Bibliometric and visualization analysis of risk management in the doctor-patient relationship: A systematic quantitative literature review.

OBJECTIVES: This paper analyzed the research on risk management in the doctor-patient relationship (DPR) based on a systematic quantitative literature review approach using bibliometric software. It aims to uncover potential information about current research and predict future research hotspots and trends. METHODS: We conducted a comprehensive search for relevant publications in the Scopus database and the Web of Science Core Collection database from January 1, 2000 to December 31, 2023. We analyzed the data using CiteSpace 6.2.R2 and VOSviewer 1.6.19 software to examine the annual number of publications, countries/regions, journals, citations, authors, and keywords in the field. RESULTS: A total of 553 articles and reviews that met the criteria were included in this study. There is an overall upward trend in the number of publications issued; in terms of countries/regions, the United States and the United Kingdom are the largest contributors; Patient Education and Counseling is the most productive journal (17); Physician communication and patient adherence to treatment: a meta-analysis is the most cited article (1637); the field has not yet to form a stable and obvious core team; the analysis of high-frequency keywords revealed four main research directions: the causes of DPR risks, coping strategies, measurement tools, and research related to people prone to doctor-patient risk characteristics; the causes of DPR risks, coping strategies, measurement tools, and research related to people prone to doctor-patient risk characteristics; the keyword burst analysis revealed several shifts in the research hotspots for risk management in the DPR, suggesting that chronic disease management, is a future research direction for the continued development of risk management in the DPR. CONCLUSIONS: The visualization analysis of risk management literature in the DPR using CiteSpace and VOSviewer software provides insights into the current research status and highlights future research directions.

Dual Activity of Type III PI3K Kinase Vps34 is Critical for NK Cell Development and Senescence.

Vps34 is the unique member of the class III phosphoinositide 3-kinase family that performs both vesicular transport and autophagy. Its role in natural killer (NK) cells remains uncertain. In this study, a model without Vps34 (Vps34fl/fl/CD122Cre/+) is generated, deleting Vps34 during and after NK-cell commitment. These mice exhibit a nearly 90% decrease in NK cell count and impaired differentiation. A mechanistic study reveals that the absence of Vps34 disrupts the transport of IL-15 receptor subunit alpha CD122 to the cell membrane, resulting in reduced responsiveness of NK cells to IL-15. In mice lacking Vps34 at the terminal stage of NK-cell development (Vps34fl/fl/Ncr1Cre/+), NK cells gradually diminish during aging. This phenotype is associated with autophagy deficiency and the stress induced by reactive oxygen species (ROS). Therefore, terminally differentiated NK cells lacking Vps34 display an accelerated senescence phenotype, while the application of antioxidants effectively reverses the senescence caused by Vps34 deletion by neutralizing ROS. In summary, this study unveils the dual and unique activity of Vps34 in NK cells. Vps34-mediated vesicular transport is crucial for CD122 membrane trafficking during NK cell commitment, whereas Vps34-mediated autophagy can delay NK cell senescence.

Association between dietary flavonol intake and mortality risk in the U.S. adults from NHANES database.

Using updated National Health and Nutrition Examination Survey (NHANES) follow-up data, and a large nationwide representative sample of adult U.S. citizens, the aim of this study was to explore the relationship between dietary flavonol intake, all-cause and cause-specific mortality risks. In this prospective cohort study based on NHANES (2007-2008, 2009-2010, and 2017-2018), a total of 11,679 participants aged 20 years and above were evaluated. The amount and type of food taken during a 24-h dietary recall were used to estimate dietary flavonol intake, which includes total flavonol, isorhamnetin, kaempferol, myricetin, and quercetin. Each analysis of the weighted data was dealt with in accordance with the NHANES reporting requirements' intricate stratification design. The Cox proportional risk regression model or Fine and Gray competing risks regression model were applied to evaluate all-cause and cause-specific mortality risks, respectively. The follow-up period was calculated using the time interval between the baseline and the death date or December 31, 2019 (whichever occurs first). Each data analysis was performed between October 1, 2023, and October 22, 2023. Dietary flavonol intake included total flavonol, isorhamnetin, kaempferol, myricetin, and quercetin. Up to December 31, 2019, National Death Index (NDI) mortality data were used to calculate mortality from all causes as well as cause-specific causes. A total of 11,679 individuals, which represents 44,189,487 U.S. non-hospitalized citizens, were included in the study; of these participants, 49.78% were male (n = 5816), 50.22% were female (n = 5, 863); 47.56% were Non-Hispanic White (n = 5554), 18.91% were Non-Hispanic Black (n = 2209), 16.23% were Mexican American (n = 1895), and 17.30% were other ethnicity (n = 2021); The mean [SE] age of the sample was 46.93 [0.36] years, with a median follow-up of 7.80 years (interquartile range, 7.55-8.07 years). After adjusting covariates, Cox proportional hazards models and fine and gray competing risks regression models for specific-cause mortality demonstrated that total flavonol intake was associated with all-cause (HR 0.64, 95% CI 0.54-0.75), cancer-specific (HR 0.45, 95% CI 0.28-0.70) and CVD-specific (HR 0.67, 95% CI 0.47-0.96) mortality risks; isorhamnetin intake was associated with all-cause (HR 0.72, 95% CI 0.60-0.86), and cancer-specific (HR 0.62, 95% CI 0.46-0.83) mortality risks; kaempferol intake was associated with all-cause (HR 0.74, 95% CI 0.63-0.86), and cancer-specific (HR 0.62, 95% CI 0.40-0.97) mortality risks; myricetin intake was associated with all-cause (HR 0.77, 95% CI 0.67-0.88), AD-specific (HR 0.34, 95% CI 0.14-0.85), and CVD-specific (HR 0.61, 95% CI 0.47-0.80) mortality risks; quercetin intake was associated with all-cause (HR 0.66, 95% CI 0.54-0.81), cancer-specific (HR 0.54, 95% CI 0.35-0.84), and CVD-specific (HR 0.61, 95% CI 0.40-0.93) mortality risks; there was no correlation observed between dietary flavonol intake and DM-specific mortality. According to the current study, all-cause, AD, cancer, and CVD mortality risks declined with increased dietary flavonoid intake in the U.S. adults. This finding may be related to the anti-tumor, anti-inflammatory, and anti-oxidative stress properties of flavonol.

