0.05). Interestingly, compared with early-stage patients, advanced patients had lower HDL-C level and higher LDL-C level. Regression analysis further highlighted high TC, TG, and LDL-C as significant risk factors for cervical cancer. Then a total of 188 lipid metabolism-related genes were identified and a prognostic signature based on 9 genes was established and validated. The results of the GO and KEGG functional analysis indicated that the lipid metabolism-related genes are primarily concentrated on pathways associated with fatty acid metabolism.ConclusionOur study underscores the varying degrees of dyslipidemia observed in patients with cervical cancer, emphasizing the relevance of serum lipids in disease development. Our prognostic riskScore model predicted the overall survival time of patients based on 9 genes associated with lipid metabolism. These 9 genes may be tumor biomarkers and new targets for the treatment of cervical cancer.

Sesamolin serves as an MYH14 inhibitor to sensitize endometrial cancer to chemotherapy and endocrine therapy via suppressing MYH9/GSK3β/β-catenin signaling

BackgroundEndometrial cancer (EC) is one of the most common gynecological cancers. Herein, we aimed to define the role of specific myosin family members in EC because this protein family is involved in the progression of various cancers.MethodsBioinformatics analyses were performed to reveal EC patients’ prognosis-associated genes in patients with EC. Furthermore, colony formation, immunofluorescence, cell counting kit 8, wound healing, and transwell assays as well as coimmunoprecipitation, cycloheximide chase, luciferase reporter, and cellular thermal shift assays were performed to functionally and mechanistically analyze human EC samples, cell lines, and a mouse model, respectively.ResultsMachine learning techniques identified MYH14, a member of the myosin family, as the prognosis-associated gene in patients with EC. Furthermore, bioinformatics analyses based on public databases showed that MYH14 was associated with EC chemoresistance. Moreover, immunohistochemistry validated MYH14 upregulation in EC cases compared with that in normal controls and confirmed that MYH14 was an independent and unfavorable prognostic indicator of EC. MYH14 impaired cell sensitivity to carboplatin, paclitaxel, and progesterone, and increased cell proliferation and metastasis in EC. The mechanistic study showed that MYH14 interacted with MYH9 and impaired GSK3β-mediated β-catenin ubiquitination and degradation, thus facilitating the Wnt/β-catenin signaling pathway and epithelial–mesenchymal transition. Sesamolin, a natural compound extracted from Sesamum indicum (L.), directly targeted MYH14 and attenuated EC progression. Additionally, the compound disrupted the interplay between MYH14 and MYH9 and repressed MYH9-regulated Wnt/β-catenin signaling. The in vivo study further verified sesamolin as a therapeutic drug without side effects.ConclusionsHerein, we identified that EC prognosis-associated MYH14 was independently responsible for poor overall survival time of patients, and it augmented EC progression by activating Wnt/β-catenin signaling. Targeting MYH14 by sesamolin, a cytotoxicity-based approach, can be applied synergistically with chemotherapy and endocrine therapy to eventually mitigate EC development. This study emphasizes MYH14 as a potential target and sesamolin as a valuable natural drug for EC therapy.Graphical

[Establishment of a prognostic nomogram and discussion on optimal treatment for cervical adenocarcinoma:a retrospective study based on SEER database and Chinese single-center data].