Ribosomal protein S6 kinase 2 (RPS6KB2) is a potential immunotherapeutic target for cancer that upregulates proinflammatory cytokines.

BACKGROUND: Cancer is still a leading cause of mortality. Over the years, cancer therapy has undergone significant advances driven by advancements in science and technology. A promising area of drug discovery in this field involves the development of therapeutic targets for cancer treatment. The urgent need to identify new pharmacological targets arises from the impact of tumor resistance on the effectiveness of current medications. Specifically, the RPS6KB2 gene on chromosome 11 has been implicated in cell cycle regulation and exhibits higher expression levels in tumor tissue. Given this association, there is a potential for this gene to serve as a target for cancer treatment. METHODS: We conducted an analysis using the GTEx, TCGA, and CCLE databases to explore the relationship between RPS6KB2 and immune infiltration, the tumor microenvironment (TME), microsatellite instability (MSI), and more. Cell proliferation was assessed using EDU detection, while cell invasion and migration were evaluated via wound healing and Transwell assays. Additionally, western blot analysis was employed to measure expression of Bax, Bcl-2, MMP2, MMP9, PCNA, and proinflammatory factors. RESULTS: Through data analysis and molecular biology methods, our study carefully examined the potential role of RPS6KB2 in cancer therapy. The data revealed that RPS6KB2 is aberrantly expressed in most cancers and is associated with poor prognosis. Further analysis indicated its involvement in cancer cell apoptosis and migration, as well as its role in cancer immune processes. We validated the significance of RPS6KB2 in hepatocellular carcinoma (HCC), highlighting its capacity to upregulate proinflammatory cytokines. CONCLUSION: Our research indicates that RPS6KB2 is a prognostic biomarker associated with immune infiltration in cancer that can affect antitumor immunity by increasing secretion of proinflammatory factors, providing a potential drug target for cancer treatment.

Nomogram for predicting neutropenia in patients with esophageal, gastric, or colorectal cancer treated by chemotherapy in the first cycle.

OBJECTIVES: Development and validation of a predictive model including serum vitamin concentration to estimate the risk of chemotherapy-induced grade 3/4 neutropenia in esophageal cancer, gastric cancer, or colorectal cancer patients who receive the first cycle of chemotherapy. METHODS: Data from 535 patients treated at the Affiliated Fuyang People's Hospital of Anhui Medical University from January 1, 2020, to March 2, 2022, were used to derive the predictive model. Least absolute shrinkage and selection operator regression analysis was performed to screen potential risk characteristics, and multivariate logistic regression was utilized to investigate efficient factors associated with chemotherapy-induced neutropenia. A nomogram was constructed using this logistic model. This nomogram was then tested on a temporal validation cohort containing 212 consecutive patients. RESULTS: In the cohort of all 747 eligible patients, grade 3/4 neutropenia incidence was 45.2%. Age, Eastern Cooperative Oncology Group-performance status, neutrophil count, serum albumin, and hemoglobin data were entered into the final model. The performance of the final predictive nomogram was assessed by the area under the receiver operating characteristic curve in both the development and validation datasets. The calibration curves indicated that the estimated risks were accurate. Decision curve analysis for the predictive model exhibited improved clinical practicality. CONCLUSION: In the present study, we established an accessible risk predictive model and identified valuable serum vitamin concentration parameters associated with chemotherapy-induced neutropenia. The predictive model may improve the grade 3/4 neutropenia risk prediction in patients with gastrointestinal malignancies who receive oxaliplatin- and fluoropyrimidine-based chemotherapy and help physicians make appropriate decisions for disease management.