Objective: To establish and validate a predicting nomogram for cervical adenocarcinoma based on surveillance, epidemiology and end results (SEER) database and Chinese single-center data, and to explore the optimal treatment for cervical adenocarcinoma. Methods: This study selected 2 478 cervical adenocarcinoma patients from the SEER database as the training cohort, and 195 cervical adenocarcinoma patients from Cancer Hospital of Dalian University of Technology, Liaouing Cancer Hospital and Institute as an external validation cohort. Clinicopathological information and follow-up data of the two cohorts were collected. The radiotherapy group was defined as receiving comprehensive treatment based on concurrent chemoradiotherapy after initial diagnosis, while the surgery group was defined as receiving comprehensive treatment based on radical surgery. Log-rank test and cox regression were used to evaluate factors affecting the prognosis of cervical adenocarcinoma patients. A nomogram was drawn to predict the 3-year and 5-year overall survival rates of cervical adenocarcinoma patients, and then internal validation of the training cohort from SEER database and external validation of the hospital cohort were conducted. Results: (1) In the SEER database training cohort, there were 385 patients (15.54%, 385/2 478) in the radiotherapy group and 2 093 patients (84.46%, 2 093/2 478) in the surgery group. Overall survival time of the radiotherapy group was (55.8±51.3) months, while that of the surgery roup was (94.4±61.7) months, the difference between the two groups was statistically significant (χ2=256.44, P<0.001). Log-rank test showed that age, marital status, maximum of tumor diameters, pathological grade, International Federation of Gynecology and Obstetrics (FIGO) stage, and treatments were all significant factors affecting the overall survival time of cervical adenocarcinoma patients (all P<0.001). Multivariate Cox regression analysis showed that elder (>50 years old), single status, huge tumors (>4 cm), high pathological grades (G2, G3), and advanced FIGO stages (≥Ⅱa2 stage) were independent risk factors for the overall survival time of cervical adenocarcinoma patients (all P<0.05); compared with radiotherapy, surgery was a protective factor for the prognosis of cervical adenocarcinoma patients (HR=0.619, 95%CI: 0.494-0.777; P<0.001). Further analysis of locally advanced stage and Ⅲc stage of patients showed that surgery was a protective factor for the prognosis of cervical adenocarcinoma patients with a maximum tumor diameter >4 to <6 cm (HR=0.414, 95%CI: 0.182-0.942; P=0.036) in locally advanced stage and Ⅲc T1 to T2 stage (HR=0.473, 95%CI: 0.307-0.728; P=0.001). (2) The external validation cohort consisted of 39 patients (20.00%, 39/195) in the radiotherapy group and 156 patients (80.00%, 156/195) in the surgery group. The overall survival time of patients in the radiotherapy group was (51.7±34.3) months, while that of the surgery group was (63.1±26.6) months (χ2=28.41, P<0.001). Further analysis was conducted on locally advanced stage and Ⅲc stage patients, and multivariate Cox regression analysis was performed after propensity score matching, which showed that surgery was a protective factor for the prognosis of cervical adenocarcinoma patients with a maximum tumor diameter >4 to <6 cm in locally advanced stage (HR=0.141, 95%CI: 0.023-0.843; P=0.032) and Ⅲc T1 to T2 stage (HR=0.184, 95%CI: 0.036-0.947; P=0.043). (3) Establishment and internal and external validation of nomogram: based on the six factors screened out by the multivariate Cox regression model, the nomogram was developed to predict the prognosis of cervical adenocarcinoma patients. The consistency index of the internal and external validation were 0.801 and 0.766, respectively, and the calibration curves matched well with the ideal fitting line. Conclusions: The key to the treatment of cervical adenocarcinoma is to prioritize radical surgery for patients with conditions for radical tumor resection. Compared with concurrent chemoradiotherapy, patients with locally advanced stages (Ⅰb3, Ⅱa2), and Ⅲc (T1, T2) stages cervical adenocarcinoma could benefit from comprehensive treatment based on radical surgery. The nomogram of this study has been validated internally and externally, and show good survival prediction efficacy for cervical adenocarcinoma patients.

[The Expression of METTL14 in Patients with Newly Diagnosed Acute Myeloid Leukemia and Its Clinical Significance].

To detect the expression of RNA methyltransferase 14(METTL14) in bone marrow of patients with newly diagnosed acute myeloid leukemia (AML), and to investigate the clinical and prognostic significance of METTL14 expression in newly diagnosed AML. Bone marrow samples were collected from 100 patients with newly diagnosed AML as observation group and 60 patients with iron deficiency anemia AML as control group. And collected the clinical data of the AML patients. Real-time quantitative PCR (qRT-PCR) was used to detect the expression level of METTL14 in AML and IDA patients. The relationship between the expression level of METTL14 and clinicopathological features, prognosis was analyzed. Kaplan-Meier curves were used to analyze the effect of METTL14 on overall survival (OS) in AML patients. Cox risk regression model was used to analyze the prognostic factors affecting in patients with AML. Compared with the control group, the expression of METTL14 was significantly increased in AML patients (P < 0.05). Compared with the METTL14 low-expression group, patients in the METTL14 high-expression group had advanced age, high bone marrow cell number, poor efficacyand poor prognosis(P < 0.05). The overall survival time of patients with the METTL14 high-expression group was significantly shorter than that of the low-expression group (P < 0.05). The high expression of METTL14 was an independent risk factor for poor prognosis in AML. METTL14 is significantly overexpressed in AML patients, and its correlated with poor clinicopathological features and poor prognosis. It can be used as a prognostic marker and potential therapeutie target for AML patients.

Clinical Features of Non-Hodgkin Lymphoma-Associated Hemophagocytic Syndrome: a Retrospective Study.

This study aims to improve the understanding of lymphoma-associated hemophagocytic syndrome, and find effective methods to identify and manage this fatal disease. Patients diagnosed with non-Hodgkin lymphoma-associated hemophagocytic syndrome from January 2008 to December 2022 in our center were included. Univariate and multivariate analyses were also conducted using the Cox proportional hazards model. Among 26 patients, 22 patients were diagnosed with T/NK cell lymphoma, while 4 patients were diagnosed with diffuse large B cell lymphoma. A total of 16 patients died with a median follow-up of 71 (26, 236) days. Compared with B cell lymphoma-associated hemophagocytic syndrome patients, T/NK cell lymphoma patients are younger, have lower platelet count, fibrinogen concentration, and serum albumin, have higher blood β2-mi-croglobulin levels and ferritin, are more likely to be infected with Epstein-Barr virus, are more inclined have a simultaneously occurrence of lymphoma and hemophagocytic syndrome. In multivariate analysis, fibrinogen, albumin, cholinesterase, uric acid, triglyceride, and ferritin are significantly associated with overall mortality. LAHS is a rare disease with poor prognosis. Early anti-inflammatory treatment combined with anti-lymphoma therapy can improve the overall survival time of patients. Prospective multi-center studies with larger sample sizes and longer follow-up periods are needed to further investigate optimal treatment and prognosis.