Acceptance Factors and Psychological Investigation of Clinical Trials in Cancer Patients.

Aim: To understand the degree of oncology patients' awareness of drug clinical trials and oncology patients' willingness to participate in drug clinical trials and the factors influencing them. Methods: The differences in the relevant variables of patients' willingness to accept clinical trials were analyzed, and a descriptive analysis was done for the measurement data (mean and standard deviation). Pearson's correlation coefficient analysis was used to examine the correlation between willingness and the demographic variables. Stepwise regression analysis was used to explore the influencing factors of patients' willingness to accept clinical trials. Results: There were no statistical differences in age, gender, education level, marital status, place of residence, monthly income, medical payment method, and treatment time (P > 0.05). Patients' willingness to accept drug clinical trials differed in their cognitive degree of clinical drug trials (P = 0.002). Patients' willingness to accept drug clinical trials differed in their experience in clinical trials (P < 0.001). The correlation difference was statistically significant. The willingness to accept drug clinical trials was negatively correlated with treatment time (R = -0.16, P < 0.05) and positively correlated with awareness of clinical trials and whether they had been subjects (R = 0.16 and 0.43, P < 0.05). Multiple regression analysis showed that patients' willingness was directly influenced by age, treatment time, and whether they had been subjects (F = 21.315, P < 0.001). Conclusion: Age, treatment time, and whether they had been subjects were the direct influencing factors of patients' willingness. This study pointed out that hospitals should do a good job in the publicity of clinical trials of new drugs, expand publicity channels, increase publicity efforts, improve the awareness of clinical trials of the masses, and promote the enthusiasm of the masses to participate in clinical trials of drugs.

Effect of adjuvant radiotherapy after breast-conserving surgery in elder women with early-stage breast cancer: a propensity-score matching analysis.

Purpose: The study aimed to explore the role of adjuvant radiotherapy (RT) after breast-conserving surgery (BCS) in elder women with early-stage breast cancer (BC). Methods: BC patients with 70-79 years of age, stage T1-2N0-1M0, undergoing BCS were screened in the Surveillance, Epidemiology and End Results (SEER) database between 2010 and 2015. The clinicopathological characteristics were balanced with propensity-score matching (PSM) method. Kaplan-Meier curves and Cox regression analyses were performed to determine the impact of adjuvant RT on BC patients. Results: Ultimately, 12,310 patients treated with adjuvant RT and 4837 patients treated with no RT, were involved in the analysis. Overall, patients treated with adjuvant RT was associated with a better breast cancer-specific survival (BCSS) (HR: 1.980 [1.596- 2.456], P < 0.001) and overall survival (OS) (HR: 2.214 [1.966- 2.494], P < 0.001) than those who did not undergo RT. After 1:1 PSM, adjuvant RT still performed advantage in both BCSS (HR: 1.918 [1.439- 2.557], P < 0.001) and OS (HR: 2.235 [1.904- 2.624], P < 0.001). In the multivariate COX analysis of BCSS, widowed, divorced and separated patients, tumor grade III, T2 stage, N1 stage, no RT, molecular subtypes with luminal B and triple negative were associated with a shorter BCSS (P < 0.05). In the multivariate COX analysis of OS, age ≥74 years, widowed, divorced and separated patients, tumor grade II/III, T2 stage, no RT, no chemotherapy, molecular subtypes with triple negative were associated with a shorter OS (P < 0.05). Furthermore, the advantages of adjuvant RT were observed in all subgroup analysis. Conclusion: Adjuvant RT after BCS can improve both BCSS and OS in elderly patients with early-stage BC. Additionally, all subgroups analysis-derived BCSS and OS were in support of RT.

Comprehensive Analysis of SLC35A2 in Pan-Cancer and Validation of Its Role in Breast Cancer.

Purpose: Elucidation of the oncogenic role of SLC35A2 in human tumors and the potential function and clinical significance in breast cancer. Methods: Pan-cancer analysis was performed via various bioinformatics tools to explain the pathogenic role of SLC35A2. A prognostic nomogram was also developed based on the SLC35A2 expression and clinicopathological characteristics in breast cancer patients. In addition, the role of SLC35A2 was validated in breast cancer by in vivo and in vitro experiments. Results: SLC35A2 expression is increased in 27 tumor types, and its high expression is substantially correlated with poor prognosis in patients with a variety of cancers. Receiver operating characteristic (ROC) curves showed that SLC35A2 expression levels could accurately distinguish most tumor tissues from normal tissues. High SLC35A2 expression was linked to increased immune infiltration in myeloid-derived suppressor cells (MDSC), as well as immune checkpoints, ferroptosis-related genes, tumor mutational burden (TMB), and microsatellite instability (MSI). SLC35A2 may be involved in tumorigenesis by regulating the glycosylation process. Furthermore, multivariate Cox analysis showed that SLC35A2 was an independent prognostic factor for breast cancer. And the nomogram model had good predictive accuracy for the prognosis of breast cancer patients. Meanwhile, cellular experiments demonstrated that knockdown of SLC35A2 could significantly inhibit the proliferation, migration and invasion of breast cancer cells, while increasing the protein level of E-cadherin and decreasing N-cadherin. A nude mouse xenograft model showed that inhibition of SLA35A2 expression could significantly inhibit tumor growth. Conclusion: SLC35A2 has good diagnostic and prognostic values in multiple cancers and is closely related to tumor immune infiltration. In addition, SLA35A2 as an oncogene in breast cancer may be involved in the progression of epithelial mesenchymal transition (EMT).

Injectable Hydrogel Containing TiO Nanosheets for Synergistic Photothermal/Thermodynamic Therapy.

Tumors have become the biggest obstacle to human health, and there are various treatment methods at present. Photothermal therapy (PTT) is usually ineffective and does not inhibit tumor progression due to the inability of the lasers to penetrate deeply. Therefore, most existing studies chose a 1064 nm laser with stronger penetrating power; meanwhile, studies have shown that the inclusion of harmful free radicals can significantly improve the antitumor efficacy. Herein, TiO nanosheets (NSs) were creatively prepared and encapsulated with an alkyl radical generator {2,2'-azobis[2-(2-imidazoline-2-yl)propane] dihydrochloride, [AIPH]} in sodium alginate (ALG) hydrogel for effective tumor killing by PTT and pairing with dangerous free radicals. TiO NSs were obtained by the liquid-phase exfoliation method, together with AIPH, which were in situ coencapsulated multifunctional hydrogels formed by the combination of Ca2+ and ALG. This ALG hydrogel could enrich TiO NSs and AIPH at the tumor site for a long time, and through the excellent photothermal properties of TiO NSs, AIPH could slowly and effectively generate alkyl radicals at the tumor site, which, in turn, gave it a better antitumor effect compared with that of TiO NSs in the deep hypoxic environment of the tumor. The AIPH + TiO + ALG hydrogel has distinctive anticancer capabilities based on the results of both in vivo and in vitro experiments. This material also has good biosafety. By combining PTT and free radical treatment, this work provides a novel therapeutic method to achieve oxygen-independent free radical production and enhance therapeutic efficacy.

Dysregulated expression of microRNA involved in resistance to osimertinib in EGFR mutant non-small cell lung cancer cells.

Background: An increasing amount of evidence has confirmed that the altered expression of microRNAs (miRNAs) is critical to the mechanism underlying primary and even acquired resistance to tyrosine kinase inhibitors (TKIs). However, studies on the linkage between the altered miRNAs expression and osimertinib resistance are few, and the effect of miRNAs in this context is still unclear. In the light of this, we hypothesized that the differential expression of multiple miRNAs is the driver in the osimertinib resistance process. Thus, the aim of our study was to find differentially expressed miRNAs in non-small cell lung cancer cells resistant to osimertinib. Methods: An AZD9291(Osimertinib)-resistant cell line model was constructed, and the differential miRNAs between epidermal growth factor receptor (EGFR)-sensitive cell lines A549 and H1975 and the corresponding drug-resistant cell lines were identified via biosynthesis analysis. Results: In the A549 osimertinib-resistant cell line, 93 miRNAs were upregulated and 94 miRNAs were downregulated. In the H1975 osimertinib-resistant cell line, 124 miRNAs were upregulated and 53 miRNAs were downregulated. Finally, 7 significantly different miRNAs were screened using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Conclusions: This study on the mechanism of target therapy in lung cancer systematically and comprehensively examined the miRNAs involved in osimertinib resistance. It was found that miR-708-5p, miR-708-3p, miR-10395-3p, miR-7704 miR-34a-5p, miR-19b-1-5p, and miR-219a-5p may play key roles in osimertinib resistance.

Predictive Value of Serum Heat Shock Protein 90α on the Prognosis of Patients with Lung Adenocarcinoma.