Repeat Resection for Recurrent Glioblastoma in the WHO 2021 Era: A Prospective Matched Case-Control Study

INTRODUCTION: The role of resection for recurrent glioblastoma remains unclear. METHODS: Patients who underwent repeat resection for recurrent IDH-wild-type glioblastoma were prospectively matched with 1:1 control cohort (n = 30:30). The two groups signed the consent and were matched for age, gender, comorbidities, eloquent vs. non-eloquent location, preoperative tumor volume and extent of resection in first surgery, neuropathological features as in WHO 2021 classification, time to progression, tumor volume at the time of recurrence, Park Score, ventricular wall involvement, use of steroids or multiple antiseizure medications and adjuvant therapy. Primary aim was to evaluate the overall survival in two cohorts. The secondary aim was to determine predictive factors for long term survival after repeat resection. RESULTS: After matching, patients had a long term follow up until death. Median overall survival times for patients who underwent repeat and one resection was 23.8 months vs 9.1 months, respectively (Log-Rank p &lt; 0.001). Two predictive factors for long term survival after repeat resection were preoperative Karnofsky Performance Score &gt;70 and Glasgow Coma Scale &gt;13 (Fisher p = 0.07 and p &lt; 0.001, respectively) while age, time to surgery, preoperative volume, extend of resection in repeat resection, location of tumor, its extension to ventricular wall, ependymal enhancement, comorbidities, tumor histological and molecular features did not correlate with postoperative survival. CONCLUSIONS: This is the first prospective matched case-control study revealing survival benefit of repeat resection for recurrent gliomas with long term follow up in a select group.

Identification of ferroptosis-related subtypes, characteristics of TME infiltration and development of prognostic models in gastric cancer

BackgroundFerroptosis is a distinct form of cell death characterized by unique morphology, biochemistry, and genetics, playing a crucial role in the initiation, progression, prognosis, and therapeutic strategies of tumors. However, the impact of ferroptosis-related genes (FRGs) on the tumor microenvironment (TME) remains unclear. This study may advance the existing knowledge of FRGs in gastric cancer, and push ahead with more effective prognostic assessment and the development of more effective immunotherapy approaches. MethodsFRGs were acquired from the FerrDb database and a consensus clustering technique was adopted to categorize patients with GC into groups in line with the expression profiles of 44 FRGs in order to further investigate the expression properties of these proteins. Assessment of the immune status, microsatellite instability (MSI) and cancer stem cell (CSC) index between the high- and low- risk groups to assess the proportion of TIICs in the TME, ssGSVA was adopted to detect the abundance of infiltrating immune cells from the low-risk and high-risk groups. Expression levels of eight ferroptosis-related genes of prognostic signature in GC tissues and adjacent normal tissues was detected by RT-PCR. ResultsIn the GC cohort, TP53 has the highest mutation frequency (44 %), and was shown to be highly linked with the expression levels of 11 FRGs. In accordance with the Kaplan-Meier curve, the overall survival time of patients with subtype A (Low FRG-score) discernibly exceeded that of patients with subtype B (High FRG-score).In addition, there is a significant difference in the infiltration of most immune cells between subtype A and subtype B, and some important immune checkpoints (CTLA4, PDCD1, CD274, LAG3, PDCD1LG2, and HAVCR2) have higher expression in cluster A. Finally, low FRG-scores were significantly associated with MSI-H status, while high FRG-scores were significantly associated with microsatellite stable status (MSS). FRG-score is negatively related to the cancer stem cell (CSC). ConclusionLow FRG-score, due to its high microsatellite instability (MSI-H), high mutational load and immune activation, indicates the possible advantage of OS. In addition, the FRG-score was closely related to the cancer stem cell (CSC) index and the sensitive degree of chemotherapeutic drug.

Construction and validation of a risk-prediction model for anastomotic leakage after radical gastrectomy: A cohort study in China

ObjectivesAnastomotic leakage (AL) stands out as a prevalent and severe complication following gastric cancer surgery. It frequently precipitates additional serious complications, significantly influencing the overall survival time of patients. This study aims to enhance the risk-assessment strategy for AL following gastrectomy for gastric cancer. MethodsThis study included a derivation cohort and validation cohort. The derivation cohort included patients who underwent radical gastrectomy at Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, from January 1, 2015 to December 31, 2020. An evidence-based predictor questionnaire was crafted through extensive literature review and panel discussions. Based on the questionnaire, inpatient data were collected to form a model-derivation cohort. This cohort underwent both univariate and multivariate analyses to identify factors associated with AL events, and a logistic regression model with stepwise regression was developed. A 5-fold cross-validation ensured model reliability. The validation cohort included patients from August 1, 2021 to December 31, 2021 at the same hospital. Using the same imputation method, we organized the validation-queue data. We then employed the risk-prediction model constructed in the earlier phase of the study to predict the risk of AL in the subjects included in the validation queue. We compared the predictions with the actual occurrence, and evaluated the external validation performance of the model using model-evaluation indicators such as the area under the receiver operating characteristic curve (AUROC), Brier score, and calibration curve. ResultsThe derivation cohort included 1377 patients, and the validation cohort included 131 patients. The independent predictors of AL after radical gastrectomy included age ≥65 y, preoperative albumin <35 g/L, resection extent, operative time ≥240 min, and intraoperative blood loss ≥90 mL. The predictive model exhibited a solid AUROC of 0.750 (95% CI: 0.694–0.806; p < 0.001) with a Brier score of 0.049. The 5-fold cross-validation confirmed these findings with a calibrated C-index of 0.749 and an average Brier score of 0.052. External validation showed an AUROC of 0.723 (95% CI: 0.564–0.882; p = 0.006) and a Brier score of 0.055, confirming reliability in different clinical settings. ConclusionsWe successfully developed a risk-prediction model for AL following radical gastrectomy. This tool will aid healthcare professionals in anticipating AL, potentially reducing unnecessary interventions.

Preoperative visceral fat index predicts the survival outcomes of patients with gastric cancer after surgery.

Visceral adipose tissue and skeletal muscle mass are associated with carcinogenesis and clinical outcomes in patients with cancer. The aim of the present study was to determine the influence of body composition parameters on postoperative survival in patients with gastric cancer. Demographic data and systemic inflammatory response data were obtained from patients with gastric cancer undergoing radical gastrectomy. The patient's skeletal muscle and visceral fat were assessed using computed tomography, and the corresponding skeletal muscle index (SMI) and visceral fat index (VFI) were calculated. Univariate and multivariate analyses were then performed. Of the 342 patients from whom information was collected, 125 of these patients eventually succumbed to the disease. A total of 271 (79.24%) of the patients were male and 71 (20.76%) were female. Regarding the entire cohort, the mean age was 64 years [interquartile range (IQR), 56-74 years], while the mean body mass index collected was 21.53 (IQR, 19.27-24.22). The median SMI and VFI of the patients were 47.73 (IQR, 41.67-55.51) and 41.28 (IQR, 36.62-45.36), respectively. It was concluded that a low SMI and VFI were associated with worse survival outcomes. However, the neutrophil-to-lymphocyte ratio and perioperative blood transfusion were not significantly associated with overall survival (OS). Among the indicators assessed, a low VFI was an independent risk factor associated with the worst OS time (hazard ratio 1.59; confidence interval, 1.03-2.45; P=0.038). Finally, a prognostic nomogram was constructed which included the VFI to assist clinicians in making more informed decisions. In conclusion, after data collection and analysis, it was found that there was a significant correlation between a low VFI and a shorter OS time in patients with gastric cancer following gastrectomy, suggesting that VFI may be a promising therapeutic target for postoperative interventions to improve patient survival further.

Prediction of Prognosis in Pancreatic Cancer According to Methionyl-tRNA Synthetase 1 Expression as Determined by Immunohistochemical Staining.

The serum level of CA 19-9 is a prognostic marker for pancreatic ductal adenocarcinoma (PDAC). We evaluated the ability of the expression level of methionyl-tRNA synthetase 1 (MARS1)-which facilitates cancer growth by modulating protein synthesis and the cell cycle-to predict the prognosis of PDAC. Immunohistochemical (IHC) staining was performed on pancreatic specimens obtained from patients with PDAC who were undergoing surgery. High MARS1 expression was defined as equal to, or greater than, that in normal acinar cells. Low MARS1 expression was defined as weaker than in normal acinar cells, and stronger than in the pancreatic duct epithelium. Univariate and multivariate analyses were performed on other factors related to prognosis. Among 137 PDAC patients, no significant differences in baseline characteristics were found between those with high (n = 82) and low (n = 55) MARS1 expression. The median overall survival time of patients with high MARS1 expression was shorter than that of those with low expression (15.2 versus 17.2 months, log-rank test p = 0.044). The median disease-free survival (DFS) was not significantly different between the two groups. However, the DFS was shorter in patients with high than in those with low MARS1 expression (8.9 versus 11.2 months, log-rank test p = 0.067). In a multivariate analysis, lymph node metastasis and high MARS1 expression were associated with a poor prognosis of PDAC. Elevated MARS1 expression detected by IHC staining is associated with a poor prognosis of PDAC, suggesting that MARS1 has potential as a prognostic marker.

Unraveling the Role of Hepatic PGC1α in Breast Cancer Invasion: A New Target for Therapeutic Intervention?