Purpose: Heat shock protein 90α (HSP90α) is highly expressed in tumors, and predicts tumor progression. This study analyzed the correlation between the expression level of HSP90α in the serum and the prognosis of patients with lung adenocarcinoma. Patients and methods: The medical records of patients with 228 lung adenocarcinoma from September 2015 to December 2021 were analyzed. HSP90α expression in the patients' serum was detected by ELISA and the cut-off value (93.76 ng/mL) was determined according to the ROC curve, then the patients were divided into high- and low-level groups. The differences in the medical records of the two groups were compared using the X2 test, and Univariate and multivariate Cox regression analyses showed that serum HSP90α level were independent risk factors for both PFS and OS (P < 0.05). Results: HSP90α was positively correlated with TNM staging (P < 0.01) by One-way analysis of variance. The results of the correlation analysis and the Kaplan-Meier survival curve showed that the expression levels of HSP90α and CEA of patients were positively correlated (R=0.54, P < 0.001), and patients with high HSP90α and CEA levels had the worst OS (P < 0.001). Conclusion: HSP90α expression is negatively correlated with the prognosis of patients with lung adenocarcinoma and is a potential prognostic marker.

Circ_0008726 promotes malignant progression of ESCC cells through miR-206/HOXA13 pathway.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors of the gastrointestinal tract. Circular RNAs (circRNAs) are involved in the pathogenesis of cancer. This study aimed to elucidate the role and molecular mechanism of circ_0008726 in ESCC. METHODS: The expression levels of circ_0008726, microRNA (miR)-206 and homeobox A13 (HOXA13) were detected by quantitative real-time PCR (QRT-PCR). Cell counting kit-8 (CCK-8) and 5-Ethynyl-2'-deoxyuridine (EdU) assays were conducted to detect the proliferative ability of ESCC cells. Apoptosis and invasion of ESCC cells were detected by flow cytometry and transwell assays. Tube formation assay was used to detect the angiogenesis of ESCC cells. The expression of related proteins was detected by western blot analysis. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were performed to confirm the interactions among circ_0008726, miR-206 and HOXA13. Xenograft mice model was established to study the in vivo effect of circ_0008726 knockdown. RESULTS: Expression of circ_0008726 was up-regulated in ESCC tissues and cells. Knockdown of circ_0008726 repressed proliferation, invasion, angiogenesis, and promoted apoptosis of ESCC cells. Circ_0008726 acted as a sponge for miR-206, and HOXA13 was a target of miR-206. The suppressive effects of circ_0008726 knockdown on cell proliferation, invasion, and angiogenesis were abated by miR-206 down-regulation. Meanwhile, overexpression of HOXA13 partially reversed the suppressive effects of miR-206 enrichment on ESCC cell malignant behaviors. Knockdown of circ_0008726 inhibited ESCC tumor growth in vivo. CONCLUSION: In short, circ_0008726 exerted the carcinogenic effects to regulate the proliferation, invasion, angiogenesis and apoptosis of ESCC cells by targeting miR-206/HOXA13 axis.

ANGPTL4 Regulates Lung Adenocarcinoma Pyroptosis and Apoptosis via NLRP3\ASC\Caspase 8 Signaling Pathway to Promote Resistance to Gefitinib.

Background: Prior research has identified ANGPTL4 as a key player in the control of the body's lipid and glucose metabolism and a contributor to the onset of numerous cardiovascular conditions. Recently, it has been shown that ANGPTL4 also plays a critical role in tumor growth and progression. Nowadays, the number of EGFR-TKI resistant patients is increasing, and it is important to investigate the role of ANGPTL4 in regulating gefitinib resistance in PC9/GR non-small-cell lung cancer (NSCLC). Methods: The expression of ANGPTL4 in A549, PC9, H1975, BEAS-2B and PC9/GR cells was verified by Western blot and qRT-PCR assays, and the effect of gefitinib on the proliferative ability of each cell was probed by CCK-8 assay. By using shRNA to inhibit ANGPTL4 expression in cells, the effect of ANGPTL4 on cell migratory ability was examined and the effect of ANGPTL4 on cellular gefitinib sensitivity was confirmed using the CCK-8 assay and the edu proliferation test. Mouse transplantation tumors were constructed, and the effect of ANGPTL4 on cellular gefitinib sensitivity was investigated in vivo by flow cytometry, Tunel staining assay, immunohistochemical staining, and ROS fluorescence staining assay. ANGPTL4 expression in homoRNA overexpression cells was constructed, and the changes in the expression levels of ASC\NLRP3\Caspase 8 pathway and focal and apoptotic proteins were investigated in vitro, in vivo, afterknockdown and overexpression of ANGPTL4 expression by Westen blot assay. Results: ANGPTL4 was highly expressed in PC9/GR cells. Interfering with ANGPTL4 expression resulted in decreased proliferation and migration ability, decreased resistance to gefitinib, and increased scorching and apoptosis in PC9/GR cells. Interfering with ANGPTL4 expression in PC9/GR cells was shown to promote sensitivity to gefitinib and to mediate the NLRP3/ASC/Caspase 8 pathway to induce cell scorching and apoptosis. Conclusions: ANGPTL4 promotes gefitinib resistance in PC9/GR cells by regulating the NLRP3/ASC/Caspase 8 pathway to inhibit scorch death. ANGPTL4 may be an effective new target for inhibiting EGFR-TKI resistance in lung adenocarcinoma cells.

Multiple-dose up-titration study to evaluate the pharmacokinetics, safety and antitumor activity of apatinib in advanced gastric adenocarcinoma.

Background and purpose: The objective of this study was to investigate the pharmacokinetics, safety, and antitumor activity of apatinib, a vascular endothelial growth factor receptor 2 inhibitor, in advanced gastric adenocarcinoma or gastroesophageal junction adenocarcinoma and evaluate the effect of dose titration on dosage optimization for individual patients. Methods: Patient with advanced gastric adenocarcinoma progressed after at least one line of chemotherapy were enrolled. Apatinib was given orally once daily starting at 500 mg for 14 days, then up-titrated to 750 mg for 14 days, and then proceeded to a maximum dose of 850 mg. Dose up-titration determination was based on toxicity. The 28-day treatment cycles continued until disease progression, intolerable toxicities, withdrawal of consent, or investigator' decision. Results: A total of 60 patients were enrolled, with 17, 18, and 25 patients receiving a maximum dose of 500 mg, 750 mg, and 850 mg, respectively. The pharmacokinetic parameters varied considerably, with the interpatient coefficient of variation for steady state areas under the plasma concentration time curve (AUCss) and the mean maximum concentration of both > 50%. During 500 mg and 750 mg dosing stage, drug exposures in patients with a maximum dosage of 850 mg were lower than in those not titrated to 850 mg. Patients with total gastrectomy exhibited significantly lower AUCss than patients with partial or no gastrectomy (p = 0.004 and 0.032, respectively). Toxicities were tolerable, and disease control rate was 39.5% (95% CI 25.0%-55.6%). Conclusions: Apatinib dose titration based on toxicity could be used in clinical practice to provide optimal dosage for individual patients. Clinical Trial registration: https://clinicaltrials.gov/ct2/show/NCT02764268?term=NCT02764268&draw=2&rank=1, NCT02764268.

The Efficacy of the Systemic Immune-Inflammation Index and Prognosis Nutritional Index for the Diagnosis of Venous Thromboembolism in Gastrointestinal Cancers.

Purpose: This study aimed to analyze the association between venous thromboembolism (VTE) and inflammatory markers like systemic immune-inflammation index (SII) and prognosis nutritional index (PNI), and to evaluate their efficacy for the diagnosis of VTE in patients with gastrointestinal malignancies. Patients and Methods: A total of 1326 patients with the initial diagnosis of gastrointestinal cancer in the First Affiliated Hospital of Anhui Medical University (AHMU) were enrolled in the training cohort. Univariate and multivariate analysis was used to pinpoint independent predictors of VTE, which were eventually visualized as the nomogram models. The Akaike Information Criterion (AIC) was used to screen the best model. The receiver operating characteristic curve (ROC) and the clinical decision curve analysis (DCA) were utilized to evaluate the models' predictive performance in the training queue and another external sample of 250 patients at the Second Affiliated Hospital of AHMU. Results: A total of 476 patients were complicated with VTE in the training cohort. Multifactorial analysis of clinical characteristics and inflammatory markers showed that PNI, SII, age, tumor location, and therapy were independent risk factors of VTE, visualized as model A. Another model B was constructed by adding coagulation markers to the previous analysis. Model B was the best prediction model with the minimum AIC value, followed by model A with an AUC of 0.806 (95% CI 0.782~0.830) which was similar to model B's 0.832 (95% CI 0.810~0.855) but significantly higher than the currently widely used Khorana score's 0.592 (95% CI 0.562~0.621) and the CATS score's 0.682 (95% CI 0.653~0.712). The external verification yielded similar findings, with the AUC being 0.792 (95% CI 0.734~0.851), 0.834 (95% CI 0.778~0.890), 0.655 (95% CI 0.582~0.729), and 0.774 (95% CI 0.699~0.849) respectively. The DCA curves demonstrated that new models had excellent usefulness in screening patients with a high VTE risk. Conclusion: The SII and PNI were simple and viable inflammatory markers associated with VTE, and the nomogram based on them and clinical features had a meaningful clinical utility for VTE in patients with gastrointestinal malignancies.