Breast cancer (BC) is the most common cancer among women worldwide and the main cause of cancer deaths in women. Metabolic components are key risk factors for the development of non-alcoholic fatty liver disease (NAFLD), which may promote BC. Studies have reported that increasing PGC1α levels increases mitochondrial biogenesis, thereby increasing cell proliferation and metastasis. Moreover, the PGC1α/ERRα axis is a crucial regulator of cellular metabolism in various tissues, including BC. However, it remains unclear whether NAFLD is closely associated with the risk of BC. Therefore, the present study aimed to determine whether hepatic PGC1α promotes BC cell invasion via ERRα. Various assays, including ELISA, western blotting, and immunoprecipitation, have been employed to explore these mechanisms. According to the KM plot and TCGA data, elevated PGC1α expression was highly associated with a shorter overall survival time in patients with BC. High concentrations of palmitic acid (PA) promoted PGC1α expression, lipogenesis, and inflammatory processes in hepatocytes. Conditioned medium obtained from PA-treated hepatocytes significantly increased BC cell proliferation. Similarly, recombinant PGC1α in E0771 and MCF7 cells promoted cell proliferation, migration, and invasion in vitro. However, silencing PGC1α in both BC cell lines resulted in a decrease in this trend. As determined by immunoprecipitation assay, PCG1a interacted with ERRα, thereby facilitating the proliferation of BC cells. This outcome recognizes the importance of further investigations in exploring the full potential of hepatic PGC1α as a prognostic marker for BC development.

[High-Throughput Sequencing Technology for Detection of Gene Mutations in Myeloid Malignancies and Its Clinical Prognostic Significance].

To detect the gene mutations in patients with myeloid malignancies by high-throughput sequencing and explore the correlation between gene mutations and prognosis. A retrospective analysis was performed on 56 patients with myeloid malignancies who were hospitalized in the department of hematology, Peking University International Hospital from January 2020 to May 2021. The genetic mutations of the patients were detected by next-generation sequencing technology, and the correlation between the genetic mutations and prognosis of myeloid malignancies was analyzed. In 56 patients, the number of mutated genes detected in a single patient is 0-9, with a median of 3. Sequencing results showed that the most common mutated genes were RUNX1(21.4%), TET2(17.9%), DNMT3A(17.9%), TP53(14.3%) and ASXL1(14.3%), among which the most common mutations occurred in the signaling pathway-related genes (23.3%) and the transcription factor genes (18.3%). 84% of the patients carried multiple mutated genes (≥2), and correlation analysis showed there were obvious co-occurring mutations between WT1 and FLT3, NPM1 and FLT3-ITD, and MYC and FLT3. TP53 mutation was more common in MDS patients.The overall survival time of patients with NRAS mutation was significantly shortened (P =0.049). The prognosis of patients with TP53 mutation was poor compared with those without TP53 mutation, but the difference wasn't statistically significant (P =0.08). The application of next-generation sequencing technology is of great significance in myeloid malignancies, which is helpful to better understand the pathogenesis of the disease, to judge the prognosis and to find possible therapeutic targets.

Preoperative Prognostic Nutritional Index Predict Survival in Patients with Resectable Adenocarcinoma of the Gastroesophageal Junction: A Retrospective Study Based on Propensity Score Matching Analyses.

This study evaluated the value of PNI to predicting relapse-free survival (RFS) and overall survival (OS) in patients with resectable gastroesophageal junction adenocarcinoma (AGE). Between 2016 and 2020, there were 236 resectable AGE patients underwent a retrospective review via propensity score matched (PSM) analysis. The PNI values were computed for each patient prior to surgery [PNI= 10×albumin (gr/dL) + 0.005×total lymphocyte count (mm3)]. By using disease progression and mortality as the end points, a receiver operating characteristic(ROC) curve was plotted to identify the PNI cut-off value. Kaplan-Meier curves and Cox proportional hazard models were used for survival analysis. The ROC curve indicated that the ideal cutoff value was 45.60. After propensity score matching, there were 143 patients in our retrospectivestudy, which included 58 patients in the low-PNI group and 85 patients in the high-PNI group. When compared to the low PNI group, the high PNI group substantially increased RFS and OS (p<0.001, p=0.003, respectively) according to the Kaplan-Meier analysis and Log rank test. Advanced pathological N stage (p=0.011) and poor PNI (p=0.004) were also significant risk factors for a shorter OS, according to a univariate analysis. Multivariate analysis revealed that the N0 plus N1 group had an endpoint mortality risk that was 0.39 times lower than the N2 plus N3 group's (p=0.008). In comparison to the high PNI group, the hazard of endpoint mortality was 2.442 times greater in the low PNI group (p = 0.003). PNI is a simplistic and practical predictive predictor of the RFS and OS time in patients with resectable AGE.

Clinicopathological Features and Prognosis of Lung Adenocarcinoma Patients With K-RAS Gene Mutation.

To investigate the relationship between K-RAS gene mutation and clinicopathological features and prognostic factors in lung adenocarcinoma. A total of 795 patients with lung adenocarcinoma diagnosed and tested for ten genes from January 1, 2016, to December 31, 2019, were reviewed. One hundred forty patients with K-RAS gene mutation lung adenocarcinoma were screened, of which 82 cases were included in this group, and complete follow-up data were obtained. PD-L1 immunohistochemistry was further performed, and the correlation between K-RAS mutation patients and clinicopathological features and related driver genes was analyzed. The survival curve was drawn by Kaplan-Meier curve. The effects of clinicopathological features on patients' survival were analyzed by Cox univariate and multivariate analysis. The age of onset of 82 patients with K-RAS gene mutation lung adenocarcinoma was 46 to 89 years old, and the median age of onset was 69 years old. There were 64 male patients (78.05%) and 18 female patients (21.95%), including 68 smokers (82.93%). Tumor size: 2 to 5.5 cm, with an average tumor size of 3.5 cm. Histopathologic types: solid type in 60 cases (73.17%), micropapillary type in 2 cases (2.43%), and invasive mucinous type in 20 cases (24.39%). The degree of tumor differentiation: well-differentiated: 0 cases, moderately differentiated: 10 cases (12.20%), poorly differentiated: 72 cases (87.80%). Fifty cases (60.98%), 29 cases (35.37%), 29 cases (35.37%), 59 cases (71.95%), and 35 cases (42.68%) were complicated with nerve invasion, vascular invasion, visceral pleura invasion, lymph node metastasis, and distant organ metastasis, respectively. Among them, distant organ metastasis included 24 cases (68.57%) of bone metastasis and 11 cases (36.67%) of brain metastasis. Tumor Ki-67 proliferation index ≥50%: 54 cases (65.85%). Related driver gene mutations: There were 6 cases (7.31%) with a deletion mutation of exon 19 in EGFR or L858R mutation of exon 21 in EGFR, respectively. Immune factor PD-L1 ≥50%: 65 cases (79.27%). The patients were followed up for 402 to 1221 days, with a median follow-up of 612 days. Thirty-five cases died during the follow-up. The 1-, 3-, and 5-year overall survival rates were 100%, 62.20%, and 57.31%, respectively. Cox univariate analysis showed that the degree of tumor differentiation, vascular invasion, distant organ metastasis, Ki-67 index, deletion mutation of exon 19 in EGFR, and high expression of PD-L1 (≥50%) could all affect the prognosis of patients ( P < 0.05). Cox multivariate analysis showed that high expression of PD-L1 (≥50%) was an independent predictor of prognosis in patients with K-RAS gene mutation in lung adenocarcinoma. K-RAS mutant lung adenocarcinoma is a malignant tumor with high invasiveness and high mortality. The degree of tumor differentiation, vascular invasion, distant organ metastasis, Ki-67 index, deletion mutation of exon 19 in EGFR, and high expression of PD-L1 (≥50%) in patients with K-RAS mutation lung adenocarcinoma can affect the overall survival time of patients. The high expression of PD-L1 (≥50%) is an independent risk factor affecting the prognosis (survival time).

Combination of 5-FU plus KRAS G12D inhibitor MRTX1133 against human colorectal and pancreatic cancer cells and the affects on inhibition of pERK and immune-stimulatory cytokine patterns in in KRAS G12D and KRAS G12V tumor cells.

e16301 Background: Colorectal cancer (CRC) &amp; pancreatic cancer are among deadliest cancers with great disease burden. The most commonly mutated oncogenic alteration in human cancers is KRAS, which is prevalent in pancreatic, colorectal malignancies. KRAS is considered an especially difficult, if not "undruggable" target. The KRAS G12D is present in more than 40% of PDAC &amp; 34.2% of CRC cases. KRAS mutation subtypes are associated with different downstream pathways and varied clinical outcomes in cancer. MRTX1133 has been identified as a noncovalent, potent, and selective inhibitor of KRASG12D which has been shown to suppress KRASG12D signaling in cells and in vivo. We hypothesized that combination of MRTX1133 with 5-FU will be more effective at slowing or stopping tumor growth, and prolonging overall survival time for patients while allowing lower dose 5-FU with less side effects. Methods: We investigated synergistic effects on pERK inhibition and changes in immune tumor killing with 5-FU plus KRAS G12D inhibitor MRTX1133 in pancreatic and colon cancer cell lines. Human CRC (N=6) and pancreatic (N=4) cancer cell lines with different KRAS mutations were used in experiments evaluating drug effects on pERK at 6 and 24 hours. We evaluated changes at 48 hours in cytokine profiles in treated cells using a custom panel of 62 cytokines, chemokines, and growth factors associated with tumor growth, immune stimulation or immune suppression. Results: Colorectal and pancreatic cancer cell lines had IC50 sensitivities ranging from 7 to 12 microM 5-FU, and &gt;100 nM to &gt;5 microM for MRTX1133 (G12D N=4: LS513, 120 nM; HPAF-II, 1.8 microM; SNUC2B, 5.7 microM; PANC-1, 2.8 microM). For non-G12D, the range of IC50 for MRTX1133 was in the range of 2 to 9 microM for CRC lines with G12V, G13D, or wild- type KRAS (N=7). Synergies between 5-FU and MRTX1133 were observed regardless of presence of KRAS G12D mutation with combination indices of &lt;0.5 indicating strong synergy. pERK was suppressed by MRTX1133 treatment of tumor cells regardless of KRAS G12D mutation. IL8/CXCL8, MICA, Angiopoietin 2, VEGF and TNF-alpha were reduced while IL-18/IL-1F4 increased. Conclusions: Our studies reveal strong synergy between MRTX1133 &amp; 5-FU in human pancreatic &amp; colon cancer models at much lower than IC50 dosage which is important for avoiding side effects. This is the first description that effect of KRAS G12D inhibitor MRTX1133 is active on KRAS G12V. The surprising synergy in KRAS G12V samples with combination therapy and the important synergistic change in cytokine patterns suggests potential strong immune stimulatory anti-cancer effects of MRTX1133 &amp; 5FU against mCRC and pancreatic cancer cells regardless of KRAS G12D mutation which should be considered when including patients with respective mutations in clinical trials.