Survival outcomes of adjuvant taxanes, platinum plus fluoropyrimidines versus platinum and fluoropyrimidines for gastric cancer patients after D2 gastrectomy: a retrospective propensity score-matched analysis.

BACKGROUND: To evaluate whether the addition of taxanes to platinum and fluoropyrimidines in adjuvant chemotherapy would result in longer survival than platinum plus fluoropyrimidines in gastric cancer patients who received D2 gastrectomy. METHODS: Data of patients with gastric adenocarcinoma who received D2 gastrectomy and adjuvant chemotherapy with platinum plus fluoropyrimidines or taxanes, platinum plus fluoropyrimidines was retrospectively collected and analyzed. 1:1 Propensity score matching analysis was used to balance baseline characteristics between two groups. Survival curves were estimated using Kaplan-Meier method, and the differences were compared using the log-rank test. RESULTS: Four hundred twenty-five patients in the platinum plus fluoropyrimidines group and 177 patients in the taxanes, platinum plus fluoropyrimidines group were included into analysis. No statistical differences in disease-free survival and overall survival were observed between two groups. After propensity score matching, 172 couples of patients were matched, the baseline characteristics were balanced. The median disease-free survival were 15.8 months (95% CI, 9.3~22.4) in the platinum plus fluoropyrimidines group and 22.6 months (95% CI, 15.9~29.4) in the taxanes, platinum plus fluoropyrimidines group (HR = 0.63; 95% CI, 0.48~0.85; P = 0.002). The median overall survival was 25.4 months for patients in the platinum plus fluoropyrimidines group (95% CI, 19.4~31.3) and 33.8 months (95% CI, 23.5~44.2) for those in the taxanes, platinum plus fluoropyrimidines group (HR = 0.68; 95% CI, 0.53-0.87; log-rank test, P = 0.002). CONCLUSIONS: For gastric adenocarcinoma patients, the adjuvant triplet combination of taxanes, platinum, and fluoropyrimidines regimen after D2 gastrectomy was superior to platinum plus fluoropyrimidines regimen in disease-free survival as well as overall survival. TRIAL REGISTRATION: This project has been registered in the Chinese Clinical Trial Registry ( ChiCTR1800019978 ).

Decrease of peripheral blood mucosal-associated invariant T cells and impaired serum Granzyme-B production in patients with gastric cancer.

Mucosal-associated invariant T (MAIT) cells are an invariant T cell subset, which have been reported to play an antimicrobial role in infectious diseases. However, little is known about it in malignant diseases and tumors, especially in gastric cancer (GC). So in this study, we aim to examine the frequency, phenotype, partial functional capacity and clinical relevance of this cells from GC patients' peripheral blood by flow cytometry. It was shown that the frequency of peripheral blood MAIT cells was negatively correlated with their increasing age in healthy adults. Importantly, comparing to the healthy controls (HC), the frequency and the absolute number of MAIT cells from GC patients' peripheral blood with or without chemotherapy were both significantly lower than those. For the phenotype, the proportion of CD4-MAIT cell subset in GC patients without chemotherapy was lower than in HC, but higher than in GC patients with chemotherapy. Whereas, the proportion of CD4-CD8+MAIT cell subset in GC patients without chemotherapy was significantly lower than that in HC. Finally, the level of Granzyme-B (GrB), a molecule associated with MAIT cells was markedly lower in GC patients. But the correlation between the serum levels of GC-associated tumor antigens and the percentages of MAIT cells in GC patients was not observed. In conclusion, our study shows the decreased frequency, changed phenotypes and partial potentially impaired function of MAIT cells in GC patients, suggesting a possible MAIT cell-based immunological surveillance of GC.

FGL1 regulates acquired resistance to Gefitinib by inhibiting apoptosis in non-small cell lung cancer.

BACKGROUND: This study investigated the role of fibrinogen-like protein 1 (FGL1) in regulating gefitinib resistance of PC9/GR non-small cell lung cancer (NSCLC). METHODS: The effect of different concentrations of gefitinib on cell proliferation were evaluated using the CCK-8 assay. FGL1 expression in the normal human bronchial epithelial cell line Beas-2B, as well as four lung tumor cell lines, H1975, A549, PC9, and PC9/GR, was investigated by using western blotting and qRT-PCR. FGL1 was knocked down using small interfering RNA to evaluate the effects of FGL1 on PC9 and PC9/GR. The correlation between FGL1 expression and gefitinib resistance was determined in vitro via CCK-8 and colony formation assays, and flow cytometry and in vivo via flow cytometry and immunohistochemistry. RESULTS: FGL1 expression was significantly upregulated in non-small cell lung cancer cells with EGFR mutation and higher in the gefitinib-resistant NSCLC cell line PC9/GR than in the gefitinib-sensitive NSCLC cell line PC9. Further, FGL1 expression in PC9 and PC9/GR cells increased in response to gefitinib treatment in a dose-dependent manner. Knockdown of FGL1 suppressed cell viability, reduced the gefitinib IC50 value, and enhanced apoptosis in PC9 and PC9/GR cells upon gefitinib treatment. Mouse xenograft experiments showed that FGL1 knockdown in PC9/GR tumor cells enhanced the inhibitory and apoptosis-inducing actions of gefitinib. The potential mechanism of gefitinib in inducing apoptosis of PC9/GR cells involves inhibition of PARP1 and caspase 3 expression via suppression of FGL1. CONCLUSIONS: FGL1 confers gefitinib resistance in the NSCLC cell line PC9/GR by regulating the PARP1/caspase 3 pathway. Hence, FGL1 is a potential therapeutic target to improve the treatment response of NSCLC patients with acquired resistance to gefitinib.

High Preoperative Fibrinogen and Systemic Inflammation Response Index (F-SIRI) Predict Unfavorable Survival of Resectable Gastric Cancer Patients.

PURPOSE: This study was to investigate the prognostic significance of the preoperative fibrinogen and systemic inflammation response index (F-SIRI) in a Chinese cohort of resectable gastric cancer. MATERIALS AND METHODS: Baseline characteristics, preoperative fibrinogen levels and peripheral neutrophil, monocyte, and lymphocyte counts were retrospectively reviewed in 240 patients who underwent radical gastrectomy. The optimal cut-off values for fibrinogen and SIRI were defined as 4.0 g/L and 1.2. Then patients with hyperfibrinogenemia (≥4.0 g/L) and high SIRI (≥1.2) were assigned with an F-SIRI of 2 (both of these hematological abnormalities), 1 (one of these abnormalities), and 0 (neither abnormality), respectively. The prognostic value was examined by univariate and multivariate survival analysis. RESULTS: Preoperative F-SIRI was significantly correlated with tumor size, fibrinogen level, and adjuvant chemotherapy. Whereas there was no significant difference in age, gender, tumor location or other characteristics between groups. In addition, high preoperative F-SIRI was significantly associated with worse disease-free survival (DFS) (hazard ratio [HR], 2.299; 95% confidence interval [CI], 1.482-3.566; P<0.001) and overall survival (OS) (HR, 2.461; 95% CI, 1.584-3.824; P<0.001) by univariate survival analysis. Moreover, it remained an independent predictor for impaired DFS (HR, 2.023; 95% CI, 1.273-3.215; P=0.003) and OS (HR, 2.341; 95% CI, 1.480-3.705; P<0.001) in multivariate Cox regression analysis. CONCLUSIONS: Preoperative F-SIRI could serve as a significantly prognostic marker for long-term survival in Chinese patients who underwent radical gastrectomy.

Suberoylanilide hydroxamic acid overcomes erlotinib-acquired resistance via phosphatase and tensin homolog deleted on chromosome 10-mediated apoptosis in non-small cell lung cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as erlotinib and gefitinib, are widely used to treat non-small cell lung cancer (NSCLC). However, acquired resistance is unavoidable, impairing the anti-tumor effects of EGFR-TKIs. It is reported that histone deacetylase (HDAC) inhibitors could enhance the anti-tumor effects of other antineoplastic agents and radiotherapy. However, whether the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) can overcome erlotinib-acquired resistance is not fully clear. METHODS: An erlotinib-resistant PC-9/ER cell line was established through cell maintenance in a series of erlotinib-containing cultures. NSCLC cells were co-cultured with SAHA, erlotinib, or their combination, and then the viability of cells was measured by the 3-(4,5-Dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and apoptosis was determined by flow cytometry and western blotting. Finally, the expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was assessed by western blotting. RESULTS: The half-maximal inhibitory concentration of parental PC-9 cells was significantly lower than the established erlotinib-acquired resistant PC-9/ER cell line. PC-9/ER cells demonstrated reduced expression of PTEN compared with PC-9 and H1975 cells, and the combination of SAHA and erlotinib significantly inhibited cell growth and increased apoptosis in both PC-9/ER and H1975 cells. Furthermore, treating PC-9/ER cells with SAHA or SAHA combined with erlotinib significantly upregulated the expression of PTEN mRNA and protein compared with erlotinib treatment alone. CONCLUSIONS: PTEN deletion is closely related to acquired resistance to EGFR-TKIs, and treatment with the combination of SAHA and erlotinib showed a greater inhibitory effect on NSCLC cells than single-drug therapy. SAHA enhances the suppressive effects of erlotinib in lung cancer cells, increasing cellular apoptosis and PTEN expression. SAHA can be a potential adjuvant to erlotinib treatment, and thus, can improve the efficacy of NSCLC therapy.