The role of initial sodium and globulin values in the prognosis prediction of patients diagnosed with colon cancer

Aims: Early prediction of prognosis in malignancies can help determine life expectancy and take necessary further measures accordingly. There is no consensus on using any biomarker in predicting prognosis in colon cancer cases. A study reported that the sodium/globulin ratio is a valuable biomarker in predicting the prognosis of gastric cancer. This study aimed to investigate the role of baseline sodium, globulin, and sodium/globulin ratio in the prediction of prognosis and survival in colon cancer cases. Methods: The files of patients diagnosed with colon cancer who applied to Kırıkkale University Faculty of Medicine Medical Oncology Clinic between January 1, 2015, and December 31, 2020, were retrospectively analyzed. The relationship between the clinical and laboratory characteristics of the cases and their progression and survival were investigated. Results: 140 patients diagnosed with colon cancer were included in the study (82 men, 58 women). The average age at diagnosis was 64.1±12.6 years, 99.3% of them were adenocarcinoma, and 32.9% of them were stage 4 cancers. It was determined that 42.1% of the patients died (average survival time 54.0±3.2 months), and progression developed in 18.6% during the study period. The average baseline sodium/globulin ratio was 51.10±8.70. No significant correlation was found between initial serum sodium level, globulin level, sodium/globulin ratio, survival time, and progression status (p&gt;0.05). Baseline serum globulin level showed a weak negative correlation with both progression-free and overall survival time (r=-0.23, p&lt;0.05 and r=-0.24, p&lt;0.05, respectively), while the sodium/globulin ratio showed a weak positive correlation with progression-free survival time (r=0.26, p&lt;0.01) and overall survival time (r=0.25, p&lt;0.01). The ROC curve analysis determined that initial serum sodium and globulin levels and sodium/globulin ratio were not predictive of progression and survival at any cut-off point (p&gt;0.05). Conclusion: Although baseline serum sodium level, globulin level, and serum sodium/globulin ratio were weakly correlated with progression-free and overall survival time of patients diagnosed with colon cancer, they were not valuable in predicting progression and survival.

Natural Bacterial and Fungal Peptides as a Promising Treatment to Defeat Lung Cancer Cells.

Despite the increasing availability of modern treatments, including personalized therapies, there is a strong need to search for new drugs that will be effective in the fight against cancer. The chemotherapeutics currently available to oncologists do not always yield satisfactory outcomes when used in systemic treatments, and patients experience burdensome side effects during their application. In the era of personalized therapies, doctors caring for non-small cell lung cancer (NSCLC) patients have been given a powerful weapon, namely molecularly targeted therapies and immunotherapies. They can be used when genetic variants of the disease qualifying for therapy are diagnosed. These therapies have contributed to the extension of the overall survival time in patients. Nevertheless, effective treatment may be hindered in the case of clonal selection of tumor cells with acquired resistance mutations. The state-of-the-art therapy currently used in NSCLC patients is immunotherapy targeting the immune checkpoints. Although it is effective, some patients have been observed to develop resistance to immunotherapy, but its cause is still unknown. Personalized therapies extend the lifespan and time to cancer progression in patients, but only those with a confirmed marker qualifying for the treatment (gene mutations/rearrangements or PD-L1 expression on tumor cells) can benefit from these therapies. They also cause less burdensome side effects than chemotherapy. The article is focused on compounds that can be used in oncology and produce as few side effects as possible. The search for compounds of natural origin, e.g., plants, bacteria, or fungi, exhibiting anticancer properties seems to be a good solution. This article is a literature review of research on compounds of natural origin that can potentially be used as part of NSCLC therapies.

Omentectomy as Part of Radical Surgery for Gastric Cancer: 5-Year Follow-Up Results of a Multicenter Prospective Cohort Study

Introduction: Curative therapy for gastric cancer usually consists of perioperative chemotherapy combined with a radical (R0) gastrectomy. In addition to a modified D2 lymphadenectomy, a complete omentectomy is recommended. However, there is little evidence for a survival benefit of omentectomy. This study presents the follow-up data of the OMEGA study. Methods: This multicenter prospective cohort study included 100 consecutive patients with gastric cancer undergoing (sub)total gastrectomy with complete en bloc omentectomy and modified D2 lymphadenectomy. Primary outcome of the current study was 5-year overall survival. Patients with or without omental metastases were compared. Pathological factors associated with locoregional recurrence and/or metastases were tested with multivariable regression analysis. Results: Of 100 included patients, five had metastases in the greater omentum. Five-year overall survival was 0.0% in patients with omental metastases and 44.2% in patients without omental metastases (p = 0.001). Median overall survival time for patients with or without omental metastases was 7 months and 53 months. A (y)pT3–4 stage tumor and vasoinvasive growth were associated with locoregional recurrence and/or metastases in patients without omental metastases. Conclusion: The presence of omental metastases in gastric cancer patients who underwent potentially curative surgery was associated with impaired overall survival. Omentectomy as part of radical gastrectomy for gastric cancer might not contribute to a survival benefit in case of undetected omental metastases.

Abstract 310: CHAF1A promotes the translesion DNA synthesis pathway in response to DNA replication stress

Abstract Objective: Translesion DNA synthesis (TLS) pathway allows cancer cells to bypass the damage, allowing the blocked replication fork to move forward and helping cancer cells avoid genomic instability and cell death caused. Although some PCNA partners have previously been reported to participate in the TLS pathway, the mechanisms that regulate the TLS pathway remain unclear. Here, we revealed that CHAF1A is a new important regulator of TLS pathway. Methods: Cell models of CHAF1A gene knockdown (A549, KYSE510, KYSE450, etc.) were constructed by siRNA/shRNA knockdown method. We used DNA damage stimulation (HU, APH and UV) combined with western blotting to explore the effect of CHAF1A on PCNA monoubiquitination. The interaction of CHAF1A and its partners was demonstrated by immunoprecipitation and Duolink PLA assay. Cell fractionation assay was employed to measure protein binding to chromatin. DNA fiber assay was used to observe the condition of DNA replication fork. Micronucleus analysis was used to quantify cell micronucleus. The sensitivity of cells to DNA replication stress was tested by cloning formation assay and cell death assay. Kaplan-Meier survival analysis were used to analyze the clinical significance of CHAF1A expression. Results: CHAF1A enhances the interaction between PCNA and E3 ubiquitin protein ligase RAD18 and promotes PCNA monoubiquitination, thereby promoting the recruitment of Y-family DNA polymerase Pol η and enhancing cancer cell resistance to stimuli that trigger replication fork blockade. Mechanistically, CHAF1A-mediated PCNA monoubiquitination is independent of CHAF1A-PCNA interaction. CHAF1A interacts with both RAD18 and replication protein A2 (RPA2), mediating RAD18 binding on chromatin in response to DNA replication stress. Moreover, high expression of CHAF1A is significantly associated with poor prognosis in cancer patients. Conclusion: CHAF1A is a key TLS pathway regulator that is essential for cancer cell survival under DNA replication stress. The overall survival time of patients with high CHAF1A expression in lung, liver and esophageal cancers was significantly reduced. CHAF1A can be used as a key potential anti-tumor target, which has important clinical significance for enhancing the sensitivity of patients to radiotherapy and chemotherapy (This work was supported by the National Natural Science Foundation of China (82273108 and 82173034), the Innovative Team Grant of Guangdong Department of Education (2021KCXTD005), the Science and Technology Special Fund project of Guangdong Province in 2021 (No. 210729156901797) and the 2020 Li Ka Shing Foundation Cross-Disciplinary Research Grant (2020LKSFG07B)). Citation Format: Bing Wen, Li-Yan Xu, En-Min Li. CHAF1A promotes the translesion DNA synthesis pathway in response to DNA replication stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 310.

Prognostic value of circWWC3 as a novel survival‑related biomarker for clear cell renal cell carcinoma.

The aim of the present study was to assess the prognostic value of circular RNA WW and C2 domain-containing protein 3 (circWWC3) in patients with clear cell renal cell carcinoma (ccRCC). The clinicopathological data were collected for patients with ccRCC treated between January 1, 2012, and February 31, 2014, at The Fourth Hospital of Hebei Medical University Hospital (Shijiazhuang, China). A total of 150 patients who underwent nephrectomy were included in the study. Analysis of stored tissues and long-term follow-up data was performed. Fluorescence in situ hybridization was used to detect the relative circWWC3 expression in fresh-frozen cancerous and adjacent para-cancerous tissue samples from patients with ccRCC. A χ2 test was used to analyze the association between circWWC3 expression levels and the clinicopathological parameters of the patients. A Cox proportional risk regression model was used to analyze the clinical factors affecting patient prognosis. The survival curve was plotted using the Kaplan-Meier method, and the association between circWWC3 expression levels and patient survival status was tested using the log-rank test. circWWC3 expression in cancerous tissues was higher than that in the adjacent normal tissues. Additionally, circWWC3 expression was significantly associated with T stage (P=0.005) and pathological grade (P=0.033). Univariate Cox regression analysis showed that overall survival (OS) was associated with T stage, pathological Fuhrman grade and circWWC3 expression levels (all P<0.05). Multivariate Cox regression analysis also yielded similar results in patients with ccRCC (P<0.05). Moreover, the OS time of patients with high circWWC3 expression was significantly shorter than that of patients with low circWWC3 expression. In conclusion, high circWWC3 expression is an independent risk factor affecting patient prognosis, and is expected to be an important prognostic biomarker and novel therapeutic target for patients with ccRCC.